Impacts of Antibiotic-Resistant Bacteria

September 1995

OTA-H-629

GPO stock #052-003-01446-7
Recommended Citation: U.S. Congress, Office of Technology Assessment,

Impacts of Antibiotic-Resistant Bacteria, OTA-H-629 (Washington, DC: U.S.

Government Printing Office, September 1995).
iii

Foreword

enicillin, the first antibiotic, and the more than 100 other antibiotics now available to physicians are the primary weapons

in mankind's battle against bacterial diseases. They revolutionized medicine, providing cures for formerly life-threatening diseases and preventing many previously inevitable deaths from

infected wounds. They still do, but within a short time of each antibiotic's introduction into medicine, some bacteria became resistant to it,

and the antibiotic lost its effectiveness against some diseases. Currently, few bacteria are resistant to all antibiotics, but many more are

resistant to all but one or all but a few antibiotics, and the expectation

is that resistant bacteria will continue to emerge and spread. The fear

is that many bacteria will become resistant to all antibiotics, plunging

humanity back into the conditions that existed in the pre-antibiotic

age.

OTA's report discusses what is known about the emergence and

spread of antibiotic-resistant bacteria and describes research and

development aimed at controlling those organisms. It concludes that

efforts are necessary both to preserve the effectiveness of currently

available antibiotics and to develop new antibiotics. It discusses issues

that arise in these activities, and it presents options for taking action.

This report was requested by the House Committee on Energy and

Commerce in the 103d Congress (now the House Committee on Commerce). The Senate Committee on Labor and Human Resources in the

same Congress endorsed the request for the study.

OTA was assisted in this study by an advisory panel of scientists

and physicians from academia, industry, and state government chaired

by Gail Cassell, Ph.D., of the University of Alabama at Birmingham.

OTA gratefully acknowledges the contribution of each advisory panel

member as well as that of many other experts who supplied information for the report and participated in reviews of the report as it was

prepared. As with all OTA reports, the final responsibility for the content of the assessment rests with OTA.

ROGER C. HERDMAN

Director

P
iv

Advisory Panel

Gail Cassell, Ph.D.

Professor and Chairman

Department of Microbiology

University of Alabama at 

Birmingham/University 

Station 

Birmingham, AL 35294

Anne Bolmstrom

President

AB Biodisk

Pyramidvagon 7

S-17136 Solna

Sweden

Robert J. Bywater, Ph.D.

Director, Anti-Infective 

Assessment

SmithKline Beecham Animal 

Health

Walton Oaks

Dorking Road

Tadworth

Surrey KT20 7NT

UK

Barry Eisenstein, M.D.

Vice President, Lilly Research 

Labs

Lilly Corporate Center, 0434

Indianapolis, IN 46285

Prabhavathi B. Fernandes, 

Ph.D.

Vice President, Drug 

Discovery

Biomolecular Screening

Bristol-Myers Squibb

PO Box 4000

Princeton, NJ 08543-4000

Winston Frederick, M.D.

Infectious Disease Research

Howard University Hospital

2041 Georgia Ave., NW, 

Room 5C-43

Washington, DC 20060

Joshua Lederberg, Ph.D.

Professor

The Rockefeller University

New York, NY 10021-6399

Stephen Lerner, M.D.

Professor of Medicine

Wayne State University School 

of Medicine

Harper Hospital/Division of 

Infectious Diseases

3990 John R

Detroit, MI 48201

Stuart Levy, M.D.

Professor of Medicine and of 

Molecular Biology and 

Microbiology

Tufts University Medical 

School

136 Harrison Ave.

Boston, MA 02111-1800

Robert C. Moellering, Jr., 

M.D.

Physician-In-Chief and 

Chairman

New England Deaconess 

Hospital

Department of Medicine/Room 

6A

110 Francis Street

Boston, MA 02215-5553

Barbara Murray, M.D.

Professor of Medicine and of 

Microbiology and Molecular 

Genetics

Infectious Diseases

University of Texas Medical 

School at Houston

6431 Fannin

Houston, TX 77030
v

Tom O'Brien, M.D.

Medical Director

Microbiology Laboratory

Brigham and Women's 

Hospital

75 Francis Street

Boston, MA 02115

Lone Simonsen, Ph.D.

926 Waverly Way, Apt. A

Atlanta, GA 30307

Harry Taber, Ph.D.

Acting Director, Division of 

Infectious Diseases

NY State Department of 

Health

Wadsworth Center

David Axelrod Institute

PO Box 22002

Albany, NY 12201-2002

Alexander Tomasz, Ph.D.

Professor and Head/Laboratory 

of Microbiology

The Rockefeller University

1230 York Ave., Box 152

New York, NY 10021-6399

Richard Wenzel, M.D., M.Sc.

Associate Chairman

Department of Internal 

Medicine

The University of Iowa

Iowa City, IA 52242

Craig Townsend, Ph.D.

Chairman, Department of 

Chemistry

The Johns Hopkins University

Charles and 34th Streets

Baltimore, MD 21218

Michael Zasloff, M.D., Ph.D.

President, Magainin Research 

Institute

5110 Campus Drive

Plymouth Meeting, PA 19462
vi

Project Staff

Clyde J. Behney

Assistant Director, OTA

Sean Tunis

Health Program Director

ADMINISTRATIVE STAFF

Charlotte Brown

Word Processing Specialist

Monica Finch

Word Processing Specialist

Louise Staley

Office Administrator

Carolyn Swann

PC Specialist

PRIMARY STAFF

Michael Gough

Project Director

Elise Berliner

Congressional Fellow

Dwayne L. Smith

Research Assistant

Jacqueline T. Keller

Research Analyst

CONTRIBUTING STAFF

Beth Hadley

Senior Analyst

CONTRACTORS

Michael J. Bennett

Washington, DC

Mitchell Burken

Philadelphia V.A. Hospital

Julian Davies

The University of British 

Columbia

Susan Feinman

Potomac, Maryland

David Frankel

The Lancet

Sandra Handwerger

Rockefeller University

Kathie E. Hanna

Churchton, Maryland

Judith Hellerstein

Northwestern University

James H. Jorgensen

University of Texas

Karen Kaunitz

Jacksonville Baptist Medical 

Center

Calvin Kunin

Ohio State University

David H. Persing

Mayo Clinic Rochester

David Relman

Stanford University

Barbara Rosenkrantz

Harvard University

Lee Sabath

University of Minnesota
vii

Contents

1 Summary, Conclusions, Issues and Options 1

Summary 1

Origins of the Antibiotic Era 2

Survey of Antibiotic Resistance 3

Costs of Antibiotic-Resistant Bacterial Diseases 6

Reducing the Impacts of Antibiotic-Resistant Bacteria 8

Conclusions 18

Issues and Options for Prolonging Effectiveness of 

Antibiotics 19

Issues and Options for Encouraging Development 

of New Antibiotics 28

2 Introduction 33

The Discovery of Antibiotics 36

Confronting Antibiotic Resistance 45

References 46

3 Antibiotic Use and Resistance in the 

Community 49

Introduction 49

Populations Susceptible to Antibiotic-Resistant 

Bacteria 53

Factors in the Emergence of Bacterial Diseases 57

Changes in Disease Patterns 59

Surveillance of Antibiotic-Resistant Bacteria 61

Conclusions 63

References 65

4 Antibiotic Use in Hospitals 69

Infections Acquired in the Hospital 69

The Rise of Antibiotic-Resistant Infections in 

Hospitals 71

The Uses of Antibiotics in Hospitals 73

Legal Aspects of Antibiotic Use 75

Controlling the Emergence and Spread of Antibiotic 

Resistance in Hospitals 76
viii

Hospital Accreditation and Infection Control Regulations 

Under Medicare 80

Costs of Controlling the Emergence and Spread of 

Antibiotic-Resistant Bacteria 93

Conclusions 96

References 96

5 Antibiotic Development 101

Designing New Antibiotics 101

Antibiotics in Current Clinical Use 104

Antibiotics That Inhibit or Block DNA Replication or 

Protein Synthesis 109

Development of New Antibiotics From Old 110

New Research Tools 113

Antibiotics From New Sources 113

Getting New Antibiotics to Market 118

Patents 120

Pricing of Drugs Developed in Part by Federal 

Research 121

Conclusions 121

References 122

6 New Technologies for Infection Diagnosis and 

Control 127

Diagnostic Methods 127

Vaccines 142

Stimulating the Immune System 146

Targeted Delivery of Antibiotics 146

Reducing Infections by Modifying Devices 147

Old Therapies 150

Summary 151

References 151
ix

7 Antibiotics in Animal Husbandry 155

Antibiotic Use in Food Production 158

Antibiotic-Resistant Bacteria in Humans 159

Controversy About Antibiotic Use in Raising 

Livestock 162

Controversy Over Fluoroquinolones in Food 

Production 164

References 165

Appendix A: Coverage of Antibiotic Resistance in 

the Popular Literature, 1950 to 1994 167

Appendix B: Glossary 173

Appendix C: Acknowledgments 181
| 1

1

Summary,

Conclusions,

Issues and

Options

SUMMARY

s more and more bacteria become resistant to the effects of antibiotics and as

the flow of new antibiotics into medical

practice slows, it is clear that the pronouncement of the Surgeon General of the

United States nearly a quarter century ago that it

was time to “close the book on infectious diseases” was premature.1 Indeed, the popular press

and some experts worry that we are headed

toward an era of infectious diseases akin to the

one that existed before antibiotics were introduced over a half-century ago.

This Office of Technology Assessment (OTA)

report is a response to congressional requests

(see box 1-1) for a description of the threat posed

by antibiotic-resistant bacteria to our society.

This report explores the biological bases for the

development of bacterial resistance to antibiotics, describes new antibiotics that are in research

and development, and outlines a number of strategies to control the proliferation of antibioticresistant bacteria.

1 Citations to the literature are not included in this summary. Complete citations are included in other chapters.

❚ Impacts of Antibiotic-Resistant 

Bacteria:

■ Difficult-to-treat infections: Many strains of

bacteria are resistant to one or more of the 100

antibiotics now in use. Physicians may have to

try a number of different antibiotics until one

proves effective. ■ Untreatable infections: Some strains of bacteria are resistant to all available antibiotics.

Currently, infections caused by these bacteria

are fairly uncommon, but they are rapidly

increasing. Additionally, other bacteria are

resistant to all but one antibiotic, and they are

expected to become resistant to all antibiotics. ■ Antibiotic use increases the spread of antibiotic-resistant bacteria: Antibiotic use creates

“selective pressure” that promotes the spread

of resistant bacteria. Susceptible bacteria are

killed or inhibited, and resistant bacteria survive and multiply. As bacteria become resistant to increasing numbers of antibiotics, the

remaining effective antibiotics are used more

often—increasing the selection pressure for

bacteria to become resistant to them.

A
2 | Impacts of Antibiotic-Resistant Bacteria

■ Costs: OTA estimates the in-hospital costs of

hospital-acquired (nosocomial) infections

caused by six common kinds of antibioticresistant bacteria to be a minimum of $1.3 billion. The estimate ignores the costs of infections caused by other kinds of antibioticresistant bacteria, costs of lost work days, and

costs for post-hospital care. If these factors

were considered, the total cost to society

would be at least several billion dollars per

year. Further, these costs can be expected to

increase rapidly as the numbers of antibioticresistant bacteria increase.

■ Antibiotic-resistant bacteria spread internationally: Antibiotic-resistant bacteria are

found all over the world and are spread among

countries as people and goods are transported

internationally.

❚ Controlling Antibiotic-Resistant 

Bacteria

■ Prolong the effectiveness of currently available antibiotics through three primary

activities:

1) Prudent use of antibiotics: Studies indicate

that many antibiotics are overused or used

inappropriately. Physicians who prescribe

antibiotics in the hospital or in their office

practices often face difficult choices in

deciding whether to prescribe an antibiotic

and which one to prescribe. Surveillance

systems to track the emergence and spread

of disease-causing bacteria are essential.

New technologies that quickly and accurately identify bacteria will improve use of

antibiotics.

2) Vaccines: Vaccines prevent infections and

reduce the need for antibiotics. Effective

vaccines against bacteria will reduce the

use of antibiotics.

3) Infection control: Effective infection control efforts range from simple procedures

such as diligence in hand-washing to new

materials for use in medical devices that

impede the growth of bacteria.

■ Develop new antibiotics: New antibiotics are

necessary to treat bacteria that are resistant to

currently available antibiotics. Pharmaceutical companies are currently searching for

new antibiotics by screening biological compounds for antibacterial activity and by use of

new techniques to design molecules that are

active against specific biochemical pathways

in bacteria.

ORIGINS OF THE ANTIBIOTIC ERA

A century ago, physicians had few effective

medicines to treat infectious diseases. Plenty of

medicines existed, but most had no effect except

to offer the relief associated with narcotics and

alcohol. Physicians prescribed elixirs, nostrums,

and potions for all sorts of illnesses. Systematic

examination of their effectiveness, which began

in the 1890s, showed that few had worth. With

few effective treatments, the physician’s role was

limited to informing the patient and family about

the expected course of the disease and keeping

the patient comfortable, clean, and nourished

BOX 1-1: Origins of This OTA Study

In 1994, two Committees of Congress asked OTA to prepare a report that describes the incidence of

infections with antibiotic-resistant bacteria in hospitals and in the community and any information about

the costs of such infections. Moreover, the request asked how surveillance of antibiotic-resistant bacteria

can be improved and for descriptions of the relationships between virulence and antibiotic resistance in

bacteria, the state of the search for new antibiotics, and the success or lack of success in efforts to control the ongoing spread of antibiotic-resistant bacteria. In addition, OTA was asked to discuss issues that

arise in attempts to control the impacts of antibiotic-resistant bacteria and to present options for actions

by Congress and other organizations.
Chapter 1 Summary, Conclusions, Issues and Options | 3

while waiting for the body’s immune system to

overcome the infection, if it could.

In 1928, the English microbiologist Alexander

Fleming discovered that a common mold (Penicillium) produced a substance—penicillin—that

killed bacteria. This became the foundation of a

new era in treatment of infectious diseases.

About a decade later, a British research and engineering team led by H.W. Florey developed

methods for the large-scale production of penicillin. Penicillin became known as the “wonder

drug,” and diseases that were once life-threatening became manageable.

Over time, however, bacteria demonstrated

their ability to “fight back.” In 1945, shortly after

penicillin’s debut into hospitals, scientists isolated Staphylococcus aureus strains that were

resistant to the drug, and by the 1950s, such

strains were a common cause of disease in hospitals where penicillin had been heavily used. The

semi-synthetic penicillin methicillin was temporarily effective against hospital strains of Staph.

aureus, but only one year after methicillin’s

introduction in 1960, a study reported strains

resistant to it. By 1991, more than 40 percent of

Staph. aureus strains in some large hospitals

were methicillin-resistant, and some of those

strains were resistant to all antibiotics except

vancomycin.

Vancomycin-resistant Enterococcus (VRE)

are strains of Enterococcus resistant to the antibiotic vancomycin. Some strains of VRE are resistant to all Food and Drug Administration (FDA)-

approved antibiotics.2 In 1994, 15 percent of the

enterococcus infections in intensive care units

(ICUs) were resistant to vancomycin, as were

almost 10 percent of the enterococcal strains

acquired outside the ICUs.

Today, antibiotics remain effective against

most bacterial diseases, but some antibiotics are

no longer effective against infectious diseases

that they defeated only a few years ago. Moreover, the spread of methicillin-resistant Staphylo2 A drug now in the final stage of clinical trials may work against some strains of VRE, and it is available under an FDA emergency-use

program, upon request to the manufacturer (Rhone-Poulenc Rorer, 1995).

coccus aureus (MRSA) and VRE and the

expectation that other bacteria will develop resistance to all or almost all antibiotics warn that we

may be entering a post-antibiotic era.

SURVEY OF ANTIBIOTIC RESISTANCE

❚ The Microbial Battlefield

The ongoing survival contest between microorganisms and antibiotics dates back millions of

years. Bacteria live in the soil and other places

where they compete with other bacteria and

microorganisms for nutrients. Over time, some

microorganisms, such as the Penicillium mold,

have evolved the biochemical machinery to produce antibiotics, such as penicillin, that inhibit

growth of or kill bacteria. This eliminates competitors for nutrients.

“Antibiotic-resistant bacteria” are strains of

bacteria that were once susceptible to an antibiotic but have since acquired resistance after the

introduction of antibiotics into medical practice.

Antibiotic resistance operates through one of

four general mechanisms. The resistant bacterium: 1) does not absorb the antibiotic, or 2)

expels it, or 3) degrades it, or 4) has altered the

usual molecular target for the antibiotic so that

the drug has no effect.

Resistance results from mutations that arise

spontaneously in bacteria. Mutation is a rare

event—occurring once in a few million or a few

hundred million bacteria, for instance—but the

probability of a mutation occurring during an

infection is the product of mutation and the number of bacteria, and millions of bacteria can be

present in an infection. If a mutation for resistance to an antibiotic does occur, and if the person is being treated with that antibiotic, the

antibiotic will kill off or inhibit the non-resistant

or “susceptible” bacteria (see figure 1-1), leaving

the antibiotic-resistant bacteria to multiply and

flourish. This is the process of “selection.” More
Bacterial colony Resistant bacterium Resistant colony

NOTE: A mutation that makes a bacterium resistant to an antibiotic can arise spontaneously when the antibiotic is applied: only the resistant bacterium can grow and divide.

SOURCE: Time, September 12, 1994, p. 67.

frequent use of antibiotics creates more pressure

for the selection of antibiotic-resistant bacteria.

Many antibiotic-resistant bacteria can transfer to

other bacteria the genetic material that makes

them resistant to antibiotics, contributing greatly

to the spread of antibiotic-resistant bacteria.

Because the use of antibiotics selects for the

emergence and spread of antibiotic-resistant bacteria, it is important to use antibiotics carefully.

According to some estimates, as much as

50 percent of antibiotic use is inappropriate

because the uses do not benefit the patient.

These uses do increase selection pressure for

the emergence and spread of antibiotic-resistant bacteria. Physicians often face difficult

choices in deciding whether to prescribe an antibiotic. Understanding how some of those decisions are made is essential for understanding the

problem of inappropriate use of antibiotics.

❚ Antibiotic Use in Hospitals

At any given time, about 25 to 35 percent of hospital patients are under antibiotic treatment for

active infections or to prevent potential infections. The large volume of antibiotic use exerts

enormous selective pressure for the emergence

and spread of antibiotic-resistant bacteria. Therefore, untreatable bacteria, such as some strains of

VRE, and hard-to-treat bacteria are much more

common in hospitals than in the community at

large.

❚ Antibiotic Use in Physicians’

Office Practice

A parent who brings in a child with one of the

24.5 million middle ear infections (otitis media)

that occur annually hopes for an immediate diagnosis and treatment. The child is cranky; the parent is probably missing work to take care of the

child; and the parent may know that recurrent ear

infections can result in impaired speech, language and cognitive development. By age three,

about three-fourths of all American children will

have had at least one episode of otitis media, and

more than one-third will have had recurrent

infections.

A physician usually refrains from puncturing

the ear drum to obtain a sample of material for

laboratory identification. Waiting for the earache

to clear up on its own may leave the child in

unnecessary pain, increase the number of sleepless nights for the child and family, and potentially contribute to more serious illness.

Consequently, physicians often prescribe antibiotics, though studies show that only one-third to

one-half of otitis media cases benefit from antibiotics. Many otitis media cases that do not

respond to antibiotics are caused by viruses,

against which no antibiotic has any effect. Studies also show that many bacterial infections will

go away without antibiotic treatment, although

use of antibiotics may shorten the course of the

illness.
Chapter 1 Summary, Conclusions, Issues and Options | 5

Faced with the uncertainties of diagnosis and

the certainty that at least some of their patients

will benefit from antibiotics, most physicians

will prescribe an antibiotic, generally amoxicillin, because it is usually effective against all

three of the common bacterial causes of otitis

media. Even so, amoxicillin will be ineffective

against 10 to 15 percent of infections caused by

the three common bacterial agents of otitis media

because the bacteria will be resistant. Another

antibiotic may have to be prescribed in those

cases.

Experience of treatment failures with amoxicillin may encourage the physician to routinely

prescribe antibiotics other than amoxicillin.

Antibiotic prescription patterns are also influenced by patient expectation or demand (see

box 3-1 in chapter 3 for misperceptions about

antibiotic use) and promotion by pharmaceutical

companies.

❚ Antibiotic Resistance in the Community

Everyone is at risk for infections caused by antibiotic-resistant bacteria, but some populations

are at particularly high risk. Those communities

range from the poor, who often live in crowded

conditions with less than optimal hygiene and

medical care, to middle-class children in daycare

centers, who are at high risk for otitis media and

other infectious diseases. Other populations at

higher risk are people in institutions such as hospitals, nursing homes, prisons and military installations. People with diseases or conditions that

suppress the immune system are also at increased

risk. However, once antibiotic-resistant bacteria

emerge in these populations, they can be spread

widely to other groups.

Factors in the Emergence of AntibioticResistant Bacteria

Some of the bacteria acquired in the community

are antibiotic-resistant and have been carried into

the community by people returning from hospitals where antibiotic-resistant bacteria are more

common. Some arrive by other means. Modern

transportation has fostered global accessibility

and allows humans and their microbes to travel

more quickly than ever before. For example, epidemiologists have tracked the spread of a multiple-resistant strain of Streptococcus pneumoniae

from Spain to Iceland. Other factors that contribute to the emergence and spread of antibioticresistant bacteria, as well as the spread of other

bacteria in the community are improper food

preparation practices both in homes and commercial establishments, inadequate water treatment and inspection, and poor sanitation and

hygiene.

Prevalence of Antibiotic-Resistant Bacterial 

Diseases in the Community

No one knows how common antibiotic-resistant

bacteria are in the community. The United States

has no surveillance system to track antibioticresistant bacteria over wide areas, and our

knowledge of community patterns is restricted to

a few studies in specific geographic areas and to

information about antibiotic resistance in gonorrhea and tuberculosis. Both are “notifiable diseases,” and cases of these diseases are to be

reported to the Centers for Disease Control and

Prevention (CDC). Even so, information about

the antibiotic susceptibility or resistance of those

bacteria is often not obtained or reported.

Gonorrhea

Penicillin-resistant strains of Neisseria gonorrhoeae are now found in at least 17 countries.

Between 1988 and 1991, CDC documented a

50 percent increase in the proportion of penicillin- or tetracycline-resistant N. gonorrhoeae.

This finding led CDC to discourage the use of

penicillin or tetracycline as first-line treatment

for the disease. Gonorrhea is an example of

widespread resistance forcing the use of newer,

more expensive antibiotics as primary treatment.

In welcome contrast, Treponema pallidum, the

cause of syphilis, remains universally susceptible

to penicillin.

Tuberculosis

Public health measures and the use of antibiotics

reduced the number of tuberculosis (TB) cases
6 | Impacts of Antibiotic-Resistant Bacteria

from 135,000 in 1947 to 22,000 in 1985 and

fueled the expectation that the disease would be

conquered. By 1992, however, the number of

cases had resurged to 30,000.

Drug-resistant strains of TB present a major

challenge to health officials. In 1991, in New

York City, 14 percent of all newly diagnosed TB

cases were resistant to one or more antibiotics

used for primary treatment, and 60 percent of the

relapse cases in the first 12 weeks of the year

were multiply drug resistant (MDR). These

strains spread from impoverished homeless populations of New York City to their health care

providers, jail guards, fellow patients inside hospitals, and other parts of the country. Table 1-1

illustrates the MDR-TB outbreaks in the United

States and Puerto Rico from 1985 to 1992.

❚ Antibiotic Use in Animal Husbandry

Probably no other issue about antibiotic-resistant

bacteria elicits more emotion than questions

about the impact of the use of antibiotics in animal husbandry on the appearance of antibioticresistant bacteria in humans (see chapter 7).

About half, by weight, of the antibiotics used

in the United States are used in the production of

food animals, such as swine, cattle, and poultry,

and the most used antibiotics are “old” ones, penicillin and the tetracyclines. Almost 90 percent of

the agricultural use is for prophylaxis or growth

promotion, rather than for treatment of sick

animals.

Long-term use of antibiotics such as penicillin

and tetracyclines decreases the time necessary to

raise an animal to marketable weight or reduces

the amount of feed necessary to reach such

weights. Perhaps because those uses are equated

only with economic gain, the strongest criticisms

have usually been addressed at such long-term

uses.

There is no question that agricultural uses of

antibiotics select for antibiotic-resistant bacteria

just as do medical uses. For instance, some antibiotic-resistant Salmonella cases have been

traced back to meat from animals fed antibiotics.

Questions arise about the quantitative public

health importance of antibiotic-resistant bacteria

from agriculture. No differences in the prevalence of antibiotic-resistant bacteria were found

between groups of people who ate meat and

groups who did not eat meat. Indeed, there was a

slightly increased frequency of multiply resistant

bacteria in the vegetarians. These results are consistent with the conclusion that meat is not the

only source of antibiotic-resistant bacteria, but

they do not show that meat is unimportant nor do

they pinpoint the other sources of antibioticresistant bacteria in the diet.

Over the last two decades, the FDA, the

National Academy of Sciences, OTA, and official boards and committees overseas have examined the evidence for the contribution that

agricultural uses of antibiotics make to human

diseases or to the prevalence of antibiotic-resistant bacteria. None was able to pinpoint data that

show the extent of the problem, and all have

pointed to the great difficulties in studying this

issue.

COSTS OF ANTIBIOTIC-RESISTANT 

BACTERIAL DISEASES

Because of the costs involved in controlling and

monitoring the spread of antibiotic-resistant bacteria, it would be useful to know how much

would be saved by reducing the impacts of antibiotic-resistant bacteria. Calculation of the costs

imposed by antibiotic-resistant bacteria can

include such factors as the direct cost of time in a

hospital, the costs of extra physicians’ visits

when antibiotics are ineffective, the extra hospitalizations due to community-acquired resistant

infections, and the costs of newer antibiotics to

replace antibiotics to which bacteria have

become resistant. Other costs include lost work

days and deaths, if they occur. Only one such

study has been published, and it included the

estimate that the cost of antibiotic-resistant bacteria nationwide was between $100 million and

$30 billion annually, with different values

attached to the cost of a life accounting for most

of the wide range of the estimate. A medical
Chapter 1 Summary, Conclusions, Issues and Options | 7

TABLE 1-1: MDR-TB Outbreaks in the United States and Puerto Rico, 1985-1992

Location Drug resistance Year(s) Index case(s) Secondary case(s)

Texas, California, 

Pennsylvania

INH, RIF, SM, 

PZA, EMB

1987 Male, diagnosed with 

TB in 1971; recalcitrant, 

in/out of medications. 

Died in 1987.

9 family members and relatives

Mississippi, rural INH, SM, PAS 1976 High school student Fellow students and their families

Boston, homeless 

shelters

INH, SM 1984, 1985 2 possible, both 

homeless men

Fellow sheltered homeless

Miami outpatient 

AIDS clinic or HIV 

ward

INH, RIF, EMB, 

ETH

1988-1991 1 patient 22 HIV patients

New York State 

Prison

INH, RIF, PZA, 

EMB, SM, KM, 

ETH

1990-1991 Prisoner 7 inmates and 1 prison guard

New York City 

Jail, Rikers Island

Various 1988-1992 Prisoners Spread within jail; diagnosis rate of 

500 per 100,000. Average daily 

census of jail is 20,000

New York City Jail Various 1991 Prisoners 720 cases of MDR-TB diagnosed in 

prisoners

Waupun Jail, 

Wisconsin

NS 1993 Prisoners 22 prisoners

Nassau County 

Jail, New York

NS 1988-1990 Prisoners 45 prisoners

Lincoln Hospital, 

New York City

INH, RIF, EMB, 

SM

1991 Noncompliant AIDS 

patient

1 AIDS patient 

7 New York City 

hospitals

INH, SM, RIF, 

EMB

1988-1991 Patients More than 100 patients; 19 healthcare workers; all but 6 of whom were 

HIV infected

San Juan, Puerto 

Rico, hospital

12 to INH, RIF, 

PZA, EMB

1989 Patient(s) All 17 health-care providers on HIV 

ward infected

New York City 

hospital

NS 1989-1991 Patient(s) 23 patients, 21 of whom were HIVinfected; 12 health-care providers 

infected; no active cases

New York City 

hospital

INH, SM, RIF, 

EMB

1989-1990 Patient(s) 18 AIDS patients

Cook County 

Hospital, Chicago

NS 1991 Patient(s) 12 health-care providers infected; 

no active cases

Miami hospital INH, RIF 1990-1991 Patient 36 patients, 35 of whom were HIVinfected

Miami hospital INH, RIF 1987-1990 Patient(s) 29 patients, 13 health-care 

providers; no active cases

INH=isoniazid; RIF=rifampin; EMB=ethambutol; PZA=pyrazinamide; SM=streptomycin; PAS=para-amino-salicylic acid; ETH=ethionamide;

KM=kanamycin; NS=not specified 

SOURCE: Garrett, L. 1994.
8 | Impacts of Antibiotic-Resistant Bacteria

society subsequently estimated the costs of such

diseases at $4 billion.

In this report, OTA calculates the direct hospital costs from five classes of nosocomial infections associated with only six different strains of

antibiotic-resistant bacteria and concluded that

the minimum nationwide hospital costs of those

infections was $1.3 billion in 1992 dollars. Adding other infections associated with other bacteria and other costs in addition to direct hospital

costs would increase the total to several billion

dollars. This number can be expected to increase

as the numbers of antibiotic-resistant bacteria

increase.

REDUCING THE IMPACTS OF 

ANTIBIOTIC-RESISTANT BACTERIA

The impacts of antibiotic-resistant bacteria can

be reduced by preserving the effectiveness of

current antibiotics through infection control, vaccination and prudent use of antibiotics, and by

developing new antibiotics specifically to treat

infections caused by antibiotic-resistant bacteria.

❚ Preserving the Effectiveness 

of Current Antibiotics

Reducing infection rates, which will reduce the

demands for antibiotics, will reduce the pressures

for selection of antibiotic-resistant bacteria.

Surveillance

Surveillance systems are necessary to track patterns of antibiotic resistance. At the local level,

physicians can use the information to choose

appropriate antibiotics. At the national level,

pharmaceutical companies can use the information to plan new drug development.

Many hospitals have surveillance systems to

track the spread of disease-causing organisms,

including antibiotic-resistant bacteria, and to provide information to physicians about the use and

effectiveness of antibiotics. These systems have

saved hospitals money; for example, a system in

the LDS Hospital in Salt Lake City, Utah, monitored the use of prophylactic antibiotics before

surgery. This system reduced unnecessary antibiotic use and saved $42 per patient, resulting in a

projected cost savings to the hospital of $89,000

per year.

At the state level, the New Jersey Department

of Health collects data about antibiotic-resistant

bacteria from microbiology laboratories in each

of the 95 acute care general hospitals licensed by

the Department. Since its inception in 1991, all

New Jersey hospitals have submitted monthly

reports to the Department of Health, which collects and analyzes the data and makes it available

to all participating hospitals and to the public.

The surveillance system has been used to study

many questions about antibiotic-resistant bacteria including: patient risk factors for VRE bacteremia, the role of antibiotic usage in VRE

bacteremia, the effectiveness of infection control

practices in preventing nosocomial transmission

of VRE, and VRE susceptibility to the experimental drug quinupristin/dalfopristin. The system’s operation requires about a day’s work by

one person each month in the State Department

of Health.

SCOPE, Surveillance and Control of Pathogens of Epidemiological Importance, is a

national effort established by the University of

Iowa and Lederle Laboratories (now WyethAyrst Lederle Laboratories) in 1995. The program expects to collect reports of all nosocomial

bloodstream infections in 48 hospitals nationwide as well as samples of the organisms isolated

from the infected patients. The reports will provide information about the spread of antibioticresistant bacteria in the hospitals.

There are also other industry-funded surveillance systems. A number of academic and commercial laboratories conduct surveillance under

contract to pharmaceutical companies, but they

are not necessarily designed to obtain information most useful for public health purposes.

The CDC-run National Nosocomial Infection

Surveillance (NNIS) is the single nationwide surveillance system that produces information about

antibiotic-resistant bacteria. While it is limited to

reports on nosocomial infections from about 200

hospitals, it is the source for most of the data in

this report about MRSA, VRE, and other drug-
Chapter 1 Summary, Conclusions, Issues and Options | 9

resistant bacterial infections. NNIS publishes

results infrequently and at long intervals after the

data are collected. NNIS, in whatever form it

continues, should be urged to publish in a timely

fashion so that data can be used more efficiently.

CDC is in the early stages of establishing

nationwide surveillance of drug-resistant S.

pneumoniae (DRSP), which will cover infections

whether or not they occur in a hospital. Successful establishment and operation of that system

could provide a model for surveillance of all

antibiotic-resistant bacteria, but the full system

would require additional funding. As an early

step in setting up the DRSP system, and at

CDC’s request, the Council of State and Territorial Epidemiologists has recommended DRSP for

inclusion on the list of notifiable diseases, and

four states now report it. The CDC initiated

DRSP in 20 laboratories in New Jersey in April

1995, and if funds are available, CDC expects

that most of the nearly 2,000 hospital and commercial laboratories that now have computerized

record keeping will be on the system by 1998. As

laboratories add computer capabilities, the CDC

will encourage them to enlist in the system,

expecting that all of the nearly 5,000 laboratories

in the country will eventually participate. If the

DRSP system works, CDC envisions expanding

it to include other antibiotic-resistant bacteria.

WHONET, an established surveillance

project, is a computer-based system that is sponsored by the World Health Organization. It tracks

the resistance patterns of bacteria in clinical

microbiology laboratories in hospitals worldwide

and provides the participating hospitals with

methods to follow the spread of antibiotic-resistant bacteria and to examine the efficacy of local

infection control procedures. WHONET was

established by two people, and it is maintained

single-handedly by Dr. Thomas O’Brien of the

Brigham and Women’s Hospital, Boston, MA.

Even with its limited resources, WHONET

has about 100 participating hospitals, and some

of those hospitals report information from large

areas, up to the size of countries. It is a primary

source of data about antibiotic-resistant bacteria

around the world, and it provides a method to

track the flow of bacteria from country to country. It also provides scientists in the participating

hospitals a powerful tool to analyze the spread of

antibiotic-resistant bacteria in their own hospitals.

Vaccines

Vaccines now protect millions of people from

bacterial and viral diseases, and as shown in figure 1-2, successful vaccines can have a rapid,

profound effect on bacterial disease rates. Vaccines that are successful against pathogenic bacteria will protect against both antibiotic-sensitive

and antibiotic-resistant strains and reduce the

need for antibiotics and the selection pressure for

the emergence of resistance. While the rate of

introduction of new vaccines has been slow in

years past, new developments in molecular biology research may increase the rate in the near

future.

The policies surrounding vaccine development in the United States are not a focus of this

OTA report, but the Federal National Vaccine

Program is often described as faltering and

research as underfunded.

Infection Control

Infection control measures are a crucial element

in preserving the effectiveness of current antibiotics. A 1976 CDC study showed that hospitals

with intensive infection control and surveillance

programs could reduce the approximately two

million infections acquired in hospitals per year

by 32 percent. The report identified handwashing, improved hygiene, and patient isolation as

successful infection control efforts.

Despite whatever infection control methods

were put in place, the number of bloodstream

infections increased by 70 percent in large teaching hospitals and 279 percent in small non-teaching hospitals during the 1980s. These increases,

in part, reflect the increased life-saving capacity

of modern medicine that includes increased surgery rates with attendant catheterizations and

other invasive procedures, organ and tissue transplants that require immunosuppression to pre-
19831984 1985 1986 1987 1988 1989 19901991 1992

SOURCE: Division of Microbiology and Infectious Diseases, National

Institute of Allergy and Infectious Diseases. 1994. Annual Report, p.1.

vent rejection of the transplant, and more

aggressive treatment of cancer and other diseases

with chemicals and radiation that also cause

immunosuppression. All of these procedures

increase the risk of infection.

Even simple infection control measures may

be difficult to institute in practice. In one study,

nurses believed they adhered to hand washing

practices nearly 90 percent of the time, when the

actual observed rate was between 22 and

29 percent. However, professional organizations,

such as the Association for Professionals in

Infection Control and Epidemiology (APIC) and

the Society of Healthcare Epidemiology of

America (SHEA), provide forums for hospital

staff and other health care professionals to study

and understand the transmission of infections

and methods to control it. They support independent organizations for the certification of individuals as being qualified to work in infection

control on the basis of education and knowledge.

Materials and Device Design

to Reduce Infections

Many of the several hundred thousand annual

nosocomial infections associated with the use of

body; and coating or impregnating catheters with

antibacterial agents has also reduced rates of

infections in some studies.

New Antibiotic Delivery Systems

Direct application of antibiotics to infected areas

or areas likely to be infected can produce local

concentrations of antibiotics sufficiently high to

overcome some resistant bacteria without producing high concentrations of circulating antibiotics. Researchers at the Walter Reed Army

Institute of Research have developed microsphere of biodegradable polymers and antibiotics that can be dusted directly into wounds, and

other researchers have used an antibiotic-impregnated polymer to cement bone fractures and

prostheses in place, and a new material, which

can also be impregnated with antibiotics, can be

used as cement and as replacement for destroyed

bone.

Possible Alternatives to Antibiotics

Before antibiotics were available, physicians

used other therapies against bacterial infections.

Serum therapy consists of using blood (or blood

fractions) from animals that have survived a particular bacterial infection to treat humans

infected with the same organism. This treatment

is complicated by the adverse side-effects that

accompany injection of foreign blood proteins,

but it has been shown effective in treating infections caused by Escherichia coli O 157:H7 in laboratory animals. That bacterium produces a toxin

that can be inactivated by serum treatment; antibiotics have no positive effect on the infections,

and may make them worse by liberating the

toxin.
Chapter 1 Summary, Conclusions, Issues and Options | 11

“Phage” or “bacteriophage” are viruses that

infect and kill bacteria. Physicians used them to

treat human infections in the years between the

World Wars, and they were the research project

of the physician in Arrowsmith. Some scientists

believe study of their possible use in a post-antibiotic era may be justified.

While both phage and serum therapy are

sometimes suggested as alternatives to antibiotics, the rapid disappearance of both therapies

after the introduction of antibiotics points to their

less-than-successful past. These old therapies are

not likely to receive serious consideration unless

effective antibiotics disappear.

Optimizing Antibiotic Use

A comparison of prescription records to verified

causes of disease shows that antibiotics are often

prescribed for viral infections, for which they

have no value, and for self-limited infections that

would have cleared up whether or not an antibiotic had been prescribed. Of course, the prescriptions are often, necessarily, written in advance or

in the absence of the laboratory testing required

to verify causes. While these cases offer evidence of inappropriate use of antibiotics, many

of them are, at least partially, understandable.

Clearly inappropriate, however, is the administration of prophylactic antibiotics at times

greater than two hours before or after surgery; antibiotics administered at these times

are ineffective for preventing surgical wound

infections. Reducing inappropriate uses should

retard the development of antibiotic resistance,

and over the years, academicians and scientists

have urged better education of physicians about

antibiotic use and resistance.

A new educational initiative being planned by

a number of pharmaceutical companies, the

American Society for Microbiology, and CDC

will produce educational materials encouraging

more appropriate use of antibiotics. Other organizations are making similar efforts. Evaluation

of the success of those efforts could pinpoint the

items in the educational package that make the

most difference. OTA’s 1994 report Identifying

Health Technologies That Work describes the

features of successful programs designed to

influence physician behavior.

Past educational efforts have had limited

effect, partially because not all cases of “overuse” are as clearly defined as the case of inappropriately prescribing prophylactic antibiotics. For

example, different interpretations are possible of

the wisdom of giving a prophylactic dose of antibiotics to the President after his exposure to a

low risk of contracting an infection (see box 1-

2). Another example is one type of ear infection

(otitis media with effusion). The Agency for

Health Care Policy and Research recently wrote

a guideline to clarify treatments for otitis media

(not necessarily to promote prudent use of antibiotics) and concluded that:

Meta-analysis for Guideline development

showed a 14 percent increase in the probability

that otitis media with effusion would resolve

when antibiotic therapy was given versus no

treatment....When this small improvement in

resolution of otitis media with effusion is

weighed against the side effects and cost of

antibiotic therapy, antibiotic therapy may not be

preferable to observation in management of otitis media with effusion in the otherwise healthy

young child....

A physician who elected not to prescribe an

antibiotic, foregoing the 14 percent increased

probability that the condition “would resolve,”

might be liable for legal action. Such potential liability might encourage physicians to prescribe

antibiotics even when they may not be indicated.

The above guidelines do not instruct physicians to

consider the spread of antibiotic resistance in the

decision to prescribe antibiotics, only the cost and

risk vs. benefit of the antibiotic to the patient.

Some hospitals control drug use by establishing formularies, listings of approved drugs for

various medical indications. Some Denver, Colorado, area hospitals combined their formularies

with a computerized antibiotic order form that

requires physicians to enter the suspected cause

of infection. The system saved the hospitals

money, and allowed officials there to change the

formularies when susceptibility tests revealed a

new pattern of antibiotic resistance.
12 | Impacts of Antibiotic-Resistant Bacteria

Managed care plans are beginning to employ

Pharmacy Benefit Managers (PBMs) to monitor

pharmacy use. PBMs analyze pharmacy use data

to control costs and they may be helpful in setting guidelines for appropriate antibiotic use.

The LDS hospital in Salt Lake City, Utah,

developed a computerized antibiotic monitoring

system, which is part of a larger computerized

patient record system that automatically collects

surveillance data and generates profiles of antibiotic resistance in the hospital’s bacteria. Clinicians enter the results of susceptibility tests into

the computer which checks to be certain that any

prescribed antibiotic will work and generates an

alert when an antibiotic is inappropriate. Another

part of the hospital’s system is a computerized

antibiotic consultant, which uses surveillance

data along with information about the site of

infection and patient allergies to determine the

best choice of empiric antibiotic therapy. As

judged by a panel of infectious disease experts,

this computer consultant “chose” the appropriate

antibiotic 94 percent of the time, as compared to

a 77-percent rate for the physicians. These systems require up-front costs with no guarantee

that the costs will be recouped. Thus, convincing

hospital administrators to invest in such a system

in financially strapped times appears difficult,

despite the advantages such a system could bring

to a hospital.

Diagnostic Technologies

Sore throats, as well as ear aches, are often mentioned in connection with the overuse of antibiotics. When a physician sees a patient with a sore

throat, the physician asks about the patient’s

symptoms, examines the patient’s throat, notes

the inflammation, and may swab the throat to

pick up any organisms that are there. If the physician is like more than 40 percent of all primary

BOX 1-2: The President's Doctor's Dilemma

On June 13, 1995, President Clinton took antibiotics to prevent a possible case of meningitis after

shaking hands with a college student who was diagnosed with the disease (Washington Post, June 14,

1995, page A6).

Meningitis is often caused by Hemophilius influenzae type b (Hib), Neisseria meningitidis, or Streprococcus pneumoniae. A standard textbook (Mandell, Douglas and Bennett's Principles and Practices of

Infectious Disease, 4th Edition, pages 856–857) describes considerations for deciding when prophylactic

antibiotics are necessary after contact with a patient with meningitis. For meningitis caused by Hib, the

textbook states that prophylaxis is indicated for household contacts, and possible for day care contacts,

“...in day care centers that resemble households where children have prolonged contact.” For meningitis

caused by N. meningitidis, the textbook states that “Chemoprophylaxis is recommended for close contacts of the index case, defined as household contacts or close contacts in a closed community such as

a military barracks or boarding school, and medical personnel performing mouth-to-mouth resuscitation.”

For meningitis caused by S. pneumoniae, the textbook states that in one outbreak in a day care center,

chemoprophylaxis “...did not prevent new acquisition of this organism by three children and one family

member. Further studies are needed before chemoprophylaxis is recommended for contacts of

patients....”

Prescribing a dose of antibiotics for the President after he shook hands with someone with meningitis

is an example of individual vs. public health considerations in the use of antibiotics. Shaking hands is a

pretty minor contact; far less intense than those for which the textbook recommended prophylaxis. However, even the insignificant chance that the President was infected was considered worth one dose of

antibiotics. This illustrates a dilemma about appropriate antibiotic use. The President had the benefit of

the antibiotic preventing a very small risk. The use of the antibiotic might increase the spread of antibioticresistant bacteria. Millions of such cases, justified on similar individual bases, would add together to

increase the risk of spread of antibiotic resistance.
Chapter 1 Summary, Conclusions, Issues and Options | 13

care physicians, he will begin antibiotic treatment without any more information. This is

partly because of the time necessary for a laboratory to identify the bacteria associated with an

illness.

Chapter 6 describes methods currently used to

identify bacteria and to determine their antibiotic

susceptibility. Methods to determine susceptibility rely on putting the bacteria into culture media,

where the bacteria will grow, and also putting

them into culture media with known concentrations of antibiotics. Laboratory personnel then

determine which antibiotics and which concentrations of antibiotics inhibit the growth of or kill

the bacteria.

More rapid methods for making diagnosis

might improve the physician’s decisions about

prescribing antibiotics, but only if the results

have high reliability. “Quick strep” tests for sore

throats produce results in 20 minutes. If the test

result is positive, 95 percent of the time the result

is accurate and strep is present. If the test does

not indicate strep, there’s a 20–30 percent chance

that strep was present, but the test missed it.

Guidelines recommend a follow-up culture for

all negative “quick strep” tests. The result is that

the “quick strep” test probably affects practice

only marginally. All patients with a positive

“quick strep” test will surely get an antibiotic,

and many with a negative test will get antibiotics

as well (at least until the results of a standard culture assay are available). This result differs little

from what would likely happen in the absence of

the test. The test provides an advance in the right

direction, but further advances are necessary.

A strep test that employs DNA methods

reportedly produces results sufficiently accurate

so that they do not have to be verified by standard tests. However, the test is so involved that

its use will probably be restricted to large practices or hospitals. Moreover, it produces results

in a few hours, not in a few minutes. Even if this

test proves to be as good as it appears and it is

adopted where there are large numbers of

patients, it will not produce results during the

course of an office visit. The physician may elect

to give the patient a prescription with instructions to call the office in a few hours to learn the

test results before the prescription is filled (or

discarded). Of course, the patient might have the

prescription filled regardless and save it for

another time. The impact of any test will depend

a great deal on the interactions between physician and patient until the results are so rapid that

they are complete before the patient leaves the

office.

Faster tests may have a marked impact in the

diagnosis of tuberculosis so that patients can be

treated before they pass the infectious disease to

others. Isolation of the slowly growing Mycobacterium causing tuberculosis requires three to

eight weeks, and susceptibility testing by traditional methods can add 20 days to six weeks.

New diagnostic tests based on identifying mycobacterial DNA are being developed to allow physicians to identify Mycobacteria in the sputum of

patients within a few hours to a few days.

New diagnostic technologies raise some new

issues. For instance, the DNA test for tuberculosis might be so sensitive that it can detect the

DNA of Mycobacteria already killed or inhibited

by previous treatment. To act entirely on the test

result might result in treatments that are unnecessary.

Tests which directly measure the presence of

an antibiotic-resistance gene in bacteria also

bring a new set of considerations. A gene for

resistance that is detectable by the new tests

might not be “expressed,” and its detection might

not accurately predict whether the bacteria will

be resistant or susceptible. Or a resistance gene

may have undergone a mutation that does not

affect its function, but alters it so that a genetic

test might not register the presence of the antibiotic-resistant gene. All these issues are anticipated in designing genetic tests and bringing

them to clinical practice.

Practice Guidelines

Practice guidelines are medical protocols that are

intended to assist practitioners in making clinical

decisions. For example, the Agency for Health

Care Policy and Research (AHCPR), a federal

agency empowered to establish practice guide-
14 | Impacts of Antibiotic-Resistant Bacteria

lines, encourages health care providers to adopt

its guidelines to improve patient care, patient

outcomes, and quality of life. Practice guidelines

that are written to balance patient benefits and

public health effects and that provide specific

direction about antibiotic use might reduce overuse. Nationwide data cannot capture the localized nature of antibiotic-resistant bacteria, but an

online computer system linking health care practitioners in a geographic area could provide that

information. Such a system would allow health

care practitioners to consult with specialists in

determining the best way to comply with the

practice guidelines and would also allow health

care practitioners to enter the specifics of their

cases.

❚ Designing New Antibiotics

In the arms race with resistant bacteria, drug

manufacturers have research programs to isolate

or synthesize new antibiotics or to develop derivatives of old ones that have greater antibacterial

activity, fewer side effects, or that can be administered orally rather than requiring injections.

Researchers are continuing to search through

samples of soils and other materials rich in molds

and bacteria, which have yielded many of the

existing antibiotics, and they have widened the

search to include carbohydrates, proteins, and

steroids from many biological sources. Companies are investigating the use of modern chemical

techniques to design new molecules for specific

purposes. While the payoff from any line of

research remains uncertain, many small, new

companies as well as the older, established pharmaceutical companies are sufficiently confident

of producing useful products that they are investing in antibiotic research (see chapter 5). Table

1-2 lists some currently used and in-development

antibiotics.

New antibiotics can be divided between those

that are improvements on already-existing drugs,

which depend on known mechanisms of action,

and those drugs that have new mechanisms of

action. None of the nine antibiotics approved by

FDA in 1992 and 1993 had a new mechanism of

action, and no antibiotic was approved in 1994.

Antibiotics that depend on “old” mechanisms

of action can be very useful (and profitable). For

instance, cefaclor, a third-generation cephalosporin, accounted for 15 percent of a major

pharmaceutical company’s sales when its patent

expired in 1992. It remains a clinically useful

drug, and the company expects to retain a major

part of the market for cephalosporins even after

the expiration of patent protection. In general,

however, antibiotics with new mechanisms of

action might be expected to be more successful

as therapies against certain antibiotic-resistant

bacteria because no similar antibiotics exerted

pressure for the selection of resistance to them in

the past. Many of the substances currently being

examined as potential antibiotics have novel

mechanisms of action, and some may not foster

the development of resistance (see chapter 5).

The isolation or synthesis of a chemical with

antibiotic activity starts a long process of evaluation in the microbiology lab, laboratory animals,

and ultimately, in humans. At the end of those

tests, FDA reviews the results and considers

approving it as a new drug (see figure 1-3). The

entire process between discovery and final

approval takes years; frequently a potential drug

fails a critical test—for instance, it is found to

have toxic side effects—and is discarded. The

risks of toxicity may be re-evaluated against the

benefits of an antibiotic, however, if the antibiotic proves useful against a disease with few or

no other treatments.

Pharmaceutical firms are largely responsible

for antibiotic research and development, but the

federal government supports a small research

program aimed at antibiotic-resistant bacteria at

the National Institute of Allergy and Infectious

Diseases. In 1994, the institute spent about

$13 million on that program, and about the same

amount in 1995.

Antibiotic Resistance and Markets

Antibiotic resistance both limits and creates new

markets. Although drugs may lose their efficacy

and market life because of resistance, their slide
Ch

apter1Summary,Conclusions,IssuesandOptions|15

TABLE 1-2: Antibiotics in Use and Under Development

Action Family/Class Example(s) Source StatusAntibiotics that inhibit cell wall synthesis

Beta-lactams

Natural penicillins Penicillin G Penicillin notatum Used since 1940sSemi-synthetic penicillins

MethicillinPiperacillin

Semi-synthetic penicillin derivatives

In use since 1960s; among the most widely prescribed antimicrobials

Cephalosporins Cephalexin C. acremonium Widely used class of antibioticsCarbapenems Imipenem Derived from thienamycin, a 

compound produced by Streptomyces cattleya

In use; wide spectrum (active against many species of bacteria including cephalosporin-resistant Enterobacteriaceae)

Monobactams Aztreonam Derived from a compound 

produced by Chromobacterium violaceum

In use; tolerated by patients with penicillin allergies; spectrum limited to aerobic gram-negative bacteria

Penicillinase inhibitors Clavulanate potassium 

(used clinically with amoxicillin or ticarcillin)Subtraction (used with ampicillin)Tazobactam sodium (used clinically with piperacilllin)

Streptomyces clavuligeriusSemi-synthetic penicillin derivativeSemi-synthetic penicillin derivative

Used since 1970s; clavulanate combinations used for wide range of disordersSimilar to amoxicillin/clavulanateTazobactam/piperacillin effective against intra-abdominal infections

VancomycinTeicoplanin

VancomycinTeicoplanin

Strep. orientalisActinoplanes teichomyceticus

Introduced in 1956; used against staphylococcal and enterococcal infectionsExperimental in the U.S., available for compassionate use

 Vancomycin derivatives

with catalytic activity

Semi-synthetic Experimental

(continued)
16

| Impacts of Antibiotic-Resistant Bacteria

TABLE 1-2: Antibiotics in Use and Under Development (Cont’d.)

Action Family/Class Example(s) Source StatusAntibiotics that increase membrane permeability

Peptides

Bactericidal/PermeabilityIncreasing Protein (BPI)

Mammalian cells Experimental

 Magainins African clawed frog Experimental Cecropins Silk moth, other insects, 

mammals

Experimental

 Defencins Mammalian cells ExperimentalSteroids Dogfish sharks Experimental

Metabolic interference

SulfonamidesTrimethoprim

SulfamethoxazoleTrimethoprim

Azo dyesSynthetic

In use since 1930s; first antimicrobial agent used in manSynthesized in 1968, commonly used together with sulfanimides

Protein synthesis inhibitors

Aminoglycosides Streptomycin

KanamycinTobramycinGentamicin

Streptomyces griseus

Streptomyces kanamyceticus

Streptomyces tenebrarius

Micromonspora purpurea and 

echinospora

In use since 1940s; important class of antibiotics

Fusidanes Fucidin Sodium salt of fusidic acid, 

derived from the fungus 

Fusidium coccineum

In clinical use since 1962, but not available in US (except through compassionate release); active against some strains of methicillin-resistant Staph. aureus (MRSA)

Tetracyclines Chlortetracycline

OxytetracyclineMinocyclineDoxycycline

Streptomyces aurofaciens 

Streptomyces rimosus

Semi-synthetic derivativeSemi-synthetic derivative

First introduced in 1948, found by screening soil samples for antibacterial activity

(continued)
Chapter 1 Summary, Conclusions, Issues and Options | 17

TABLE 1-2: Antibiotics in Use and Under Development (Cont’d.)

Action Family/Class Example(s) Source Status

Chloramphenicol Chloramphenicol Streptomyces venezuelae First introduced in 1949, currently 

second line antibiotic because of side effect of aplastic anemia

 Macrolides Azalides

ErythromycinAzithromycin 

Streptomyces erythreussemi-synthetic derivative of erythromycin

Discovered in 1952Available in 1992

 Lincosamides Clindamycin Semi-synthetic derivative of 

lincomycin derived from 

Streptomyces lincolnensis

Available since the mid 1960s; active against aerobic bacteria

Mupirocin Mupirocin Pseudomonas fluorescens Introduced in the mid 1980s; topical 

antibiotic

Interference with RNA synthesis

Rifamycins Rifampin Streptomyces mediterranei First isolated in 1957, important 

tuberculosis drug

Toxic effect through DNA binding

Nitroimidazoles Metronidazole Synthetic Introduced in 1959, active against 

anaerobes such as B. fragilis

Block DNA replication or RNA transcription

Antisense nucleotides Laboratory Experimental

DNA replication Quinolones

Fluoroquinolones

Nalidixic acidCiprofloxacin, Ofloxacin

Semi-synthetic First identified in 1962

Usage began in 1980s; some of the most widely used antibiotics

Anti-tuberculosis drugs

Isoniazid (INH)Pyrazinamide (PZA)Ethambutanol 

SyntheticSyntheticSynthetic

Shown to be effective in 1952Important tuberculosis drug since 1980Important tuberculosis drug since 1974

Decoy receptors Carbohydrates Laboratory Experimental

 SOURCE: Office of Technology Assessment, 1995.
o 1 2 3 4 5 6 7 8 9 10

Development time (years)

A

NDA

Filing

KEY: IND = investigational new drug; NDA = new drug application.

SOURCE: GOOtZ, 1990,

from use opens up markets for new drugs. OTA

estimated that a new antibiotic that was limited

to the treatment of MRSA has a maximum potential market of about $60 million annua11y,3 a relatively small market for a pharmaceutical.

Ironically, if strains of MRSA became resistant

to vancomycin, the potential market would be a

lot larger, since the price of the drug to treat otherwise incurable strains could be set much

higher. The current market for a drug to treat

MRSA, small in comparison with that of many

drugs, would discourage marketing of an antibiotic only for MRSA infections. Since the antibiotic would probably be effective against bacteria

that cause upper respiratory infections or middle

ear infections, it would almost certainly be prescribed for other conditions, increasing the

potential markets, and, at the same time, increasing selection pressure for the spread of resistance

to the drug.

One issue relevant to antibiotics is the possibility of extending a period of market exclusivity

to the manufacturer of an antibiotic in exchange

for targeted, restricted marketing of the drug for

only particular, specified infections. The

restricted marketing would arguably prolong the

useful life of the drug by reducing the emergence

and spread of bacteria resistant to it (see options).

CONCLUSIONS

The problems caused by antibiotic-resistant

bacteria can be ameliorated through two major

routes: 1) prolonging the effectiveness of currently available antibiotics through infection

control and optimal use of existing antibiotics

and 2) developing new antibiotics to treat resistant bacteria.

Similar conclusions have been reached before,

and the issues that stem from them have also

been discussed (table 1-3). In the following section, OTA discusses 10 issues that arise in efforts

to reduce the negative impacts of antibiotic-resistant bacteria. For two issues, OTA has no options

for action by Congress or other organizations.

While providing additional resources to support

ongoing activities in vaccines and diagnostic

technologies is a possibility, and careful monitor3 Calculated by multiplying the estimated cases of MRSA times the estimated cost of the new drug assuming that the new drug would be

priced similar to vancomycin (which is currently used to treat MRSA). The maximum potential market is the market expected if the new drug

was used to treat all cases of MRSA. (Note that it is unlikely that a new drug would capture the market so long as vancomycin is still available for and useful in the treatment of MRSA. )

I
Chapter 1 Summary, Conclusions, Issues and Options | 19

ing and oversight of federal programs and their

progress are important, no options for such incremental changes are presented. For the remaining

issues, OTA proposes one or more options. Some

of these options would involve greater research

support by the federal government, and OTA

underlines the reasons for such support and, in

some cases, why it is expected to bring savings

in costs. Box 1-3 contains an outline of the issues

and options. All of these efforts will have to be

sustained, as the quote in box 1-4 underlines. 

ISSUES AND OPTIONS FOR PROLONGING 

EFFECTIVENESS OF ANTIBIOTICS

❚ Issue A: Surveillance

If officials decide to design a nationwide surveillance system, they must resolve many issues

before its implementation. Often, Congress or an

executive branch agency turns to a commission

or panel to make recommendations, and any such

group could be instructed to consider the following questions in the design of a national surveillance system.

TABLE 1-3: Publications/Articles on Antibiotic-Resistant Bacteria

The problem of antibiotic-resistant bacteria has existed for years, and many articles and publications have discussed 

issues surrounding the dilemma. The following is a sample listing of some of them. A full bibliography follows.

Year Author Issue

1959 Finland, et al. Antibiotic use and resistance

1973 Kunin, et al. Problem and solution of antibiotic usage 

1979 Buckwold, et al. Antimicrobial misuse

1985 Burke and Levy Worldwide antibiotic resistance

1992 Cohen Epidemiology of drug resistance

1992 Institute of Medicine Emerging infections

1992 Levy The antibiotic paradox

1992 Neu The crisis in antibiotic resistance

1994 Murray Can antibiotic resistance be controlled?

1994 Tomasz Multiple-antibiotic-resistant pathogenic bacteria

1995 CISET Emerging and re-emerging infectious diseases

SOURCES:

Finland, M., et al., “Occurrence of Serious Bacterial Infections Since Introduction of Antibacterial Agents,” Journal of the American Medical Association, 170:2188–2197, 1959.

Kunin, C.M., Tupasi, T., and Craig, W.A., “Use of Antibiotics: A Brief Exposition of the Problem and Some Tentative Solutions,” Annals of Internal

Medicine 79:555–560, 1973.

Buckwold, F.J. and Ronald, A.R., “Antimicrobial Misuse—Effects and Suggestions for Control,” Journal of Antimicrobial Chemotherapy 5:129–

135, 1979.

Burke, J.P. and Levy, S.B., “Summary Report on Worldwide Antibiotic Resistance: International Task Forces on Antibiotic Use,” Reviews of Infectious Diseases 7:560–564, 1985.

Cohen, M.L., “Epidemiology of Drug Resistance: Implications for a Post-Antimicrobial Era,” Science 257:1050–1055, 1992.

Institute of Medicine, Emerging Infections: Microbial Threats to Health in the United States, J. Lederberg, R.E. Shope, S.C.J. Oaks (Eds.), 1992.

Levy, S.B., “The Antibiotic Paradox: How Miracle Drugs Are Destroying the Miracle,” 1992.

Neu, H.C., “The Crisis in Antibiotic Resistance,” Science 257:1064–1073, 1992.

Murray, B.E., “Can Antibiotic Resistance Be Controlled?” New England Journal of Medicine 330:1229–1230, 1994.

Tomasz, A., “Multiple-Antibiotic-Resistant Pathogenic Bacteria—A Report on the Rockefeller University Workshop,” New England Journal of Medicine 330:1247–1251, 1994.

Executive Office of the President, National Science and Technology Council, Committee on International Science, Engineering, and Technology

Working Group, Emerging and re-emerging infectious diseases: global microbial threats in the 1990s. (Washington, DC: 1995).
20 | Impacts of Antibiotic-Resistant Bacteria

BOX 1-3: Conclusions, Issues and Options

The problems caused by antibiotic-resistant bacteria can be ameliorated through the major routes:

1) prolonging the effectiveness of currently available antibiotics through infection control and optimal

use of existing antibiotics, and

2) developing new antibiotics to treat resistant bacteria.

Issues that arise in efforts to prolong the effectiveness of currently available antibiotics:

Issue A: Surveillance

Option 1: Congress could support the establishment of a national surveillance system, including providing funding.

Issue B: Vaccines

Issue C: Infection control

Option 2: Congress could encourage all States to adopt guidelines for the coordination of infection

control measures between acute care and long-term care facilities and to include all antibiotic-resistant

bacteria.

Option 3: Hospitals should consider instituting antibiotic-use subcommittees in their infection control

committees.

Issue D: Research funding

Option 4: Congress can make money available for studies of the development, transfer, and persistence of antibiotic resistance.

Option 5: Congress can make money available for research into the basic biology of bacteria.

Option 6: Congress can make resources available for the study of appropriate use of devices that

present infection risks to hospitalized patients.

Issue E: Diagnostic technologies

Issue F: Controlling antibiotic use

Option 7: Review Medicare and Medicaid reimbursement policies for their unanticipated effects on

antibiotic prescription patterns.

Issue G: Antibiotics in animal husbandry

Option 8: Collect information about associations between animal husbandry uses of antibiotics and

antibiotic-resistant bacteria in humans.

Option 9: Design a study to determine the sources of antibiotic-resistant bacteria in the human diet.

Option 10: Study the benefits of antibiotic use in animal husbandry.

Issues that arise in efforts to develop new antibiotics:

Issue H: Cooperative research among government, industry, and academia

Option 11: NIH could solicit applications for grants to fund cooperative research between universities

and pharmaceutical firms to discover new antibiotics.

Issue I: Negotiated marketing agreements for antibiotics

Option 12: Congress can provide FDA with authority to negotiate extended market exclusivity to manufacturers that agree to restrictions on marketing of antibiotics.

Issue J: Development of off-patent compounds as antibiotics

Option 13: Congress could authorize FDA to extend market exclusivity for “off-patent” antibiotics that

are shown to be effective against antibiotic-resistant bacteria.

Option 14: Congress could provide research support for a federal program to conduct clinical trials of

antibiotics to determine if they have uses against antibiotic-resistant bacteria.
Chapter 1 Summary, Conclusions, Issues and Options | 21

■ Which antibiotics and organisms will be

included in the system? There are more than

100 different antibiotics and many possible

organisms, and it will be impossible to maintain surveillance of all “drug-bug” combinations. Some regional adjustments might be

considered because of geographical variations

in antibiotic usage.

■ How many hospitals and laboratories will

participate in the system? Will all participate,

or will a representative sample of hospitals

and laboratories comprise the network?

■ What kinds of laboratory-determined data will

be incorporated into the system? This will be a

major issue in any surveillance system for

antibiotic-resistant bacteria because of the

variety of techniques already available and the

major changes in diagnostic technologies that

are now underway.

■ How will the system assure the quality of test

results? Would the surveillance system collect

raw data as WHONET does? Or insist on use

of standard guidelines to interpret the data?

Who would develop the guidelines? How

would results from genotypic tests, which

directly measure the presence of a gene for

resistance, be compared to phenotypic tests,

which measure the ability of the bacteria to

survive in the presence of an antibiotic?

■ Who will have access to the system? Will

access be restricted to the medical community,

or would others, such as pharmaceutical companies and private computer owners, be able to

gain entry to the system?

■ Would banking of samples be part of the system? Some small, currently operating systems

collect and bank some bacterial samples to

allow rechecking of identification. Would

pharmaceutical companies be provided access

to banked samples to test new antibiotics?

■ Will hospitals link pharmacy records, patient

data, and laboratory information? This linkage would be ideal, because it would allow

researchers to correlate data about the effect of

antibiotic usage and resistance directly and to

correlate clinical outcomes with test data.

■ Should the system be extended internationally? Antibiotic-resistant bacteria travel from

country to country, posing an international

problem. Therefore, it may be in the best interest of the U.S. to include other countries in a

surveillance system. How would this be done?

■ What role would surveillance system personnel take in training of hospital personnel to

use the results of the surveillance system? The

success of the system will depend on the use

that is made of its results, and system personnel may have to devote some time to make

sure the results are well used.

The cost of the system will have to be considered. The more complex the system, the more it

will cost. However, some successful surveillance

systems, such as WHONET and the New Jersey

State System, have been built on very small budBOX 1-4: The Myth of Sisyphus and Antibiotics

“The search for and development of new drugs by the pharmaceutical industry will go a long way

toward conquering the growing microbial resistances to available antibiotics. But there is much more to

be done than merely generating new antibiotics—the pace of which cannot keep up with the microbial

resistance responses....

“The history of antibiotics reminded our student Raul Borbolla of the Greek myth of Sisyphus, the king

of Corinth who, as punishment for his hubris, was condemned by the gods to push a boulder up a mountain, only to have the boulder roll to the bottom, from which Sisyphus had to start pushing again. Again

the boulder would roll to the bottom, and the cycle was repeated into perpetuity. The rational and controlled use of antibiotics may prevent medicine from facing Sisyphus's fate.”

SOURCE: C.F. Amabile-Cuevas, M. Cardenas-Garcia and M. Ludgar (1995), American Scientist 83:320–329.
22 | Impacts of Antibiotic-Resistant Bacteria

gets. The CDC estimates that bringing their

DRSP system to each state would require startup costs of about $200,000 for each state, for a

total of $10 million and annual operating costs

between $2.5 and $5 million. If a surveillance

system prevents even 1 percent of infections

caused by antibiotic-resistant bacteria (which

OTA estimates cost a minimum of $1.3 billion

per year in 1992 dollars), the system would pay

for itself.

An alternative to surveillance systems is a

program to investigate outbreaks of infectious

diseases as they are reported. A difficulty with

the alternative is that in the absence of a surveillance system, not all cases will be reported to

health officials. According to CDC, 27 illnesses

caused by E. coli O157:H7 were confirmed in

New Jersey in June 1994, compared to five cases

in the same period in 1993. This “pseudo-outbreak,” as CDC called it, resulted from better

reporting as a result of institution of a surveillance system that required laboratory testing of

some clinical laboratory samples for the E. coli.

It illustrates that many opportunities to intervene

and disrupt transmission of infectious diseases

can be missed without a surveillance system.

Congress could support the establishment of a national surveillance system, including providing funding.

A surveillance system is essential for understanding the spread of antibiotic-resistant bacteria and planning interventions so as to preserve

the efficacy of currently available antibiotics.

Because of these public health considerations,

and the likelihood that a surveillance system

would decrease medical costs, including costs to

Medicare, Congress could consider funding a

nationwide surveillance system.

The features of current, limited systems can be

incorporated and combined to produce a system

of desired size, complexity, and cost. It may be

advantageous to begin with a less complex system (such as some of the operating systems

described in this report), and then add more features. Any system must have a strong advisory

group that includes diagnostic laboratory and

computer experts, clinicians, hospital administrators, pharmaceutical company researchers, academic scientists, and federal and state regulatory

and health officials. The advisors could work to

assure that the surveillance system collects and

disseminates the information in the forms for its

best use.

❚ Issue B: Vaccines

The biotechnology revolution is expected to produce many new potential vaccines. This would

be a welcome change from the slow rates of discovery and development of recent years, and it

will benefit from and may, indeed, require new

mechanisms for vaccine testing, development,

and approval. If this effort is successful, effective

vaccines would reduce the need for some antibiotics and would, therefore, help control antibiotic

resistance.

The private sector conducts much of the current vaccine research, but current federal policies

restrict the income from vaccines sales, and that

may inhibit research activities. To provide lowincome Americans with vaccines, the federal

government now purchases up to 80 percent of

all vaccines at a fixed, low price. GAO, however,

reports that the price of vaccines for children has

little effect on vaccination rates, largely because

poor children are entitled to free vaccine. As

Congress considers the Vaccines for Children

program, it can be expected that vaccine manufacturers will argue that the price cap and

reduced profits have created an adverse effect on

new vaccine development. Determining the

impact of the price cap on research could be an

objective of the congressional inquiries.

GAO describes efforts that have fallen short in

reaching various federal goals for immunization

rates. Although Medicare pays for the administration of pneumococcal vaccine to the elderly,

73 percent of them have never received it. That

and other observations made by GAO indicate

that there is much to be done to increase vaccination rates, and the reports make some

suggestions.

OPTION
Chapter 1 Summary, Conclusions, Issues and Options | 23

Encouragement of adult vaccination deserves

special consideration in light of changes around

the world. Currently, diphtheria is epidemic in

Eastern Europe, and as many as 50 percent of

United States adults over 30 are susceptible to

that disease because they have not had immunization booster shots. Since 1988, the few confirmed cases of diphtheria in the United States

have been related to importation of disease from

other countries, illuminating the international

nature of the spread of infectious diseases, which

can include those caused by antibiotic-resistant

bacteria.

❚ Issue C: Infection Control

Several new medical techniques and devices are

designed to reduce infections, and private organizations, such as insurance companies and hospitals, have a financial incentive to institute

effective infection control procedures that can

save money, reduce hospitalization rates, and

help control antibiotic-resistant bacteria. The

government, acting as an insurer through Medicare and Medicaid, may also have an interest in

funding research to develop new techniques and

methods and to apply them.

Some devices and techniques that reduce

infection rates are available, and their adoption

has been demonstrated to reduce in-hospital time

and costs. Most importantly, the patients benefited from fewer hospitalizations. Nevertheless,

adoption of such improvements may hinge on

events as distant as Medicare reimbursement

procedures. Medicare reimburses dialysis centers

and hospitals separately, and there is no financial

incentive for dialysis centers to invest in these

new technologies.

The Joint Commission for the Accreditation

of Health Care Organizations (JCAHO) is beginning to collect data on infection control from

hospitals on a voluntary basis, with about 400

hospitals now participating. Analysis of these

data may be a very useful tool in understanding

the differences between successful and not-sosuccessful infection control in hospitals. This

program provides limited information; it is not

mandatory and it collects no data on antibiotic

resistance. Nevertheless, it provides information

for research efforts, and it can be expanded.

With recent changes in the health care system,

hospitals discharge many patients more quickly

than in the past, and many patients are moved to

long-term care facilities. Some of these patients,

when discharged to the long-term facilities, have

active infections or are at high risk for infection

because of indwelling invasive devices such as

catheters or intravenous lines or because they are

on dialysis. Further, the large concentrations of

antibiotics used in these facilities (like the large

concentrations used in hospitals) selects for the

emergence and spread of antibiotic-resistant bacteria, as is demonstrated by the high prevalence

of MRSA in nursing homes. Patients infected

with antibiotic-resistant bacteria in nursing

homes frequently return to the hospital, where

the antibiotic-resistant bacteria can spread

further.

 Congress could encourage all states to

adopt guidelines for the coordination of infection control measures between acute care and long-term care

facilities and to extend guidelines to include all antibiotic-resistant bacteria.

Many state health departments have recognized the problems of transfer of MRSA between

hospitals and long-term care facilities and have

published extensive guidelines for coordination

of the admission, discharge and transfer of

MRSA-colonized patients between two facilities.

Wider adoption of these procedures should

reduce the transmission of infections caused by

antibiotic-resistant bacteria (and other bacteria)

while simultaneously lowering costs and optimizing patient care.

 Hospitals should consider instituting

antibiotic-use subcommittees in the infection control

committees.

Every hospital has an infection control committee. Assigning a subcommittee responsibility

for monitoring antibiotic use and relating that use

to the spread of antibiotic-resistant bacteria

OPTION

OPTION
24 | Impacts of Antibiotic-Resistant Bacteria

would focus attention on these problems and

bring them to the attention of hospital staff.

❚ Issue D: Research Funding

The current federal belt-tightening era has produced a reluctance to commit new sums of

money to research, which may make it necessary

to transfer money from other research areas to

support research related to antibiotic-resistant

bacteria. Such decisions are difficult, but without

additional research support, the country may fall

further behind in trying to counter antibioticresistant bacteria. One consequence of increased

support of such research will be the training of

scientists and physicians in skills necessary to

teach others the newest methods in research and

in the application of research findings.

 Congress can make money available for

studies of the development, transfer, and persistence

of antibiotic resistance.

Scientists understand the basic principles of

the emergence and spread of antibiotic resistance

and of the genetic transfer of resistance between

bacteria, but they do not have enough details to

predict how the patterns of use of antibiotics will

affect the prevalence of resistance genes. For

example, restricting the use of an antibiotic often

leads to a decrease in the prevalence of antibiotic

resistance. That would appear to pave the way

for reintroducing the antibiotic, but it is uncertain

what will happen when the antibiotic is reintroduced because the time course for the reappearance of resistance is unknown.

 Congress can make money available for

research into the basic biology of bacteria.

The molecular organization and function and

the biochemistry of bacteria differ from those of

animal and human cells, and pharmaceutical

companies have exploited those differences in

developing antibiotics. Basic research directed at

better understanding of bacterial biochemistry

may reveal new targets for antibiotics; in any

case, it will produce information that will be useful in understanding bacterial growth and pathogenesis.

The amounts of federal money spent on nonAIDS research have not increased in parallel

with the increasing inroads being made by antibiotic-resistant bacteria. For instance, the federal

government gave CDC a $6.7 million increase in

its non-AIDS budget specifically to combat

emerging infectious diseases. However, only

about 10 to 15 percent of that money will be used

for antibiotic resistance, and it is unclear how

much of that amount will be used for research.

Relatively small increases, a few million dollars

in the total federal budget directed at antibioticresistant bacteria, could produce a marked

increase in the amount of research being done.

 Congress can make resources available for the study of appropriate use of devices that

present infection risks to hospitalized patients.

Many nosocomial infections result from the

use of invasive devices such as catheters and

mechanical ventilators, often routinely used in

intensive care units. There is little research about

when such devices improve outcomes. Such

research will probably not be funded by manufacturers that benefit from the sales of equipment. Learning about the risks and benefits of

these devices may depend on government funding. This information would guide decisions

about when to use these devices, probably reducing their use (and associated costs) and reducing

infection rates.

❚ Issue E: Diagnostic Technologies

The most powerful weapon in the arsenal

directed at antibiotic-resistant bacteria are techniques for the rapid and accurate identification of

bacteria and determination of their susceptibility

to antibiotics. New techniques are necessary.

When available, they will provide the most certain information for appropriate antibiotic use.

The lack of rapid in-office methods to screen

for and to identify bacteria and to characterize

their antibiotic-resistance patterns probably reinforces physicians’ tendency to prescribe broadOPTION

OPTION

OPTION
Chapter 1 Summary, Conclusions, Issues and Options | 25

spectrum antibiotics for presumed bacterial

infections. As quicker tests become available,

some of which are likely to be quite simple to

perform and present few problems in interpretation, more conflicts are expected between the

provisions of the Clinical Laboratory Improvement Act (CLIA) and physicians’ desires to use

the new tests. CLIA requires that physicians register their offices and fulfill (largely record-keeping) requirements in order to carry out laboratory

tests. One solution to the conflict is to excuse

physicians’ offices from CLIA, and legislation

has been introduced to exempt clinical laboratories in physicians’ offices from having to comply

with CLIA regulations.

Another way to improve the use of diagnostic

tests in physician offices would be encouragement of manufacturers to develop test kits to

meet the performance specifications for products

in the “waived” category of tests under CLIA.

This would preserve the positive effects of

CLIA. For example, CLIA has had a positive

effect on the way tests are manufactured: many

currently waived tests contain built-in controls to

comply with CLIA. These controls make it easier

for the person performing the test to determine

whether it has been performed correctly. CDC,

which determines the categorization of tests

under CLIA, has already taken steps in this direction by sending a letter to manufacturers to

inform them of the possibility of including their

tests in the waived category and outlining the

requirements for tests in this category. Groups

such as the American Medical Association could

determine which tests are most useful for physician offices and work together with the manufacturers and CLIA administrators to provide tests

suitable for the waived category.

With no action taken at all, potential conflicts

between physicians’ desires to carry out in-office

tests and CLIA will diminish. Over the next few

years, group practices that develop sufficient test

volumes to require comprehensive laboratories

will seek CLIA approval as a matter of course.

Smaller offices, however, will persist in rural

areas, and CLIA may be more of an issue in

those locations.

The term “service labs” is generally used to

refer to laboratories in hospitals or to commercial

laboratories that identify and characterize bacteria and other infectious organisms. In a draft

report about a new surveillance system for antibiotic-resistant S. pneumoniae (see option 1),

CDC states that laboratories may not be using the

most up-to-date standards. CDC suggests that the

National Committee for Clinical Laboratory

Standards (NCCLS) guidelines could be published in the Morbidity and Mortality Weekly

Report (MMWR) and as letters to clinical laboratory journals to inform both physicians and laboratories about appropriate standards. This seems

a reasonable step. Since CDC publishes MMWR,

it should be able to disseminate the guidelines

through that publication.

New diagnostic technologies, such as those

based on DNA identification, have advanced rapidly, but regulatory procedures have not kept

abreast of the new technologies. This slow pace

has resulted in conflicting signals about the use

of the tests, which can be illustrated by the case

of tuberculosis diagnostic tests. The public health

benefits of rapid and specific diagnostic tests

include reducing the transmission of tuberculosis

through optimal use of the few beds reserved for

tuberculosis patients and the better treatment of

infected individuals, reducing unnecessary use of

antibiotics and the resulting selection for resistant bacteria. Many hospitals in areas with high

tuberculosis rates currently rely on DNA diagnostic tests for these applications.

Despite the great advantage in speed and the

current use of such tests, CDC and the FDA have

advised that physicians should use conventional

methods until DNA techniques are better

defined. Even so, conventional tests are not without problems. Culture tests for tuberculosis are

difficult to perform accurately and obtaining

reproducible results is difficult. Also, different

testing laboratories have produced conflicting

results in measuring susceptibility to the tuberculosis drug pyrazinamide, demonstrating that conventional tests are not without problems.

Even in the absence of a CDC approval of the

new DNA-based tests, some private insurers will
26 | Impacts of Antibiotic-Resistant Bacteria

pay for them. However, tuberculosis is a disease

that disproportionately affects poor people, and

Medicare and Medicaid coverage of these procedures would improve those people’s access to

these methods. Such coverage would result in

health benefits of prompt treatment and reduced

transmission of tuberculosis to health care workers and the community.

To date, the FDA has not approved a kit for

tuberculosis testing. However, some service laboratories perform tests using devices of their own

making or devices that are licensed for research

but not clinical applications. There are, however,

no guidelines for proficiency testing of laboratories. The adoption of guidelines for ensuring proficiency testing of laboratories performing new

tests should be a priority of government organizations such as CDC. In this way, access to and

quality of new diagnostic technologies can be

maximized.

Service labs are likely to face these difficulties

for many tests. Some bacteria are so rare that no

test kits will ever be made to identify them; the

market is too small. But microbiology service

labs will devise their own tests, and those tests

will raise many of the same issues as the issues

raised by new tuberculosis tests.

❚ Issue F: Controlling Antibiotic Use

Numerous organizations, including state and federal agencies, insurance companies, and health

professional associations, have developed practice guidelines that address a range of clinical

conditions. Practice guidelines might influence

the use of antibiotics.

For example, a physician considering whether

or not to prescribe an antibiotic may decide to do

so because of a possible malpractice action if he

or she does not and the patient fails to improve.

The physician might want to rely on a practice

guideline as an authority for the decision he or

she made, but it might not be sufficient defense

in a malpractice suit. Currently, the use of practice guidelines in medical malpractice litigation

is a complicated and controversial issue. Moreover, guidelines may actually have the effect of

encouraging the use of antibiotics because a

guideline which admits any benefit of the use of

antibiotics for a specific illness may be used as

evidence against a physician who chose not to

prescribe antibiotics.

Hospitals use formularies to restrict the number of antibiotics available and that can require

approval by an infectious disease specialist for

use of some antibiotics. A 1994 review of these

restrictive measures documented reduced

expenses for antimicrobial acquisition and

administration, reduced adverse drug reactions in

a limited number of cases, and improved appropriateness of drug choice. It also found disadvantages, including difficulties of implementation in

the community hospital setting, inconvenience

for the prescribing physician, and increased

administrative costs. Antibiotic control programs

were associated with a decrease in antibiotic

resistance in a few hospitals, but disappointingly,

the resistance increased “abruptly when control

or monitoring was relaxed or removed.” This

phenomenon suggests that permanent control or

monitoring is necessary for prolonged decreases

in antibiotic resistance.

Change of at least one federal policy might

reduce the use of vancomycin, the antibiotic of

last resort in some infections.

 Review Medicare and Medicaid reimbursement policies for their unanticipated effects on

antibiotic prescription patterns.

Medicare generally does not pay for intravenous medications in the home but does pay for

medications that require the use of an infusion

pump. This policy has caused some physicians to

prescribe vancomycin, which requires the use of

an infusion pump and therefore is covered under

this policy, rather than other antibiotics that are

not covered. This policy runs counter to CDC’s

recommended judicious use of vancomycin.

Should Medicare change this policy, it may also

influence private insurers to consider unanticipated effects on antibiotic prescription patterns,

and there may be other examples of policies having such undesirable effects on antibiotic use.

OPTION
Chapter 1 Summary, Conclusions, Issues and Options | 27

❚ Issue G: Antibiotics in Animal 

Husbandry

The overriding uncertainty about agricultural

uses of antibiotics is their contribution to antibiotic-resistant bacteria and to complications in the

treatment of human diseases. Years of expert

review testify to the difficulty of coming to any

generally accepted conclusions about the

effects of long-term, low-level feeding of antibiotics to food animals and the appearance of

antibiotic-resistant bacteria in humans (see

chapter 7), and it is unreasonable to expect

that another review of existing data would

provide resolution. The following three options,

if adopted, would provide for the collection of

new information. Importantly, however, careful

analysis needs to precede any study because it is

quite possible that no study can produce information sufficiently definitive to justify the expense

of the study, and that analysis would have to

involve agricultural interests, pharmaceutical

companies, farmers, farmers organizations, public health officials, environmental organizations,

organic food processors, and scientists from all

those organizations as well as universities and

the government. All have a stake in any study

about antibiotic use in animal husbandry.

 Collect information about associations

between animal husbandry uses of antibiotics and

antibiotic-resistant bacteria in humans.

Any serious study of the risks from animal

husbandry uses of antibiotics will require the

expertise of epidemiologists, and many of those

scientists are at the CDC. Congress could provide money to CDC to convene a group of scientists to examine the prospects of designing a

study about the transfer of antibiotic-resistant

bacteria from animals to humans. The scientists,

representing all the interests involved in this

issue, would be required to estimate the cost and

time necessary for the study and the size of the

impact that they can detect. For instance, would

it be possible to design a study to answer the

question: “Does agricultural use of antibiotics

contribute 2 (or 5, or 10) percent of the antibiotic-resistant bacteria in humans?”

One possible outcome of the scientists’ deliberations would be the conclusion that the study

could not provide any certain information. FDA,

in making comments on an earlier draft of this

report, said it is convinced that such a study cannot be done, and OTA’s 1993 assessment

Researching Health Risks discusses the difficulties of investigations of environmental health

risks; some of those are applicable here. A decision that the study would not answer the questions could be accompanied with advice about

what new techniques might alter the decision in

the future.

If this study were undertaken, a study of gene

transfer from bacteria from food animals to bacteria important to human health could be built

into it.

 Design a study to determine the

sources of antibiotic-resistant bacteria in the human

diet.

A study to investigate the sources of antibiotic-resistant bacteria need not be so demanding.

It could be designed to collect a sample of marketed foods, isolate bacteria from the foods, and

characterize their antibiotic resistance. The characterization could be done at the molecular level

to determine the source of the bacteria.

The successful completion of this study would

be informative about the levels and perhaps

sources of antibiotic-resistant bacteria in common foods. That information might lead to interventions in some food handling processes to

reduce bacterial contamination, and it might lead

to consumers’ being more careful in food preparation. On the other hand, since it is well-known

that food poisoning is a risk and people take precautions against it, the information about transfer

of antibiotic-resistant bacteria might have no or

few effects on behavior.

OPTION

OPTION
28 | Impacts of Antibiotic-Resistant Bacteria

 Study the benefits of antibiotic use in

animal husbandry.

Reviews of the information about health

impacts of antibiotic use in animal husbandry

often point to possible risks. Statements about

risk are often countered by claims that the benefits of continued use of antibiotics for growth

promotion outweigh the risk, and farmers’ continued use of subtherapeutic doses is offered as

evidence for those benefits.

An analysis of written information could

probably determine the costs of the antibiotics in

feeds. It might also be possible to determine the

benefits of their use from the literature. More

likely, however, some feeding experiments

would be necessary to make quantitative determination of the benefits as measured by

increased yields. This information about benefits

could be considered in efforts to sort out the

costs and benefits of subtherapeutic doses of

antibiotics.

ISSUES AND OPTIONS FOR 

ENCOURAGING DEVELOPMENT 

OF NEW ANTIBIOTICS

Until recently, new antibiotics had been developed at such a rate that no bacteria were resistant

to all of them. Today, this is no longer true.

Manufacturers develop antibiotics in anticipation of markets and profits. In the 1980s, the

market was saturated with more than 100 antibiotics, which reduced the profit to be expected

from yet another entry in a crowded field.

Although research and development expenditures in pharmaceutical companies greatly

increased in the 1980s, the percentage of

research and development devoted to anti-infectives decreased. Because of the long times necessary for discovery, testing, and development of

new drugs, the decisions in the 1980s account in

part for the shortage of new antibiotics in the

1990s. Reports of pharmaceutical companies hiring new senior-level scientists for antibiotic

research and the interest of many biotechnology

companies in antibiotics indicate that they now

see opportunities in antibiotic development (see

box 1-5), but consolidations and purchases of

pharmaceutical firms have also reduced the number and size of research departments and the

number of industry-employed scientists devoted

to antibiotics.

Because of the importance of drugs to public

health, Congress has provided assistance and

incentives to pharmaceutical companies, including tax credits for research, increased patent life

to compensate for the years of patent protection

lost to regulatory delays, a commitment to more

rapid review of new drug applications at the

FDA, and active technology transfer of drugs

developed in whole or in part by government scientists. These tax, patent and research and development policies are discussed in chapter 5 of this

report, and in detail in the 1993 OTA report

Pharmaceutical R&D: Costs, Risks and

Rewards. Here OTA considers four options

directed specially at antibiotics.

❚ Issue H: Cooperative Research Among 

Government, Industry, and Academia

The National Cancer Institute (NCI) has funded

the National Cooperative Drug Discovery Program since 1983. The program solicits applications from consortia of university researchers

and pharmaceutical companies to search for new

anti-cancer drugs. The awards are limited to the

support of pre-clinical research. Generally, the

principal investigator is from a university with

co-principal investigators from industry. While

the research can take different directions, it generally involves university researchers doing basic

research, and industry scientists developing

methods for widespread application of the

research methods. Through the end of 1994, NCI

had invested about $100 million in this program,

and several compounds discovered in the program-sponsored research have entered clinical

trials.

OPTION
Chapter 1 Summary, Conclusions, Issues and Options | 29

 NIH could solicit applications for grants

to fund cooperative research between universities

and pharmaceutical firms to discover new antibiotics.

The National Institute of Allergy and Infectious Diseases (NIAID) could develop a similar

program for antibiotics. Such an effort would

have the advantages of forging relationships

between university and industry researchers,

increasing the speed of dispersion of “academic”

ideas to industry, and producing a community of

university-industry research groups that could

speed up drug discovery. Moreover, such joint

research activities would quickly deliver promising substances to pharmaceutical company scientists who could evaluate them against criteria for

pharmaceuticals: penetrability, toxicity, specificity, and bioavailability.

There are disadvantages as well. It is unlikely

that additional money will be provided to NIAID

in the near future, and in FY 93, NIAID spent

about $10 million on research directed at antibiotic resistance, which is about the average annual

amount spent by NCI on its Cooperative Drug

Discovery Program. To set up an expensive antibiotic discovery program would require diverting

funds from other research programs. This may

not be the optimal use of limited government

funding for research, especially in light of basic

research needs for which industry support is

unlikely (see Issue D).

❚ Issue I: Negotiated Marketing 

Agreements for Antibiotics

A pharmaceutical company that discovers and

develops an antibiotic that is effective against

particularly troublesome antibiotic-resistant bacteria as well as against many other bacteria might

be willing to restrict its marketing to use against

the antibiotic-resistant bacteria in exchange for

longer market exclusivity. The trade-off, simply

put, is that 10 years of a protected market might

generate as much profit as five years of higher,

less-restricted sales that resulted in faster development of antibiotic resistance.

BOX 1-5: Industry-Funded Cooperative Research

“The Action TB Initiative is an international 5-year programme of collaborative research sponsored by

Glaxo. The ultimate objective from Glaxo’s point of view is to discover ways to produce new anti-tuberculosis medicines and vaccines....

“In the UK, an ambitious research programme is being pursued under the initiative at centers in London and Birmingham, and scientists at Glaxo are conducting their own research in collaboration. In South

Africa, the Medical Research Council is coordinating research programmes at various institutes throughout the country. At the London School of Hygiene and Tropical Medicine, a wide-ranging programme was

initiated in July, 1993....

“Apart from the scientific progress achieved already, tangible benefits for the London School have

included laboratory renovations and the appointment of new staff. The three project supervisors in London each have their counterpart at Glaxo, and the scientist-to-scientist collaborations are deemed valuable. At this juncture skeptics might reasonably ask ‘what’s in this for the company?’. Clearly short-term

goals have been eschewed, but as a public relations exercise the initiative is unquestionably a success.

Moreover, Glaxo has by this means secured an impressive array of medical research expertise to

sharpen its competitive edge. Although not all academic researchers would feel comfortable with such

an arrangement, as an example of an effective partnership between the pharmaceutical industry and

academic health sciences it has much to offer.”

SOURCE: Lancet (May 13, 1995)

OPTION
30 | Impacts of Antibiotic-Resistant Bacteria

 Congress can provide FDA with authority to negotiate extended market exclusivity to manufacturers that agree to restrictions on marketing of

antibiotics.

Usually, a drug enjoys an exclusive market

until its patent protection expires. The exclusivity means that generic compounds that are identical to it cannot be marketed. Congress has

granted FDA the authority to extend the length of

exclusivity under certain conditions when a manufacturer shows that its product is safe and effective against a new indication. Congress could

extend the same authority to FDA to negotiate

agreements for extended exclusivity in exchange

for restricting marketing to uses against particular antibiotic-resistant bacteria or against diseases likely to be complicated by antibioticresistant bacteria.

The advantage of such an action could be

longer effective usefulness of the antibiotics.

Moreover, FDA authority to negotiate such

arrangements would leave pharmaceutical companies free to consider different marketing strategies and to choose the most beneficial one in

terms of profits, public relations, or other factors.

Extended exclusivity would not preclude

another company’s efforts to develop antibiotics

for similar conditions. If the other company produced a comparable or better drug, the company

with the extended exclusivity might see its

potential profits disappear.

Physicians commonly prescribe drugs “offlabel” for indications other than those approved

by the FDA and that could weaken the restricted

marketing program. On the other hand, exclusivity extensions could include provisions to allow

FDA to be certain that companies with such

agreements not sponsor research or research dissemination activities that would promote such

off-label uses.

An examination of how such a system might

have affected the sales of, and the development

of resistance to, antibiotics that are no longer of

clinical use because of resistance would inform

any congressional decision about this option.

While pharmaceutical companies might be willing to fund the analysis, public funding might be

necessary for a credible study and results.

❚ Issue J: Development of Off-Patent 

Compounds as Antibiotics

Many chemical compounds were discovered and

patented but never developed as pharmaceuticals

for various reasons. For instance, a substance

with antibiotic activity might not have been

brought to market because it was no better than

marketed antibiotics against susceptible bacteria

or because it was somewhat more toxic than marketed antibiotics. In screening materials for antibiotic activity against antibiotic-resistant

bacteria, companies often re-discover such old

compounds. Although they might appear promising because of activity against antibiotic-resistant bacteria, no company will do the research

and development necessary to bring them to market because patent protection is or soon will be

gone.

As an example, fusidic acid is an antibiotic

that was never brought to market in the United

States but that has been used in other countries,

including Canada, for years. It is used in the

treatment of MRSA in other countries, but its

manufacturer perceives that the return on investment would be too low to warrant pursuing clinical trials for use against MRSA in this country. A

licensing agreement with a United States firm

faces a similar obstacle; if the trials were successful, any other company could manufacture

and sell the off-patent substance, greatly reducing the opportunities for the foreign-United

States company venture to recoup its losses and

make a profit.

 Congress could authorize FDA to

extend market exclusivity for “off-patent” antibiotics

that are shown to be effective against antibiotic-resistant bacteria.

Such legislation might result in pharmaceutical companies’ ferreting out effective antibiotics

from the thousands that have been patented, but

it would leave FDA with the difficult problem of

deciding when the advantages of an antibiotic

justified the granting of exclusivity. Market

exclusivity is one privilege granted under the

orphan drug law, and it is possible that antibiotOPTION

OPTION
Chapter 1 Summary, Conclusions, Issues and Options | 31

ics that are effective against antibiotic-resistant

bacteria would meet the requirements of an

orphan drug.

 Congress could establish a federal program to conduct clinical trials of antibiotics to determine if they have uses against antibiotic-resistant

bacteria.

An antibiotic that is off-patent and manufactured generically could be reported to be active

against infections caused by antibiotic-resistant

bacteria. No company, however, would be interested in paying for the clinical trials necessary to

demonstrate that the drug is useful because it

could not expect to reap sufficient profit from

sales of a generic drug.

A federal program could be established to

conduct such trials. The advantage would be the

identification of useful antibiotics. The disadvantage would be the shouldering of clinical trial

costs, traditionally the responsibility of pharmaceutical companies, by the government. Moreover, it is possible that such a program, as any

research program, might have no successes.

OPTION
| 33

Introduction 2

any of the organisms living around,

on, and in human beings are too small

to be seen without a microscope.

They include viruses, bacteria, fungi,

and protozoa (figure 2-1).

Viruses are short lengths of genetic material—deoxyribonucleic acid (DNA) or ribonucleic acid (RNA)—enclosed in a protein coat. So

small that they have no room for the structures

and processes for the biochemistry of their replication, viruses are obligate internal parasites.

They must invade cells—human, animal, plant,

or bacterial, depending on the virus—take over

the cells’ genetic apparatus, and direct the biochemistry of the cell to produce viral nucleic acid

and protein and package them into new viruses.

Bacteria, the single-celled organisms that are

the subject of this report, carry the structures and

functions necessary for their replication in their

cytoplasm. They generally are about one thousandth of a millimeter wide and nearly 500 times

smaller than the average animal cell (Watson et

al., 1986.). Bacteria are classified as prokaryotes because, unlike eukaryotes, such as fungi,

protozoa, plants and animals, they have no internal membrane (the nuclear envelope) separating

their genetic material from other components of

the cell (figure 2-2). Bacteria differ from eukaryotes in having some molecular structures and

biochemical processes that are absent from

eukaryotes or that differ in significant ways from

those of eukaryotes. Most antibiotics1

 work by

interfering with a structure or process that is

present in bacterial and not in other cells. This

selectivity accounts for the rarity of serious sideeffects associated with most antibiotics; the

drugs find no good targets in human (or other

eukaryotic cells) and cause few effects there.

Figure 2-3 illustrates the differential effects of

penicillin on animal cells, which do not have cell

walls, and bacteria, which do, and a photo shows

the destruction of a bacterial cell by penicillin.

Antibiotics have no effect on viral infections;

viruses use the molecular structures and functions of the infected cells and viral-infected cells

offer no targets for antibiotics.

Fungi and protozoa are eukaryotes. Antibiotics have no effect on most of these microorgan1 OTA uses the term “antibiotics” to refer to substances that kill or inhibit the growth of bacteria. It is sometimes used to refer to substances that kill or inhibit organisms other than bacteria, but it is used here only to refer to substances with antibacterial activity.

M
BACTERIA

Retrovirus (AIDS)

Diameter of each

staphylococcus =

Staphylococci (food poisoning, toxic shock syndrome)

1 μ m

Mycobacterium tuberculosis (tuberculosis)

FUNGI

Herpes (fever blisters)

Each streptococci

Streptococci (pheumonia, rheumatic fever)

6 μ m

Treponema pallidum (syphilis)

PROTOZOA

50pm

=1 μ m

Candida albicans (yeast infections, thrush) Aspergillus (aspergillosis) Plasmodium (malaria)

SOURCE: Office of Technology Assessment, 1995.
Chromosome (DNA) Plasmids (DNA) reticulum

Nuclear membrane or

Cell wall nuclear envelope

Plasma membrane Chromosomes

(DNA)

~1 μ m ~10-30 μ m

Bacteria Animal cell

SOURCE: Office of Technology Assessment, 1995.

isms. Other chemical agents have been isolated

and developed to treat fungal and protozoan

infections. Just as with bacteria, which are developing resistance to antibiotics, fungi and protozoae are developing resistance to the drugs used

to treat them.

Some bacteria play a role in keeping people

healthy. More than 1,000 different species of

bacteria normally live benignly in and on the

human body. These bacteria, such as Escherichia

coli (see box 2-1 for a note on bacterial nomenclature) living in the intestine or Staphylococcus

aureus living on the skin, are called commensal

organisms. Intestinal bacteria, which are found in

concentrations of about 1011 (100 billion) bacteria per. gram and account for about 30 percent of

the bulk of human feces, produce essential vitamins that are absorbed by the body and provide a

barrier against other bacteria becoming established in the intestine. For example, a person

may ingest small numbers of a pathogenic Salmonella bacteria but not get sick because the Salmonella is prevented from growing to large

numbers by the presence of commensal bacteria

in the intestine.

Despite the human body’s reliance on bacteria

for health, bacteria are far better known as causes

of disease. In 1830, infectious diseases caused by

bacteria and other microorganisms were a major

cause of death, and only 50 percent of the population lived past the age of 25. In the next century, improved sanitation (water purification,

sewage systems, pasteurization of milk), general

increases in living standards, and the introduction of vaccines reduced the incidence of infectious disease and profoundly changed longevity.

By 1935, 50 percent of the population lived past

62 (Schlesinger, 1993).

The capacity of bacteria to cause disease is

called pathogenicity. Virulence is used as a
Bacterial cell

Flexible outer membrane

Rigid cell wall

SOURCE: National Institute of General Medical Sciences, Sept. 1993, Medicines by Design: The Biological Revolution in Pharmacology, NIH

Pub. No, 93-474. Bethesda, MD: National Institutes of Health,

measure of the speed and severity of the resulting

disease; more virulent bacteria cause more serious, more rapidly progressing disease, Even

commensal bacteria may be harmful under certain conditions. While the skin and mucous

membranes normally protect the body from

infections, an opportunistic infection may result

from a bacteria such as S. aureus being introduced into the tissues and organs of the body via

an open wound, invasive surgery, or use of an

invasive device (e.g., a urinary catheter).

Antibiotics often destroy some of the body’s

commensal bacteria, making way for other infections. For example, the use of some types of antibiotics can allow the organism Clostridium

difficile, normally present in small numbers in

healthy humans, to proliferate and cause the disease pseudomembranous colitis. Yeast infections

are common in women treated with antibiotics

when antibiotics kill or inhibit commensal bacteria in the vagina. Antibiotics may destroy commensal bacteria in the gut, allowing ingested

bacteria, typically resistant to antibiotics, to pervade and cause disease. In two antibiotic-resistant Salmonella outbreaks, it was found that

many of the infected people had recently taken

antibiotics which may have given the antibioticresistant Salmonella an opportunity to become

established and cause illness (Holmberg et al.,

1984; Spika et al., 1987).

THE DISCOVERY OF ANTIBIOTICS

Before the 1940s, there was little that medicine

could do against bacterial infections. Superficial

or localized infections could be lanced or surgically opened and cleaned, and locally acting antiseptics could be used to sterilize the area. But

once an infection had become “systemic” and
Penicillin-treated bacteria cell bursting at three different places.

Photo courtesy of National Institute of General Medical Sciences, National Institutes of Health, Bethesda, MD.

lived in dread that they or their relatives would

develop a bacterial pneumonia and die or that a

bacterial endocarditis (infection of the heart

valves) would doom a child.

In 1906, chemist Paul Ehrlich provided the

first weapon for combating bacterial infection

when he discovered that the chemical compound

salvarsan was effective against syphilis. In 1936,

Gerhard Dogmagk discovered that Prontosil, a

synthetic dye, had antibacterial activity. The

active chemical component of Prontosil, sulfanilamide, was the first of the sulfonamide (or

“sulfa”) drugs, and sulfa drugs are still used

widely today.

In 1928, Alexander Fleming, an English

microbiologist, discovered that a common mold

(Penicillium) produced a substance that killed

bacteria. Dr. Fleming returned from a weekend

Bacteria and bacterial diseases are our daily companions. There are bacteria literally everywhere in the environment, and a few cause human diseases. Just as in sports where a scorecard is necessary to know the players, some knowledge of bacteria will help the reader, Humans—from the smallest children learning to talk to the

astronomer studying craters on other planets—identify and name things So it is with microbiologists who study

bacteria and biologists who study other forms of life. Everyone recognizes different mammals—humans, dogs,

cats, rats, mice, etc.—and recognizes their unique and salient features if not their scientific names—Homo sapiens, Canis familiaris, Felis catus, Rattus rattus, Mus muscus. Such easy familiarity is not possible with organisms that cannot be seen, and everyone has to rely on scientists’ identification and nomenclature to talk about

bacteria.

OTA associates bacteria with specific disease states, whenever possible, and uses standard scientific

nomenclature. For example, the cause of cholera is Vibrio cholerae, where “Vibrio” is the name of a bacterial

genus and “cholerae” is the name of a species. After the first use of such a name, the generic name is usually

abbreviated, as in V. cholerae. When both generic and specific names are used, the words are italicized. When

reference is made to a genus, such as “Enterococcus, ” the name is capitalized but not italicized, The terms “different bacteria” or “several bacteria” refer to ill-defined collections of different genera. “Strains” refers to further

divisions among a species; in particular, there are antibiotic-sensitive strains and antibiotic-resistant strains.

I
Reconstruction of Fleming’s work bench in the room in which

penicillin was discovered. St. Mary’s Hospital Medical School,

Paddington, London, England.

away to his laboratory at St. Mary’s Hospital in

London and looked at a number of Petri plates

that he had seeded with bacteria. The plates had

been incubated in his absence and the agar surfaces were sprinkled with colonies of Staphylococcus, a common bacterium frequently found

on human skin. Dr. Fleming expected that outcome. One plate was different, however. In addiFleming’s original culture plate showing fewer and Iysed Staphylococcal colonies near the mold. St. Mary’s Hospital Medical School, Paddington, London, England.

releasing an agent that killed and lysed the bacteria. He called the agent “penicillin.” (While the

Fleming discovery opened the door to the antibiotics era, there is some circumstantial evidence

that people long ago may have benefited from

antibiotics; see box 2-2.)

Almost a decade later, at Oxford, a group of

researchers and engineers led by H.W. Florey

accomplished what Fleming had been unable to

do. They scaled up the production of penicillin so

that the antibiotic was available in sufficient

A production worker pouring penicillin-containing culture

medium into a trough for collection in a milk can, mid-1940s.

Photo courtesy of The National Museum of American History,

Smithsonian Institution, Washington, DC,
Chapter 2 Introduction | 39

quantities to be released to the Armed Forces to

treat wounded servicemen as well as those with

diseases. Early production methods included

growing hundreds of cultures of Penicillium in

glass bottles (sometimes milk bottles were used),

collecting the culture broth, and purifying, concentrating, and packaging the penicillin for shipment. The collection of the penicillin-containing

culture medium could be done with devices as

simple as a metal trough and a milk can. Currently, the growth (fermentation) of the organisms that produce penicillin and other antibiotics

is done in automated factories and with much

higher efficiencies than were possible in the

1940s.

By 1944, penicillin supplies were large

enough that some of the antibiotic was released

for civilian use, and the first antibiotic that could

be ingested or injected without toxic side effects

entered medical practice. The cover of this report

is a reproduction of a 1944 advertisement for

penicillin. Penicillin was not made a prescription

drug until the 1950s, and, for about a decade, it

was available directly to the public (Levy 1992,

p. 9).

Other “wonder drugs” followed penicillin, and

many dreaded infectious diseases became treatable; people were saved from death and from

prolonged periods of disability. Tuberculosis

sanatoriums closed because antibiotics were sufficient treatment; people with burns over large

areas of their bodies, who would have died in

earlier years, survived; childhood meningitis

(infections of membranes around the brain or

spinal cord), formerly a death sentence, was

treatable; prolonged, dangerous, and only-sometimes-effective treatments for syphilis and gonorrhea were replaced by injection or ingestion of

an antibiotic. According to Schlessinger (1993),

the use of antibiotics, along with nutrition and

health education, increased the median lifespan

by eight years, from 62 to 70 years, between

1935 and 1955. (There has been little change in

median lifespan since 1955.)

❚ The Limits of Antibiotics

Antibiotics can fail to cure an illness because the

bacteria are intrinsically resistant toward the

drugs or because they acquire resistance. Resistance is a property of bacteria that confers the

capacity to inactivate or exclude antibiotics or a

mechanism that blocks the inhibitory or killing

effects of antibiotics. Acquired resistance, hereafter simply “resistance,” which is characterized

by changes in bacteria such that organisms that

were formerly treatable with an antibiotic

become untreatable, is the focus of this report.

Most bacterial infections can be successfully

treated with one antibiotic or another, but the

emergence of resistance to older antibiotics, such

as penicillin, leads physicians to prescribe newer

antibiotics as the first choice in treating many

diseases. The use of the newer antibiotic

increases selective pressure for the emergence

and spread of bacteria resistant to it, and the

more an antibiotic is used, the greater the chance

that resistance to it will emerge and spread.

BOX 2-2: Antibiotic Use by Ancient Civilizations?

Perhaps unknowingly, earlier civilizations may have benefited from antibiotics. Bassett, Keith, Armelagos, et

al. (1980) found evidence for the antibiotic tetracycline in the bones of Nubians who had been buried between

350 and 550 A.D. Streptomycetes, the bacteria from which many antibiotics are derived, are common in the

Nubian Sudanese desert, and it is to be expected that the bacteria would have been picked up when the Nubians harvested grain for bread and beer. Conditions in grain storage bins would have favored the growth of the

Streptomycetes, which could have been the source of the antibiotic. Drawing upon other information, Bassett et

al. state that infectious disease rates were low among this population of Nubians. Regardless of the details, this

evidence indicates that humans have interacted with antibiotics from well before 1928.

SOURCE: E.J. Bassett, M.S. Keith, G.J. Armelagos, et al. 1980. “Tetracycline-labeled bone from ancient Sudanese Nubia.” Science

209:1532-1534.
biochemical pathways somewhat different from

those of bacteria. Other microorganisms, such as

fungi (e.g., yeast) and protozoa, also have biochemical pathways different from those of bacteria and, as a result, antibiotics will not work

against them. Antibiotics have no effect on

viruses because viruses do not have their own

biochemistry; they use the biochemical machinery of their host cells that presents no targets for

antibiotic action. Despite knowledge that antibiotics work only against bacterial infections,

patients request—and physicians prescribe—

antibiotics for viral infections, such as the common cold. The consequences of this “inappropriate use” or “overuse” are discussed in chapters 3

and 4.

, 

structure as other bacteria (figure 2-4), and penicillin will not affect growth of mycobacteria

because there is no target for its action.

Mycobacteria walls are a specific example of

properties that render some bacteria intrinsically

resistant to one or more antibiotics. As a more

general example, bacteria are classified as either

Gram positive or Gram negative on the basis of

their capacity to be colored by a biological stain,

and the cell walls of the Gram positives differ

from those of the Gram negatives. Some antibiotics are effective against only Gram-positive bacteria, some are effective against only Gramnegative bacteria, and some, the “broad-spectrum antibiotics,” are effective against both.

(Left) Most of the Gram-positive bacteria are covered by a porous peptidoglycan layer, which does not exclude most antimicrobial agents.

(Middle) Gram-negative bacteria are surrounded by the outer membrane, which functions as an efficient barrier against many antibiotics.

(Right) Mycobacteria produce an unusual bilayer, which functions as an exceptionally efficient barrier

SOURCE: H Nikaido, 1994 “Prevention of drug access to bacterial targets: Permeability barriers and active efflux. ” Science 264:383. Copyright

1994, American Association for the Advancement of Science.
Chapter 2 Introduction | 41

Some bacteria are virulent and can kill

quickly: A virulent strain of group A streptococcus causes a disease called toxic shock-like syndrome (TSLS) which killed Muppeteer Jim

Henson. Because this strain and other virulent

bacteria can “fell otherwise healthy people

within hours of the onset of symptoms” (Wright,

1990), antibiotics have to be administered very

early in order to defeat the infection.

Some bacteria grow in biofilms that cannot

be easily penetrated by antibiotics: Biofilms

are multilayer bacterial populations embedded in

a film that is attached to some surface. Some

examples of bacteria growing in biofilms are the

plaque that causes tooth decay, films of

Pseudomonas aeruginosa that infect lung tissue

especially in cystic fibrosis patients, and films

that grow on the surfaces of medical devices

such as catheters (see chapter 6). Antibiotics

often cannot penetrate biofilms; therefore, even

though the antibiotic may be effective against the

strain of the bacteria in the laboratory, the antibiotic may be ineffective against the infection.

❚ Mechanisms for the Emergence 

and Spread of Resistance

When a new antibiotic is introduced, many bacteria are susceptible to it. Hughes and Datta

(1983) demonstrated that bacteria preserved

from 1917-1954 (the “pre-antibiotic” era) had

little if any antibiotic resistance except intrinsic

resistance. However, since the dawn of the antibiotic age, acquired resistance to every known

antibiotic has been observed in one or more bacterial strains. This resistance sometimes arises in

an individual patient during the course of treatment, but more often people are infected by

resistant bacteria that are acquired from the community or the hospital environment.

Mutations

Antibiotic resistance arises through processes

that involve mutations and selection. Mutations

occur spontaneously in bacterial DNA that modify or eliminate a target for an antibiotic’s action,

or that cause changes in the bacteria surface so

that the antibiotic is not taken up, or that cause

the production of an enzyme that inactivates the

antibiotic, or that cause the antibiotic to be

excreted from the bacterial cell. These mutations

happen in the absence of any exposure to antibiotics, but the presence of an antibiotic favors the

growth of the bacteria that contain a mutation for

resistance, or in the usual jargon, the antibiotic

“selects for” the mutant bacteria. Weiner (1995

at pp. 257-262) discusses the origins of mutations to antibiotic resistance and the selection of

those mutations in an evolutionary context.

Mutations are of three general kinds. Point

mutations are “single letter” mistakes that occasionally occur in copying the DNA code, and

they can cause a small change in an enzyme or

structural protein. The other two kinds of mutations, insertions and deletions, generally have

more far-reaching effects; they can completely

eliminate an enzyme activity or destroy a structural protein. Mutations are passed on to future

generations of bacteria, and the number of resistant bacteria can increase very rapidly. Under the

most favorable conditions, some bacteria can

duplicate every 20 minutes.

As shown on figure 2-2, bacterial DNA is

present on “chromosomes” and “plasmids.”

Chromosomes usually contain all the genes necessary for the life of the bacteria, and some genes

that confer resistance to antibiotics are found on

the chromosome. Plasmids, smaller pieces of

DNA that replicate separately from the chromosome, can also be present. They can and often do

carry genes for antibiotic resistance, and, as discussed below, they can be transferred from bacterium to bacterium.

Chromosomal mutations

Genes for resistance to fluoroquinolone antibiotics (e.g., ciprofloxacin and ofloxacin) are known

to occur, so far, only on chromosomes and not on

plasmids. Single courses of therapy with fluoroquinolones may produce only low levels of resistance, but multiple mutations selected by

repeated exposure to increasing doses of fluoroquinolones can confer high levels of resistance

(Hooper and Wolfson, 1991). Even though muta-
I

six developed low levels of resistance (Jensen et

al., 1987). Three months after the end of treatment, the average resistance of the patients’ P.

aeruginosa to ciprofloxacin or ofloxacin

remained somewhat higher than before treatment. Similarly, Chow et al. (1991) observed the

development of antibiotic resistance in strains of

Enterobacter during therapy.

Plasmids and gene transfer

Plasmids are able to pass directly between bacteria through the process of conjugation, in which

a newly replicated plasmid is transferred from

the donor cell to the recipient cell through a pilus

Cm Chloramphenicol

Su Sulfonamide

Sm Streptomycin

Ap Ampicillin

Km Kanamycin

Is1 Transposon insertion factor

SOURCE: Office of Technology Assessment, 1995.

A Micrograph of conjugation between two bacteria. Photo courtesy of Dr. Charles Brinton, University of Pittsburgh.

or conjugation tube. When the process is complete, both bacteria contain a copy of the plasmid, and both have the capacity to replicate and

transfer the plasmid.

Plasmids can recombine with DNA from other

plasmids, and that process can produce a single

plasmid that carries multiple genes for resistance

to different antibiotics (Condit and Levin 1990).

This has important clinical consequences

because the use of any one of the antibiotics

shown in figure 2-5 could select for the plasmid

that contains genes for resistance to all the antibiotics shown there.

Scientists confirmed the role of plasmids and

conjugation in spreading antibiotic resistance

during a dysentery epidemic in Japan in the late

1950s (Watanabe, 1963). The epidemic was

characterized by increasing numbers of Shigella

dysenteriae strains that were resistant to as many

as four antibiotics simultaneously. Such bacteria

became so frequent that health officials concluded that their emergence could not be attributed to repeated mutations arising in one

bacterium after another because mutations occur
Chapter 2 Introduction | 43

too rarely. Scientists showed that conjugational

transfer of multiple-resistant plasmids accounted

for the epidemic and established plasmids as

major agents in the spread of antibiotic-resistant

genes.

Hughes and Datta (1983), who examined preserved bacterial strains from the pre-antibiotic

era, showed that plasmids were present in many

of the bacteria and that 24 percent of the plasmids were able to be transferred by conjugation

between bacteria. However, very few of the preserved bacteria were resistant to antibiotics and

those few were resistant to only one antibiotic.

This indicates that multi-resistance plasmids

must have been created in the decades following

the discovery of penicillin, when the use of antibiotics became extensive. Importantly, however,

the pre-existing transferable plasmids in bacteria

became the vehicle for transfer of multiple antibiotic-resistant genes.

Resistance genes can also travel on transposons, small pieces of DNA that can transfer to

different sites on bacterial chromosomes and

plasmids in the same bacterial cell or in different

bacterial cells. Hall and coworkers (Hall and

Stokes, 1993) have been studying the structure of

some transposons called integrons that carry

antibiotic-resistance genes. The integrons are

like freight trains: sequences of DNA necessary

for the functioning of the integrons at the front

and the back are like the engine and the caboose,

and any number of “cassettes” of resistance

genes, like the cars of the train, can be carried

between them. Different cassettes can insert into

integrons, and this facilitates the acquisition of

resistance genes by bacteria. Collis and Hall

(1995) have also found that the expression of the

integrons depends on their position in the cassette: resistance coded by genes close to the front

of the train is stronger than resistance from genes

near the back of the train. This helps explain the

variability in the levels of resistance between different strains of bacteria.

The origin of the resistance genes that can be

transferred between bacteria on plasmids and

transposons is unknown, but some, at least,

might have originated as a self-protective mechanism in antibiotic-producing organisms. For

example, some strains of streptomyces that produce aminoglycosides (streptomycin is an aminoglycoside) also produce aminoglycosidemodifying enzymes (Benveniste and Davies,

1973).

Genes can be transferred between different

species of bacteria. In a 1979 outbreak in a Kentucky hospital (Tauxe, Holmberg, and Cohen,

1989), 31 patients and personnel became infected

with a strain of Staph. aureus that was resistant

to methicillin, penicillin, gentamicin, erythromycin, clindamycin and tetracycline. Bacteria isolated from all of those affected contained the

same resistance plasmid. Plasmids of a similar

size were also found in the common skin commensal organism Staph. epidermis from the

affected patients. Analysis of the plasmids by

molecular techniques suggested that the same

plasmid had been transferred between Staph.

aureus and Staph. epidermis.

In another study that demonstrated inter-species transfer, Tauxe, Cavanagh, and Cohen

(1989) examined multiple-antibiotic-resistant E.

coli and Shigella flexneri that were isolated from

a hospitalized patient. Their analysis indicated

that the resistant genes had been transferred from

the E. coli to the S. flexneri and that the antibiotic-resistant S. flexneri had then become the

cause of a small outbreak of infections in the

community. These examples show that resistance

genes can be transferred between different bacterial species and demonstrate a pathway for widespread distribution of antibiotic-resistant genes.

There are two other mechanisms for gene

transfer in addition to conjugation: transduction

and transformation. In transduction, genes are

transferred by bacterial viruses (called “bacteriophages” or “phages”). In transformation,

pieces of DNA in the bacteria’s environment are

taken into the bacteria and incorporated into the

bacterial chromosome. Hemophilus influenzae

takes up DNA from its surroundings, and

recently reported data indicate that transformation may play an important role in the survival of

those bacteria (box 2-3).
44 | Impacts of Antibiotic-Resistant Bacteria

❚ International Spread of Antibiotic 

Resistance

Antibiotic-resistance genes move with travelers

from one country to another, making antibiotic

resistance an international problem. O’Brien et

al. (1985) document the intercontinental spread

of an antibiotic-resistant gene on a plasmid, and

Soares et al. (1992) reported the introduction of

strains of multiple-resistant Streptococcus pneumoniae from Spain to Iceland in the late 1980s.

These examples illustrate that antibiotic use and

bacterial resistance patterns all over the world

will have an impact on the United States and

indicate the importance of international cooperation in dealing with the antibiotic-resistance

problem.

❚ Persistence of Antibiotic Resistance 

Genes in the Absence of Antibiotics

The extent to which antibiotic resistance can be

controlled by limiting the use of antibiotics may

be answered by studying the molecular mechanisms of transposon and plasmid replication and

the behavior of populations of bacteria. Antibiotic use selects for bacteria that carry antibioticresistance genes, but the resistant bacteria might

be less efficient or use more energy because they

carry “excess baggage” of altered or extra genes.

BOX 2-3: The Complete DNA Sequence of Haemophilus influenzae

Using a variety of newly discovered methods, scientists have been working to sequence the DNA of

several different organisms, from humans to mice to bacteria. These sequences, when complete, locate

every “base“ or “nucleotide,“ the chemical units that carry the genetic code in an organism’s genome.

H.O. Smith and J.C. Venter led a group of scientists who completely mapped the DNA sequence of

Haemophilus influenzae Rd (Fleischmann et al., 1995). Their success marked the first complete DNA

sequence for any free-living organism, and Venter has announced that sequences for two other bacteria

are nearly completed (Nowak, 1995).

The speed at which these sequences can be completed opens up a new era in understanding how

bacterial DNA directs the activity of bacterial metabolism, and, in particular, it will enable scientists to

understand the genes that are involved in virulence. For instance, H. influenzae Rb is a non-pathogenic

“laboratory strain“ which is closely related to the human pathogen H. influenzae b. By comparing the

DNA sequences from the Rb and b strains of H. influenzae, Fleischmann and colleagues (1995) were

able to demonstrate that eight genes that code for proteins necessary for the b strain to adhere to host

cells were missing from the Rb strain. This suggests that the Rb strains may not be pathogenic, at least in

part, because they cannot attach firmly to host cells.

H. influenzae can take up DNA from its environment and recombine the taken-up DNA into its own

DNA through the process called transformation. Smith et al. (1995) found that certain DNA sequences

occur at 1,465 different locations on the H. influenzae DNA and that these sequences cause the bacteria

to preferentially take up and incorporate DNA from its own species.

This feature enhances the capacity of H. influenzae to take up DNA from other H. influenzae that have

died. Why it would be desirable to take up DNA from bacteria that have been killed is unclear; presumably, the bacteria that die were less fit for their environment. However, the fact that the bacteria have so

many recognition sequences suggests that the sequences, which increase opportunities for recombination between the DNA of the dead bacteria and the surviving bacteria, are of survival advantage to the

bacteria.

SOURCES: R.D. Fleischmann, M.D. Adams, O. White, O., et al. 1995. “ Whole-genome random sequencing and assembly of Haemophilus influenzae Rd.” Science 269:496-512; Nowak, R. 1995. “Bacterial genome sequence bagged.” Science 269:468-470;

H.O. Smith, J.-F. Tomb, B.A. Dougherty, et al. 1995. “Frequency and distribution of DNA uptake signal sequences in the Haemophilus influenzae Rd genome.” Science 269:538-540.
Chapter 2 Introduction | 45

Such genes can make the difference between survival and death in the presence of an antibiotic,

but their maintenance in an antibiotic-free environment might put bacteria that bear them at a

competitive disadvantage with bacteria that do

not carry such genes.

Simonsen (1991) discusses the fate of plasmids in the absence of selection pressure from

antibiotics. The “excess baggage” theory predicts

that easing the selective pressure by decreasing

the use of antibiotics would lead to a decrease in

the carriage of antibiotic-resistance genes by

bacteria. But Bouma and Lenski (1988) showed

that this may not always be the case. They

inserted a plasmid that carried a tetracyclineresistance gene into a strain of E. coli. The E.

coli carrying the plasmid grew poorly as compared to E. coli without it (the plasmid is “excess

baggage”). Of course, in the presence of tetracycline, the bacteria that did not have the plasmid

would not grow. As expected, after 500 generations of growth in tetracycline, all bacteria contained the plasmid. Moreover, even in the

absence of tetracycline, the plasmid-bearing bacteria now grew better than the bacteria without

the plasmid. The bacteria had somehow adapted

in those 500 generations to become more efficient while retaining the plasmid.

This result leads to the suggestion that evolution can produce plasmid-carrying bacteria that

are not at significant disadvantage in competition

with other bacteria in antibiotic-free environments. It can also be interpreted to indicate that

plasmid-carrying bacteria will not be eliminated

by eliminating antibiotics. 

On the other hand, there are many examples in

which controlling the use of antibiotics leads to a

decrease in the frequency of bacteria carrying

antibiotic-resistance genes. This may reflect that

antibiotic-susceptible bacteria (those without

“excess baggage”) usually outgrow antibioticresistant bacteria so that the resistant bacteria

become a smaller and smaller proportion of the

total population. However, this process may be

very slow, and the resistance does not decrease to

zero. The observation that the antibiotic-resistant

bacteria do not disappear (drop to zero) may be

consistent with the results of Bouma and Lenski,

because bacteria may adapt so that carrying plasmids containing resistance genes provides an

advantage, even in the absence of the antibiotic.

CONFRONTING ANTIBIOTIC RESISTANCE

Currently, half a century after the introduction of

“wonder drugs,” scientists, physicians and the

public fear the re-emergence of infectious diseases caused by antibiotic-resistant bacteria.

Krause (1992) observed

[M]icrobes are not idle bystanders, waiting for

new opportunities offered by human mobility,

ignorance or neglect. Microbes possess remarkable genetic versatility that enables them to

develop new pathogenic vigor, to escape population immunity by acquiring new antigens, and

to develop antibiotic resistance.

Scientists who contributed to the biological

research that produced antibiotics warn that society has unwisely tolerated the risk that was evident in reports of the proliferation of genetic

alterations in bacteria that spread antibiotic resistance:

The stunning success of the pharmaceutical

industry in the United States, Japan, the United

Kingdom, France and Germany in creating new

antibiotics over the past three decades has

caused society and the scientific community to

become complacent about the potential of bacterial resistance... [D]espite all these antibiotics,

a person could die in a hospital in New York,

San Francisco, Paris, Barcelona, Tokyo, or Singapore as a result of a resistant bacterial infection (Neu, 1992).

There are many questions surrounding antibiotic resistance. Is it possible that alternative strategies of scientific research and antibiotic

development could have prevented this outcome? Have antibiotics been improperly prescribed or inappropriately requested by patients?

If evidence was available from the start that disease-carrying bacteria could become resistant to

antibiotics, what postponed the crisis for 50

years? Although the Institute of Medicine identified antibiotic-resistant microorganisms as only

one of six factors contributing to the rising risk
46 | Impacts of Antibiotic-Resistant Bacteria

of morbidity and mortality from infection, it

warned that antibiotic resistance “may be a

greater threat to the public than the emergence of

a new disease” (IOM, 1992).

The following chapters discuss what is known

about antibiotic resistance and address the

important questions of what can be done now to

help slow the emergence and spread of antibiotic-resistant bacteria, to preserve the capacity to

treat bacterial infectious diseases with available

antibiotics, and to develop new antibiotics.

REFERENCES

Benveniste, R., and J. Davies. 1973. Aminoglycoside antibiotic-inactivating enzymes in

actinomycetes similar to those present in

clinical isolates of antibiotic-resistant bacteria. Proceedings of the National Academy of

Science, U.S.A. 70(8):2276–2280.

Bouma J.E., and R.E. Lenski. 1988. Evolution of

a bacteria/plasmid association. Nature 335:

351–352.

Chow J.W., M.J. Fine, D.M. Shlaes, et al. 1991.

Enterobacter bacteremia: clinical features

and emergence of antibiotic resistance during therapy. Annals of Internal Medicine

115:585–590.

Collis, C.M., and R.M. Hall. 1995. Expression of

antibiotic resistance genes in the integrated

cassettes of integrons. Antimicrobial Agents

and Chemotherapy 39:155–162.

Condit, R., and B.R. Levin. 1990. The evolution

of plasmids carrying multiple resistance

genes: the role of segregation, transposition,

and homologous recombination. The American Naturalist 135:573–596.

Fleischmann, R.D., M.D. Adams, O. White, et al.

1995. Whole-genome random sequencing

and assembly of Haemophilus influenzae

Rd. Science 269:496–512.

Hall, R.M., and H.W. Stokes. Integrons: novel

DNA elements which capture genes by sitespecific recombination. Genetica 90:115–

132.

Holmberg, S.D., J.D. Wells, and M.L. Cohen.

1984. Animal-to-man transmission of antimicrobial-resistant Salmonella: investigations of U.S. outbreaks, 1971–1983. Science

225:833–835.

Hooper, D.C., and J.S. Wolfson. 1991. Fluoroquinolone antimicrobial agents. New

England Journal of Medicine 324:384–394.

Hughes, V.M., and N. Datta. 1983. Conjugative

plasmids in bacteria of the “pre-antibiotic”

era. Nature 302:725–726.

Institute of Medicine. 1992. Emerging Infections.

Microbial Threats to Health in the United

States. Washington D.C. National Academy

Press.

Jensen, T., S.S. Pedersen, C.H. Nielsen, et al.

1987. The efficacy and safety of ciprofloxacin and ofloxacin in chronic Pseudomonas

aeruginosa infection in cystic fibrosis. Journal of Antimicrobial Chemotherapy 20:585–

594.

Krause, R.M. 1992. The origin of plagues: old

and new. Science 257:1073–1082.

Levy, S. 1992. The Antibiotic Paradox. New

York, NY. Plenum Press.

Neu, H.C. 1992. The crisis in antibiotic resistance. Science 257:1064–1073.

O'Brien, T.F., M. Del Pilar Pla, K.H. Mayer, et

al. 1985. Intercontinental spread of a new

antibiotic resistance gene on an epidemic

plasmid. Science 230:87–88.

Schlessinger, D. 1993. Biological basis for

antibacterial action. In: M. Schaechter, G.

Medoff and B.I. Eisenstein (eds.) Mechanisms of Microbial Disease: Second Edition

Baltimore, MD. Williams and Wilkins, pp.

77–89.

Simonsen, L. 1991. The existence conditions for

bacterial plasmids: theory and reality.

Microbial Ecology 22:187–205.

Smith, H.O., J.-F. Tomb, B.A. Dougherty, et al.

1995. Frequency and distribution of DNA

uptake signal sequences in the Haemophilus

influenzae Rd genome. Science 269:538–

540.
Chapter 2 Introduction | 47

Soares, S., K.G. Dristinsson, J.M. Musser, et al.

1992. Evidence for the introduction of a

multiresistant clone of serotype 6B Streptococcus pneumoniae from Spain to Iceland in

the late 1980s. Journal of Infectious Diseases 168:158–163.

Spika, J.S., S.H. Waterman, G.W. Soo Hoo, et al.

1987. Chloramphenicol-resistant Salmonella

newport traced through hamburger to dairy

farms. New England Journal of Medicine

316:565–570.

Tauxe, R.V., T.R. Cavanagh, and M.L. Cohen.

1989. Interspecies gene transfer in vivo producing an outbreak of multiple resistant

shigellosis. The Journal of Infectious Diseases 160:1066–1070.

Tauxe, R.V., S.D. Holmberg, and M.L. Cohen.

1989. The epidemiology of gene transfer in

the environment. In: S.B. Levy and R.V.

Miller (eds.) Gene Transfer in the Environment. New York, NY. McGraw-Hill Publishing Company, pp. 377–403.

Watanabe, T. 1963. Infective heredity of multidrug resistance in bacteria. Bacteriological

Reviews 27:87–115.

Watson, J.D., N.H. Hopkins, J.W. Roberts, et al.

1986. Molecular Biology of the Gene:

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Menlo Park, CA. Benjamin/Cummings Publishing Co., p 123.

Weiner, J. 1995. The Beak of the Finch: A Story

of Evolution in Our Time. New York, NY.

Alfred A. Knopf.

Wright, K. 1990. Bad news bacteria. Science

249:22–24.
| 49

3

Antibiotic

Use and

Resistance in

the Community

he introduction of antibiotics nearly a

half century ago controlled many lifethreatening diseases, reduced the tolls of

death and illness, and increased the life

expectancy of Americans (Schlessinger, 1993).

However, treatment with antibiotics can select

for resistant bacteria that are not killed by the

drugs, and those bacteria flourish and spread in

environments where antibiotics are present (see

chapter 2). As a result, bacterial resistance to

antibiotics accompanied the use of the “wonder

drugs,” and some antibiotics lost their effectiveness in treating certain bacterial diseases. Antibiotic-resistant bacteria complicate treatment of

illnesses ranging from ear infections to pneumonia and tuberculosis (TB). Patients infected with

these organisms are more likely to require hospitalization, have a longer hospital stay, and die

(McCaig and Hughes, 1995). Antibiotic-resistant

bacteria are more common in hospitals, where

antibiotic concentrations are high (see chapter 4),

but they are also present in the community.

This chapter describes antibiotic use and resistance in the community, which in this report

refers to those persons not in hospitals or nursing

homes. The first section of this chapter discusses

non-hospital use of antibiotics with an emphasis

on physicians’ office practice. The second section describes the populations that are most susceptible to antibiotic-resistant bacteria, the

diseases to which they are most vulnerable, factors in the emergence of antibiotic-resistant bacteria, and changes in disease patterns related to or

complicated by antibiotic-resistant bacteria. It

also discusses the paucity of information about

the prevalence of antibiotic-resistant bacteria as

well as some surveillance systems used to obtain

information about other infectious organisms.

INTRODUCTION

A mother takes her 2-year-old son to the doctor’s

office for a middle ear infection, also known as

otitis media.1

 This visit is one of nine such visits

over the past year. About every four to six weeks

her son’s physician switched antibiotics because

the drugs had stopped working. She has had similar problems with her 4-year-old son, who has

1 Otitis media is a bacterial disease that is prevalent in young children and more common in those in day care. Children in day-care are an

at-risk population that are susceptible to all infectious diseases, some of which are caused or worsened by antibiotic-resistant bacteria. This

issue is discussed further later in this chapter.

T
50 | Impacts of Antibiotic-Resistant Bacteria

had about six ear infections during the same time

period. This scenario is becoming more prevalent

with increasing resistance to antibiotics. From

1975 to 1990, the annual visit rate to office-based

physicians for otitis media more than doubled;

for children under 15 years of age, the rate

increased almost 150 percent (Schappert, 1992).

Ninety percent of all American children will

have had at least one ear infection before age six,

and the national cost of treating them is $3.5 billion each year (Williams, 1994).

One of the causative agents in these recurring

infections is Streptococcus pneumoniae (“pneumococcus”), which is a leading cause of illness

and death in the United States, causing an estimated 7 million cases of otitis media; 50,000

cases of bacteremia; and 3,000 cases of meningitis annually. Scientists at the Centers for Disease

Control and Prevention (CDC) and other

researchers have documented increasingly common resistance to penicillin in S. pneumoniae.

From 1979 through 1987, 0.02 percent of S.

pneumoniae isolated from invasive infections

were resistant to penicillin. By 1992, that percentage had jumped 60-fold to 1.3 percent.

Resistance is much higher in some communities,

where at least 30 percent of isolates are either

intermediately or highly resistant to penicillin

(Jernigan et al., 1995). Among the states, the

highest documented penicillin resistance rate

was 26 percent in Alaska, with rates in other

parts of the country ranging from 1 to 16 percent

(Tan et al., 1993).

Like antibiotic-resistant bacteria in general,

penicillin-resistant S. pneumoniae are an international problem. They emerged in Australia and

South Africa in the 1960s and 1970s. By the late

1980s, 40 percent of community-acquired and 95

percent of hospital-acquired S. pneumoniae

infections in South Africa were penicillin-resistant. The strains spread rapidly and had been

identified in Southeast Asia, other parts of

Africa, and Europe in the 1980s. Hungary had

the highest resistance rate in Europe in the late

1980s: up to 69 percent of S. pneumoniae isolated from children were resistant. In other countries, such as Spain and Romania, penicillinresistance rates ranged between 22 and 44 percent (Klugman, 1990; Tan et al., 1993).

By the 1990s, some S. pneumoniae strains had

become resistant to all penicillin-type drugs, as

well as the aminoglycoside-type antibiotics,

chloramphenicol, and erythromycin, leaving

physicians with few treatment options, and causing epidemiologists to worry about when resistance to vancomycin—one of the last antibiotics

available to treat some multidrug resistant organisms such as Staph. aureus—would emerge

(Levine et al. 1991).

❚ Antibiotic Use and Resistance

Any use of antibiotics, whether “appropriate” or

“inappropriate,” can contribute to the emergence

and spread of antibiotic-resistant bacteria.

Appropriate uses are those that benefit the

patient, by treating a bacterial infection, and the

risks of increasing the spread of antibiotic-resistant bacteria are offset by those benefits. Inappropriate uses are those that do not benefit the

patient, but that increase the use of antibiotics

and the risk of encouraging the spread of antibiotic-resistant bacteria. The term “overuse” is

commonly used in reference to inappropriate use.

Numerous studies have shown a direct relationship between use of antibiotics and the spread

of antibiotic-resistant bacteria (McGowan, 1983;

Mouton et al., 1990; Moller, 1989; Ringertz and

Kronvall, 1987; and Sogaard et al., 1974). Studies

also indicate that reducing use of antibiotics may

lower the frequency of antibiotic-resistant bacteria (Ballow and Schentag, 1992; McGowan,

1983). The focus in reducing antibiotic use has

been on reducing inappropriate uses.

Resistant microbes would have emerged even

if antimicrobial drugs were always used for the

proper indication and at the proper dose and

duration. However, the selective pressure would

not have been as great, the pace of development

of resistance would have been slower, and the

extent of the problem in terms of the number of

people involved would have been less. Once

resistant strains are selected, they can infect other

individuals and spread within a community or
Chapter 3 Antibiotic Use and Resistance in the Community | 51

institution. They can also transfer the genetic

information for resistance to other bacteria.

While the natural history of the spread of antibiotic-resistant genes is not known with certainty

and probably varies depending on the bacteria in

which the mutation arose, the process can be

described in a general way. Mutations occur and

bacteria that bear them are selected by exposure

to antibiotics. The frequency of the mutations

may remain constant and low for many years and

then spurt upwards, most likely as a result of the

transfer of resistant genes among bacteria and the

increased selection by antibiotic usage.

❚ Factors in Prescribing Antibiotics

The most common infectious conditions seen in

office practice are diseases of the respiratory system, nervous or sense organs (mostly otitis media

in children), skin and subcutaneous tissue, and

genitourinary system. In sum, these conditions

account for more than 80 percent of office visits

in which antimicrobial drugs are prescribed.

Antibiotics are not only used to treat infections

but to prevent them. Physicians prescribe antibiotics prophylactically to protect people who have

been exposed to individuals with infectious diseases and to prevent commensal organisms—

those bacteria that are naturally found in the

digestive system or on the skin—from spreading

as a result of disease or injury from their usual

residence to normally sterile parts, the blood, tissues, and organs of the body. For example, penicillin may be administered prophylactically to

patients who have damaged heart valves to prevent bacterial infections in the bloodstream and

heart when they undergo dental or minor surgical

procedures in dental or medical offices. (In-hospital prophylaxis is discussed in chapter 4.)

Many respiratory and ear infections are caused

by viruses. Antibiotics have no effect on viruses,

and there is no clinical evidence that antibiotics

will prevent secondary or superimposed bacterial

infections in a patient with a viral infection. Antibiotics prescribed for viral infections are wasted

and are examples of inappropriate use and overuse. Moreover, some bacterial diseases will clear

up in the same time with or without antibiotics.

For instance, despite their widespread use for

earaches, antibiotics do not always convey a benefit: about 20 percent of middle ear infections are

caused by viruses. Perhaps one-third of them are

caused by bacteria that cause self-limiting infections that will “go away” without treatment

(Klein, 1994), although antibiotics may help

them go away faster.

Physicians can obtain information about the

causes of middle ear infections only by obtaining

fluid samples from behind the patient’s eardrum.

Those samples are then sent to laboratories

where the possible infecting organisms are cultured, identified, and classified as either susceptible or resistant to antibiotics (see chapter 6).

These activities take several days, and often

involve an invasive procedure, such as puncturing the eardrum to obtain a sample, which most

physicians and patients want to avoid. The physician seeing a patient is not likely to wait several

days for laboratory results before prescribing an

antibiotic, and the patient is almost certainly not

going to want to wait. Generally, the physician

knows that there may be several types of bacteria

that may be causing the infection. Therefore, he

or she will usually prescribe a broad-spectrum

antibiotic that will work against any of the several bacteria most likely to be causing the infection.

However, it would be preferable to treat

patients with a narrow-spectrum antibiotic targeted at the specific cause of infection and save

broad-spectrum antibiotics for the treatment of

bacteria resistant to other antibiotics. But empiric

treatment is the standard of care and, in some

infections, the only possible course of action.

Even so, some prescriptions are written with no

more information than the patient’s complaint or

in response to the patient’s request (see box 3-1).

Improvements in diagnostic technologies that

would enable the rapid identification of bacteria

and their patterns of antibiotic-susceptibility and

resistance would reduce the need for empiric

therapy. However, rapid technologies that would

produce useful diagnostic results during the

course of an office visit are not on the immediate
52 | Impacts of Antibiotic-Resistant Bacteria

horizon. Moreover, to produce significant

changes in antibiotic usage, the use of new technologies would probably have to be accompanied by changes in physicians’ and patients’

attitudes and expectations (see chapter 6).

Forces other than those created by the technical challenges of diagnosis influence and indeed

promote the use of antibiotics. Antibiotics are

sometimes referred to as the “drugs of fear”

(Kunin et al., 1973) because they can be used to

mitigate the physicians’ fear of failing to provide

patients with the very best care. Patients’ fears of

the unknown and expectations for rapid cure are

fostered by exaggerated stories in the news

media of dread diseases and new miracle cures.

Pharmaceutical advertisements and sales representatives encourage “empiric, broad-spectrum

coverage,” perhaps glossing over the need for a

full diagnostic assessment (Kim and Gallis,

1989; DiNubile, 1990). In addition, the physician

may work for a health plan that prefers paying

for antibiotics over paying for a test that may

require another office visit.

Fundamentally, the risks, benefits, and costs

of antibiotic treatment are not spread equally.

The patient can expect to benefit from treatment

with an antibiotic; there are few side effects from

the antibiotics used in office practice, and out-ofpocket costs are likely to be relatively low. In the

case where the antibiotic is not effective, and the

patient recovers regardless, he or she has borne

the very low risk of side effects and any out-ofpocket costs. The significant risks and costs of

antibiotic use, including overuse, are borne by

society as a whole. The contribution to antibiotic

resistance from one person taking antibiotics is

not that significant. Therefore, it might seem to a

physician treating a specific patient that it is betBOX 3-1: Misperceptions About Antibiotic Usage

An OTA staff member went to the doctor because of a persistent sore throat. The physician asked,

“Want some antibiotics?” There was no physical examination, and the physician did not take a throat culture.

OTA staff understand the proper use of surveys and how they should be conducted to obtain data that

are representative of the population. However, there are times when informal, non-scientific surveys can

provide a snapshot of ideas and attitudes on a particular subject. The “Want some antibiotics?” event

prompted a survey of all OTA staff by electronic mail to find out their attitudes toward antibiotic use. Of

the nearly 200 OTA employees and contractors onsite, 95 responded. Here are some of the results:

Within the past year, 59 percent of respondents or their family members had used antibiotics, with the

most common conditions being ear infections, sinusitis, and upper respiratory infections. About half of

the respondents, at one time or another, had requested antibiotics from their doctor, and 30 percent of

the respondents indicated that a physician had offered them an antibiotic without an examination. 

Most of those responding apparently understood the importance of taking all of their own prescribed

antibiotics; 56 percent of the respondents indicated that they always completed their full course of prescribed antibiotics. One person reported that he did not complete his full course of antibiotics for an ear

infection and stored the remainder of the prescription in his medicine cabinet because he felt better. He

later had to reach into the cabinet for those same antibiotics because the ear infection got worse. This

respondent’s attitude toward “left-over” or “unused” antibiotics was common. Thirty-seven percent

replied that they had later taken unfinished antibiotics that were stored in their medicine cabinets, and 10

percent said that they had taken antibiotics that someone else had stored in the medicine cabinet. Taking

medicine prescribed for other persons is not only illegal, but it can have serious side effects.

Finally, most of the respondents were aware that antibiotics only work for bacterial infections and not

colds, which are caused by viruses. But there were a few exceptions. Fifteen percent indicated they had

taken antibiotics for a cold.
Chapter 3 Antibiotic Use and Resistance in the Community | 53

ter to prescribe a broad-spectrum antibiotic, for

example, than to wait for test results or for the

infection to possibly clear on its own. However,

collectively, these prescribing habits contribute

to the spread of antibiotic-resistant bacteria. Nevertheless, the request for this study and the current attention given to antibiotic-resistant

bacteria point to society’s need to collectively

alter the uses of antibiotics to preserve the efficacy of these drugs.

❚ Trends in Antibiotic Use

A 1995 study of antibiotic use shows no change

in the number of prescriptions for antibiotics, but

indicates that older antibiotics, such as the

penicillins, are being used less frequently in

favor of the newer, more expensive drugs, such

as cephalosporins (McCaig and Hughes, 1995).

Currently, the most-used drugs are the new and

expensive macrolides (azithromycin and clarithromycin), the fluoroquinolones (ciprofloxacin,

ofloxacin, and others), and newer cephalosporins

(cefuroxime, ceflacor, and cefixime) (Kunin,

1995).

Ciprofloxacin provides an example of the

enthusiastic use of a new antibiotic among community and hospital physicians. Its low toxicity

and broad-spectrum activity make it the primary

choice for treating a wide range of conditions.

Two years after its introduction in 1987, ciprofloxacin became the fourth most commonly prescribed antimicrobial at total sales value of $248

million (Frieden, 1990). This use may have contributed to the emergence of ciprofloxacin-resistant strains of MRSA (methicillin-resistant

Staph. aureus), which is a common cause of serious infections in hospitals (see chapter 4)

POPULATIONS SUSCEPTIBLE TO 

ANTIBIOTIC-RESISTANT BACTERIA

Antibiotic-resistant bacteria pose a threat to the

population as a whole but are more likely to

cause illness in populations at greater overall risk

of contracting infectious diseases. The following

section examines those susceptible populations,

the factors that contribute to their vulnerability,

and the infectious agents to which they are most

susceptible.

❚ The Poor

The poor and those who do not have adequate

access to sanitary living conditions or proper

health care are particularly susceptible to infectious diseases. In underdeveloped countries most

of the poor live in overcrowded urban areas, have

poor hygiene, use unsanitary water, and have

poor nutrition and inadequate waste disposal.

Half of the city dwellers of developing countries,

who are not classified as homeless, live in shantytowns and slums that, among other things, lack

safe drinking water. Forty percent of them are

without public sanitation or sewage facilities and

a third live in areas in which there are no garbage

or solid waste collection services (Garrett, 1994).

As well illustrated by Levy (1992) and others,

antibiotic-resistant bacteria that arise in foreign

countries migrate to the United States when residents of foreign lands visit or immigrate here and

when American citizens visit other countries and

return with illnesses.

Even in this country, where sanitary standards

are much better, other deplorable conditions

exist. Many urban areas are laced with inadequate housing. Drug addiction, alcoholism,

homelessness, incarcerations, and general economic impoverishment is a way of life for some

inner-city residents, many of whom are ethnic

minorities. These factors provide a ripe breeding

ground for disease-causing organisms and the

vectors that carry and spread them throughout

the population.

❚ People Without Adequate Health Care

Approximately 37 million Americans do not

have medical insurance, and most of them are the

working poor and their dependents (Hammond,

1994). Because this population generally cannot

afford health care, many of their medical conditions go undiagnosed, or they may delay treatment because they have to choose between

meeting basic living expenses and living with an

illness that they think is not severe or life-threat-
54 | Impacts of Antibiotic-Resistant Bacteria

ening. Those who are poor, uninsured, and without a regular physician delay seeking medical

care 40 to 80 percent more often than other

patients; most think their problems are not serious. Overall, patients who are poor or uninsured

are 12 times more likely than other patients to

delay seeking health care because of cost (Weissman et al., 1991).

A 1992 OTA study confirmed this phenomenon. The report analyzed American studies on

the relationships between having health insurance and individual health outcomes and found

that, all other being essentially equal, uninsured

people were up to three times more likely than

privately insured individuals to experience lower

health care utilization, potentially inadequate

health care, and adverse health outcomes (OTA,

1992). These delays can worsen medical conditions and allow contagious diseases, like TB, to

spread. Hospital stays of patients who reported

delays in seeking medical care are 9 percent

longer than hospital stays of other patients

(Weissman et al., 1991). Once hospitalized, the

patient may be at higher risk of a nosocomial

infection (hospital-acquired infections) because

the delay in treatment has lowered the body’s

natural resistance.

Lack of adequate medical care may have contributed to an outbreak of multiply resistant

pneumococcal infections in Oklahoma in 1989 to

1990. Among the hardest hit were infants, the

elderly, and the state’s poor African American

population, whose overall rate of disease was 60

percent higher than in whites. Overall, more than

15 percent of the patients who developed the

pneumonia died (Haglund et al., 1993).

❚ The Incarcerated

During the 1980s, the United States’ “War on

Drugs” produced a 126 percent increase in drugrelated arrests (Skolnick, 1992). Most federal

and state prisons were not equipped to handle

this sudden onslaught of prisoners, many of

whom came from disadvantaged backgrounds

and did not have a history of adequate preventive

health care (Anderson, 1990). Almost one-third

of the newly admitted inmates in New York State

reported having been homeless just before incarceration, and the majority of inmates had histories of substance abuse (OTA, 1993). These

individuals are at high risk for infections, especially for TB and pneumococcal diseases,

because both are diseases spread by airborne

transmission and can move easily through badly

ventilated, overcrowded areas (Anderson, 1990;

Hoge et al., 1994).

Additionally, the inmate population is transient and provides a constant flow of people and

their infectious organisms between the prison

and the community. As many as half the inmates

detained in a large New York City correctional

complex, for example, are released within the

first 48 hours after admission (Chisolm, 1988).

Of the 15,000 to 20,000 or more inmates on any

given day at Riker’s Island, a correctional facility

in New York City, half are discharged within a

week (Navarro, 1993; Bellin et al., 1993).

Although the National Commission on Correctional Health Care recommends that medical

screening or a review of the medical screening of

a prisoner’s health be performed on or before the

14th day after initial booking, many prisoners are

not screened or treated for asymptomatic communicable diseases. In Los Angeles County, for

example, the average stay is less than 14 days.

Even when screening is performed, the results

may not be available until after the inmate has

been released. Subsequently, those at risk may

not be located and treated (Cohen et al., 1992).

The lack of adequate screening can result in

dire consequences, not only for the inmates but

to the community in which they are released, as

well as for the workers at correctional facilities.

From 1990 to 1992, 11 outbreaks of multipledrug-resistant TB occurred in correctional facilities in 8 states, killing 13 inmates and one correctional officer. An outbreak in an Arkansas State

prison spread to the community when a released

inmate infected his wife and two children, one of

whom died of probable tuberculous meningitis.

Also, a news reporter covering the problems of

overcrowding in urban jails became infected

with TB after working on a story about a New
Chapter 3 Antibiotic Use and Resistance in the Community | 55

York City jail (Skolnick, 1992). Because of overcrowding, the lack of adequate screening, and the

transient populations, TB has emerged in epidemic proportions in the nation’s prisons. In

1988, the new case rate of active TB infection in

the United States was 13.7 per 100,000, while the

average rate was 75 per 100,000 among inmates

of state and federal prisons. Some correctional

facilities had higher rates. In 1991, Riker’s Island

in New York City had an active infection rate of

400 to 500 per 100,000 (Skolnick, 1992).

Prison overcrowding can also be a factor in

the spread of pneumococcal disease among

inmates. After two Houston, Texas, inmates died

from pneumococcal sepsis on the same day,

health officials uncovered an epidemic of pneumococcal disease, a rare occurrence in the era of

antibiotics. The jail, which had been designed to

house 3,500 persons, was accommodating 6,700

residents at the time of the outbreak. Over a fourweek period, 46 inmates developed acute pneumonia or invasive pneumococcal disease.

Besides overcrowded conditions, investigators

also discovered that inmate susceptibility and

inadequate ventilation for the number of inmates

in the building were cofactors responsible for the

outbreak. Although none of the strains of S.

pneumoniae were resistant, the re-emergence of

pneumococcal disease, coupled with sharp

increases in the number of strains that are multiple-drug-resistant raises questions about the need

for isolation wards in prisons and the vaccination

of institutionalized persons at risk for pneumococcal disease (Hoge, et al., 1994).

❚ The Homeless

Finding an accurate estimate of the homeless

population is elusive. The estimates range from

192,000 to 3 million people. Regardless of the

true number, the homeless are at greater risk for

immune suppression because of poor nutrition,

inadequate rest, and concurrent medical illness

(Paul, 1993). Homeless shelters and shelters for

battered women provide ideal conditions for

transmission of infectious diseases, especially

TB: large numbers of people in close quarters,

poor ventilation, the presence of undiagnosed or

untreated infectious cases, and prolonged exposure during lengthy stays, particularly in winter

months. Several outbreaks of drug-resistant TB

have emerged among the homeless in south

Texas, New York, and Boston. Resistance rates

in some of those areas were as high as 57 percent

(Morris and McAllister, 1992; Pablos-Mendes et

al., 1990; Barry et al., 1986; Gross and Rosenberg, 1987.)

❚ Military Personnel

Military personnel in wartime field conditions

live in close quarters, experience rudimentary

food and water sanitation services, and have few

opportunities to exercise good personal hygiene.

Even peacetime training is characterized by

crowding and confined quarters, which favor

transmission of infectious diseases.

Historically, respiratory diseases are a common and serious problem in the military. As far

back as 1500, historians recorded apparent streptococcal pneumonia epidemics. Recently, the

U.S. military has experienced an increase in

streptococcal-related disease. Outbreaks of S.

pyogenes pharyngitis, acute rheumatic fever, and

cases of streptococcal-induced toxic shock-like

syndrome have caused concern among military

health officials. Respiratory disease caused by

the bacterium S. pneumoniae has also emerged as

a problem. During the winter of 1989-1990, 124

Marine trainees developed pneumococcal pneumonia. Despite the Navy’s administration of

thousands of doses of pneumococcal vaccine and

penicillin G to the troops, this Marine population

continued to have the highest rates of pneumonia

hospitalization in the Navy. In late 1991 and

early 1992, a pneumonia outbreak on two U.S.

Navy ships located in Italian waters afflicted 25

of the more than 1,700 crew members over a

four-month period and killed two of them (Gray

et al., 1994). These recent outbreaks, coupled

with the emergence of drug-resistant strains of

streptococci, could present increasing difficulties

for military health officials and impede the military’s performance.
56 | Impacts of Antibiotic-Resistant Bacteria

❚ Children in Daycare Facilities

An upsurge of women in the paid work force and

the increasing number of single-parent families

contribute to the increased use of daycare facilities. About 90 percent of families with preschool

children use full- or part-time child daycare services (Thacker et al., 1992). As children spend

more time in daycare, the risk for some infectious diseases has increased. Close physical contact, inadequate hygiene, and lack of toilet

training facilitate the transmission of infectious

agents within childcare settings. These agents are

spread by the fecal-oral route, contact with skin,

excretions, or bodily fluids, or transmission by

aerosols or respiratory droplets. The two most

common ailments for children in daycare are

acute upper-respiratory tract illnesses and otitis

media. By age two, children attending daycare

have approximately seven or eight episodes of

acute respiratory illness per year, which is 1.6

times greater than among children not attending

daycare facilities (Thacker et al., 1992). Interpretation of these data is complicated because not all

infections recognized in children in daycare are

acquired in the daycare environment; some are

acquired elsewhere but first recognized in the

daycare facility (Sterne et al., 1986).

Many cases of drug-resistant bacteria have

been reported in the daycare setting. One study

showed that 57 percent of the children attending

a particular daycare center were colonized with

trimethoprim-resistant Escherichia coli, while

another study detailed the hospitalization of two

infants from the same daycare center in Texas,

who had contracted sepsis and meningitis due to

a multiple-resistant strain of S. pneumoniae (Fornasini et al., 1992; Rauch et al., 1990).

❚ The Elderly

Although the elderly, those aged 65 and older,

are a relatively small proportion of the population, their numbers are increasing. By the year

2025, the elderly will comprise a little more than

10 percent of the population (USBC, 1994).

Almost all of the nation’s nursing home population and a substantial part of the hospital population are elderly. Because of their diminishing

immune systems, the presence of underlying diseases, and the use of invasive medical devices,

the elderly are more susceptible to infectious

organisms, including antibiotic-resistant bacteria

(OTA, 1987). Hospitalized elderly patients are

two to five times more likely to develop nosocomial infections than hospitalized younger

patients. These infections are often fatal, in part

because they are frequently caused by agents that

are resistant to antibiotics. The elderly are susceptible to endocarditis, pneumonia, bacteremia,

and bacterial meningitis, which is caused by S.

pneumoniae in more than half the cases worldwide (Madhavan, 1994). (See chapter 4 for information about in-hospital disease, which is

generally applicable to diseases in nursing

homes.)

❚ The Immunosuppressed

Immunosuppression, which is a result of a lowered immune system response, can be caused by

a number of factors, including the following conditions:

■ Prematurity (neonates);

■ Inherited diseases;

■ Malnutrition;

■ Pregnancy;

■ Concurrent infections;

■ Severe trauma and burns;

■ Infection with the human immunodeficiency

virus (HIV);

■ Malignancy;

■ Radiation treatment;

■ Immunosuppressive medications for transplantation, cancer chemotherapy, or treatment

for autoimmune disease;

■ Aging.

Immunosuppression can result in opportunistic infections in an individual who otherwise

would have been able to fight illness. These

infections are caused by typically non-threatening organisms that take advantage of a person’s

weakened state. Although opportunistic infections have received a great deal of attention over
Chapter 3 Antibiotic Use and Resistance in the Community | 57

the past decade with the onset of the HIV pandemic, they are not new. It is well known that the

very young and the elderly are at the greatest

danger of succumbing to disease. Also, new

medical treatments and invasive technologies

have created additional openings for opportunistic pathogens (IOM, 1992). Therefore, drugresistant bacterial infections can exacerbate

health problems for the already immunocompromised.

FACTORS IN THE EMERGENCE OF 

BACTERIAL DISEASES

❚ Global Accessibility

Travel involves the movement of people and

microbes from one region to another and has

always been a factor in the emergence of infectious disease. Whether new diseases emerge

depends on the novelty of the microbe being

introduced, its transmissibility, and the existence

of an environment suitable for maintaining the

disease and its agent. Therefore it is important to

distinguish between transient introductions or

acquisitions of new diseases, which occur frequently, and the establishment and propagation

of a new pathogen, which occurs rarely (IOM,

1992).

For example, travelers from industrialized

nations to developing countries may unknowingly transport virulent pathogens on their return.

One traveler who smuggled South American

crabs back to the United States was the origin of

a cholera outbreak, and other infected travelers

have brought the same disease to the United

States from South America (Levine and Levine,

1995).

❚ Improper Food Preparation Practices

Foodborne pathogens account for up to 7 million

cases of foodborne illnesses yearly and in 1992

caused more than 9,000 deaths, most of which

were associated with meat and poultry products

contaminated by pathogenic micro-organisms

(Cassell, 1995). Moreover, these estimates may

be low because the surveillance systems for such

diseases are passive, meaning they are based on

voluntary reporting by state and local health

departments.

Foods contaminated with pathogenic microorganisms can lead to infection and illness in two

major ways. The first is by direct consumption of

the contaminated food under conditions that

allow the survival of the pathogen or its toxin,

such as when a meat or poultry product is consumed raw or undercooked, or when products

that are pre-cooked during processing are recontaminated before consumption (AMA, 1993).

For example, in 1982 a virulent bacterial

strain, E. coli O157:H7, caused serious hemorrhages of the colon, bowel, and kidneys in 47

people in Oregon and Michigan (Riley et al.,

1983). Nine years later an outbreak of E. coli in

Massachusetts produced serious illness in 27

people, 10 of whom required hospitalization.

Health officials traced the disease to batches of

apple cider, which were made from apples on

trees that were fertilized with livestock manure

(Besser et al., 1993). In Washington State in January 1993, an E. coli outbreak caused severe illness in 144 people, many of whom ate

undercooked hamburgers prepared by Jack-inthe-Box fast-food restaurants. A majority of the

seriously ill were young children, who had to

undergo kidney dialysis for weeks. Although

media reports indicated that the outbreak killed

four children, health officials could only link one

of those deaths to the hamburger from the restaurant chain (Garrett, 1994).

The second method by which contaminated

foods can cause illness is through cross-contamination in the kitchen or other food-handling

areas. Salmonella bacteria, which can contaminate eggs, meat, and poultry, can cause severe

but rarely fatal symptoms and are transmitted

through improper food handling (Maurice,

1994). For example, when raw chicken or beef

with a Salmonella-contaminated exterior contaminates a cutting board, countertop, kitchen

utensil, or a person’s hands, the bacteria can then

come in contact with other foods, some of which

are consumed raw, such as salad. Symptoms of

Salmonella food poisoning are nausea and vom-
58 | Impacts of Antibiotic-Resistant Bacteria

iting, followed by abdominal cramps and diarrhea, which last about three or four days,

accompanied by fever in about half of the individuals infected. The most common source of

Salmonella is food; only about 10 percent of

transmissions are from person to person, and in

some of those instances the ultimate source of

the infecting organism was food (Cohen and

Tauxe, 1986). Salmonella outbreaks have been

reported in nursing homes and hospitals, particularly pediatric wards and nurseries, and on airline

flights (Villarino et al., 1992; Hatakka and

Asplund, 1993; Tauxe et al., 1987).

In addition to causing foodborne illness, many

Salmonella are resistant to multiple antibiotics

and are capable of transferring that resistance

(Snydman and Gorbach, 1982; Lee et al., 1994).

In 1983, the Minnesota State Department of

Health discovered an antibiotic-resistant strain of

Salmonella newport that caused six persons to be

hospitalized for more than a week. Officials

traced the outbreak to beef that had been fed low

levels of antibiotics. All the bacterial strains

found in the infected persons were resistant to

penicillin, ampicillin, carbenicillin, and tetracycline (Garrett, 1994; Holmberg et al., 1984).

❚ Sanitation and Hygiene

Improved public sanitation and personal hygiene

practices have dramatically reduced the incidence of certain infectious diseases, especially in

developed countries. The U.S. experience with

cholera is an example of the success of such

efforts. Between 1830 and 1896, the nation’s

major cities’ populations swelled and produced

crowded slums and fetid water and sewage “systems.” These conditions caused a widespread

death toll. In 1832, cholera killed thousands of

New York City residents and during a threemonth epidemic in 1849 claimed 10 percent of

the population of St. Louis, Missouri. Reform

was soon to follow. New York City officials,

outraged by municipal filth, financed the construction of the Croton Aqueduct, which brought

clean drinking water to the city for the first time.

Eventually, the squalid slums were slowly

upgraded, and subsequent outbreaks of the disease claimed fewer lives (Garrett, 1994). In contrast, in January 1991, cholera reached epidemic

levels in South America for the first time in

almost a century, demonstrating the health consequences of disruptions in sanitation. Vibrio

cholerae, the bacterium that causes cholera,

probably was introduced into the harbor at Lima,

Peru, through the dumping of bilge water by a

ship arriving from the Far East. Once in the

water, the bacteria contaminated the fish and

shellfish, which were then consumed by humans.

After causing these initial seafood-related

cases in humans, the organisms probably were

spread by fecal contamination of the water supply, which may have been inadequately chlorinated (IOM, 1992). In Latin America the

epidemic raged well into 1994, and officials at

the World Health Organization see no end in

sight. As of 1995, Latin American governments

have spent more than $200 billion for emergency

repairs of water, sanitation, and sewage systems,

according to the Pan American Health Organization. One of the substrains of the bacterium carried genes for resistance to the antibiotics

ampicillin, trimethoprim, and sulfamethoxazole.

Clean water supplies and their protection from

human and other wastes are fundamental public

health principles in the United States. Where

good sanitary practices are followed, many diseases that were once epidemic are successfully

controlled. The same may be said for personal

hygiene. Hand washing is effective in preventing

the spread of many infectious agents. In addition,

safe food-handling practices, including proper

storage, cleaning, and preparation, have resulted

in fewer cases of bacterial food poisonings. Also,

the pasteurization of milk, which was instituted

to prevent the transmission of bovine TB to

humans, has been equally effective against other

diseases such as brucellosis and salmonellosis

(IOM, 1992).

The emergence of antibiotic-resistant bacteria,

which makes bacterial disease more difficult to

treat, increases the importance of sanitation and

hygiene to prevent occurrences of these diseases.
Chapter 3 Antibiotic Use and Resistance in the Community | 59

Proper sanitation breaks the route of transmission, thereby bettering public health.

❚ Inadequate Water Treatment and 

Inspection and Failing Infrastructure

Although the U.S. Environmental Protection

Agency recommends that each state evaluate all

components of its public water systems, most of

them do not, according to a 1994 General

Accounting Office report. The report found that

45 states did not perform the recommended evaluations, primarily because responsible state

agencies lack sufficient funds for inspection and

verification once problems are corrected (GAO,

1994).

In Missouri in the winter of 1989, a drug-resistant strain of E. coli in the drinking water supply

killed two persons and hospitalized 32. The

strain, which was resistant to sulfisoxazole, tetracycline, and streptomycin, was the first, and still

largest, waterborne outbreak of E. coli and the

first due to a multiple-resistant organism. The E.

coli outbreak probably resulted from sewage

contamination of the water distribution system.

The bacteria survived and spread into the water

system because there was no hyperchlorination

to kill them (Swerdlow et al., 1993).

About two-thirds of the water systems in the

United States are not disinfected, and many of

them are in disrepair. The existence of antibioticresistant bacteria increases the risks from water

systems that do not adequately control bacterial

contamination, and outbreaks such as the one in

Missouri may become more common. It is

entirely possible that other waterborne outbreaks

have involved antibiotic-resistant bacteria

because there is no surveillance system from

which to obtain accurate information.

CHANGES IN DISEASE PATTERNS

❚ Sexually Transmitted Diseases

Transmission patterns of sexually transmitted

diseases have changed a great deal in the last 20

years. In the 1980s, scientists initially recognized

HIV as a sexually transmitted disease, and investigators discovered sexually transmitted etiologies for such diverse medical conditions as

infertility, ectopic pregnancy, other adverse outcomes of pregnancy, anogenital cancers, and

protocolitis—an inflammation extending from

the rectum to the colon.

Also, syphilis re-emerged. Following World

War II, the widespread availability of penicillin

led to a 95 percent reduction of infectious syphilis in the United States. But after 1956, when the

infection rate was four cases per 100,000, the

incidence rose sharply to a 40-year peak of 20

cases per 100,000 in 1990. During this time

period the target population for the disease

shifted. From about 1960 to 1980, the disease

targeted homosexual men, but during the last

decade, the disease has had its greatest impact

among minority heterosexuals as a result of the

sex-for-crack cocaine epidemic. However, the

incidence among minority heterosexuals involved

in the trade is declining (Morse, 1995). The causative organism for syphilis, Treponema pallidum, remains completely sensitive to penicillin,

and the re-emergence of this disease is not coupled with decreased treatment efficiency.

In contrast to syphilis, treatment of gonorrhea,

which is caused by the bacterium Neisseria gonorrhoeae, has been complicated by rapid and

repeated emergence of new types of antimicrobial resistance. Between 1988 and 1991, CDC

documented a 50 percent increase in the proportion of resistant “gonococcal” isolates, most of

them being resistant to penicillin or tetracycline

(Wasserheit, 1995). As a result, CDC discouraged the use of the two drugs as first-line therapies against the organisms (Schwarcz et al.,

1990). The origins of antibiotic-resistant gonococcus are unknown, but the organism has spread

rapidly. In 1976, CDC found two cases of gonorrhea caused by organisms that produced an

enzyme that destroyed penicillin. By the following year, health officials identified a strain called

penicillinase-producing N. gonorrhoeae (PPNG)

in 17 countries. In the United States most of the

cases were in New York City, with three cases in

1977 involving resistance to penicillin, ampicillin, and spectinomycin. By 1981, treatment of
60 | Impacts of Antibiotic-Resistant Bacteria

gonorrhea had become far more complicated

because of resistance to antibiotics (Garrett,

1994). The major impact of antibiotic resistance

on gonorrhea is the cost of treatment. A nonresistant case of gonorrhea costs less than a dollar, but a resistant case may increase treatment

anywhere between 12 and 15 times that amount

(Morse, 1995).

❚ Tuberculosis

Once thought to be conquered, tuberculosis

(TB)an airborne disease that is spread through

the air when a person with active infection

coughs, sneezes, or speaks, expelling contaminated droplets from the lungshas re-emerged

as a public health threat, with drug-resistant

strains greatly complicating treatment. In 1947,

when antibiotic therapy for TB was still considered a novel treatment and disease prevention

technique, nearly 135,000 cases of the disease

were reported in the United States. By 1985 the

uses of streptomycin, rifampin, isoniazid, and

other antibiotics, coupled with an aggressive

public health effort to identify and treat TB

cases, had brought the nation’s caseload down to

a little more than 22,000. By 1992, however,

there were nearly 30,000 newly reported cases

(OTA, 1993).

Well before the actual numbers of TB cases

began to swell, the demographics of the disease

shifted. Between 1961 and 1969 more than 80

percent of all active TB cases in the United

States were among people over 62 years of age,

and the majority of them were elderly individuals

of European descent who had carried the Mycobacterium tuberculosis microbes in their bodies

for decades, only falling ill as their aging

immune systems failed to keep the bacteria in

check. Most of these people were readily treated

without hospitalization through basic long-term

antibiotic therapy. Between 1975 and 1984 the

numbers of active TB cases reported among the

elderly declined sharply. By 1984, only 29 percent of TB patients were over 62 years of age. In

the non-white population, less than one out of

every five active TB cases that year involved

someone over 62, and fully 20 percent were

between the ages of 25 and 34. During that

decade, white male cases dropped 41 percent,

and white female cases fell 39 percent. While TB

was declining across the board, its downturn

among non-whites was slower; only 25 percent

for males and 26 percent for females.

The warning signs were clear. Between 1980

and 1986 five different surveys documented a

relationship between rising homelessness and the

surge of TB in young adult populations, and by

1984 new resistant strains of drug-resistant TB

were spreading among the urban indigent. By

1986, nearly half of all active TB cases reported

in the United States were among non-whites,

most of them African Americans. More specifically, TB now occurs disproportionately among

individuals who lack stable housing, abuse alcohol or intravenous drugs, become incarcerated,

are employed as migrant farm workers, and who,

for various reasons, are exposed to people who

do not adhere to treatment guidelines (OTA,

1993).

Geographically, the disease shifted from rural

areas to scattered urban areas such as New York

City and Miami. CDC noted the shift in 1986,

which coincided with the first upward trend in

TB cases reported in the United States since

1953. Agency officials believe that the impaired

immune systems associated with HIV infection

may be largely responsible for the increase in TB

in New York City and Florida. However, other

factors also can contribute to the spread of TB. A

recent case in Minnesota prompted health officials there to theorize that heavy alcohol consumption may play a role in the weakening of the

immune system, permitting initial infections to

progress to active TB (Boodman, 1995).

In the mid-1980s, budget cuts in New York

City forced a three-fold reduction in the number

of TB clinics and disbanded public health clinics.

During that same period, federal and state officials slashed TB control and surveillance budgets. For example, budget cuts eliminated New

York City’s surveillance system for multipledrug resistant TB (MDR-TB) in 1986. Inadequate treatment and the lack of surveillance led
Chapter 3 Antibiotic Use and Resistance in the Community | 61

to the increase in the number of MDR-TB cases.

Frieden et al. (1995) analyzed TB surveillance

data and discovered that drug resistance among

patients who had never been treated increased

from 10 percent in 1983 to 23 percent in 1991.

Nearly 25 percent of patients with TB in New

York City had multiple drug-resistant strains,

and the proportion of new patients with MDRTB had more than doubled from 1984 to 1991

(Freiden et al., 1995). From 1985 to 1992, public

health officials documented outbreaks of MDRTB in more than a dozen hospitals, homeless

shelters, prisons, and other areas in the United

States and Puerto Rico. Those cases are illustrated in table 3-1 (Garrett, 1994).

By the time politicians realized the scope of

this re-emergence, TB, and especially MDR-TB,

was draining already tight budgets and had

become a public health crisis. When all the costs

of the 1989-1994 MDR-TB epidemic were

totaled, health officials had spent more than $1

billion to tackle the resistant bacteria (Garrett,

1994). Only after this crisis were federal dollars

allocated and a modified surveillance system for

MDR-TB reinstated (Berkelman et al., 1994). As

a result of the revised surveillance system, along

with directly observed therapy (in which healthcare workers observe patients as they take each

dose of medicine), New York City reported a 19

percent decline in all TB cases and a 44 percent

decline in the MDR-TB cases from 1991-1992 to

1993-1994 (Freiden et al., 1995). Despite the

recent successes, New York City has not controlled TB. The case rate there is still more than

four times the national rate, and there are more

patients in the city with MDR-TB than in the rest

of the United States combined. However, New

York City’s experience shows that TB can be

curtailed despite the prevalence of drug-resistant

strains and immunosuppressed populations.

SURVEILLANCE OF ANTIBIOTICRESISTANT BACTERIA

Diseases are transmitted in the community, and

some of those diseases are caused by antibioticresistant bacteria. How commonly that occurs is

unknown. Almost all of the information about

antibiotic-resistant diseases in the community

comes from episodic reports, and it is unknown

how many go unreported or unnoticed. Some

exceptions are TB, syphilis, and gonorrhea, all of

which are notifiable diseases, which means that

CDC obtains and combines records from the

states to provide national data on those infections. Public health officials at state health

departments, CDC, and the Council of State and

Territorial Epidemiologists recommend annual

additions and deletions to the national notifiable

disease list, which is published in CDC’s Morbidity and Mortality Weekly Report. Generally,

diseases are added to the list as new pathogens

emerge and are deleted as their incidence

declines. However, health officials in each state

ultimately decide which diseases they will report

on the nationally notifiable list. Table 3-2 shows

a listing of nationally reportable diseases. Of the

50 diseases notifiable to CDC, 31 are bacterial

and are therefore subject to antibiotic resistance.

Drug-resistant S. pneumoniae (DRSP) was

added to the list of reportable diseases in 1995 as

a result of a CDC-convened working group that

identified methods for prevention and control of

the bacterium. The working group, consisting of

public health practitioners, clinical laboratory

professionals, health-care providers, and representatives of professional societies, established

DRSP, which is associated with many illnesses,

as a nationally reportable condition. Currently,

only a few states have made DRSP a reportable

condition on a national level. If more states

reported DRSP nationally, the system not only

would provide better surveillance information

but could serve as a model for surveillance of

other antibiotic-resistant bacteria.

More surveillance information about the prevalence of drug-resistant microbes such as S.

pneumoniae, for example, would enable physicians to prescribe antibiotics more effectively,

thereby possibly reducing resistance, the added

costs associated with treating an antibiotic-resistant disease, and in some cases death. Had the

surveillance program for MDR-TB in New York

City not been eliminated, perhaps more money
62 | Impacts of Antibiotic-Resistant Bacteria

TABLE 3-1: MDR-TB Outbreaks in the United States and Puerto Rico, 1985-1992

Location Drug resistance Year(s) Index case(s) Secondary case(s)

Texas, California, 

Pennsylvania

INH, RIF, SM, 

PZA, EMB

1987 Male, diagnosed with TB 

in 1971; recalcitrant, in/

out of medications. Died 

in 1987.

9 family members and relatives

Mississippi, rural INH, SM, PAS 1976 High school student Fellow students and their families

Boston homeless 

shelters

INH, SM 1984, 1985 2 possible, both 

homeless men

Fellow sheltered homeless

Miami outpatient 

AIDS clinic or HIV 

ward

INH, RIF, EMB, 

ETH

1988-1991 1 patient 22 HIV patients

New York State 

Prison

INH, RIF, PZA, 

EMB, SM, KM, 

ETH

1990-1991 Prisoner 7 inmates and 1 prison guard

New York City 

Jail, Rikers Island

Various 1988-1992 Prisoners Spread within jail; diagnosis rate of 

500 per 100,000. Average daily 

census of jail is 20,000

New York City Jail Various 1991 Prisoners 720 cases of MDR-TB diagnosed in 

prisoners

Waupun Jail, 

Wisconsin

NS 1993 Prisoners 22 prisoners

Nassau County 

Jail, New York

NS 1988-1990 Prisoners 45 prisoners

Lincoln Hospital, 

New York City

INH, RIF, EMB, 

SM

1991 Noncompliant AIDS 

patient

1 AIDS patient 

7 New York City 

hospitals

INH, SM, RIF, 

EMB

1988-1991 Patients More than 100 patients; 19 healthcare workers, all but 6 of whom were 

HIV infected

San Juan, Puerto 

Rico, hospital

12 to INH, RIF, 

PZA, EMB

1989 Patient(s) All 17 health-care providers on HIV 

ward infected

New York City 

hospital

NS 1989-1991 Patient(s) 23 patients, 21 of whom were HIVinfected; 12 health-care providers 

infected; no active cases

New York City 

hospital

INH, SM, RIF, 

EMB

1989-1990 Patient(s) 18 AIDS patients

Cook County 

Hospital, Chicago

NS 1991 Patient(s) 12 health-care providers infected; 

no active cases

Miami hospital INH, RIF 1990-1991 Patient 36 patients, 35 of whom were HIVinfected

Miami hospital INH, RIF 1987-1990 Patient(s) 29 patients, 13 health-care 

providers; no active cases

INH=isoniazid; RIF=rifampin; EMB=ethambutol; PZA=pyrazinamide; SM=streptomycin; PAS=para-amino-salicylic acid; ETH=ethionamide;

KM=kanamycin; NS=not specified 

SOURCE: Garrett, L. 1994.
Chapter 3 Antibiotic Use and Resistance in the Community | 63

could have been saved in treatment, and more

importantly, more deaths could have been prevented. However, since its reinstatement, the

New York City TB surveillance system, along

with directly observed therapy, as mentioned

previously, has resulted in dramatic decreases in

the number of TB and MDR-TB cases. Experiences in Washington State and Nevada in 1993

also demonstrate the usefulness of surveillance

systems. Washington requires that hospitals

report cases of illness caused by E. coli O157:H7

to the state health department. After health officials learned of a few cases, they determined that

the bacteria were coming from fast-food hamburgers and recalled more than 250,000 hamburgers. This action ended the outbreak. Cases of

E. coli infection derived from the same source

had occurred earlier in Nevada, but without a

surveillance system officials in that state were

unaware of them until after the Washington

health officials had detected their cases.

Nevada’s outbreak caused 58 cases of bloody

diarrhea and acute kidney failure. None had been

reported to the health department because physicians and laboratories were not testing for that

particular pathogen.

CONCLUSIONS

Antibiotics have produced a great paradox. After

their introduction into medical practice nearly 50

years ago, the drugs controlled many life-threatening diseases, reduced death and illness, and

increased the life expectancy of Americans.

Since then, the use of antibiotics, including inappropriate uses that have little benefit to the

patients, has fostered antibiotic resistance and

caused many antibiotics to lose their effectiveness against some bacterial diseases. As a result,

some illnesses that were once easily treatable

now pose problems for patients and physicians.

One solution is the development of new drugs

against antibiotic-resistant strains. However,

TABLE 3-2: Infectious Diseases Classified as Notifiable at the National Level (United States, 1994)

AIDS

Amebiasis*

Anthrax

Aseptic meningitis

Botulism

Brucellosis

Chancroid*

Cholera

Congenital rubella syndrome

Diphtheria

DRSP**

Encephalitis

Escherichia coli O157:H7*

Gonorrhea

Granuloma inguinale

Haemophilus influenzae 

Hepatitis A

Hepatitis B

Hepatitis, non-A, non-B

Hepatitis, unspecified

Legionellosis

Leprosy (Hansen disease)

Leptospirosis

Lyme disease

Lymphogranuloma venereum*

Malaria

Measles

Meningococcal infection

Mumps

Pertussis

Plague

Poliomyelitis

Psittacosis

Rabies, animal

Rabies, human

Rheumatic fever*

Rocky Mountain Spotted fever 

(Typhus fever, tickborne)

Rubella

Salmonellosis*

Shigellosis

Syphilis

Syphilis, congenital

Tetanus

Toxic shock syndrome

Trichinosis

TB

Tularemia

Typhoid fever

Varicella (chicken pox) +*

Yellow fever*

* Reports of these diseases are not printed weekly in Table I or Table II of the Morbidity and Mortality Weekly Report.

** Drug-resistant Streptococcus pneumoniae was added in 1995.

+ Although varicella is not officially a nationally notifiable disease, the Council of State and Territorial Epidemiologists encourages reporting cases

of varicella to CDC.

SOURCE: Centers for Disease Control and Prevention. 1994. Morbidity and Mortality Weekly Report 43 (43):801.

NOTE: Boldface indicates bacterial diseases.
64 | Impacts of Antibiotic-Resistant Bacteria

strains resistant to the new antibiotics are likely

to develop eventually. Therefore, a more longterm solution includes the more prudent use of

antibiotics that are currently available.

Outbreaks of illnesses and diseases caused by

antibiotic-resistant bacteria are increasing. How

common these outbreaks are is unknown because

of inadequate surveillance. Almost all of the

information about antibiotic-resistant illnesses

and diseases is episodic, and it is unknown how

many go unreported or unnoticed. Surveillance is

the essential element for health officials to identify, isolate, and control these outbreaks. The

importance of a surveillance system was demonstrated in the E. coli outbreak in Washington

State and Nevada in 1993. Health officials in

Washington traced the outbreak’s origin to

undercooked hamburger from a fast-food chain.

The finding led to the recall of more than

250,000 hamburgers and the end of the outbreak.

In contrast, an outbreak from the same source

had occurred earlier in Nevada and caused 58

cases of bloody diarrhea and acute kidney failure. Because of inadequate surveillance, the

Nevada health officials did not identify their

cases until after the Washington State cases

occurred. Although these cases were not antibiotic-resistant, they serve as an example of how

surveillance could track cases that are. In those

instances, time is essential to prevent the spread

of antibiotic-resistant illnesses that are generally

harder to treat.

Although all persons are susceptible to illnesses related to antibiotic-resistant bacteria,

some are more than others. The poor, people

without adequate health care, the incarcerated,

the homeless, military personnel, children in

daycare facilities, the elderly, and the immunosuppressed are more susceptible to these illnesses than the general population. However,

because most of the general public comes in contact with members of these vulnerable populations daily, the general public is at risk because

the diseases or illnesses can spread from person

to person. Because of the potential of widespread

illnesses caused by resistant bacteria, better use

of current antibiotics and more adequate surveillance systems would help control antibiotic resistance and reduce its effects on the general

population.

Therefore, it is crucial that the scientific and

medical communities, the pharmaceutical industry, and the general public cooperate to find solutions that will slow the pace of antibiotic

resistance and lessen the impact of illness on

public health.
Chapter 3 Antibiotic Use and Resistance in the Community | 65

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4

Antibiotic

Use in

Hospitals

t any given time, 25 to 35 percent of

hospitalized patients are receiving systemic antibiotics (Eickhoff, 1991) to

treat active infections or to prevent

potential infections. The heavy use of antibiotics

in the hospital exerts enormous selective pressure for the emergence and spread of antibioticresistant bacteria. Consequently, many of the two

million bacterial infections acquired in the hospital are antibiotic-resistant, and a few are resistant

to every antibiotic currently approved for use.

Some hospitals have reduced infections from

antibiotic-resistant bacteria through a combination of infection control procedures that prevent

the spread of the resistant organisms and through

monitoring and control of antibiotic use.

This chapter 1) describes antibiotic use in hospitals and its contribution to the rise of antibioticresistant nosocomial infections, 2) discusses current efforts to control antibiotic-resistant infections, 3) explores medical and financial factors

that make such efforts difficult to implement in

hospitals, and 4) discusses some possible solutions.

INFECTIONS ACQUIRED IN 

THE HOSPITAL

The Centers for Disease Control and Prevention

(CDC) estimates that 1 out of 20 patients

(2 million per year) acquire infections in the hospital (Haley et al., 1985).1 Nosocomial infections

cost $4.5 billion a year (1992 dollars) in terms of

extra treatment and days of hospitalization,

directly cause 19,000 deaths, and contribute to

58,000 deaths annually (table 4-1). The 19,000

deaths per year directly caused by nosocomial

infections makes them the 11th leading cause of

death in the U.S. population (Martone et al.,

1992).

Recent data from the National Nosocomial

Infections Surveillance (NNIS) system show that

nosocomial infections are increasing (figure 4-1).

The number of blood stream infections increased

279 percent in small non-teaching hospitals, 196

percent in large non-teaching hospitals, by 124

percent in small teaching hospitals, and by 70

percent in large teaching hospitals during the

1980s. It might be discouraging that the rates of

blood stream infections have been increasing

1 Based on data from CDC’s 1976 Study on the Efficacy of Nosocomial Infection Control (SENIC). This number is still widely quoted in

recent reports (see, for example, IOM, 1992).

A
70 | Impacts of Antibiotic-Resistant Bacteria TABLE 4-1: Estimated Extra Days, Extra Charges, and Deaths Attributable to Nosocomial Infections Annually in U.S. Hospitals Extra days Extra charges Deaths directly caused by infections Deaths to which infections contributed Avg. per infectiona Est. U.S. totalb Avg. extra charges per infection in 1992 dollarsc Est. U.S. total in 1992 dollarsb Est. U.S. totalb Est. U.S. totalb Surgical wound infection 7.3 3,726,000 $3,152 $1,609,000,000 3,251 9,726 Pneumonia 5.9 1,339,000 $5,683 $1,290,000,000 7,087 22,983 Bacteremia 7.4 762,000 $3,517 $362,000,000 4,496 8,844 Urinary tract infection 1.0 903,000 $680 $615,000,000 947 6,503 Other site 4.8 1,946,000 $1,617 $656,000,000 3,246 10,036 All sites 4.0d 8,676,000 $2,100 $4,532,000,000 19,027 58,092

a Adapted from R.W. Haley et al., Extra days and prolongation of stay attributable to nosocomial infections: A prospective interhospital comparison. American Journal of Medicine 70:51, 1981, bypooling data from the three SENIC pilot study hospitals.b Estimated by multiplying the total number of nosocomial infections estimated in the SENIC Project (R.W. Haley et al., The nation-wide nosocomial infection rate: A new need for vital statistics. American Journal of Epidemiology 121:159, 1985) by the average extra days, average extra charges, or percentage of infections causing or contributing to death, respectively.c 1992 dollars estimated from R.W. Haley et al., Amer. J. Med. 70:51, 1981, by pooling data from the three hospitals and adjusting for the annual rate of inflation of hospital expenses from 1976 to1992 (range 5.0 to 12.3 percent) obtained from the American Hospital Association’s National Panel Survey. Estimates for inflation rates in 1991 and 1992 were projected from 1987 to 1990 trend.d Nationwide estimate obtained by summing the products of the site-specific estimate of the average extra days, average extra charges, or the percentage of infections causing or contributing todeath, respectively, from the SENIC pilot studies (R.W. Haley et al., Amer. J. Med. 70:51, 1981), and the nationwide estimate of the proportion of nosocomial infections affecting the site from the mainSENIC analysis (R.W. Haley et al., Amer. J. Epidemiol. 121:159, 1985).SOURCE: W.J. Martone, W.R. Jarvis, D.H. Culver, et al. 1992. Incidence and nature of endemic and epidemic nosocomial infections. In: J.V. Bennett and P.S. Brackman (eds.) Hospital InfectionsThird edition. Boston, MA. Little, Brown and Company, pp. 593.
immunosuppression so that the foreign tissue is

not rejected by the transplant recipient. Consequently, immunosuppressed patients are dependent on antibiotics to control bacterial infections.

Treatment with an antibiotic may suppress

enough normal microbial flora (commensals) to

leave a patient susceptible to infection by other

organisms—especially antibiotic-resistant bacteria-unaffected by the antibiotic. Kollef (1 994)

cites studies that show intensive care unit

patients who had received antibiotics were more

likely to develop ventilator-associated pneumo-

,

80 81 82 83 84 85 86 87 88 89

SOURCE: S.N. Banerjee, T.G. Emori, D.H. Culver, et al, 1991. American Journal of Medicine 91 (Suppl. 3B):86S-89S

untary information from approximately 200 hospitals, and through NNIS, CDC has documented

increases in the number of nosocomial infections

caused by antibiotic-resistant bacteria. Two

important cases are the increasing numbers of

infections caused by methicillin-resistant Stap/ty10CoCCUS aureus (MRSA) and vancomycin-resistant Enterococci (VRE). Resistant strains of

Klebsiella, Pseudomonas, Escherichia coli, and

coagulase-negative Staphylococci also cause

serious problems in hospitals.

❚ Methicillin-Resistant Staphylococcus

aureus (MRSA)

Nosocomial Staphylococcus aureus infections

have been a recurrent problem in hospitals for

many years. This is partially due to the high rate

of colonization in the population: about

50 percent of the population are intermittent carriers of Staph. aureus, and about 30 percent of

the population are prolonged carriers of the bacteria in their nostrils or on their skin (Waldvogel,

1995). When these colonizing organisms enter

internal organs of the body through invasive surgery, catheterizations, or other hospital procedures, they can cause infection. Strains resistant

to penicillin were identified soon after its introduction (Spink and Ferris, 1945). Currently,

more than 90 percent of all Staph. aureus are

resistant to penicillin (Mandell and Sande, 1990).

These strains of staphylococci were most likely

resistant through the production of beta -lactamases

that destroy penicillin and penicillin-like antibiotics.

The synthetic penicillin, methicillin, introduced in 1960, is not affected by many beta-lactamases. However, strains of staphylococci that
resistant to these antibiotics. NNIS data docu

ment the increase in MRSA (figure 4-2). By

1992, more than 40 percent of Staph. aureus

infections in large hospitals were methicillinresistant. Some strains of MRSA are resistant to

all antibiotics currently approved by the U.S.

Food and Drug Administration (FDA), with the

exception of vancomycin; others are susceptible

to other antibiotics as well as vancomycin (see

chapter 5).

❚ Vancomycin-Resistant Enterococcus

Some strains of Enterococcus are resistant to all

available antibiotics approved by FDA, and they

are, therefore, untreatable with antibiotics. NNIS

data showing the increase in VRE are presented

in figure 4-3. As of 1994, almost 13 percent of

enterococci acquired in intensive care units

(ICUs) were resistant to vancomycin, and about

8 percent of enterococci acquired outside of

ICUs were resistant. There is currently no FDAapproved antibiotic to treat many of these infections. 2

❚ Vancomycin-Resistant MRSA?

A huge fear among clinicians and epidemiologists is the possibility of the emergence of vancomycin-resistant strains of MRSA that are both

highly virulent and untreatable. As this report

goes to press, no confirmed vancomycin-resistant strain of MRSA has been reported to public

health officials at CDC or elsewhere. However,

Noble, Virani, and Cree (1992) demonstrated the

1975 77 79 83 85 87 89 91

SOURCE: National Nosocomial Infections Surveillance System,

Centers for Disease Control, Atlanta, GA

1989 1990 1991

SOURCE: National Nosocomial Infections Surveillance System

Centers for Disease Control, Atlanta, GA.

transfer of a vancomycin resistance gene from an

Enterococcus to Staph. aureus in the laboratory,

indicating that the clinical emergence of vanco2 Chapter 5 describes two new drugs, quinupristin/dalfopristin and teicoplanin, currently in clinical trials that may have activity against

some strains of VRE, These drugs are available from the manufacturers on a compassionate-use basis to patients with VRE infections (The

Medical Letter on Drugs and Therapeutics, 1994, at p. 31).
Chapter 4 Antibiotic Use in Hospitals | 73

mycin-resistant MRSA is possible. The only

treatment available for some strains of MRSA is

vancomycin, and the emergence of vancomycinresistant MRSA may be inevitable. It will present

a crisis in treatment.

THE USES OF ANTIBIOTICS IN 

HOSPITALS

❚ Prophylactic Use of Antibiotics

In large surgical hospitals, half of all antibiotics

are used to prevent possible infections (prophylaxis) (Kernodle and Kaiser, 1990). More than 30

years ago, Burke (1961) showed that prophylactic use of antibiotics before surgery reduces postoperative infection rates. Classen et al. (1992)

investigated the timing of administration of antibiotics for prophylaxis and confirmed that antibiotics can prevent infections when administered

two hours prior to surgery. They also suggested

that antibiotics given at times other than in the 2

hours before surgery (one-third of all prophylactic antibiotics were given earlier than 2 hours

before surgery or after surgery in this study of

2,847 patients) are not as effective in preventing

infections (see table 4-2). Approximately

12 percent of the patients received antibiotics

more than 2 hours before surgery; and more than

70 percent of the antibiotics given had half-lives

ranging from 0.7–1.9 hours (Wenzel, 1992), suggesting that these antibiotics washed out of the

patients’ system before surgery began. In these

cases it is clear that the use of antibiotics was

inappropriate and that appropriate use of antibiotics would reduce the rate of infections and their

associated costs because of decreases in the number of days that a patient is hospitalized. Moreover, appropriate use would reduce antibiotic use

and help control antibiotic resistance.

Studies raise questions about the effects of

prophylactic antibiotic use other than to prevent

surgical wound infections. Kollef (1994a) found

that prophylactic use of antibiotics for selective

digestive decontamination designed to reduce

nosocomial pneumonia reduced the incidence of

pneumonia, but it had no effect on mortality.

Apparently this phenomenon occurred because

antibiotic-resistant bacteria that colonized some

patients following the prophylactic treatment

were harder to treat.

Classen et al. (1992) reported that more than

50 percent of the nosocomial infections they

TABLE 4-2: Temporal Relation between the Administration of Prophylactic Antibiotics and 

Rates of Surgical-Wound Infection

Time of administration* No. of patients No. (%) of infections Relative risk (95% CI) Odds ratio** (95% CI)

Early 369 14 (3.8)‡ 6.7 (2.9–14.7) 4.3a (1.8–10.4)

Preoperative 1708 10 (0.59) 1.0

Perioperative 282 4 (1.4)b 2.4 (0.9–7.9) 2.1c (0.6–7.4)

Postoperative 488 16 (3.3)‡ 5.8‡ (2.6–12.3) 5.8d (2.4–13.8)

All 2847 44 (1.5) ——————— ——————

* For the administration of antibiotics, “early” denotes 2 to 24 hours before the incision, “preoperative” 0 to 2 hours before the incision, “perioperative” within 3 hours after the incision, and “postoperative” more than 3 hours after the incision.

** As determined by logistic-regression analysis.

‡ P<0.0001 as compared with preoperative group (all P values were determined by logistic-regression analysis).

a P = 0.001.

b P = 0.12 as compared with preoperative group.

c P = 0.23.

d P = 0.0001.

SOURCE: C. Classen, R.S. Evans, S.L. Pestotnik, et al. 1992. The timing of prophylactic administration of antibiotics and the risk of surgicalwound infection. New England Journal of Medicine 326(5):283.
74 | Impacts of Antibiotic-Resistant Bacteria

studied were caused by organisms resistant to the

antibiotic used. In these cases the infections may

have been caused because the resistant organisms were able to multiply when the susceptible

normal bacterial flora of the patients was inhibited by the prophylactic antibiotics. Siegel et al.

(1980) reported an especially tragic example of

prophylactic use gone awry based on examination of the results of giving a single dose of penicillin to ward off streptococcal infections in

some 9,000 newborns. Although penicillin-sensitive infections were reduced by the prophylactic

treatment, infections with penicillin-resistant

bacteria were more frequent in the babies who

received the antibiotic, and mortality was higher

from the resistant infections (15 of 35) than from

the sensitive infections (3 of 27). Overall, the

death rate from streptococcus infections was

3 times higher in the babies that received penicillin (1.2/1,000 vs. 0.43/1,000 live births).

❚ Antibiotic Use to Treat Active Infections

The remainder of antibiotic use in hospitals is for

treatment of active infections. It takes at least

two days to identify the bacteria causing an

infection and to determine its antibiotic susceptibility (see chapter 6). Therefore, the physician

often has to make an empirical judgment about

the identity of the bacteria and prescribe an antibiotic before the laboratory test results are available. If a patient is very sick, the physician will

often use multiple antibiotics. If the patient is

improving when the laboratory tests arrive, the

physician might ignore the results of the tests and

continue the patient on the empiric antibiotics. It

is difficult to determine inappropriate antibiotic

use and how to improve use in such cases.

The appearance of unexpected resistant organisms in one patient may influence a physician to

routinely prescribe newer or broader spectrum

antibiotics. A letter to the editor of the New

England Journal of Medicine (Lonks et al.,

1995) illustrates a case where a patient suffered

because he was infected with an unlikely resistant strain. Physicians knew that no highly resistant strains of pneumococci had been reported in

Providence, Rhode Island; only 2.3 percent of

isolates obtained in hospitals in 1990 and 1991

showed intermediate-level resistance to penicillin, and none was highly resistant. An otherwise

healthy 33-year-old man, who lived a little more

than 30 miles from the city, was treated in the

hospital for a Streptococcus pneumoniae infection. Assuming that the strain was not ceftriaxone-resistant, doctors treated the patient with

dexamethasone and ceftriaxone for the first four

days. After initial improvement, encephalitis

developed, and doctors switched drugs to vancomycin and rifampin based on antibiotic-susceptibility test results that showed the infecting strains

were resistant to penicillin and ceftriaxone. The

patient’s condition eventually improved and he

was sent home. Based on this experience, the

authors concluded that “all patients with the presumptive diagnosis of pneumococcal meningitis

should receive high-dose ceftriaxone (or cefotaxime) plus vancomycin, with or without

rifampin, until the isolate is proved to be susceptible to penicillin or ceftriaxone” [emphasis

added]. It may be true that following this advice

will prevent a few adverse outcomes such as

those described in the letter to the journal. However, if similar reasoning is applied in many

cases, the widespread use of antibiotics such as

vancomycin will increase the risk for the emergence of antibiotic-resistant organisms.

In a study of the reasoning strategies used by

physicians in empiric antibiotic selection, Yu et

al. (1991) found that unexpected organisms

appeared in 3.8 percent of all blood cultures. In

these cases, antibiotics had been prescribed

which were not the antibiotics of choice based on

logical reasoning, but which did cover the unexpected organisms. The authors comment that

“[t]hese memorable situations may have a disproportionate influence in these physicians’

future selection of antibiotic therapy.” They further conclude that “our disturbing and unexpected finding is that reflex prescription of

broad-spectrum antibiotic therapy that is so often

decried by academicians may have a rational

basis” and that “educational efforts that emphasize narrow, rather than broad-spectrum prescribing may be inadequate to change physician

prescribing habits.”
Chapter 4 Antibiotic Use in Hospitals | 75

LEGAL ASPECTS OF ANTIBIOTIC USE

Malpractice concerns might provide an additional incentive to prescribe antibiotics. According to data published by St. Paul Fire and Marine

Insurance Company, a large nationwide malpractice insurer, a significant number of claims are

related to infection-related illnesses and antibiotic use (St. Paul Fire and Marine Insurance Co.,

1995). It is reasonable to speculate that fear of

malpractice litigation may contribute to prescription of overly broad spectrum antibiotics or of

antibiotics in cases where the chance of a bacterial infection is small. Box 4-1 contains excerpts

from a commentary in the medical journal Lancet discussing the medical and legal controversy

over the use of prophylactic antibiotics to prevent neonatal bacterial sepsis caused by Group B

streptococcus.

BOX 4-1: Group B Streptococcus: The Controversy

Group B streptococcus (GBS) is the leading cause of neonatal bacterial sepsis in the United States,

infecting about 12,000 newborns annually. Some newborns infected with GBS may die or have permanent neurological damage from meningitis. In 1992, both the American Academy of Pediatrics (AAP) and

the American College of Obstetricians and Gynecologists (ACOG) issued protocols regarding the

screening of pregnant women to detect and treat carriers of GBS in an effort to prevent neonatal GBS

sepsis.

AAP called for universal prenatal GBS screening for all pregnant women at 26–28 weeks’ gestation.

Because certain population groups are more likely to carry GBS, ACOG advocated for optional screening

targeted to certain populations where the incidence of neonatal GBS infection is inordinately high, such

as populations where sexually transmitted diseases are common.

Inasmuch as GBS is part of the normal gut flora of some women and may or may not become a pathogen during pregnancy, both AAP and ACOG recommended intrapartum (during delivery) antibiotic treatment only to women with positive cultures who have additional high-risk factors such as preterm labor or

premature rupture of the membranes before 37 weeks’ gestation, fever in labor, multiple births, rupture of

membranes for more than 18 hours at any gestational age, or a previous affected child.

The AAP and ACOG protocols leave a number of issues unresolved that expose obstetricians, family

practitioners, and nurse midwives to considerable medicolegal liability. Screening for GBS during pregnancy does not provide certainty as to whether or not intrapartum antibiotic treatment is warranted. A

study found that in women who were culture-positive at 28 weeks’ gestation, 30 to 50 percent were culture-negative at the time of delivery; in women who were culture-negative at 28 weeks, 8 to 15 percent

were culture-positive at the time of delivery. Consequently, some women will be treated unnecessarily

and some who need treatment will be ignored.

Moreover, if only certain groups are targeted for screening in keeping with ACOG’s protocol, can

excluded groups hold health care professionals responsible if their newborn babies developed undetected GBS sepsis? Further, would the withholding of treatment in a pregnant woman with a positive culture

who has no additional risk factors absolve a health care professional from medicolegal liability if that baby

were affected?

The best approach to the management of GBS sepsis would be a rapid screening test during labor to

determine whether antibiotic therapy is warranted, but the poor sensitivity of such tests currently renders

them clinically useless. Until these tests are improved, health care professionals will most likely err on the

side of caution and prescribe antibiotics even in extremely low-risk cases.

SOURCE: C.V. Towers, 1995, Lancet 346:197–198.
76 | Impacts of Antibiotic-Resistant Bacteria

The following review of some malpractice

suits exemplifies the dramatic consequences that

can occur due to undertreating with antibiotics.

In Hellwig v. Potluri (Case No. WL 285712,

Ohio Court of Appeals 7th Circuit, 1991), the

defendant emergency room physician was held

liable for failing to prescribe antibiotics for the

plaintiff who had stepped on a rusty nail at his

home. The plaintiff developed osteomyelitis

which forced him to “wear an appliance in his

shoe and have an altered gait for the rest of his

life.” In Toler v. United States of America a

plaintiff claimed that failure of a Veterans

Administration (VA) hospital to administer an

adequate course of antibiotics resulted in sepsis

and death. In Griffith v. West Suburban Hospital

(Case No. 86L-23904, Cook County, Illinois Circuit Court, 1993), a jury returned a $3.5-million

verdict for failure to diagnose and timely treat a

Group B Strep infection. In this case, a patient

showed signs of respiratory distress shortly after

birth, and although he was moved to an intensive

care crib, antibiotics were not administered.

Seven hours later, after being transferred to

another hospital which then administered antibiotics, the patient died.

The medical and financial consequences of

failing to prescribe prophylactic antibiotics for

endocarditis can be considerable. In 1993, a dentist was held liable in Orbay v. Castellanos (Case

No. 91-36124, Dade County Circuit Court,

Miami, Florida, 1993) for failing to prescribe

prophylactic antibiotics prior to tooth extraction.

Soon after the tooth extraction, the plaintiff was

diagnosed with bacterial endocarditis and underwent open heart valve replacement surgery. The

defendant was held liable for failure to prescribe

prophylactic antibiotics and failure to obtain a

full medical history or medical clearance for a

patient at risk of developing bacterial endocarditis. The jury awarded the plaintiff $1.24 million,

which was reduced to $964,000 to reflect the

decision that the plaintiff was 20 percent comparatively negligent for failure to take appropriate care of himself. However, a standard medical

textbook comments:

The issue of professional liability in the prophylaxis of endocarditis often has led to allegations of negligence and malpractice suits. . . . [It

is hard] to prove that the failure of a physician

or dentist to administer antibiotics was the

direct cause of a patient acquiring endocarditis.

If a strict demonstration of proximate cause

were always required, it is doubtful that any

claim based on the failure to administer prophylaxis could succeed, but juries are sometimes

capricious in deciding liability in malpractice

cases. . . (Mandell et al., 1990).

The “capricious” nature of the juries might

bias physicians in favor of prescribing antibiotics, even when the risk of endocarditis (or other

disease) is very minimal.

CONTROLLING THE EMERGENCE AND 

SPREAD OF ANTIBIOTIC RESISTANCE IN 

HOSPITALS

Part of the difficulty in controlling antibiotic

resistance in hospitals is incomplete understanding of all the factors that contribute to the emergence and spread of antibiotic resistance in

general. Most hospital personnel would agree

that infection control is critical, but there are

many disagreements about the benefits vs. cost

of various infection control procedures. Few, if

any, scientists disagree that the use of antibiotics

is related to the emergence and spread of antibiotic resistance. Nevertheless, there are many

controversies about how to implement programs

to control the use of antibiotics.

❚ Infection Control in Hospitals

In 1847, Ignac Semmelweis noticed that the rate

of childbed fever in new mothers was much

higher when the babies were delivered by obstetricians and medical students than by midwives

and midwifery students. Semmelweis surmised

that the high rate was due to the transmission of

infectious particles from cadavers by the obstetricians and medical students and instituted the

measure of handwashing in a chlorine solution.

This measure greatly decreased the incidence of

childbed fever (reviewed by Sanford, 1992).
Chapter 4 Antibiotic Use in Hospitals | 77

In hospitals today, infection control procedures are considered absolutely essential. In

1976, CDC conducted a comprehensive Study on

the Efficacy of Nosocomial Infection Control

(SENIC) that measured the extent and effectiveness of infection control procedures in U.S. hospitals. The SENIC study included a survey of all

hospitals in the United States and detailed interviews with representative hospitals. Twenty

years later, the study remains the most comprehensive survey of the effectiveness of infection

control procedures.3

 The study concluded that

hospitals with intensive infection surveillance

and control programs were able to reduce the rate

of nosocomial infections by 32 percent (Haley et

al., 1985). Yet the study found that only about

0.2 percent of U.S. hospitals had programs that

effectively controlled all four of the major types

of infections: surgical wound infection, urinary

tract infection, primary bloodstream infection,

and lower respiratory tract infection.

❚ Infection Control Activities

The SENIC study concluded that a successful

infection control program required leadership by

a trained infection control physician, an infection

control nurse for every 250 beds, organized

infection surveillance efforts, and a system for

reporting infection rates to practicing surgeons.

Handwashing and Other Precautions

Simple infection control procedures, such as

handwashing and wearing gloves, reduce the

spread of infections in hospitals, lowering the

need for antibiotics and thereby reducing selective pressure for the spread of antibiotic-resistant

bacteria. Health care workers have a large incentive to follow procedures such as universal precautions4

 because they were designed to protect

them from infection from organisms such as the

3 SENIC data have the serious shortcoming that they were collected before implementation of current infection control procedures such

as universal precautions, which were instituted beginning in 1985 largely because of the fear of transmission of the human immunodeficiency

virus (HIV). 4 Universal precautions include requirements that gloves be worn when handling bodily fluids, that needles and other sharp objects be

disposed of in special containers to help prevent needle-stick accidents, and that health care workers with open or infected wounds have

restricted contact with patients or patient care equipment (Garner, 1993).

human immunodeficiency virus (HIV). However, in the hospital setting health care workers

who respond to a life-threatening emergency

often do not have time to put on gloves and follow proper infection control procedures. Willy et

al. (1990) found that health care workers’ perception of their own risk and potential spread of

infections to patients is surprisingly low. In an

anonymous nationwide survey of health care

workers who might have frequent exposure to

blood and other bodily fluids, only 55 percent of

those responding reported routinely practicing

universal precautions.

Human nature seems to prevent the full implementation of one of the simplest, yet most effective infection control method: handwashing.

Handwashing is a proven method for reducing

nosocomial infections, but the practice is not

strictly followed. Handwashing compliance rates

of less than 50 percent were observed in two

studies of intensive care units (Simmons et al.,

1990; Doebbeling et al., 1992). Goldmann and

Larson (1992) make the following comments

about the lack of compliance with handwashing:

Experts in infection control coax, cajole,

threaten, and plead, but still their colleagues

neglect to wash their hands.... Education and

persuasion do not generally lead to sustained

improvement in handwashing. Physicians have

been particularly refractory. Innovative

approaches are needed desperately, but few

have emerged.... There is so little confidence in

hand-washing habits that hospital isolation policies now assume noncompliance.... [Original

references not included].

Simmons et al. (1990) revealed one clue to

handwashing noncompliance: nurses who were

questioned about their handwashing practices

believed they were washing their hands nearly
78 | Impacts of Antibiotic-Resistant Bacteria

90 percent of the time, when actual rates were

between 22 and 29 percent.

Research into the seemingly simple question

of which soap to use for washing hands may be

useful in helping to prevent infections. Several

studies have shown that a 7- to 10-second handwash with a non-antibacterial soap increased the

transmission of bacteria due to the shedding of

bacteria-laden skin cells, but that handwashing

with antiseptic soaps reduces the rates of nosocomial infections (Martin, 1994). Rotter (1988)

compared the efficacy of different antiseptics for

washing hands and found that antiseptics containing isopropanol alcohol were significantly

better at reducing skin bacteria than liquid soap.

Applying Infection Control Procedures to 

Control Antibiotic-Resistant Bacteria: 

Some Case Studies

Box 4-2 describes the successful countrywide

control of MRSA in Denmark. The following

case studies describe attempts to apply infection

control procedures to control MRSA in nursing

homes and hospitals in the United States.

Case 1: Successful control in a (mostly 

chronic care) VA medical center (MurrayLeisure et al., 1990)

The Lebanon, Pennsylvania, Medical Center is

an 884-bed facility which successfully controlled

an epidemic of MRSA patients during 1988–

1989 within six months of instituting aggressive

interventions. These interventions included confining known active MRSA carriers and MRSAinfected patients to one nursing unit, screening

patients transferred into the facility for MRSA,

using gown and glove isolation and treating both

colonized and actively infected patients with topical and enteral antibiotics.

Case 2: Unsuccessful control in a VA medical 

center (Strausbaugh et al., 1992)

The Portland, Oregon, VA Medical Center Nursing Home Care Unit (NHCU) is a 120-bed facility that attempted to control MRSA primarily

through administration of the antibiotics

rifampin, trimethoprim-sulfamethoxazole, and

clindamycin, used either alone or in different

combinations, to asymptomatic carriers of

MRSA. Other measures included restricting

MRSA-infected or colonized patients to a small

cluster of rooms, glove use to prevent the spread

of any body fluids, and frequent environmental

surface decontamination. The majority of MRSA

patients in this facility remained either colonized

or became recolonized during a 30-day followup period after treatment. Furthermore, a most

disturbing byproduct of the Portland VA study

was the emergence of resistance to rifampin after

therapy.

Case 3: Coordination of infection control 

practices between a hospital and nursing 

homes to manage MRSA (Jewell, 1994)

The Christ Hospital and Medical Center, Oak

Lawn, Illinois, is an 823-bed teaching hospital

that serves many patients who live in regional

nursing homes. Before 1991, nursing homes

often required three successive test results showing the patient was not carrying MRSA before

they would accept a patient from the hospital.

This led to extended stays in the hospital for

patients who were colonized with MRSA, but

otherwise did not need to be in the hospital. A

quality improvement team including clinicians,

hospital administrators, and nursing home representatives adopted guidelines that allowed colonized patients to be returned to the nursing

homes. When these new guidelines were

adopted, the hospital did not see any change in

the number of patients infected or colonized with

MRSA. It did see an average decrease of over

10 days in the length of stay in the hospital, a

reduction in the readmission rate of patients colonized with MRSA from 8.7 to 2.7 percent in

1992, and total cost savings of over $1.9 million.

These case studies illustrate the complexities

in determining which infection control practices

are the most likely to help control antibioticresistant bacteria such as MRSA. In the first

case, a combination of isolation of patients colonized or infected with MRSA and antibiotic therapy seemed to control MRSA, but in the second

case similar procedures failed to produce posi-
In Denmark the frequency of methicillin-resistant Staph aureus (MRSA) rose to 15 percent between

1967 and 1971, but decreased to 0.2 percent by 1984, and has remained at that low level (see figure).

Hans Jern Kolmos of the Hvidovre Hospital, University of Copenhagen, discussed the

dramatic decline in MRSA at a recent meeting

of the Association of Practitioners of Infection

Control and Epidemiology. Kolmos attributes

the decline to strict control of antibiotic use in

hospitals. He acknowledges one of the fundamental dilemmas in antibiotic prescribing: “In

a situation of doubt, where the clinician

stands face to face with an ill patient, fear of

overlooking an infection-or pressure from

the patient—will often outweigh the fear of

side effects in the doctor’s mind, and the

result will be prescription for safety’s sake, ”

Kolmos stresses the value of including clinical

microbiologists in the decision-making process: “In Denmark the clinical microbiologist

is a medical doctor, who has a clinical education in addition to his laboratory education.

Frequency of Methicillin-Resistant

Staphylococcus aureus (MRSA) in Denmark

I

I

1960 1965 1970 1975 1980 1985

SOURCE: V.T. Rosdahl, and AM. Knudson. 1991. The decline of

methicillin resistance among Danish Staphylococcus aureus strains.

Infection Control and Hospital Epidemiology 12(2):83-88.

This means that he takes part not only in laboratory work, but also in the treatment of patients, either bedside or at conferences with the clinical staff. Formally, he is only an advisor; it is the clinician who has the

power to decide. However, the influence of the clinical microbiologist is great, partly because he is wellknown from his frequent visits to the clinical units and partly because he has the same educational background as the clinicians. ”

The low rates of MRSA in Denmark may also be due to strict compliance with infection control procedures. Westh et al. (1992) note that “Isolation of a methicillin-resistant strain triggers an immediate visit to

the patient involved and the staff caring for that patient by a microbiologist and an infection control nurse.

Patients are isolated, and hygienic precautions are taken in an effort to prevent acquisition and carriage

of the resistant strain by staff members. ” They also comment that “Such precautions at institutions in

countries not yet overwhelmed by high rates of isolation of methicillin-resistant S. aureus might likewise

hinder the spread of these strains. ”

SOURCES: V.T. Rosdahl and A.M. Knudson, 1991. The decline of methicillin resistance among Danish Staphylococcus aureus

strains. Infection Control and Hospital Epidemiology 12(2):83-88; H. Westh, J.0. Jarlov, H. Kjersem, et al. 1992. The disappearance of multiresistant Staphylococcus aureus in Denmark: Changes in strains of the 83A complex between 1969 and 1989. Clinical Infectious Diseases 14(6) .1186-1194
80 | Impacts of Antibiotic-Resistant Bacteria

HOSPITAL ACCREDITATION AND 

INFECTION CONTROL REGULATIONS 

UNDER MEDICARE

Current hospital accreditation and Medicare regulations recognize that each hospital must analyze conditions in its own facility to determine

the best methods of infection control. 

Loeb and O’Leary of The Joint Commission

on Accreditation of Healthcare Organizations

(JCAHO) explain that

The Joint Commission historically has used

compliance with contemporary standards as its

basic measure of health care quality in the

accreditation process. In recent years, however,

there has been growing interest in monitoring

and evaluating the actual results of care. . .

JCAHO has recently developed a system for

performance measurement called the Indicator

Measurement System (IMSystem). Beginning in

1996, the system will include several measurements related to antibiotic use and infection control: timing of administration of prophylactic

antibiotics, surveillance and prevention of surgical site infection, surveillance and prevention of

ventilator-associated pneumonia, and surveillance and prevention of primary blood stream

infections. JCAHO has recognized “. . . the

already tremendous information burdens on most

organizations” and therefore has designed

“. . . the IMSystem to be parsimonious, that

is, to collect only those data elements that are

needed and to use all the elements that are collected. Whenever possible, the IMSystem uses

data elements likely to be already collected by

health care organizations” (IMSystem General

Information, JCAHO).

Participation in this system, which is voluntary, has great potential to help hospitals identify

specific problems in infection control.

Medicare regulations state that as a condition

of participation in Medicare, hospitals must have

a quality assurance program in which “nosocomial infections and medication therapy must be

evaluated” (42 CFR 482.21a2). Further, “there

must be an active program for the prevention,

control, and investigation of infectious and communicable diseases” (42 CFR 482.42). This program includes the designation of an infection

control officer who “must develop a system for

identifying, reporting, investigating, and controlling infections and communicable diseases of

patients and personnel” (42 CFR 482.42a1) and

“must maintain a log of incidents related to

infections and communicable diseases” (42 CFR

482.42a2).

In the past, regulations for accreditation and

Medicare participation were more specifically

worded, and specifically acknowledged the problems of antibiotic resistance: for example, hospitals had to have “measures which control the

indiscriminate use of preventive antibiotics in the

absence of infection, and the use of antibiotics in

the presence of infection is based on necessary

cultures and sensitivity tests” (42 CFR

405.1022c6 as of Oct. 1, 1983). However, based

on past experiences such as those described in

this chapter, specific regulations such as these

may not be applicable to every facility.

❚ Surveillance of AntibioticResistant Bacteria

There is no national system for reporting the

presence and pattern of antibiotic-resistant bacteria, leaving physicians and scientists in the dark

about the prevalence of those organisms in different geographical areas. Although many inhospital, small-scale surveillance systems,

designed to track the spread of disease-causing

organisms, including antibiotic-resistant bacteria, provide information to physicians about

which antibiotics remain effective, there is no

standard format for the collection and dissemination of data. Antibiotic prescriptions and microbiology test results are often recorded on

separate slips of paper, making correlation of the

two sets of data almost impossible. However, the

increasing use of computer technology and the

Internet provides increased opportunities for

standardized record keeping in hospitals and

easy database collection and access.

At the state level, the New Jersey State

Department of Health started collecting data

about antibiotic-resistant bacteria in 1991. The
Chapter 4 Antibiotic Use in Hospitals | 81

system includes the 95 acute-care hospitals

licensed by the State of New Jersey and uses data

that are already routinely collected in hospital

laboratories. All hospitals make monthly reports

to the State Department of Health, which, in turn,

disseminates its compilation of information to

anyone on request. This system’s tracking of

vancomycin-resistant Enterococcus (VRE)

spurred collaborative efforts involving private

and public sector and academic organizations to

evaluate risk factors for the disease, treatment

options, effectiveness of infection-control procedures, and the in-vitro susceptibility of VRE to

antimicrobial agents during the planning of clinical trials (MMWR, 1995). The system is inexpensive to operate and simple to maintain.

SCOPE, Surveillance and Control of Pathogens of Epidemiological Importance, is a

national effort established by the University of

Iowa and Lederle Laboratories (now WyethAyerst Lederle Laboratories) in 1995. The program expects to collect reports of all nosocomial

bloodstream infections in 48 hospitals nationwide as well as samples of the organisms isolated

from the infected patients. The reports will provide information about the spread of antibioticresistant bacteria in the participating hospitals.

The bacterial samples will be banked at the University of Iowa, and the accuracy of bacterial

identification and antibiotic resistance determinations will be verified for representative samples. For a fee, the University will test new

antibiotics from any company against bacteria in

its collection. The first hospital entered the program on April 1, 1995, and 40 had entered by

June 30.

There are also other industry-funded surveillance systems. A number of academic and commercial laboratories conduct surveillance under

contract to pharmaceutical companies, but they

are not necessarily designed to obtain information most useful for public health purposes.

Instead, and understandably, they collect information about the efficacy of producers’ products.

The National Nosocomial Infection Survey

(NNIS), which is run by CDC, is the single

nationwide surveillance system that produces

information about antibiotic-resistant bacteria.

While it is limited to reports on nosocomial

infections, it is the source for most of the data in

this OTA report about MRSA, VRE, and other

drug-resistant bacterial infections.

CDC is in the early stages of establishing

nationwide surveillance of drug-resistant Streptococcus pneumoniae (DRSP), which will cover

infections whether or not they occur in a hospital.

The system requires that participating laboratories test all S. pneumoniae isolated from blood

and cerebrospinal fluid for antibiotic susceptibility by using standard testing methods, and that

all test results be reported to the state health

departments. The CDC initiated this system in 20

laboratories in New Jersey in April 1995, and if

funds are available, the organization expects that

most of the nearly 2,000 hospital and commercial

laboratories that now have computerized record

keeping will be in the system by 1998. As laboratories add computer capabilities, CDC will

encourage them to enlist in the system, and it

expects that all of the nearly 5,000 laboratories in

the country will participate. If the DRSP system

works, CDC envisions expanding it to include

other antibiotic-resistant bacteria. As an early

step in setting up the DRSP system, and at

CDC’s request, the Council of State and Territorial Epidemiologists has recommended DRSP for

inclusion on the list of notifiable diseases, and

four states now report it.

WHONET, a surveillance project of the

World Health Organization, was established and

operated by two scientists, and it functions on a

shoestring budget. The system collects information about resistance patterns in bacteria from

about 100 hospitals all over the world, makes the

data available to researchers, and provides much

of the available information about the international flow of antibiotic-resistant bacteria.

One of WHONET’s great strengths is that it

has demonstrated that laboratories around the

world can produce data that can be interpreted

and incorporated into a system that provides

results that are comparable from country to country. To do this, the network collects laboratory

data, not interpretations of the data. While rules

for interpreting susceptibility test results differ
82 | Impacts of Antibiotic-Resistant Bacteria

among various countries, WHONET can make

international comparisons based on the raw data.

Participating institutions also gain from

WHONET. The network provides laboratories

with a computer program, which can be taught in

about six hours, and, where necessary, a computer. The software of WHONET, set up to identify unusual patterns of resistance, allows the

infection control practitioner at the hospital to

trace the spread of individual strains of bacteria

and use that information to modify infection control procedures.

WHONET is inexpensive, it requires little

supervision, and it obtains raw data, the data of

most value to researchers (see chapter 6). It has

been successful in obtaining information from

developing countries as well as developed ones,

and it provides an example of the feasibility of

collecting and reporting antibiotic-resistance

information for little money.

❚ Controlling the Use of Antibiotics

Much evidence links the use of antibiotics to the

emergence and spread of antibiotic resistance.

Table 4-3 summarizes some studies which demonstrate relationships between increased use of

antibiotics and prevalence of resistance in hospital organisms. There are also many examples

where the prevalence of resistance in hospital

organisms decreased when the use of antibiotics

was decreased (table 4-4). McGowan (1994)

recently asked the question: “Do intensive hospital antibiotic control programs prevent the spread

of antibiotic resistance?” and concluded that

TABLE 4-3: Some Studies Demonstrating a Temporal Relationship Between Increased Usage of 

Antimicrobial Agents and Increased Prevalence of Resistant Hospital Organisms

Year Reference Setting for use of antimicrobials Organism(s) Antimicrobial(s) used

1953 1 General use Staphylococcus aureus Erythromycin

S. aureus Penicillin

S. aureus Chlortetracycline

1956 2 Burn ward S. aureus Chloramphenicol

S. aureus Chlortetracycline

1967 3 Surgical prophylaxis S. aureus Neomycin cream

1971 4 Burn ward Pseudomonas aeruginosa Gentamicin

1978 5 Surgical prophylaxis P. aeruginosa Gentamicin

Serratia Gentamicin

1979 6 Postoperative use Serratia Gentamicin

1. M.H. Lepper, B. Moulton, H.F. Dowling, et al. 1953. Epidemiology of erythromycin-resistant staphylococci in a hospital population—effect on

the therapeutic activity of erythromycin. In: H. Welch and F. Martí-Ibáñez (eds.) Antibiotics annual 1953–1954. New York, NY. Medical Encyclopedia, pp. 308–313.

2. C.D. Gibson, Jr., and W.C. Thompson, Jr. 1956. The response of burning wound staphylococci to alternating programs of antibiotic therapy. In:

H. Welch and F. Martí-Ibáñez (eds.) Antibiotics annual 1955–1956. New York, NY. Medical Encyclopedia, pp. 32–34.

3. P.M. Rountree, M.A. Beard, J. Loewenthal, et al. 1967. Staphylococcal sepsis in a new surgical ward. British Medical Journal 1:132–137.

4. J.A. Shulman, P.M. Terry, and C.E. Hough. 1971. Colonization with gentamicin-resistant Pseudomonas aeruginosa, pyocine type 5, in a burn

unit. Journal of Infectious Disease 124(suppl):S18–23.

5. N.J. Roberts, Jr., and R.G. Douglas, Jr. 1978. Gentamicin use and Pseudomonas and Serratia resistance: effect of a surgical prophylaxis regimen. Antimicrobial Agents and Chemotherapy 13:214–220.

6. V.L. Yu, C.A. Oakes, K.J. Axnick, et al. 1979. Patient factors contributing to the emergence of gentamicin-resistant Serratia marcescens. American Journal of Medicine 66:468–472.

SOURCE: J.E. McGowan, Jr. 1983. Antimicrobial resistance in hospital organisms and its relation to antibiotic use. Reviews of Infectious Diseases 5(6):1033–1048.
Chapter 4 Antibiotic Use in Hospitals | 83

TABLE 4-4: Some Studies Demonstrating a Temporal Relationship Between Decreased Usage of 

Antimicrobial Agents and Decreased Prevalence of Resistant Organisms

Year Reference Setting for use of antimicrobials Organism(s) Antimicrobial(s) used

1953 1 General use Staphylococcus aureus Chloramphenicol

1954 2 General use S. aureus Erythromycin

1956 3 Burn ward S. aureus Chlortetracycline

S. aureus Chloramphenicol

1960 4 General use S. aureus Penicillin

1960 S. aureus Tetracycline

1966 5 Pediatric ward S. aureus Erythromycin

1967 6 Surgical prophylaxis S. aureus Neomycin cream

1970 7 General use Escherichia coli Streptomycin

Klebsiella, Enterobacter Streptomycin

1970 8 Neurosurgical unit Klebsiella “All”

1970 9 General use S. aureus Erythromycin

S. aureus Novobiocin

1971 10 Burn ward Pseudomonas aeruginosa Gentamicin

1972 11 Burn ward “Enterobacteriaceae” Carbenicillin

Pseudomonas aeruginosa Carbenicillin

1973 12 Nursery “Enterobacteria” Carbenicillin

1974 13 Urology ward “Gram-negative bacilli” 5 agents

1975 14 Nursery E. coli Kanamycin

1978 15 Surgical prophylaxis Pseudomonas aeruginosa Gentamicin

16 Serratia Gentamicin

1. W.M.M. Kirby, and J.J. Ahern. 1953. Changing pattern of resistance of staphylococci to antibiotics. Antibiotics and Chemotherapy 3:831–835.

2. M.H. Lepper, B. Moulton, H.F. Dowling, et al. 1953. Epidemiology of erythromycin-resistant staphylococci in a hospital population—effect on

the therapeutic activity of erythromycin. In: H. Welch and F. Martí-Ibáñez (eds.) Antibiotics annual 1953–1954. New York, NY. Medical Encyclopedia, pp. 308–313.

3. C.D. Gibson, Jr., and W.C. Thompson, Jr. 1956. The response of burning wound staphylococci to alternating programs of antibiotic therapy. In:

H. Welch and F. Martí-Ibáñez (eds.) Antibiotics annual 1955–1956 New York, NY. Medical Encyclopedia, pp. 32–34.

4. M. Barber, A.A.C. Dutton, M.A. Beard, et al. 1960. Reversal of antibiotic resistance in hospital staphylococcal infection. British Medical Journal

1:11–17.

5. A.W. Bauer, D.M. Perry, and W.M.M. Kirby. 1960. Drug usage and antibiotic susceptibility of staphylococci. Journal of the American Medical

Association 173:475–480.

6. J.O. Forfar, A.J. Keay, A.F. Maccabe, et al. 1966. Liberal use of antibiotics and its effect in neonatal staphylococcal infection, with particular

reference to erythromycin. Lancet 2:295–300.

7. P.M. Rountree, M.A. Beard, J. Loewenthal, et al. 1967. Staphylococcal sepsis in a new surgical ward. British Medical Journal 1:132–137.

8. R.J. Bulger, E. Larson, and J.C. Sherris. 1970. Decreased incidence of resistance to antimicrobial agents among Escherichia coli and Klebsiella-Enterobacter: observations in a university hospital over a 10-year period. Annals of Internal Medicine 72:65–71.

9. D.J.E. Price, and J.D. Sleigh. 1970. Control of infection due to Klebsiella aerogenes in a neurosurgical unit by withdrawal of all antibiotics. Lancet 2:1213–1215.

10. M. Ridley, D. Barrie, R. Lynn, et al. 1970. Antibiotic-resistant Staphylococcus aureus and hospital antibiotic policies. Lancet 1:230–233.

11. J.A. Shulman, P.M. Terry, and C.E. Hough. 1971. Colonization with gentamicin-resistant Pseudomonas aeruginosa, pyocine type 5, in a burn

unit. Journal of Infectious Disease 124(suppl):S18–23.

12. E.J.L. Lowbury, J.R. Babb, and E. Roe. 1972. Clearance from a hospital of gram-negative bacilli that transfer carbenicillin-resistance to

Pseudomonas aeruginosa. Lancet 2:941–945.

13. J.A. Franco, D.V. Eitzman, and H. Baer. 1973. Antibiotic usage and microbial resistance in an intensive care nursery. American Journal of Diseases of Children 126:318–321.

14. H. Søgaard, C. Zimmermann-Nielsen, and K. Siboni. 1974. Antibiotic-resistant gram-negative bacilli in a urological ward for male patients during a nine-year period: relationship to antibiotic consumption. Journal of Infectious Disease 130:646–650.

15. J.B. Howard, and G.H. McCracken, Jr. 1975. Reappraisal of kanamycin usage in neonates. Journal of Pediatrics 86:949–956.

16. D.L. Palmer. Epidemiology of antibiotic resistance. 1980. Journal of Medicine 11:255–262.

SOURCE: J.E. McGowan, Jr. 1983. Antimicrobial resistance in hospital organisms and its relation to antibiotic use. Reviews of Infectious Diseases 5(6):1033–1048.
84 | Impacts of Antibiotic-Resistant Bacteria

. . . in a few institutions there has been an

increase in susceptibility to antimicrobials following intensive control or monitoring . . . in a

few hospitals, intensive antibiotic control for

selected drug-organisms pairs was associated

with a high prevalence of susceptibility, and the

proportion susceptible fell abruptly when control or monitoring was relaxed or removed.

This latter finding indicates that the decrease

in resistance may not be stable: reintroduction of

the antibiotic can cause the resistance to immediately return.

There are also counterexamples where antibiotic control programs do not increase susceptibility. In one example, resistance patterns in

Enterobacter cloacae but not Pseudomonas

aeruginosa were related to ceftazidime use in 18

different hospitals in different geographical locations (Ballow and Schentag, 1992). Silber et al.

found that “facilities with restriction programs

were as likely as those without to have had a case

of VRE bacteremia.” In Denmark the use of

methicillin increased substantially in the 1970s

while the prevalence of MRSA decreased substantially. The decrease in MRSA was correlated

with a decrease in the use of tetracycline and

streptomycin (Rosendal et al., 1977). This might

be explained by the use of tetracycline and streptomycin selecting for bacteria with multi-resistant plasmids (see chapter 2) also containing

genes for resistance to methicillin. Taken

together, these examples indicate that it is not

simple to determine the specific relationship

between antibiotic use and antibiotic resistance.

CDC recently began a systematic study of the

relationship between antibiotic use and antibiotic

resistance. In the initial phase of the I-CARE

(Intensive Care Antimicrobial Resistance Epidemiology) project, eight pilot hospitals monitored

the use of antibiotics and the numbers of antibiotic-resistant bacteria. The results for MRSA

(shown in figure 4-4) indicate that some hospitals use large amounts of methicillin and have

high frequencies of resistant organisms

(hospital B), while others use very little methicillin, but still have high frequencies of resistant

organisms (hospital E).

One possible explanation for this is suggested

by the Klebsiella results in figure 4-5: hospital E

may be receiving many patients from another

hospital (or nursing home) that uses a lot of

methicillin. Hospital H is interesting in that it has

one of the lowest rates of MRSA and the highest

use of methicillin of any of the eight pilot hospitals. This result might be related to a recent result

from a French 15-year study (Loulergue et al.,

1994) that showed the prevalence of MRSA was

unrelated to cloxacillin (a semisynthetic penicillin derivative closely related to methicillin) use

on some wards of a hospital where none of the

staff was a carrier of MRSA. This study indicated that carriage of MRSA by hospital staff is

one risk factor for patients becoming infected

with MRSA. The data from I-CARE correlate the

emergence and spread of antibiotic resistance

with different causes in different hospitals.

Moreover, the pilot study demonstrates how useful a system such as I-CARE can be in comparing an individual hospital to national trends and

using that comparison to design antibiotic use

and infection control procedures specifically tailored to the problems in the individual hospital.Antibiotics are widely used by physicians in

community practice as well as by physicians in

the hospitals. In one study (table 4-5), about half

of the cardiac surgery patients colonized with

cefazolin-resistant strains of bacteria were colonized upon admission to the hospital.5 Therefore, some antibiotic-resistant strains arise in the

community, indicating that antibiotic use must be

5 Cefazolin is commonly administered to cardiac patients as prophylaxis to prevent infections during the surgery. The risk of developing

a Staph. aureus infection after cardiac surgery has been estimated as 15-44 percent (Mandell, Bennet, Dolin, page 2747). Colonization of the

patient or attending staff with cefazolin-resistant strains would be a significant risk factor for surgical infections when cefazolin is used for

prophylaxis.
Chapter 4 Antibiotic Use in Hospitals | 85

controlled by community physicians as well as

by hospital physicians in order for hospital-based

programs to be fully effective. (For more information about antibiotic-resistant bacteria and

antibiotic use in the community, see chapter 3.

❚ Improving Antibiotic Use

Antibiograms 

To guide physicians in the use of antibiotics,

many hospitals provide “antibiograms” that

describe the susceptibility of commonly encountered bacteria to various antibiotics. As shown in

table 4-6, the vast majority of causes of bacterial

infections in both inpatients and outpatients

remain sensitive to the modern antibiotics. On

the other hand, many Staph. aureus, coagulasenegative Staphylococci, and S. pneumoniae are

resistant to many commonly used antibiotics, and

some Enterococcus are resistant to all antibiotics.

Formularies

The use of all drugs in hospitals is increasingly controlled by hospital formularies, which

were set up to control the costs of drugs. The formularies may have the added benefit of helping

to control the use of antibiotics and the antibiotic

resistance problem. In Denver, Colorado, area

hospitals (North, 1993), a formulary is combined

with a computerized antibiotic order form. This

system restricts some antibiotics to approved

indications, and use of others requires approval

by specialists in infectious disease. This system

has saved the hospitals money, and allowed them

to easily change the formulary when susceptibility testing indicated a problem of increased resistance to a specific antibiotic ) .

Physician Education

Physician education is crucial to avoid mistakes

made by inadequate knowledge of antibiotic

FIGURE 4-4a: Percent of Staphylococcus Aureus Resistant to Methicillin

SOURCE: National Nosocomial Infections Surveillance System, Centers for Disease Control, Atlanta, GA.

FIGURE 4-4b: Grams of Methicillin Used per 1,000 Patient Days

SOURCE: National Nosocomial Infections Surveillance System, Centers for Disease Control, Atlanta, GA.

FIGURE 4-4c: Percent of Staphylococcus aureus Resistant to Methicillin/Methicillin Use

SOURCE: National Nosocomial Infections Surveillance System, Centers for Disease Control, Atlanta, GA.
I

0 10 20 30 40 50

5 ,

I

0 20 40 60 80 100

5,

I

0 20 40 60 80 100

SOURCE: National Nosocomial Infections Surveillance System, Centers for Disease Control, Atlanta, GA.

I
I

1

40+

30

20

10

86 87 88 89 90 91 92 93

SOURCE: National Nosocomial Infections Surveillance System,

Centers for Disease Control, Atlanta, GA.

1

I / I

I

SOURCE: National Nosocomial Infections Surveillance System,

Centers for Disease Control, Atlanta, GA.

controlled by community physicians as well as

by hospital physicians in order for hospital-based

programs to be fully effective. (For more information about antibiotic-resistant bacteria and

antibiotic use in the community, see chapter 3.

86 87 88 89 90 91 92 93

SOURCE: National Nosocomial Infections Surveillance System,

Centers for Disease Control, Atlanta, GA.

❚ Improving Antibiotic Use

Antibiograms

To guide physicians in the use of antibiotics,

many hospitals provide “antibiograms” that

describe the susceptibility of commonly encountered bacteria to various antibiotics. As shown in

table 4-6, the vast majority of causes of bacterial

infections in both inpatients and outpatients

remain sensitive to the modern antibiotics. On

the other hand, many Staph. aureus, coagulasenegative Staphylococci, and S. pneurnoniae are

resistant to many commonly used antibiotics, and

some Enterococcus are resistant to all antibiotics.

Formularies

The use of all drugs in hospitals is increasingly controlled by hospital formularies, which

were set up to control the costs of drugs. The formularies may have the added benefit of helping

to control the use of antibiotics and the antibiotic

resistance problem. In Denver, Colorado, area

hospitals (North, 1993), a formulary is combined

with a computerized antibiotic order form. This

system restricts some antibiotics to approved

indications, and use of others requires approval
Chapter 4 Antibiotic Use in Hospitals | 87

tion about susceptibilities of different organisms.

Physicians must learn to check other reliable upto-date sources of information about antibiotics

such as The Medical Letter On Drugs and Therapeutics (New Rochelle, NY: The Medical Letter,

Inc.) and to consult with infectious disease

experts who are aware of susceptibility patterns

in the specific hospitals.

Computerized Systems for 

Antibiotic Monitoring

The LDS Hospital in Salt Lake City, Utah, has

developed a computerized antibiotic monitoring

system, which is part of a larger computerized

patient record system that automatically collects

surveillance data and generates antibiograms

(see table 4-6) (Evans and Pestotnik, 1994).

When the microbiology laboratory results are

entered into the computer, the computer checks

the susceptibilities of the organisms against the

antibiotic prescribed for the patient and generates

an alert when an antibiotic is inappropriate. In

one year, the system generated an alert for

32 percent of the patients. However, many physicians did not change the antibiotic based on the

alert, often because the patient was clinically

improving even though the susceptibility results

indicated that the antibiotic was inappropriate.6

The system also notifies physicians of the optimum time for administration of prophylactic

antibiotics. Use of the system saved $42 per

patient in the first year of use, with a projected

reduction in the costs of prophylactic antibiotics

of over $89,000 per year in a single hospital

(Evans et al., 1990).

Another part of the antibiotic monitoring system at the LDS hospital is a computerized antibiotic consultant (Evans et al., 1994). This system

uses surveillance data together with information

about the site of the infection and patient allergies to determine the best choice of empiric antibiotic therapy. The computer consultant was

better at choosing antibiotics than the physicians

in the hospital. The computer chose antibiotics to

which the infecting bacteria were susceptible

94 percent of the time; the physicians chose correctly 77 percent of the time.

Setting up a comprehensive patient data system requires significant financial investment by

hospitals. However, the hospitals will realize

cost savings just from improvement in the use of

antibiotics. Forty to fifty percent of hospital

6 Many patients recover from bacterial illnesses on their own without the help of an antibiotic.

TABLE 4-5: Characteristics of Cardiac Surgery Patients Colonized

with Cefazolin-Resistant Gram-Negative Bacilli

Location at first positive culture (% patients)

Species

Number of 

patients colonized

(n = 87) At admission

48–72 hr into 

CSICU

> 72 hr into 

CSICU

Percent of 

colonization due

to horizontal 

transmission

Percent 

developing 

clinical

infection

Enterobacter

species

58 50 34 16 16 21

Citrobacter

species

37 49 22 29 ? 3

Pseudomonas 

aeruginosa

33 55 12 33 9 27

Serratia 

marcesens

7 43 57 0 29 29

KEY: CSICU = cardiac surgery intensive care unit; ? = unknown (no typing system used).

SOURCE: Adapted from D.M. Flynn, R.A. Weinstein, and S.A. Kabins. 1988. Infections with gram-negative bacilli in a cardiac surgery intensive

care unit: The relative role of Enterobacter. Journal of Hospital Infections 11:367.
88

| Impacts of Antibiotic-Resistant Bacteria

TABLE 4-6: Antibiotic Susceptibility of Common Organisms (Numbers Indicate Percent Susceptible) January–December 1994 (Page 1 of 2)

IN PATIENTS

Staph. 

aureus

(1080)

Coagulaseneg. Staph. 

(647)

Strep. 

pneumoniae 

(75)

Enterococcus 

spp.

(612)

E.

coli

(808)

K. 

species 

(396)

C. 

diversus 

(35)

C.

freundii 

(42)

Enterobacter

species

(309)

Serratia 

species 

(55)

Proteus 

mirabilis 

(100)

P. 

aeruginosa 

(520)

A. 

anitratus 

(60)

X. 

maltophilia

 (42)

H. 

influenzae 

(128)

B. 

fragilis 

group 

(30)

Penicillin 5 6 86 3Ampicillin 88 54 0 0 0 0 0 91 75Ampicillinsulbactam *** *** 58 59 91 50 15 13 97 54 0 93Oxacillin 70 26Ticar-clavulante* *** *** 77 75 96 62 61 88 100 67 58 52 100Cephalothin** *** *** 73 71 97 3 1 0 94Cefazolin *** *** 88 78 97 7 3 0 97Cefotetan *** *** 99 88 97 68 55 92 99 70Cefuroxime *** *** 99Cefotaxime *** *** 93 99 95 97 77 66 94 99 100 76Ceftazidime 84 69 23Imipenem *** *** 100 100 96 0Chloramphenicol 99Erythromycin 91Trimeth-sulfa 83 39 77 80 77 100 58 88 93 95 70 90 88Ciprofloxacin 70 54 21 99 98 100 100 96 99 100 82 61 14Nitrofurantoin 87 96 61 45 15Gentamicin 97 91 95 93 100 98 84 66 50Amikacin**** 100 98 99 84 91 35Clindamycin 72 48 92Metronidazole 100Vancomycin 100 100 99* Piperacillin-tazobactam was added to the formulary late in the year. Its activity is equivalent to or somewhat superior to ticarcillin-clavulanate.** Tested for the oral cephalosporins, cephalexin and cephradine.*** Oxacillin-resistant staphylococci are also resistant to beta-lactamase inhibitor combinations, cephalosporins, and imipenem; oxacillin-susceptible staphylococci are susceptible to those agents.  Amikacin reported only on Gentamicin resistant isolates.
Chapter 4 Antibiotic Use in Hospitals

| 89

TABLE 4-6: Antibiotic Susceptibility of Common Organisms (Numbers Indicate Percent Susceptible) January–December 1994 (Page 2 of 2)

OUT PATIENTS

Staph. 

aureus

(966)

Coagulaseneg. Staph. 

(320)

Strep. 

pneumoniae

 (103)

Enterococcus 

spp.

(632)

Escherichia

 coli

(2558)

K. 

species 

(405)

C. 

diversus 

(76)

C. 

freundii 

(48)

E. 

species 

(136)

Serratia 

species 

(46)

Proteus 

mirabilis 

(244)

P. 

aeruginosa

 (234)

Salmonella 

species

(25)

Shigella 

species

(51)

H. 

influenzae 

(121)

Penicillin 4 13 83Ampicillin 94 53 2 0 6 2 0 89 92 33 72Ampicillinsulbactam ** * *** 72 75 95 81 37 12 97Oxacillin 89 52Ticar-clavulante* *** *** 90 90 100 90 92 93 100 85Cephalothin** *** *** 65 86 96 3 3 0 94Cefazolin *** *** 90 91 97 13 4 0 93Cefotetan *** *** 99 97 100 91 83 90 100Cefuroxime *** *** 100Cefotaxime *** *** 92 99 98 100 94 92 94 100 100 100Ceftazidime 95Chloramphenicol 92 87 100Erythromycin 84Trimeth-sulfa 92 54 80 81 83 100 61 94 88 93 100 70 94Ciprofloxacin 88 72 24 99 97 97 92 97 96 99 87 100 100Nitrofurantoin 91 99 62 91 90 51 0 0Gentamicin 99 96 100 97 98 95 95 93Amikacin**** 93 100 93Clindamycin 91 76Vancomycin 100 100 100

* Piperacillin-tazobactam was added to the formulary late in the year. Its activity is equivalent to or somewhat superior to ticarcillin-clavulanate.** Tested for the oral cephalosporins, cephalexin and cephradine.*** Oxacillin-resistant staphylococci are also resistant to beta-lactamase inhibitor combinations, cephalosporins, and imipenem; oxacillin-susceptible staphylococci are susceptible to those agents.**** Amikacin reported only on Gentamicin resistant isolates.KEY: Staph. = Staphylococci P. aeruginosa = Pseudomonas aeruginosa

Strep. = Strephcoccus A. anitratus = Acinetobacter anitratusK. species = Klebsiella species X. = Xanthomonas maltophiliaC. diversus = Citrobacter diversus H. influenzae = Haemophilus influenzaeC. freundii = Citrobacter freundii B. tragillis group = Bacteroides tragillis groupE. species = Enterobacter species

SOURCE: University Health System, San Antonio, TX, 1994. With permission of J.H. Jorgensen.
90 | Impacts of Antibiotic-Resistant Bacteria

BOX 4-3: “Food-Borne” Outbreak of Expensive Antibiotic Use

in Community Teaching Hospital

To the Editor—Drug utilization review assures cost-effective use of medications in hospitals. We

present an example of drug utilization review that began with the identification of an “index case” of a

costly therapeutic decision. Subsequent investigation lead to the identification of a prescribing outbreak

as well as its probable source.

Report of a Case—A 32-year-old man had been on a camping trip and noted an insect bite at the top

margin of his sock. The next day he noted redness and swelling at the site of the bite. The third day he

was febrile and the redness began to spread. On the fourth day, red streaks extended 15 cm above the

site of injury. He felt ill and came to the emergency department. His examination demonstrated a temperature of 39.4°C, sickly appearance, and a tender cellulitis of his lower leg. Blood pressure was normal

and he did not have a truncal rash. Therapy with a new, expensive, broad-spectrum antibiotic was initiated. When asked about his antibiotic choice, the admitting intern noted at morning report that he had

planned on giving penicillin or nafcillin, but had been overruled by the supervising resident who insisted

on a “more modern choice for a severely ill patient.”

Comment—Following discussion of this case, we evaluated the use of the new antibiotic in our hospital. We found that use had transiently increased following its addition to our formulary in February 1994,

then abruptly increased in June and July. After conducting interviews with our house officers, it was

revealed that an extravagant dinner party had been held for incoming and current house staff the third

week of June. The sponsor of this dinner was the manufacturer of the antibiotic. The increase in use of

this agent bore a striking temporal association with this dinner. Furthermore, the prescribing resident had

attended the dinner and directed the admitting intern to use the drug instead of nafcillin.

The prescribed antibiotic exhibits a broad spectrum of activity, including β-lactamase-producing

strains of staphylococci, Haemophilus influenzae, anaerobes, and facultative gram-negative rods. The

agent would be expected to be effective in most settings where nafcillin might be used. Although this

agent is not contraindicated in treating uncomplicated cellulitis, it is much more expensive ($183.20 per

day) than other effective drugs such as nafcillin ($84 per day). In this single case, the daily excess cost of

therapy would approximate $100. The relationship between pharmaceutical marketing maneuvers and

prescribing is controversial. Previous ecological studies have found an association between educational

“enticements” and hospital formulary additions and prescribing trends. However, we are not aware of a

detailed case description where a more expensive therapeutic choice was made when less expensive

therapeutic alternatives were indicated. We do not know if the resident’s attendance at the dinner caused

his therapeutic choice. However, the striking epidemiological association between resident attendance at

this drug company-sponsored event and the subsequent changes in hospital-wide prescribing practices

should prompt training programs to be wary of such outside sources of medical education.

SOURCE: Quoted from R.I. Shore and W.L. Greene, letter to the editor, Journal of the American Medical Association

273(24):1908. Copyright 1995, American Medical Association.
Chapter 4 Antibiotic Use in Hospitals | 91

FIGURE 4-6: An Antibiotic Advertisement from a Medical Journal

SOURCE: A major pharmaceutical company.
92 | Impacts of Antibiotic-Resistant Bacteria

pharmacy budgets are for antibiotics, and onefourth of that in some hospitals is for vancomycin alone (Modern Healthcare, 1994). Eliminating unnecessary use of antibiotics will decrease

total pharmacy expenditures. Treating infections

with appropriate antibiotics and administering

prophylactic antibiotics with appropriate timing

will also increase the quality of patient care and

decrease the number of days spent in the hospital. (OTA’s report Bringing Health Care Online:

The Role of Information Technologies, September 1995, discusses costs and benefits of computerized patient record systems.)

Practice Guidelines

Practice guidelines, or practice protocols, are

medical guidelines that “encompass a broad

range of strategies designed to assist practitioners in the clinical decision-making process”

(Shanz, 1993). More specifically, they are “standardized specifications for care developed by a

formal process that incorporates the best scientific evidence of effectiveness with expert opinion” (Leape, 1990). These guidelines are set by

experts from specific areas of the medical profession to advise about recommended standards of

care. For example, the goal of practice guidelines

established by the Agency for Health Care Policy

and Research, a federal agency empowered to

establish practice guidelines, is to encourage

physicians and other health care providers to

change their practice behavior, thus improving

patient care, patient outcomes, and quality of life

(AHCPR, 1994).

Practice guidelines on infection control or the

prudent use of antibiotics might be helpful in

controlling antibiotic resistance. For example,

practice guidelines might specify that older antibiotics such as amoxicillin be tried for community-acquired infections before newer, broader

spectrum antibiotics are used. Under managed

care, insurers may adopt guidelines such as these

because they will save money as older antibiotics

are generally much less expensive than newer

antibiotics.

Practice guidelines may also be of use in medical malpractice litigation. A major difficulty in

medical malpractice cases is establishing the

appropriate standard of care before “layperson”

decision-makers on juries. Practice guidelines

have the potential to reduce such difficulties. By

establishing an unbiased standard of care, practice guidelines should “significantly reduce the

most vexing problem in malpractice litigation:

the battle of the experts” (West, 1994). In theory,

a physician could rely on the practice guideline

as the appropriate standard of care without having to worry whether a judge or jury, in a medical malpractice case, would consider the care

administered appropriate. The only remaining

issues to be determined in medical negligence litigation would be whether the practice guideline

“is relevant to the case at hand, and whether it is

appropriate to use the [guideline] to establish the

standard of care” (West, 1994).

On the other hand, practice guidelines which

suggest any benefit from the use of antibiotics

may be used as evidence against the physician in

the case of a bad outcome. For example, a guideline on the treatment of otitis media with effusion

published by the Agency for Health Care Policy

and Research concludes:

Meta-analysis for Guideline development

showed a 14 percent increase in the probability

that otitis media with effusion would resolve

when antibiotic therapy was given versus no

treatment. . . . When this small improvement in

resolution of otitis media with effusion is

weighed against the side effects and cost of

antibiotic therapy, antibiotic therapy may not be

preferable to observation in management of otitis media with effusion in the otherwise healthy

young child. . . . To assist in making choices for

management of otitis media with effusion,

health care providers need to inform parents

fully as to the side effects and costs of antibiotic

therapy, as well as the benefits and harms of

other options for care (AHCPR, 1994).

A physician who elects not to prescribe an

antibiotic, foregoing the 14-percent increased

probability that the condition “would resolve,”

might be held legally liable for any negative outcome. Such potential liability might encourage

physicians to prescribe antibiotics even when
Chapter 4 Antibiotic Use in Hospitals | 93

they may not be necessary. Further, the above

guidelines do not instruct physicians to consider

the spread of antibiotic resistance in the decision

to prescribe antibiotics. If practice guidelines are

going to have an effect on promoting prudent

antibiotic use, they have to acknowledge that the

benefit to a few patients from routine use of

newer and broader spectrum antibiotics may be

outweighed by the public health benefits

expected from reducing the prevalence of antibiotic-resistant bacteria.

One concern of practice guidelines relevant to

antibiotic use is that national standards of conduct do not adequately reflect the localized

aspect of antibiotic-resistant bacteria outbreaks.

The National Health Lawyers Association

addressed this concern in its 1995 Colloquium

Report on Legal Issues Related to Clinical Practice Guidelines, which conceded that “[s]ome

local adaptation of national guidelines is probably inevitable and may be useful, because even

well-developed guidelines may have gaps and

may not foresee significant local objectives or

constraints” (National Health Lawyers Association Colloquy, 1995). One solution may be the

use of an online computer system that allows

health care practitioners in a particular geographic area to consult with each other and local

experts concerning appropriate local adaptations

to practice guidelines (Meyers, 1995). Such a

system would also allow health care practitioners

to disseminate the specifics of their cases, as well

as establish a record of compliance with the practice guidelines in the event of future litigation

(Meyers, 1995).

COSTS OF CONTROLLING THE 

EMERGENCE AND SPREAD OF 

ANTIBIOTIC-RESISTANT BACTERIA

Hospitals cannot charge costs of infection control procedures and the monitoring of antibioticresistant bacteria directly to insurance companies. As a result, although these procedures

improve the quality of patient care, hospitals’

efforts to minimize costs may retard spending on

them. Haley et al. (1987) commented that hospitals might not be placing enough emphasis on

infection control because “the direction and magnitude of the financial incentive to prevent nosocomial infections are not clear to many hospital

administrators.” They analyzed the financial

incentives for hospitals to prevent nosocomial

infections under the prospective payment system

and concluded that

Assuming an average nosocomial infection

rate of 5.7 percent, one would expect. . . a hospital with 10,000 admissions annually to have

approximately 570 nosocomial infections per

year in the absence of an effective infection

control program. If the average 1985 marginal

cost of providing extra care for a nosocomial

infection were approximately $1800, the total

cost of treating these infections would amount

to approximately $1 million per year, not counting physicians’ fees or medicolegal losses. . . .

From the nationwide SENIC project evaluation,

we know that at least 32 percent of the infections can be prevented, thus indicating that an

effective infection control program could produce a gross financial savings of approximately

$305,000 per year. . . nearly five times the costs

of the program.

A computerized antibiotic monitoring system,

such as that of the LDS Hospital, reduces costs

both by controlling the use of antibiotics and

reducing the length of hospital stays, but the LDS

system has been in development for 20 years, it

is based on obsolete computer technology, and it

is not exportable. Developing a system on current computer technology will take a significant

investment in research and development. Given

all the costs involved in control and monitoring,

it would be useful to calculate the total cost to

hospitals of antibiotic resistance to judge

whether infection control procedures and monitoring of antibiotic-resistant bacteria will have a

financial payoff.

Many different factors can be considered in a

calculation of the cost of antibiotic-resistant bacteria: the direct cost of time in the hospital, the

costs of extra physician visits when antibiotics

are ineffective, the extra hospitalizations due to

community-acquired resistant infections, and the

costs of newer antibiotics to replace antibiotics
94 | Impacts of Antibiotic-Resistant Bacteria

such as penicillin to which organisms have

become resistant. To those must be added the

indirect costs to patients from lost days of work,

increased illness, and, at worst, death. It is difficult to estimate the costs of all of these factors.

Phelps (1989) made such an estimate and concluded that antibiotic-resistant bacteria cost the

nation between $0.1 billion and $30 billion annually. Use of different values for the value of a life

accounted for almost all of the 300-fold range in

the estimate. The National Foundation for Infectious Disease (1990) estimated that the costs of

nosocomial infections caused by antibiotic-resistant bacteria could be as high as $4 billion annually, and CDC has estimated the costs of all

nosocomial infections at $4.5 billion per year, an

estimate that includes costs from both antibioticresistant and susceptible infections.

Here, OTA estimates the effects of antibioticresistant bacteria on the costs of some hospitalizations. The national costs of five classes of

nosocomial infections—surgical wound infections, pneumonia, bacteremias, urinary tract

infections, and others—are taken from the results

of the SENIC project (see table 4-1). Those costs

are shown on the first data line in table 4-7 (for

instance, the cost of all surgical wound infections

is $1.6 billion annually). The calculation of the

costs of each of the infections caused by each of

six different antibiotic-resistant bacteria is illustrated by the example of MRSA-associated surgical wound infections. Staph. aureus is

associated with 19 percent of all surgical wound

infections, and 15 percent of all Staph. aureus is

MRSA. Therefore, the hospital cost of MRSAassociated surgical wound infections is

$50 million [$1.6 billion × 0.19 × 0.15 =

$50 million]. Repeating this process for the five

kinds of infections and the six different antibiotic-resistant bacteria produces an annual total of

$661 million (1992) for hospital costs.

Using the estimate of Holmberg, Solomon and

Blake (1987) that antibiotic resistance doubles

the cost of nosocomial infections, the minimum

extra cost of antibiotic-resistant bacteria in hospitals is $661 million annually (1992 dollars) and

the minimum total cost of antibiotic-resistant

bacteria in hospitals is $1.3 billion annually

(1992 dollars). The actual hospital costs are

bound to be much higher as this calculation considers only six species of bacteria, and in some

cases considers strains of bacteria that are resistant to only one antibiotic and not other strains of

the same bacteria that are resistant to other antibiotics. Further, the trends in antibiotic resistance

indicate that the number of antibiotic-resistant

infections is likely to be increasing rapidly.

Finally, the OTA estimate considers only one

factor among many that increase the costs of

antibiotic-resistant bacteria; it ignores costs of

other infections, costs of days of work lost, and

post-hospital care, and other major costs. For

these reasons, the OTA estimate of $1.3 billion

must be considered a minimum estimate . 

CONCLUSIONS

Twenty-five to 35 percent of all hospitalized

patients receive antibiotics, which produces

enormous pressure for the selection of antibioticresistant bacteria. The result of that pressure is

increasing frequencies of antibiotic-resistant bacteria in hospitals: Some strains of vancomycinresistant Enterococcus are now resistant to all

FDA-approved antibiotics, and some strains of

Staphylococcus aureus, a common cause of

nosocomial infections, are resistant to all antibiotics except vancomycin. Many experts fear the

emergence and spread of Staph. aureus strains

resistant to all antibiotics, including vancomycin,

which would pose a major health care crisis.

Two avenues are open to reduce the spread of

antibiotic-resistant bacteria. One is infection control to reduce the rate of hospital infections, and

the other is the reduction in the use of antibiotics

to reduce selection pressures. While infection

control programs have worked well in some

institutions, similar programs have produced no

positive results elsewhere. The mixed results

indicate that more research into what makes systems work and why is needed to guide infection

control efforts. Formularies, lists of drugs that

are available for use in a hospital, were established to control drug costs, but they can be tied
Chapter 4 Antibiotic Use in Hospitals | 95

to information about antibiotic susceptibility produced by the hospital microbiology laboratory to

inform physicians’ prescription decisions. Positive results have been reported in the few places

this has been tried, but more evaluation will be

necessary before it is widely adopted.

Surveillance systems are designed to collect

and disseminate information to physicians and

others about the presence and prevalence of antibiotic-resistant bacteria. They are common in

hospitals, but far less common between and

among hospitals and across larger geographical

units. New Jersey has the only statewide system

TABLE 4-7: Costs of Stays in Hospital Associated with Antibiotic-Resistant Bacteria

Surgical wound 

infection Pneumonia Bacteremia

Urinary tract 

infection Other Total

Total cost of nosocomial infectionsa 1.6 1.3 0.36 0.61 0.66 4.5

Staph. aureus 19% 20% 16% 2% 17%

Methicillin resistant 15% 15% 15% 15% 15%

Cost of MRSAb 50 40 10 1.8 20 122

Enterococcus 12% 2% 9% 16% 5%

Vancomycin resistant 7.9% 7.9% 7.9% 7.9% 7.9%

Cost of VREb 20 2 2.6 10 2.4 37

Pseudomonas 8% 16% 3% 11% 6%

Imipenem resistant 7.8% 16.9% 10.3% 6.9% 12.5%

Cost of impenem-resistant 

pseudomonasb

10 40 1 4.6 5 61

Coagulase-negative 

Staphylococcus (CoNS)

14% 2% 31% 4% 14%

Methicillin resistant 50% 50% 50% 50% 50%

Cost of methicillin-resistant 

CoNSb

112 13 56 12 46 239

E. Coli 8% 4% 5% 25% 4%

Ampicillin resistant 35% 35% 35% 35% 35%

Cost of ampicillin-resistant 

E. Colib

45 18 6 5 9 83

Enterobacter 7% 11% 4% 5% 4%

Resistant 37% 37% 37% 37% 37%

Cost of resistant enterobacterb 41 52 5 11 9.7 119

TOTAL COSTb 661

a In billions of 1992 dollars.

b In billions of 1992 dollars.

NOTE: The costs were estimated by multiplying the total cost of nosocomial infections from a specific category (e.g., urinary tract infections) by

the fraction of infections in that category caused by a specific organism (e.g., E. coli) and the fraction of the organism resistant to one specific

antibiotic (e.g., ampicillin). The data from the fraction of infections caused by specific organisms and organisms resistant to a specific antibiotic

were taken from the CDC/NNIS system. This calculation represents a minimum estimate of the costs of antibiotic resistant bacteria: it only

accounts for charges in a hospital for nosocomial acquired infections due to six different antibiotic resistant species.

SOURCE: Office of Technology Assessment, 1995, based on data from the Centers for Disease Control, National Nosocomial Infections Surveillance (CDC/NNIS) System, Atlanta, GA.
96 | Impacts of Antibiotic-Resistant Bacteria

in the country, and CDC is only now establishing

a nationwide system for one kind of antibioticresistant bacterium. In addition, a number of privately supported surveillance systems collect

data for pharmaceutical companies, but, understandably, those systems collect information for

their clients rather than for general public health

information. On the international level, WHONET collects data from over 100 institutions

around the world. Chapter 1 discusses some features that could be built into a national surveillance system directed at antibiotic-resistant

bacteria and offers an option for its implementation.

One estimate of the total costs associated with

antibiotic-resistant bacteria had a range of

$100 million to $30 billion annually, with most

of the 300-fold range in cost coming from varying estimates of the value of a human life, and

another estimate said that the costs could be up to

$4 billion annually. OTA estimates the minimal

extra hospital costs associated with five kinds of

nosocomial infections caused by antibiotic-resistant bacteria to be $1.3 billion per year. The total

costs would certainly be certainly higher when

hospital costs of other antibiotic-resistant bacterial infections and non-hospital costs are considered.

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| 101

5

Antibiotic

Development

he fact that U.S. Food and Drug Administration (FDA) approved no new antibiotics in 1994 has led to fear that there are

no new ideas for antibiotics or that there

are insufficient financial incentives for new antibiotic development. Even the information that 13

new antibiotics are currently awaiting FDA

approval, and that two-thirds of the 53 antibiotics

developed by drug companies since 1960

received FDA approval after 1980 (Modern

Healthcare, 1994) must be tempered by additional information. The 13 antibiotics awaiting

approval are not “new” in terms of new mechanisms of action. They are derivatives or new

applications or formulations of antibiotics

already on the market.

As shown in figure 5-1 (and discussed below)

several years elapse between the discovery of a

chemical with antibiotic activity and its reaching

the market. The scarcity or abundance of new

antibiotics is dependent on many factors, some of

which are described in this chapter, but some of

the decisions necessary for the appearance of

new antibiotics in 1995 were made years ago.

This chapter reviews general considerations in

the development of new antibiotics and describes

some antibiotics that are now in use and how

researchers are attempting to modify them to

extend their usefulness. It also discusses the

search for new antibiotics using new chemical

and molecular biology knowledge and techniques as well as the search for new antibiotics in

biological materials not formerly examined. It

also reviews briefly some aspects of drug development and approval (those issues are covered in

greater depth in OTA’s 1993 report Pharmaceutical R&D: Risks, Costs, and Rewards).

DESIGNING NEW ANTIBIOTICS

Development of almost any drug is a matter of

science and serendipity, and antibiotics are no

different. Traditional methods, like screening of

soil and biological samples—“panning” for compounds—have been partly replaced by computerized modeling, recombinant DNA technologies,

new methods of chemical synthesis, and other

advances (Levy 1992, p. 39). Nevertheless, looking for antibiotic activity in biological materials

as exotic as frogs and the silk glands of moths is

a part of current research.

No matter how chemicals with antibiotic

properties are derived, they must still be evaluated in the microbiology laboratory, laboratory

animals, and ultimately, humans. “Preclinical

studies” are tests for efficacy and toxicity in laboratory animals, and “phases I, II, and III” are

T
o 1 2 3 4 5 6 7 8 9 10

Development time (years)

NOTE: IND = Investigational new drug: NDA = new drug application.

SOURCE: Gootz, 1990.

clinical trials in humans, with phase I being trials

to establish the safety of the drug and phases II

and III to establish efficacy (figure 5-1).

The creation of a new idea is the critical starting point for much research, and probably every

company tries methods to encourage creativity.

Once an idea is developed, the company can

speed up the pre-clinical research by pouring

additional resources into it, increasing the numbers of scientists committed to the project, and

providing more and better equipment.

❚ Toxicity

Toxicity tests in animals and humans identify

what side effects may occur; but the occurrence

of such effects does not mean that the developer

will drop the drug or that FDA will not approve

it. It does mean that the toxicity will be weighed

against the benefits in deciding what uses will be

sought by the developer and what uses will be

permitted by FDA. For instance, greater toxicity

would be acceptable in an antibiotic to treat vancomycin-resistant Enterococcus (VRE), for

which there are few or no available antibiotics,

than in one intended for routine use against respiratory infections for which there are many available antibiotics.

Most antibiotics inhibit or kill bacteria while

remaining relatively non-toxic to humans

because of differences between the structures

and metabolic characteristics of bacterial and

animal cells (see chapter 2). One major difference is the presence of the cell wall that surrounds the plasma membrane in bacteria. Cell

walls are missing from animal cells, and many

antibiotics kill bacteria by interfering with cell

wall synthesis.

Despite their generally low toxicity, antibiotics can cause allergic reactions and other side

effects. Penicillin can be allergenic, and vancomycin can cause hearing loss and kidney damage. Many promising new compounds that

inhibit or kill bacteria in the test tube are not useful as drugs because of allergenic or other toxic

side effects.

❚ Efficacy

The Infectious Disease Society of America, a

professional medical organization, under contract to FDA, developed guidelines for clinical

trials that outline the minimal acceptable information to be submitted to FDA. Because antibiotics are available for the treatment of almost all

bacterial diseases, it is unethical to test a new

antibiotic by comparison with a placebo. Instead,

one half of the patient population is given the

standard antibiotic treatment, and the other half

is given the new antibiotic. This comparison of
Chapter 5 Antibiotic Development | 103

efficacies necessarily requires more patients than

if the antibiotic were evaluated against no treatment or a placebo. If the new antibiotic is equal

to or more effective in treating the disease than

the standard treatment, FDA will approve its use.

Even if it is not quite so effective, FDA will

approve the new antibiotic if it has lower toxicity

than the standard to which it is compared.

FDA will consider the results of foreign trials

when the makeup of the test population in the

foreign country approximates the U.S. population, the distribution of antibiotic-resistant bacteria in the foreign country is about the same as in

the United States, and the disease is caused by

the same bacteria in the other country and in the

United States. The Office of Technology Assessment (OTA) did not investigate how often, if

ever, FDA has decided not to consider a foreign

trial, but there appears to be some room for disagreement between a manufacturer and FDA

about how closely the foreign conditions

approach those in the United States. On the other

hand, an FDA official stated that multi-national

companies have done one trial in a European

country and one in the United States, combined

the results, and obtained approval for the new

drug in both countries, and that FDA will make

approval decisions based solely on foreign studies (FDA, 1995).

The time necessary for FDA review has

decreased in the last few years. In the early

1990s, FDA took an average of 25 months to act

on a New Drug Application (NDA). Through

“The Prescription Drug User Fee Act of 1992

(P.L. 102-571),” Congress increased funds for

FDA to staff and run the review process. That

law requires that each manufacturer pay an

annual fee based on the number of the company’s drugs that are in use and the number of its

manufacturing plants. In addition, manufacturers may pay a fee at the time of submission of an

NDA. These fees are used to hire additional

reviewers at FDA to speed up the review process,

not to speed up the review of the particular NDA.

Since the Act’s implementation, the average time

for FDA drug approval in 1994 had dropped to

19 months.

The time line on figure 5-1 is an approximation; some drugs move more quickly through the

trials, and some move more slowly. More frequently, a drug fails some critical test and must

be abandoned. Such hurdles have always been

present. Scaling-up production of a drug from the

small quantities needed for initial testing to the

large quantities needed for phase III clinical testing and manufacture can also be significant hurdles in getting a new drug to market (box 5-1).

FDA regulations allow for an accelerated

review process when a candidate drug is a possible treatment for a life-threatening disease (such

as an antibiotic for use against VRE). FDA officials can meet with the drug sponsors at the end

of the phase I trial and design a phase II trial that

will be sufficient to make a decision about

approval of the drug. Moreover, drugs that are

entered into accelerated review go to the “head

of the line” at all stages of the review process.

A company seeking approval to market an

antibiotic for use against diseases caused by

antibiotic-resistant bacteria must demonstrate

efficacy against particular bacteria-disease combinations. For instance, an antibiotic effective

BOX 5-1: Quantities of Drugs Needed at 

Different Stages of Development

0.01 g-10 g: Discovery (performs initial benchlevel discovery, creation, or isolation of the new

entity).

10 g-100 g: Chemical process research (identifies possible ways to make the entity on a larger

scale).

1,000 g-100,000 g: Chemical process development (a collaboration between research and

development programs (R&D) and manufacturing;

scales up manufacture for toxicology and clinical

research; makes the process useful for manufacturing).

100,000 g-1,000,000 g: Manufacture (scales

up once again to make the entity in commercial

amounts).

SOURCE: Bristol-Meyers Squibb, 1995.
104 | Impacts of Antibiotic-Resistant Bacteria

against VRE in laboratory tests would have to be

shown effective against VRE-caused endocarditis to be marketed for that use, and it would also

have to be shown effective against VRE-caused

bacteremia to be marketed for use against that

indication. This raises problems because the

number of such diseases is relatively small, making it difficult to obtain as many cases for a clinical trial as are commonly required. According to

a U.S. FDA official, however, the agency could

adjust the number of cases required for the trial

of an antibiotic for use against particular diseases

caused by particular antibiotic-resistant bacteria.

ANTIBIOTICS IN CURRENT CLINICAL USE

Table 5-1 is a listing of the actions of antibiotics,

a sampling of antibiotics that display those

actions, and the development or use status of the

antibiotics. Currently, research and development

efforts are in place that seek to improve currently

used antibiotics.

❚ Sulfonamides1

The sulfonamides are synthetic, not of natural

origin, and are properly called “antimicrobials”

and not antibiotics. They are included here

because they were the first antibacterial drugs

that were not overtly toxic to humans, and their

chemical modifications foreshadowed much of

the work to improve natural antibiotics.

In 1936, a year after German researchers

reported that Prontosil (the first sulfonamide)

cured bacterial diseases, British researchers set

out to improve upon its usefulness (Colebrook

and Kenny, 1936). The British researchers’ plans

were based on the results of studies by French

investigators, who noted that the antibacterial

effects of compounds like Prontosil were lost

when some parts of the chemical were removed,

but that removal of other substituents had no

effect on antibacterial properties in mice. They

concluded that a metabolic product, paraaminobenzenesulfonamide, was responsible for

1 NOTE: An OTA mention of products and companies does not imply any endorsement, and products and

companies are included only as examples.

the activity of Prontosil, and that the full structure of the parent compound was not necessary

for bacterial killing. The involvement of

researchers from three different countries in this

research points to the international flavor of antibiotic research from its very beginning.

The British researchers tested a dozen sulfonamide analogues for antibiotic activity, but, practically, their most important discovery was that

para-aminobenzenesulfonamide was well tolerated when injected subcutaneously and that it

could be given orally. Prontosil, on the other

hand, was biologically active only when given by

injection (Buttle et al., 1936; Mandell and Sande,

1990). This finding was another harbinger of

research directions with antibiotics; low toxicity

and ease of administration increased the acceptability of an antibiotic and reduced the medical

care costs associated with it.

If bacteria were passive when faced with antibacterials, the sulfonamides would have

remained potent therapy. Bacteria are not passive. Through mutation and selection, they

become resistant to antibiotics. This sets up the

struggle between antibiotic developers and bacteria—the biological war.

Sulfonamides inhibit one step in the bacterial

synthesis of folic acid. Humans and other mammals do not synthesize folic acid; they obtain it

from food. Hence, sulfonamides have no effect

on mammalian cells. When, by the early 1960s,

many bacteria had developed resistance to the

sulfonamides, researchers postulated that the

antimicrobial action of sulfonamides might be

augmented by the co-administration of trimethoprim, which blocks another step in folic acid synthesis (Bushby and Hitchings, 1968). Blocking

two sequential enzymes on the bacterial biosynthetic pathway of a vital nutrient (such as folic

acid) was expected to act synergistically. The

reasoning proved correct, and bacteria resistant

to sulfonamide were inhibited by the sulfonamide/trimethoprim formulation. The preparation

is still used widely.
Ch

apter5AntibioticDevelopment|105

TABLE 5-1: Antibiotics in Use and Under Development

Action Family/Class Example(s) Source Status

Antibiotics that inhibit cell wall synthesis

Beta-lactams

Natural penicillins Penicillin G Penicillin notatum Used since 1940sSemi-synthetic penicillins

MethicillinPiperacillin

Semi-synthetic penicillin derivatives

In use since 1960s; among the most widely prescribed antimicrobials

Cephalosporins Cephalexin C. acremonium Widely used class of antibioticsCarbapenems Imipenem Derived from thienamycin, 

a compound produced by Streptomyces cattleya

In use; wide spectrum (active against many species of bacteria including cephalosporin-resistant Enterobacteriaceae)

Monobactams Aztreonam Derived from a compound 

produced by Chromobacterium violaceum

In use; tolerated by patients with penicillin allergies; spectrum limited to aerobic gram-negative bacteria

Penicillinase inhibitors Clavulanate potassium 

(used clinically with amoxicillin or ticarcillin)Sulbactam (used with ampicillin)Tazobactam sodium (used clinically with piperacilllin)

Streptomyces clavuligeriusSemi-synthetic penicillin derivativeSemi-synthetic penicillin derivative

Used since 1970s; clavulanate combinations used for wide range of disordersSimilar to amoxicillin/clavulanateTazobactam/piperacillin effective against intra-abdominal infections

VancomycinTeicoplanin

VancomycinTeicoplanin

Strep. orientalisActinoplanes teichomyceticus

Introduced in 1956; used against staphylococcal and enterococcal infectionsExperimental in the U.S., available for compassionate use

 Vancomycin derivatives

with catalytic activity

Semi-synthetic Experimental

(continued)
106 | Impacts of Antibiotic-Resistant Bacteria TABLE 5-1: Antibiotics in Use and Under Development (Cont’d.) Action Family/Class Example(s) Source Status Antibiotics that increase membrane permeability Peptides Bactericidal/Permeability Increasing Protein (BPI) Mammalian cells Experimental Magainins African clawed frog Experimental Cecropins Silk moth, other insects, mammals Experimental Defencins Mammalian cells Experimental Steroids Dogfish sharks Experimental

Metabolic interference

SulfonamidesTrimethoprim

SulfamethoxazoleTrimethoprim

Azo dyesSynthetic

In use since 1930s; first antimicrobial agent used in manSynthesized in 1968, commonly used together with sulfonamides

Protein synthesis inhibitors

Aminoglycosides Streptomycin

KanamycinTobramycinGentamicin

Streptomyces griseus

Streptomyces kanamyceticus

Streptomyces tenebrarius

Micromonspora purpurea and 

echinospora

In use since 1940s; important class of antibiotics

Fusidanes Fucidin Sodium salt of fusidic acid, 

derived from the fungus 

Fusidium coccineum

In clinical use since 1962, but not available in US (except through compassionate release); active against some strains of methicillin-resistant Staph. aureus (MRSA)

Tetracyclines Chlortetracycline

OxytetracyclineMinocyclineDoxycycline

Streptomyces aurofaciens 

Streptomyces rimosus

Semi-synthetic derivativeSemi-synthetic derivative

First introduced in 1948, found by screening soil samples for antibacterial activity

(continued)
Chapter 5 Antibiotic Development

| 107

TABLE 5-1: Antibiotics in Use and Under Development (Cont’d.)

Action Family/Class Example(s) Source Status

Chloramphenicol Chloramphenicol Streptomyces venezuelae First introduced in 1949, currently 

second line antibiotic because of side effect of aplastic anemia

 Macrolides Azalides

ErythromycinAzithromycin 

Streptomyces erythreussemi-synthetic derivative of erythromycin

Discovered in 1952Usage began in 1992

 Lincosamides Clindamycin Semi-synthetic derivative of 

lincomycin derived from 

Streptomyces lincolnensis

Available since the mid 1960s; active against aerobic bacteria

Mupirocin Mupirocin Pseudomonas fluorescens Introduced in the mid 1980s; topical 

antibiotic

Interference with RNA synthesis

Rifamycins Rifampin Streptomyces mediterranei First isolated in 1957, important 

tuberculosis drug

Toxic effect through DNA binding

Nitroimidazoles Metronidazole Synthetic Introduced in 1959, active against 

anaerobes such as B. fragilis

Block DNA replication or RNA transcription

Antisense nucleotides Laboratory Experimental

Interfere with DNA replication

QuinolonesFluoroquinolones

Nalidixic acidCiprofloxacin, Ofloxacin

Semi-synthetic First identified in 1962

Usage began in 1980s; some of the most widely used antibiotics

Anti-tuberculosis drugs

Isoniazid (INH)Pyrazinamide (PZA)Ethambutanol 

SyntheticSyntheticSynthetic

Shown to be effective in 1952Important tuberculosis drug since 1980Important tuberculosis drug since 1974

Decoy receptors Carbohydrates Laboratory Experimental

SOURCE: OTA, compiled from G.L. Mandell, J.E. Bennett and R. Dolin (eds.) Mandell, Douglas & Bennett’s Principles & Practice of Infectious Diseases. Churchill Livingstone: New York, NY,

1995; and A.G. Gilman, T.W. Rall, A.S. Nies, et al. (eds.) The Pharmacological Basis of Therapeutics. Pergamon Press; New York, NY, 1990.
108 | Impacts of Antibiotic-Resistant Bacteria

❚ Penicillins and Clavulanic Acid

Penicillin was the first true antibiotic. Its action

involves binding to penicillin-binding proteins

which are enzymes necessary for the synthesis of

the bacterial cell wall, inhibiting those enzymes,

which leads to the death of the cell, and uncovering or activating other enzymes that cause the

bacterial cell to burst. Shortly after penicillin’s

introduction, resistant micro-organisms began to

appear. By the mid-1940s, the enzyme penicillinase or β-lactamase, which degrades penicillin

so that it has no effect on bacteria, had been isolated from a bacterium that was not specifically

identified, and soon after, scientists found it was

present in other bacteria such as Staphylococcus

aureus. As early as 1948, 50 percent of S. aureus

in hospitals were resistant to penicillin, rising to

80 percent in 1957 (Gootz, 1990).

Semi-synthetic Penicillins

Semi-synthetic penicillins—methicillin, nafcillin, and cloxacillin—are the product of searches

for penicillins that could escape the action of

penicillinase. They were made possible by the

large-scale production of a part of the penicillin

molecule, called 6-aminopenicillanic acid, to

which chemists could add different chemical

substitutions. These penicillins resist the degrading action of penicillinases, and they found

immediate application in treating some penicillinresistant bacteria. The extremely low toxicity of

penicillin has fueled efforts to continue development of this antibiotic.

Penicillinase Inhibitors

Molds of the genus Streptomyces produce chemical compounds that “suicidally” tie up penicillinases. When administered with penicillins, the

inhibitors bind the penicillinases, leaving the

unbound penicillin free to kill bacteria (Reading

and Cole, 1977). By the early 1970s, olivanic

acid, produced by Streptomyces olivaceus, had

proved a successful penicillinase inhibitor, and it

was used with ampicillin and amoxicillin in

treating S. aureus and Klebsiella pneumonia,

both Gram-positive bacteria, but it was unable to

penetrate the Gram-negative bacterial cell wall.2

Clavulanic acid, from Streptomyces clavuligerus,

proved more effective than the olivanic acids,

and it extended the spectrum of penicillinase

activity to Gram-negative bacteria. Amoxicillin/

clavulanic acid is the mainstay of treatment for

otitis media in children caused by Hemophilus

influenzae and Branhamella catarrhalis.

The success of the penicillin/clavulanic acid

combination suggested that semi-synthetic penicillins—while promising as single-agent therapy—might not be the only solution to the

problem of antibiotic resistance. More importantly, perhaps, the notion of identifying and

attacking a specific bacterial target responsible

for resistance (in this case, penicillinases)

became a principle of antibiotic research.

❚ Other Beta-Lactam Antibiotics

The cephalosporins (see figure 5-2) share a similar chemical structure (the beta-lactam ring) and

similar mechanisms of action (inhibition of synthesis of the bacterial cell wall) with penicillin.

Cephalosporin antibiotics were first isolated

from the organism Cephalosporium acremonium in 1948 from the sea near a sewer outlet off

the Sardinian coast (reviewed in Mandell and

Sande, 1990). Chemists have modified the structure of the antibiotics and produced semisynthetic antibiotics with increased antimicrobial

activity. The resulting so-called “third generation” cephalosporins, including ceftriaxone and

ceftazidime, are widely used. Imipenem, yet

another β-lactam antibiotic, is a chemical derivative of a compound first isolated from the organism Streptomyces catleya; it is the broadestspectrum antibiotic commercially available (see

Emori and Gaynes, 1993).

2 Some bacteria take up a stain, called the Gram stain, and some do not. The difference depends on the structure of the cell wall in the two

kinds of bacteria, and the permeability of the two kinds of bacteria differ as a result of the difference in the cell walls.
I

CEPHALOSPORIN

NOTE The R groups specify the particular antibiotic; arrows indicate

the bond broken during function and during inactivation by b-lactamases

SOURCE: Frankel, 1995

❚ Vancomycin

Vancomycin is a naturally occurring glycopeptide [a protein (peptide) molecule with attached

sugars (glyco-)] antibiotic that blocks synthesis

of the bacterial cell wall. However, vancomycin

inhibits the synthesis of the bacterial cell wall by

binding to the peptidoglycan (cell-wall) precursor, a very different mechanism from that used

by the penicillins, and it does not have the betalactam ring structure of penicillins. Vancomycin

has become clinically important because it is

sometimes the only drug that can be used to treat

MRSA (methicillin-resistant S. aureus) infections, an increasingly prevalent pathogen in hospitals (see chapter 4).

Teicoplanin, a related glycopeptide antibiotic,

is widely used in Europe, but is available only as

an investigational drug in the United States. It is

potentially an effective alternative to vancomy -

cin; it requires less frequent dosing, and it is less

toxic. It is not likely to be successful in treating

bacteria resistant to vancomycin because bacteria

resistant to vancomycin are usually resistant to

teicoplanin as well (Fekety, 1995).

analogous processes in animal cells.

❚ DNA Synthesis—Ciprofloxacin, Other

Quinolones, and Fluoroquinolones

The synthetic antibiotic ciprofloxacin has

become one of the most widely prescribed antibiotics since its introduction in 1987 (Frieden and

Mangi, 1990). Ciprofloxacin, other quinolones,

and fluoroquinolones work by inhibiting the

action of a bacterial enzyme necessary for DNA

synthesis (“DNA gyrase”). Ciprofloxacin is

derived from nalidixic acid, an antibiotic discovered 15 years earlier, but never widely used.

Therefore, ciprofloxacin had a substantially

“new” mechanism of’ action. It is not known

whether quinolones bind to animal cell DNA

gyrase, but these antibiotics are relatively nontoxic.

Although resistance to ciprofloxacin occurs at

rates 100- to 1,000-times slower than resistance

to nalidixic acid (Hooper and Wolf son. 1989),

many strains of bacteria became resistant to

ciprofloxacin over a period of three years (see

table 5-2). This experience shows that resistance

can develop rapidly even when the mechanism of

action is substantially “new. ”

Ciprofloxacin and other quinolones are popular because they are effective against bacteria

that have developed resistance to other antibiotics and because they can be taken orally rather

than requiring parenteral administration (through

injection or intravenously). Oral ciprofloxacin is

equally or more effective than many parenteral

antibiotics, and oral administration costs less,

and can reduce or eliminate hospital stays.
110 | Impacts of Antibiotic-Resistant Bacteria

❚ RNA Synthesis—Rifampin

The first step in protein synthesis is the transcription of information in DNA into RNA (see chapter 2). Rifampin binds to bacterial RNA

polymerase, inhibits bacterial RNA synthesis,

and does not bind to animal cell RNA polymerase. Its principal use is in the treatment of

tuberculosis (TB).

❚ Protein Synthesis—Streptomycin 

and Other Aminoglycosides

The inactivity of penicillin G against Gramnegative bacteria led scientists to search for antibiotics with activity against those organisms. The

1944 discovery of streptomycin from a strain of

the bacterium Streptomyces griseus was followed by discovery of related compounds such

as neomycin, kanamycin, and gentamicin from

other bacteria in later years. This family of antibiotics, the aminoglycosides, inhibits bacterial

protein synthesis by binding to the small subunit

of the bacterial ribosome, which differs from the

corresponding subunit of the animal ribosome

(see chapter 2). Aminoglycoside inhibition of

protein synthesis is irreversible and lethal to the

bacteria.

Other antibiotics that inhibit protein synthesis

are the macrolides, such as erythromycin, clindamycin, and chloramphenicol, which bind to the

large subunit of the bacterial ribosome. They

inhibit bacterial growth, but they do not kill the

bacteria. (Chloramphenicol is now seldom used

in medicine because of adverse side effects.) Tetracyclines, which are widely used in medicine,

veterinary medicine, and animal husbandry (see

chapter 7), are also inhibitors of protein synthesis

with broad activity spectra. They, like chloramphenicol, are bacteriostatic rather than bactericidal.

DEVELOPMENT OF NEW ANTIBIOTICS 

FROM OLD

The development of semisynthetic penicillins

and ciprofloxacin from nalidixic acid has demonstrated the usefulness of modifying existing antibiotics so they are active against resistant strains

of bacteria. Modifications can reduce toxicity,

make the antibiotic resistant to degrading

enzymes, or improve penetration into bacterial

cells.

Frankel (1995) contacted a number of large,

established pharmaceutical companies and a

number of smaller, startup or beyond, biotechnology firms and asked about their research and

development programs in antibiotics. The section

that follows is based on his report. It is an overview and should not be taken as exhaustive

because not all firms were contacted, and not all

firms were willing to discuss their research and

development programs in antibiotics.

❚ Streptogramins

Rhone-Poulenc Rorer (1995) announced that one

of its antibiotics, now in phase III clinical trials,

is effective against antibiotic-resistant bacteria,

including some strains of VRE (Journal of

Antimicrobial Chemotherapy, 1992). The antibiotic is currently available from the company in

an FDA-reviewed program, and it is usually

shipped within 24 hours of request.

This drug is a combination of two semisynthetic derivatives of streptogramin, an antibiotic from Streptomyces pristinaespiralis. One

such antibiotic, pristinamycin, has been available in Europe for many years as an oral antistaphylococcal antibiotic. It inhibits protein synthesis by affecting ribosome function, but was

never widely used, partially because it cannot be

TABLE 5-2: Resistance to Ciprofloxacin, 

1988-1990

Organism % Resistant

1988 1989 1990

Acinetobacter anitratus 0 34 40

Enterococcus (various 

species) 8 25 35

Methicillin-resistant 

Staphylococcus aureus — — 85

Pseudomonas aeruginosa 9 35 45

Staphylococcus aureus 6 10 20

SOURCE: Adapted from Husain, 1991.
Chapter 5 Antibiotic Development | 111

made in an injectable form due to low water solubility. The new derivatives of pristinamycin—

quinupristin/dalfopristin (used in combination)—are injectable.

❚ Tetracycline Analogs

The first clinically useful tetracycline, chlortetracycline, was introduced in 1948. It was isolated

from the micro-organism Streptomyces aurofaciens and was discovered after screening samples

of Missouri farm soil (Levy, 1981). Following

this discovery, other researchers identified more

tetracyclines by further screening of soil microorganisms or by synthesis in laboratories. As

with the penicillins, manipulation of the tetracycline molecule has brought different spectrums

and properties of antibiotic activity. While all of

the tetracyclines now used in the United States

are generally considered broad-spectrum agents,

bacterial resistance to this family of agents is

widespread.

“Active efflux,” which transports tetracyclines

out of the bacteria, is a major mechanism of bacterial resistance. Since its description (Levy,

1981), it has also been shown to be a mechanism

of resistance to several other antibiotics including chloramphenicol, fluoroquinolones, erythromycin, and ß-lactams (Nikaido, 1994), and it is

present in both Gram-positive and Gramnegative bacteria. Nikaido (1994) reviews evidence about permeability barriers to antibiotic

entry into bacteria and active efflux, which can

bestow resistance to many antibiotics, and states

that, “It will be a major challenge for the pharmaceutical industry to produce compounds that are

able to overcome mechanisms of this type.”

Such research is underway. Nelson et al.

(1993) tested 30 tetracycline analogues and identified two chemical substitutions that block

active efflux. Subsequently, Nelson et al. (1994)

determined the part of the tetracycline molecule

that is essential for its antibacterial activity and

which substitutions inhibit efflux. This information may increase the usefulness of tetracycline,

an old antibiotic.

Minocycline, the last tetracycline to reach the

market, was introduced in the 1970s, and it was

the starting point for researchers who took

another look at the tetracyclines in the late 1980s.

This new tetracycline research program, a multidisciplinary effort by chemists, molecular biologists, biochemists and microbiologists, has

produced the semisynthetic glycylcycline

antibiotics. These are active against both Grampositive and Gram-negative bacteria and evade

resistance mediated by six of the known mechanisms of tetracycline resistance. Researchers are

continuing to modify the glycylcyclines to optimize their antibacterial properties (Bergeron et

al., 1994; Sum, Lee, Peterson et al., 1994), and

have recently introduced modifications that may

lead to the production of “later-generation” glycylcyclines (Sum, Lee, and Tally, 1994). When

and whether they will reach clinical application

is unknown.

❚ Dual-Action Cephalosporins 

One approach to evading bacterial resistance to

cephalosporins or quinolones is to chemically

couple the two to produce conjugates that have a

dual mechanism of action (hence the name

“dual-action” cephalosporins), reflecting the

actions of both the ß-lactam, cephalosporin, and

quinolone components.

The first of these conjugates, as reported by

Georgopapdakau et al. (1989), was found to act

initially as a cephalosporin by binding to appropriate penicillin-binding proteins, and then to

inhibit DNA replication, as would be expected

from the quinolone function. Some conjugates

appeared to act primarily as cephalosporins,

while others acted primarily as quinolones

(Georgopapdakau and Bertasso, 1993). The

pharmaceutical company that sponsored Georgopapdakau’s work is no longer supporting

research in dual-action cephalosporins, but such

research is reportedly continuing in at least one

other company.
112 | Impacts of Antibiotic-Resistant Bacteria

❚ Vancomycin Research

Vancomycin is the antibiotic of last resort in

some specific situations, and it is a popular one,

accounting for a quarter of the budget for antibiotics in some hospitals. The appearance of some

strains of VRE that are resistant to all antibiotics3

leaves physicians with no currently approved

antibiotic treatment for infections caused by

those organisms. Intravenous vancomycin is

the first choice for the antibiotic treatment of

MRSA, and the probably inevitable appearance

of vancomycin-resistant MRSA will leave physicians with no marketed antibiotic effective

against that serious nosocomial infection.

Currently, however, some strains of MRSA

are reportedly susceptible to other antibiotics:

Novobiocin, which is available only in oral form,

is active against many strains of MRSA. Minocycline (a tetracycline) has been used in successful

treatment of a few cases of endocarditis caused

by MRSA. Most isolates of MRSA are susceptible to fusicid acid. Used in combination with

other antibiotics, fusicid acid has been part of

successful therapy for a variety of MRSA-caused

diseases, but the role of fusicid acid is not

entirely clear. Emergence of resistance to all of

these antibiotics has been reported, and it is especially a problem with fusicid acid. The problems

with resistance have lead to the recommendation

that alternatives to vancomycin be used in combination—such as rifampin with fusicid acid—to

treat MRSA (Mulligan, Murray-Leisure, Ribner

et al., 1993). While these alternatives to vancomycin exist, they are less than the first choice for

treatment of MRSA.

Like penicillin and other antibiotics before it,

vancomycin is a starting compound in efforts to

produce new and more effective antibiotics.

Semisynthetic Vancomycin

Eli Lilly and Company (1995) has prepared a

semisynthetic vancomycin (LY333328) specifi3 Not all vancomycin-resistant enterococcus are resistant to all antibiotics. Enterococcus faecalis remains susceptible to ampicillin, as do

some strains of E. faecium.

cally for use against vancomycin-resistant organisms. The drug has demonstrated activity against

VRE in animal tests and against MRSA and

penicillin-resistant Strep. pneumoniae in in vitro

tests. According to a company spokesperson,

more animal tests of safety and efficacy are

required, and, if they are successful, human trials

may begin in 1996. This new compound is the

product of research centered on development of

antibiotics for use against vancomycin-resistant

organisms.

Catalytic Antibiotics

Shi and Griffin (1993) discovered that vancomycin has a catalytic (chemical-degrading action)

activity, and they are chemically altering vancomycin to develop a molecule that will not only

bind to the cell-wall precursor and inhibit cellwall synthesis, the normal activity of vancomycin, but destroy the precursor as well. If this is

achieved, it should increase the potency of vancomycin; the catalytic antibiotic should be able

to move to another cell-wall precursor after

destroying the first, and so on. Griffin (1994) is

also seeking to alter the vancomycin molecule so

that it regains its binding affinity to the altered cellwall precursors that are present in vancomycinresistant bacteria. Once affinity is restored, the

antibiotic can bind to the cell wall precursor,

inhibit the synthesis of the wall, and kill the bacteria. If researchers develop the catalytic function

so that it destroys the cell-wall precursor, that

activity could be added.

❚ The Macrolides

The macrolide antibiotics inhibit protein synthesis. Erythromycin, the most commonly used

member of the class, is effective against a broad

range of Gram-positive and Gram-negative bacteria, and is available for oral, intravenous, and

topical uses. While resistance has been noted in

the United States, it is more common in other
Chapter 5 Antibiotic Development | 113

countries, and the level of resistance appears

related to the level of use (Steigbigel, 1995).

Azithromycin, a closely related molecule, is

now being marketed with advertised advantages

in being effective against more strains of bacteria

than erythromycin, but it is being marketed on

the basis of other positive attributes as well.

Because it persists in human white blood cells

for a few days (rather than a few hours as with

some other antibiotics), two tablets of azithromycin on the first day of treatment and one tablet a

day for four more days is sufficient for most

applications (Pfizer, Inc., 1993). The convenience of this schedule is contrasted with those

for other antibiotics that require three or four

daily doses for up to 10 days. According to studies referenced in the advertising literature

(Pfizer, Inc., 1993), compliance is better, there

are fewer side effects, and patient costs are

lower. This example illuminates some of the

factors, including convenience and cost, as well

as effectiveness, that go into marketing of

antibiotics.

NEW RESEARCH TOOLS

New techniques in chemistry and molecular biology have immediate application to research and

development of antibiotics. Box 5-2 discusses

some of those techniques.

ANTIBIOTICS FROM NEW SOURCES

In addition to using new laboratory tools,

antibiotic researchers are also exploring new biological sources for antibiotic activities. Unlike

the traditional searches that have looked at products from micro-organisms, some current ones

are looking at materials from humans and other

animals.

❚ Carbohydrates

Carbohydrates called oligosaccharides [“oligo-”

a few, “saccharides” sugars] (OS), are ubiquitous

on the surface of mammalian cells, and bacteria

and viruses adhere to host cell OS as the first step

in the process of recognition, adhesion, and

infection (Rosenstein et al., 1988). Individual OS

are structurally specific for different organisms,

and microbial adherence has been referred to as a

“lock and key” phenomenon, in which only certain keys (microbial proteins, called “lectins” or

“adhesions”) “fit” into specific locks (host-cell

OS receptors).

Until recently, the complexity of OS structure

and the resulting inability to synthesize sufficient

OS at reasonable cost hindered OS drug design.

The simplest OS—a disaccharide that is composed of only two sugars—can take any of 20

different forms. The problem increases with size;

there are 35,560 possible ways to arrange four

sugars into tetrasaccharides. In comparison, four

amino acids can create only 24 distinct tetrapeptides (Hughes, 1994). These complexities contributed to the formerly high costs that ranged up

to $2 million per gram of OS. New techniques

have lowered the cost of some OS by 10,000

times to $200 per gram, and OS drug design has

accelerated (George, 1994; Glaser, 1994) with

applications in treating bacterial diseases, including ulcers.

The bacteria Helicobacter pylori causes gastric and duodenal ulcers, and the usual treatment

eradicates it and prevents the reappearance of

ulcers with a success rate of 70 to above 90 percent. Resistance of H. pylori to antibiotics used

in the usual therapy is a factor in lower treatment

success rates.

Neose Pharmaceuticals (Roth, 1995) has perfected the synthesis of the OS to which H. pylori

binds, and animal studies have shown that

administration of the OS competes with the H.

pylori binding sites in the digestive tract, causing

the H. pylori to release from those sites with the

bacteria then being eliminated from the body.

The OS is identical to an OS found in mothers’

milk, and it has extremely low toxicity in animal

tests. Phase I clinical trials for toxicity were

underway in March 1995.

Up to 80 percent of all hospital-acquired bacterial pneumonias are caused by one of six bacterial species. According to Roth (1995), all six of

those bacterial species bind to the same OS,

which opens the possibility of treating those

infections with a soluble form of the OS. Another
114 | Impacts of Antibiotic-Resistant Bacteria

BOX 5-2: Some New Methods for Research in Antibiotics 

Structure-Based Drug Design

Traditionally, that is, for 50 or so years, scientists have discovered new antibiotics by screening thousands of natural, synthetic, or semi-synthetic compounds for antimicrobial properties, analyzing the structures of active ones, and modifying active compounds for greater utility. Scientists have discovered many

antibiotics serendipitously, usually an expensive and time-consuming process and always an unpredictable one, and many have been discovered and tested in laboratories and in humans long before

researchers understood their mechanism of action.

Structure-based drug design (SBDD), on the other hand, begins with an understanding—or physical

model—of the drug mechanism, especially the ligand:receptor interaction (Kuntz, 1992). This interaction

occurs at the “active site” where the “ligand,” in this case the antibiotic, binds to some structure, the

“receptor” (or “target”) in the bacteria. SBDD employs newer research tools, such as X-ray crystallography, nuclear magnetic resonance spectroscopy, and supercomputer combinatorial chemistry to design

new compounds that will bind more tightly to the active site (Knox, 1993; Fan et al., 1994; Balbes et al.,

1994; Boyd and Milosevich, 1993).

Targeted Replacement of Segments of Antibiotic Proteins

The bacterium Bacillus subtilis produces an antibiotic called surfactin. Stachelhaus, Schneider, and

Marahiel (1995) isolated the DNA segments that code for surfactin from B. subtilis, and DNA segments

from another bacterium, Bacillis brevis, and from the fungus, Penicillium chrysogenum. Using recombinant DNA techniques, they constructed hybrid B. subtilis-B. brevis and hybrid B. subtilis-P. chrysogenum

DNA molecules that they reinserted into B. subtilis. Hybrid DNAs of the first kind coded for recombinant

proteins in which some segments of the protein came from B. subtilis and some from B. brevis hybrids of

the second kind resulted in the production of proteins with some segments from B. subtilis and others

from P. chrysogenum.

This experiment demonstrates a method to construct hybrid molecules, and it may have an application to the development of new antibiotics. Because the DNA segments can come from unrelated organisms, or even from chemical synthesis, the structure of the recombinant DNA, and the resulting protein,

can be specified. Better understanding of ligand:receptor interactions may provide the information for the

construction of recombinant DNA molecules that will code for new antibiotics.

“Unnatural” natural products

The bacterium Streptomyces coelicolor produces the antibiotics tetracyclines and erythomycin, which

are members of a class of compounds called polyketides. Scientists have discovered more than 10,000

polyketides, including many useful drugs, but the percentage of medically useful compounds in the total

number of discovered natural polyketides has decreased in recent years (Lipkin, 1995). McDaniel et al.,

(1995) have categorized the enzymes involved in the synthesis of polyketides and constructed plasmids

that contain genes for those enzymes. When expressed in S. coelicolor, the genes on the plasmids

resulted in the synthesis of new polyketides.

Based on their understanding of the activities of the enzymes, McDaniel et al., (1995) devised rules for

the bioengineered synthesis of polyketides, and they suggested that chemists will be able to generate

bioengineered (unnatural) products that will be as diverse as the thousands of polyketides already seen

in nature. The expectation is that medically useful compounds will be generated.

(continued)
Chapter 5 Antibiotic Development | 115

OS designed to lower the risk of infant infections

is modeled after naturally occurring OS found in

mothers’ milk (Neose Pharmaceuticals, 1994).

Microbial resistance to OS is predicted to be

small because two independent genetic events

would have to take place. First, the bacterium

would have to mutate so that it would no longer

bind to the OS; that would also make it noninfective because it could not bind to OS on cell

surfaces. Only a second mutation that produced a

mechanism to bind to another molecule on the

surface of the stomach cell could restore bacterial infectivity.

❚ Antibiotic Peptides

Among the most widely studied of the “new”

antibiotics are peptide antibiotics. Within this

large group of molecules are bactericidal/permeability increasing proteins (BPI), magainins, and

cecropins.4 Their common antimicrobial activity

4 These agents are included here to be illustrative; this list is not inclusive. J.E. Gabay provides a short description of these and some other

antimicrobial peptides as well as a useful reference list in “Vbigitous and natural antibiotics,” Science 264:373–374, 1994.

In vivo Expression Technology

Traditional research has sought microbial virulence factors by culturing and growing microbes in the

laboratory and then examining the products of bacterial growth that are present in the culture broth. Wellknown examples of such products are diphtheria and cholera toxins which were used for vaccine development.

Mekalanos and his colleagues (Mahan, Slauch, and Mekalanos, 1993) acted on the idea that bacteria

are “Trojan Horses,” hiding their virulence factors and toxins until specific host signals cause them to be

released. Such genes would cause the production of proteins that could be the targets for antibiotics or

antigens for the production of vaccines. Mahan et al., (1993) call the technology to explore such hidden

bacterial strategies “in vivo expression technology” (IVET), which has been heralded as “revolutionary”

(Barinaga, 1993).

IVET may be applied to the problem of antibiotic resistance in at least two ways. First, it can identify

new antimicrobial targets. Nearly half of the Salmonella genes detected with IVET were previously

unknown. The products of these genes are potential targets for new antibiotic design. Second, IVET may

guide production of new vaccines, as previously unknown products of IVET-identified genes give vaccine

developers new immunogens against which humans can be inoculated.

Antibiotics Targeted Against a Bacterial Regulatory System

In bacteria, some RNA synthesis depends on a two-step regulatory system. The first component is a

sensor protein in the bacterial membrane that can detect a signal in the environment, say, a sugar or

other nutrient of use to the bacterium. In response, the sensor chemically adds a phosphate to itself and

to another protein, the transducer. The phosphorylated transducer then activates RNA synthesis from

specific sites on the DNA, and the RNA is used to direct synthesis of enzymes necessary to transport the

nutrient into the bacterial cell, for its metabolism, or for some other aspect of biochemistry associated with

the nutrient.

Virulence genes, as detected by IVET or other methods, are probably regulated by a two-component

system, with the sensor detecting some chemical in the host animal or host cell. A substance that interferes with the regulatory system might be a useful antibiotic, and such substances have been described.

The two-component regulatory system does not exist in mammalian cells, making toxic side effects from

such antibiotics unlikely (Salyers and Whitt, 1994).

BOX 5-2: Some New Methods for Research in Antibiotics (Cont’d.)
116 | Impacts of Antibiotic-Resistant Bacteria

results from increasing bacterial permeability,

and in this regard they are similar to the topical

peptide antibiotic polymyxin B, produced by the

bacterium Bacillus polymyxa. Scientists, however, know few specifics about their mechanisms

of action (Gabay, 1994). New technologies that

allow researchers to synthesize and screen “combinatorial libraries” consisting of tens of millions

of natural and synthetic peptides (Blondelle et

al., 1994) have increased the capacity to make

and test candidate peptide antibiotics.

Bactericidal/Permeability Increasing Peptide

Weiss et al. (1978) reported isolation of a bactericidal protein from human and rabbit cells that

appeared to cause an “almost immediate” breakdown of the bacterial permeability barrier to the

entry of the antibiotic actinomycin D. While BPI

was bactericidal to several strains of E. coli and

Salmonella typhimurium, both Gram-negatives,

it had no effect on Gram-positive bacteria or the

yeast Candida.

Using molecular biology techniques, scientists

produced a fragment of the BPI molecule (called

rBPI-23) that increased bactericidal activity,

including activity against penicillin-resistant strains

of Streptococcus pneumoniae (Lambert, 1994),

and enhanced the efficacy of co-administered

antibiotics (Meszaros et al., 1994). Human subject testing has recently begun with another fragment (rBPI-23). When administered along with

low doses of endotoxin, a toxin produced by

Gram-negative bacteria, rBPI-23 blunted the

adverse effects of the endotoxin, was well tolerated by the volunteers, and was not immunogenic

(von der Mohlen, 1994).

Magainins

Science, like all human pursuits, has its own

folklore, and the discovery of the magainins

passed immediately into the legends of science.

In the late 1970s, a researcher at the National

Institutes of Health was studying RNA expression in the African clawed frog, Xenopus laevis.

He noted that the frogs never developed postoperative inflammation or wound infections–

even though surgical procedures were performed

under non-sterile conditions–and he wondered if

“there might be a ‘sterilizing’ activity in the

skin.” Zasloff (1987) isolated two closely related

peptides with broad-spectrum bactericidal activity that were also active against some singlecelled parasite species. He named the two peptides “magainin 1" and “magainin 2" (Hebrew

for “shield”).

The magainins are short peptides that insert

into the bacterial cell membrane and open up

channels that lead to the death of the bacteria.

Thousands of magainin analogues have been

synthesized with the goal of increasing antimicrobial activity (Cuervo et al., 1988). One magainin, MSI-78, is now in phase III trials, which are

expected to be completed in mid-1996. If that

schedule is kept, Magainin Pharmaceuticals

expects to file an NDA at the end of that year for

the sale of MSI-78 as a topical antibiotic (Magainin Pharmaceuticals, 1994); however, an earlier

trial of this magainin against impetigo was

suspended because of disappointing results.

Other magainins are undergoing toxicity tests in

animals in expectation that they will find application as systemic antibiotics.

Cecropins

Cecropins are peptides from the North American

silk moth, Hyalophora cecropia. They are similar in size to the magainins, and like the magainins, they increase bacterial permeability.

Researchers have chemically combined cecropin

with another natural peptide antibiotic, mellitin,

derived from bee venom. The resulting product

demonstrated activity against S. aureus and Plamodium falciparum (Blondelle and Houghten,

1992). More recently, a recombinant cecropin/

mellitin hybrid was shown to be bactericidal

against Pseudomonas aeruginosa. Other antimicrobial cecropins and cecropin-like molecules

have been recently isolated from the hemolymph

of the silk worm Bombyx mori, the male reproductive tract of the fruitfly Drosophila melanogaster, and from the intestines of pigs.
Chapter 5 Antibiotic Development | 117

Defensins

Defensins are broad-spectrum antimicrobial peptides isolated from mammalian cells, including

epithelial cells lining the human small intestine

(Blondelle and Houghten, 1992). Although similar in size to magainins and cecropins, defensins

differ in chemical structure. The isolation of a

related group of molecules isolated from cow airways, called “ß-defensins,” has added to the theory that defensins form a natural, primary

mucosal defense against microbial pathogens

and are therefore potentially powerful new antimicrobial agents (Taylor, 1993).

❚ Lactoferrin, a Substance with Antibiotic 

Properties from Human Milk

Lactoferrin, the second most abundant protein in

human milk, is bacteriostatic in vitro and in tissue culture tests against a variety of bacteria,

including MRSA. Three different mechanisms

contribute to the bacteriostatic activity of lactoferrin: It binds iron, thereby depriving bacteria of

that essential element, it increases bacterial

permeability, and it activates immunological

defenses. Ward et al., (1995) recently described a

method to produce human lactoferrin in the laboratory, and the product has the same antibiotic

properties as the human protein. Pre-clinical

studies are now under way with the laboratoryproduced chemical (Ward et al., 1995; Wyatt,

1995).

Human milk has antibacterial properties, and

some of those properties reside in lactoferrin.

Lactoferrin is also found in other external secretions—tears, nasal secretions, saliva, and genital

secretions—all of which have antibacterial properties. Those secretions have been around for

millions of years and they are still effective

against bacteria. Development of lactoferrin, or

other substances with antibiotic activity from

humans, as antibiotics might provide therapies

that will not elicit resistance.

Like all the protein antibiotics, lactoferrin presents administration difficulties because they

cannot be absorbed from the digestive tract,

thereby eliminating oral uses. They can be used

topically, as polymyxin B, and they may find use

against enteric infections and pulmonary infections, where they might be administered by aspiration.

❚ Steroid Antibiotics

The discoverer of magainins also wondered over

the rarity of infections in fetal dogfish sharks

(Squalus acanthis), despite the fact that mother

sharks flush their fallopian tubes regularly with

seawater to remove fetal wastes. Moreover, he

noted that the sharks rarely became infected after

surgery. Using the same methodology as the one

used for magainins, he and co-workers successfully isolated squalamine from shark stomach,

liver, gall bladder, spleen, testes, gills, and intestine. Squalamine is a steroid compound, closelyrelated to cholesterol (Moore et al., 1993) and

has antimicrobial activity against both Grampositive and Gram-negative bacteria as well as

fungi and protozoa. Testing of squalamine is now

at the pre-clinical stage.

❚ “Anti-Sense” Nucleotides

One of the more frequently proclaimed “magic

bullets” against drug-resistant bacteria is “antisense” molecules (Stein and Cheng, 1993) that

bind to critical DNA or RNA segments in the

bacterial cell and disrupt their functioning. A

variety of new technologies, many developed for

application in the federally funded Human

Genome Project, allow for simpler and more

rapid DNA sequencing and have made investigations of anti-sense therapy feasible.

Like many new therapies, the oligionucleotides (ON), the segments of DNA and RNA

molecules that would be used as anti-sense molecules, present many challenging problems. New

technologies need to be developed for the bulk

synthesis of ON and to transport ON through the

body and inside bacterial cells, and methods may

have to be developed to deliver the ONs to their

complementary DNA or RNA target (Rahman et

al., 1991). “Oligonucleotide-like” molecules will

be required to circumvent the instability and

rapid degradation of ON in the body, and some
118 | Impacts of Antibiotic-Resistant Bacteria

such molecules have been synthesized and

shown to have improved stability.

GETTING NEW ANTIBIOTICS TO MARKET

This chapter reviews some ideas for new antibiotics, and any of those ideas will require significant investments to support the research and

development necessary to bring it through clinical trials and to market. In 1993, OTA (1993)

comprehensively reviewed the return on investments in pharmaceutical research and development. This section contains a brief review of

some of the issues related to pharmaceutical

developments specifically focused on antibiotics.

Antibiotics are used for short periods of time,

and representatives of some pharmaceutical

companies claim that greater profit is to be made

in developing drugs for chronic illnesses such as

heart disease and arthritis, for which drugs may

be necessary every day for years at a time. The

counter-argument to that contention is that a lifesaving drug with no alternative, even if used only

rarely, can command a high price. Resistance

limits the market life of antibiotics: As they lose

some of their efficacy, they become less profitable. At the same time, antibiotic resistance

opens up new markets.

Participants at OTA advisory panel meetings

said that major pharmaceutical companies are

not likely to mount a research and development

effort for potential annual markets of less than

$100 million. They also stated that some smaller

companies, generally lumped under the rubric of

“biotech firms,” could do very well on a market

of $20 to $30 million a year.

Some antibiotics, however, have generated

major markets. As shown in box 5-3, a single

antibiotic can account for 15 percent of a major

manufacturer’s sales. Such a percentage is probably unusual, but it indicates that an antibiotic can

be a major source of revenue.

A new antibiotic that overcomes resistance

has a ready market. There are approximately

19,000 VRE cases yearly. If an antibiotic effective against VRE were developed, OTA assumes

the company that marketed it could charge a high

price because no other antibiotic is available for

that use, but OTA did not try to estimate that

price. There are about 60,000 MRSA cases annually, and some proportion of those are treatable

only with vancomycin. For illustrative purposes,

OTA assumes that all 60,000 cases are now

treated with vancomycin, that the antibiotic costs

$100 per day, and that the treatment requires 10

days. That market is then $60 million annually

(60,000 cases per year × $100 per day × 10 days

of treatment per case), and the new antibiotic

would be competing for that market with vancomycin.

A major company might not be interested in

this market; it is well below $100 million per

year. But the new antibiotic could probably be

used for many other infections, and the market

could be much larger, with, most likely, earlier

emergence and spread of resistance than if the

antibiotic were restricted to use against MRSA.

Whatever the size of market for an antibiotic,

it is expected to erode with the development of

antibiotic-resistant bacteria. Control of the emergence and spread of resistance would result in a

longer market life and greater sales and profits.

However, the major way known to slow down

resistance is to minimize the use of the antibiotic,

which would have an adverse effect on sales and

profits, at least in the short run. To return to the

hypothetical example of an antibiotic to treat

MRSA, restricting the use of the drug would prolong its effectiveness before resistance developed. That restriction would also reduce sales

compared to those expected if there were unrestricted use against all respiratory infections, for

example. This tradeoff is discussed further in the

following section.
Chapter 5 Antibiotic Development | 119

BOX 5-3: Patent Protection and Post-Patent Hurdles for Competitors

(News media clips)

“Generic Erosion for Ceclor?

“When Lilly’s Ceclor (cefaclor) comes off patent in the U.S. in 1992, unit sales of the antibiotic, which

account for roughly 15 percent of the company’s total sales, could be eroded by 70 to 80 percent by

generic competition in the first 18 months, according to Kidder, Peabody analyst James Flynn.

“This erosion will take place despite the fact that Lilly holds process patents for Ceclor which expire

between 1994 and 2006, and plans to introduce a sustained-release formulation, Ceclor AF, the analyst

predicts.

“Recent legal action in Japan, where Lilly has filed suit against 10 companies for alleged infringement

of its cefaclor patent, suggest that the company intends to defend its patents vigorously.... However, Mr.

Flynn argues that Lilly’s process patents will not be recognized in a number of countries (e.g., Italy) which

are likely to be used as manufacturing sites for generic companies planning to import formulations of

cefaclor on expiration of the product patent.

“Barr and Biocraft, which have valid cephalosporin manufacturing facilities in the U.S., may also try to

‘skirt’ Lilly’s process patents, Mr. Flynn says. Such a strategy would give these companies a ‘meaningful

cost advantage’ over importing firms, he adds.

“Ceclor AF is unlikely to be introduced in the United States much before the cefaclor product patent

expires, Mr. Flynn says. A preferred dosing regimen is the only benefit he is aware Ceclor AF would have

over generic competition. The analyst notes that Lilly’s keftabs formulation of Keflex (cefalexin) gained

less than 15 percent of Keflex’ sales after the 1987 product patent expired.”

SOURCE: “Generic Erosion for Ceclor,” Scrip World Pharmaceutical News 1594:25, 1991.

“Ceclor Market Dominance Will Continue Past Dec. 1992 Patent Expiration, Lilly Contends: 

Process Protection Thru 1994

“Lilly’s dominant position in the oral antibiotic market will survive the expiration of the U.S. patent on

Ceclor in December 1992, the company maintained at a meeting with financial analysts in New York on

Feb. 28. Based on a process protection for cefaclor and a pending NDA application for the follow-up

compound loracarbef, Lilly is forcefully declaring its intention to hold its place in the oral antibiotic field....

“Asked to comment on the impact of the upcoming patent expiration on Ceclor sales, Lilly Pharmaceutical President Gene Step said the relevant questions should be what will be Lilly’s overall position in the

oral antibiotic market and what is the likelihood of generic versions of cefaclor reaching the market.

“‘You really have to [ask] what is our participation in the oral antibiotic market and to what extent will

that be affected’ by generic cefaclor or ‘by other products that we may or may not be selling’ in the future,

Step said.

“Lilly is emphasizing the de facto protection of a difficult production process and a patent position on

a late-stage intermediate... Step declared that when all factors are considered Ceclor should ‘remain a

viable product for Eli Lilly beyond expiration of the patent.’

“As the company often has been pointing out recently, Step told the Feb. 28 meeting that Ceclor has

yet to face generic competition outside the U.S., even in markets where there is no patent protection.

‘While we cannot know what the actions of everybody else in the world will be,’ Step said, ‘it is very interesting to observe that while there isn’t patent coverage in a large part of the world for Ceclor, there isn’t

any generic Ceclor.’

(continued)
120 | Impacts of Antibiotic-Resistant Bacteria

PATENTS

Patents provide the primary protection for a

pharmaceutical company’s investment in

research, development, marketing, and production costs. The 1991 OTA report, Biotechnology

in a Global Economy, described the patent process for pharmaceuticals:

Drug companies usually secure patent protection early in drug development, before the

drug enters the regulatory process. Regulatory

approval for new drugs takes, on average, 7 to

10 years to complete. This translates into a 7- to

10-year reduction in [the usual 17-year] patent

protection for pharmaceutical products when

they reach the market, leaving such products

with, on average, 9 years of protected life.....

[T]he Drug Price Competition and Patent Term

Restoration Act of 1984... restores part of the

patent life lost due to lengthy regulatory

approval. The act allows extension of the patent

term for up to 5 years, but it does not allow

extension beyond 14 years for effective patent

life. The actual extension granted is equal to the

total time taken by the Food and Drug Administration (FDA) to review the New Drug Application, plus one-half of the clinical testing time. In

addition, the act promotes generic competition

by providing FDA with an Abbreviated New

Drug Application (ANDA) process. This process facilitates the approval of generic drugs by

eliminating the need for costly clinical studies.

An ANDA does require the sponsoring company to demonstrate its generic’s bioequivalence to the pioneer drug. This is much less

costly and time-consuming than complete clinical trials and facilitates the market entrance of

generic drugs.

The GATT (General Agreement on Tariffs

and Trade) legislation changed patent terms from

17 years from issuance to 20 years from filing

(OTA, 1991, discusses the nuances of these

terms), and in March 1995, the U.S. Patent and

Trademark Office (PTO) announced a preliminary policy statement that extensions would be

added to the new 20-year patent term. In June

1995, however, PTO reversed its position and

presented manufacturers a choice between adding any extension they had to the 17-year term or

accepting the 20-year term under GATT. Manufacturers are expected to challenge this decision

in court.

“Lilly Research Labs President Mel Perelman explained the process protection during question-andanswer. ‘The Ceclor synthetic route is so long and so complex’ that it will be difficult to duplicate, Perelman said....

“A producer of cefaclor can take a number of different routes to get to the intermediate, Perelman

explained, ‘but they can’t go through it without violating our patent. So an ethical or legal end-run seems

extremely improbable.’ The patent on the intermediate runs until December 1994. Step further pointed out

that establishing a cefaclor manufacturing process ‘will require very considerable capital investment...we

haven’t seen that yet’....”

SOURCE: Ceclor market: Quoted from “Ceclor Market Dominance Will Continue Past Dec. 1992 Patent Expiration, Lilly Contends:

Process Protection Thru 1994, Lorabid NDA Filed as Backup,” FDC Reports: Prescription and OTC Pharmaceuticals, March 4,

1991. p. 15.

“Ivax Corp. faces lawsuit from Eli Lilly”

In 1995, Eli Lilly sued Ivax Corporation, a pharmaceutical company that announced that it had

received FDA approval to manufacture cefaclor capsules, a generic version of Lilly’s Ceclor. Lilly claimed

that Ivax’s supplier of a raw material used a process that infringes on Lilly’s process patents.

SOURCE: Ft. Lauderdale, FL Sun-Sentinel. 1995. April 29, 1995. p. 8B.

BOX 5-3: Patent Protection and Post-Patent Hurdles for Competitors

(News media clips) (Cont’d.)
Chapter 5 Antibiotic Development | 121

Members of the OTA advisory panel discussed the pluses and minuses of a negotiated

agreement between a manufacturer and the PTO

to extend the patent life of an antibiotic in

exchange for restrictions on its use. Again, consider the example of an antibiotic effective

against MRSA. Could PTO, FDA, and the manufacturer work out an agreement so that the antibiotic was marketed only for use against MRSA?

Such an agreement would have a positive impact

on the emergence of resistance, but it would

present supervision or enforcement problems to

assure that the restrictions were followed. It

would also present problems for the manufacturer in estimating its returns from unrestricted

sales over a few years—until resistance becomes

common—as compared to restricted sales over

more years. How soon resistance would arise in

both cases is difficult to estimate, as are the

chances of another company developing a comparable or better drug.

Many compounds are patented but never

brought to market. If, subsequently, it was discovered that such a compound was useful against

antibiotic-resistant bacteria, probably no firm

would be interested in conducting the tests and

trials necessary to bring it to market. Without

patent protection, the firm that paid for the tests

and trials would be unable to recover its costs.

Fusidic acid, an antibiotic that has been used in

Denmark and other countries since 1962 (Mandell and Sande, 1995), provides a real-life example of such a drug. Fusidic acid is active against

at least some strains of MRSA, and it is used

against those bacteria in other countries. It has

never been marketed in the United States,

although it can be made available under compassionate use procedures to physicians in this country. Because it is off-patent, the company that

developed and sells it elsewhere is not willing to

fund clinical trials that would be necessary to

obtain FDA approval for its being marketed for

use against MRSA here.

Patent protection of the chemical substance is

not the only method by which companies can

maintain their markets. OTA (1993, p. 82-87)

describes how complicated and expensive production methods and facilities can be a major

hurdle for competitors, especially when the

methods and facilities are protected with process

patents. For example, in 1995, Ivax Corporation

announced it had received FDA approval to manufacture a generic version of a cephalosporin on

which the patent had expired in 1992. Eli Lilly

sued Ivax, claiming that Ivax’s supplier of a raw

material used a process that infringed upon

Lilly’s process patents (Fort Lauderdale SunSentinel, 1995).

PRICING OF DRUGS DEVELOPED IN 

PART BY FEDERAL RESEARCH

The Federal Technology Transfer Act of 1986

(P.L. 99-502) authorized the establishment of

CRADAs (Cooperative Research and Development Agreements) between federal intramural

laboratories and private industry to bring inventions and discoveries in federal laboratories to

market. In exchange, the private industries would

receive the profit from sales of the developed

products. In 1989, Congress directed the

National Institutes of Health (NIH) to require

“reasonable pricing” of any drugs that were

developed in cooperation between its laboratories and industry. Industry objected to the restrictions on pricing, and, in April 1995, NIH

relinquished its right to require reasonable pricing.

This change is expected to have little affect on

antibiotics. While the federal government conducts research on antiviral and antifungal agents,

it has supported little research on antibacterials,

leaving that research to the pharmaceutical firms,

and none of the six products that had been developed as of April 1995 through CRADAs was a

drug (Health News Daily, 1995).

CONCLUSIONS

Antibiotic research and development, as almost

all drug research and development in the United

States, is carried out and sponsored by pharmaceutical companies. Recent years have seen the

introduction of few new antibiotics into the mar-
122 | Impacts of Antibiotic-Resistant Bacteria

ket, which may reflect a diminished research

effort in antibiotics five, 10, and more years ago.

Currently, there is a great deal of activity in

looking for substances with antibiotic properties

in biological sources that have not been exploited

in the past and in applying new molecular biologic and chemical techniques to the synthesis of

antibiotics and to understanding their mechanisms of action. On the positive side, some of the

compounds being considered as possible antibiotics have mechanisms of action different from

those of currently used antibiotics, and they

should be especially useful against bacteria now

resistant to many or all currently available antibiotics. Despite that promise, there is great uncertainty about if and when there will be a pay-off

from the research efforts, and few experts expect

commercial availability of any antibiotics with

new mechanisms of activity in this century. The

uncertainty about availability of new antibiotics

underlines the importance of efforts to reduce the

emergence and spread of bacteria resistant to

now-used antibiotics.

The emergence of antibiotic-resistant bacteria

produces new market opportunities, and it can be

expected that pharmaceutical firms will be interested in developing products for it. Some experts

argue, however, that the profits to be expected

from an antibiotic are smaller than those from

other drugs and that pharmaceutical firms will

focus their efforts on other, more profitable

drugs. On the other side of that argument, an

antibiotic that is effective against an infection

resistant to all other antibiotics could probably be

sold at a very high price.

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| 127

6

New

Technologies

for Infection

Diagnosis and

Control

hree major options exist for the control

of bacterial diseases: 1) disrupt or halt

transfer of bacteria from person to person and from the environment to people,

2) treat cases of disease with antibiotics, and

3) prevent disease through vaccination. This

chapter describes diagnostic methods that guide

the selection and use of antibiotics, the use of

vaccines, methods for delivery of high concentrations of antibiotics to areas of localized infections, devices and materials designed to reduce

the transfer of bacteria in the hospital, and some

treatment methods used before the antibiotic age.

The cartoon, which is adapted from one that

originally appeared in Science, is a humorous

look at the serious problem posed by bacteria

resistant to all available antibiotics. Some bacteria are expected to develop resistance to any antibiotic introduced into medical practice.

Therefore, continued improvement in infection

diagnosis and control is necessary to optimize

the use of antibiotics and slow the spread of

resistant bacteria.

DIAGNOSTIC METHODS

In the future, science may develop a small

device, such as the “tricorder” used in the TV

series Star Trek, that physicians can pass over the

body of a sick person to identify the cause of a

disease. Such methods are far in the future, and

current techniques used to identify bacteria and

susceptibility patterns are “traditional methods”

that have been developed over the last century.

Newer methods that involve techniques from

molecular biology and modern instrumentation—not immediately at the level of Star Trek—

promise to make identification and characterization faster and more certain.

❚ Traditional Methods for the 

Identification of Bacteria

Some experts estimate that there may be a million different bacteria and that scientists have

identified only one percent (10,000 species) of

that total. Of those 10,000, only a fraction have

been associated with human diseases.

When seeing a patient, a physician will ask

questions, make observations, and perform tests

to determine which bacteria are likely to be associated with an illness and to choose an antibiotic

treatment. The physician may swab the throat in

the case of a sore throat or obtain a sample of

urine in the case of a urinary tract infection. The

collected material on the swab or the urine can be

stained with diagnostic dyes, such as the Gram

stain (see chapter 2), and examined under a

T
Copyright @ 1995 Sidney Harris. Reprinted with permission,

microscope. Distinctive shapes and staining

properties facilitate reliable preliminary rapid

identification of the bacteria causing infection.

Collected samples may contain such low numbers of bacteria as to make finding them under

the microscope difficult. The staining properties

and shapes of the bacteria may not be unique and

therefore not identifiable. The sample may contain a mixture of bacteria, as is common in faecal

samples. To identify the bacteria in those cases,

the physician sends a biological sample of some

kind—a volume of blood or pus or other exudate,

a scraping or swab from the throat or other

orifice, a sample of urine or feces—to a microbiology laboratory.

In the laboratory, the sample is transferred to

culture media specifically designed to encourage

the growth of certain pathogenic bacteria and to

prevent the growth of others such as commensal

bacteria that may be present in samples from

both healthy and sick individuals. The bacteria

that are able to grow form visible colonies on

agar-based media in a Petri dish or grow in broth

so that the broth becomes turbid, as apple cider

does when yeast grow in it. In both the collection

and handling of the sample, health care personnel

must be careful to avoid contamination with the

bacteria that grow literally everywhere, on the

patient’s and physician’s skin, on the surfaces of

furniture and unsterilized devices in the examining room, and on apparatus in the diagnostic laboratory.

Microbiologists can sometimes look at and

smell the colonies or liquid cultures and, based
nary tract infections, grow quickly, forming colonies in 24 hours or so, and a laboratory would

probably identify them in one or two days. Mycobacterium tuberculosis grows far more slowly,

and six weeks may pass before traditional methods can be used to identify it.

Identifying the bacteria is often critical for

choosing the most appropriate antibiotic therapy

because some antibiotics work better against certain bacteria. But identification does not provide

information about whether the bacteria are resistant to the antibiotic or susceptible to it. “Susceptibility tests” are used to determine that.

Traditional Susceptibility Tests

Information about antibiotic-resistance/susceptibility is developed by testing the bacteria isolated

from the infection against six to 12 different antibiotics, or more if necessary. The results from

these tests may support the use of the antibiotic

that was empirically selected by the physician,

indicate that other antibiotics would work as

well, or show that the disease-causing bacteria

are resistant to the antibiotic empirically chosen.

Jorgensen (1995) describes four methods that

are currently used to determine the antibiotic

susceptibility or resistance of bacteria: 1) disk

diffusion tests, 2) broth dilution tests, 3) agar

dilution tests, and 4) agar gradient methods.

Disk diffusion tests

Disk diffusion tests measure the size of a clear

area of no bacterial growth around a sterile paper

disk containing antibiotic. The size of this area,

called the “zone of inhibition,” can be measured

and reported directly, or the measurement can be

compared to criteria established by the National

Committee for Clinical Laboratory Standards

Photo of a disk diffusion (Kirby-Bauer) susceptibility test plate.

Courtesy of James H. Jorgensen, University of Texas Health

Science Center, San Antonio, TX, 7995.

(NCCLS) to classify the bacteria as susceptible,

intermediate or resistant (S, I, or R). These tests

are well standardized for certain bacteria and

may be highly reproducible. However, disk tests

are influenced by many laboratory variables that

can limit accuracy unless tightly controlled.

O’Brien (1994), who initiated and runs WHONET, the World Health Organization-sponsored

surveillance system for antibiotic-resistant bacteria, emphasizes the importance of requiring laboratories to report raw data about the size of the

zones of inhibition (figures 6-1 and 6-2) to surveillance organizations. While laboratories in

Europe and North America are consistent in their

measurement and reporting of the diameters of

zones of inhibition around antibiotic disks, they

interpret the meaning of the measurements differently (figure 6-l). Therefore, data reported as

zones of inhibition rather than as interpretations

are necessary to make any valid international

comparisons about the prevalence of antibioticresistant bacteria.

Broth dilution tests

Dilution tests measure the concentration of antibiotic that is necessary to prevent the growth of

bacteria. In these tests, known amounts of bacteria are deposited into small test tubes containing
5 7 9 11 13 15 17 19 21 23 25 27 29 31 33 35

Total number tested = 934

R = 7%

Figure Bb

S = 79%

5 7 9 11 13 15 17 1921 232527 29 31 33 35

L a Figure A represents a center in Europe (Center 1).

b Figure B represents a center in North America (Center 5).

NOTE: European and North American centers measured similar

zones of inhibition, illustrating the reproducibility of the methods.

However, the use of different break points in the two centers would

result in the centers reporting different percentages of resistant

organisms. Even if the laboratory data were identical, the centers

would’ report different percentages of resistant organisms. This example demonstrates the importance of reporting raw data for making

comparisons between laboratories.

SOURCE: WHONET, 1994.

5 7 9 11 13 15 17 19 21 23 25 27 29 31 33 35

NOTE: This histogram illustrates the ambiguity of setting breakpoints

for classifying bacteria as susceptible, intermediate, or resistant. In

particular, the breakpoint for the division between resistant and intermediate appears to fall at a peak in measured zones of inhibition.

SOURCE: WHONET, 1994

1 to 2 milliliters (a teaspoonful is about 5 milliliters) of sterile nutrient growth medium (“broth”)

containing different concentrations of antibiotic

(figure 6-3). The lowest concentration of antibiotic that prevents growth of the bacteria defines

the “Minimum Inhibitory Concentration” (MIC).

While the MIC provides information about the

concentration that will inhibit the growth of a

bacterium, it does not say whether that concentration can be reached in the treated patient or

what dose of antibiotics is needed to reach the

critical concentration. Interpretive guidelines

provided by NCCLS publications help clinical

microbiologists and physicians interpret MICs as

clinical categories of S (“susceptible”), I (“intermediate”), and R (“resistant”).

A disadvantage of this method is the large

number of test tubes and racks and large volumes

of media that are required. To test a single bacterial culture against six antibiotics would require

42,48, or 54 tubes, depending on the lowest concentration used. The miniaturization of this
I

I

2 4 8 16 32

Concentration of antibiotic A

(zero time)

Concentration of antibiotic B

o 2 4 8 16 32

Concentration of antibiotic A

2

Concentration of antibiotic B

(zero time)

NOTE: In both A and B, a small measured volume of bacterial culture is added to each test tube at time zero, Following incubation (the time of

Incubation depends on the growth characteristics of the bacteria), the test tubes in which bacteria were able to grow are turbid (the first three

tubes in A and all tubes in B). The absence of growth in the last three tubes that contain antibiotic A indicates that the bacteria are killed or inhibited by concentrations of A equal to 8 units or more, Growth in all tubes that contain antibiotic B indicates that the bacteria are resistant to all

tested concentrations of antibiotic B

SOURCE: Office of Technology Assessment, 1995.

method with microdilution trays solved that

problem. The broth micro dilution test is currently the most popular antibiotic sensitivity test

in the U.S. (table 6-I; the test using test tubes is

called the “broth macro dilution test”). The small

size of the wells and the small volumes, about

0.1 milliliter (about a drop from an eye-dropper),

require that some viewing device be used to

determine which of the wells in the test plate are

clear and which are turbid. There are a number of

commercial devices that make that determination, and some plot out the MICs from the tests.

To hold down costs and reduce the space

needed for incubation of test cultures, many laboratories do not use the entire series of dilutions

Photo of a broth microdilution susceptibility test tray with disposable inoculator.

Courtesy of James H. Jorgensen, University of Texas Health

Science Center, Sari Antonio, TX, 7995,
Agar dilution 0.2

Disk diffusion 31.8

Rapid automated 19,7

SOURCE: Jorgensen, 1995. From data collected in a 1991 Proficiency Survey of 3414 laboratories conducted by the College of

American Pathologists.

as diagramed on figure 6-3. Instead, based on

the NCCLS interpretive criteria, only two to

three dilutions of each antibiotic are used. One of

the dilutions is set to match the “break-point”

that defines the division between the resistant

and intermediate response; another dilution

matches the concentration that defines the breakpoint between the intermediate and susceptible

responses (see figure 6-2 for examples of breakpoints using disk diffusion tests). When only two

or three dilutions are used for each antibiotic, the

tests provide only an estimate rather than a quantitative measurement of the MIC. The true breakpoint might be somewhat different from the

guidelines, and this fact can cause errors in classifying the bacteria as resistant or susceptible.

Agar dilution tests

Agar dilution tests are similar to the broth dilution tests in that they measure the MIC. In these

tests, a small volume of a bacterial suspension,

usually 1–2 microliters, is transferred to each of a

series of agar plates containing known concentrations of antibiotics. Multi-prong devices are

used to transfer approximately 100 colonies at

one time.

useful for testing anaerobic and other hard-togrow bacteria.

The Etest has been cleared by the FDA for

clinical use in the U.S. The Spiral Gradient EndPhoto of five Etest strips on the surface of an agar plate. lntersection of the growth ellipses with the strips indicate the MICs.

Courtesy of James H. Jorgensen, University of Texas Health

Science Center, San Antonio, TX, 1995.

Photo of the Spiral Assay System Susceptibility Test.

Courtesy of Spiral Biotech, Inc., Bethesda, MD, 1995.

1 OTA mention of a company or product does not constitute an endorsement. Furthermore, companies and products are mentioned as

examples; competing companies and products exist.
high-level resistance to be detected. The Etest is

reportedly easy to use in most laboratory settings

and requires no complicated procedures.

Modifications of Traditional Methods To

Shorten Times Necessary To Obtain Results

The four methods discussed require at least overnight incubation to obtain results. That time can

be shortened to four to 10 hours for certain antibiotics and organisms by using optical devices

(sometimes coupled with fluorescent indicators)

more sensitive than the human eye to detect

growth in microdilution tubes. Two commercially available automated systems can produce

results in four to 10 hours.

The AutoSCAN Walk/Away (Dade Microscan, USA, Miami, Florida) uses standard

microdilution trays that are inoculated in the

standard way and placed in an automated incubator that uses a fluorometer to detect the presence

or absence of growth at different antibiotic concentrations. The Vitek System (bioMerieux

Vitek, Hazelwood, Missouri) was developed by

NASA to diagnose urinary tract infections in

astronauts in space in the 1970s. It uses creditcard size reagent cards, each of which has 30 tiny

wells for the testing of different antibiotic concentrations, and the assays can be completed in

three to 10 hours. While both systems provide

rapid results, each requires backup cultures and

other tests in case of power or mechanical failures.

In some cases, the automated machines can

fail to detect resistance. To deal with this problem, manufacturers of both of these instruments

have developed computer software that reviews

the results to identify those that may be false.

Some of these systems can also identify unexPhoto of bioMerieux Vitek susceptibility testing reagent card. It

was originally developed by NASA to diagnose urinary tract

infections in astronauts in space and had to be very small.

Courtesy of James H. Jorgensen, University of Texas Health

Science Center, San Antonio, TX, 1995.

pected resistance patterns and offer suggestions

for antibiotic treatment (Jorgensen, 1993). Computer analysis of the test results can also be

linked to the hospital pharmacy’s computer to

alert the pharmacy personnel when the wrong

antibiotic therapy is being used. As discussed in

chapter 4, computer networks such as this can

improve patient care and reduce costs.

Summary of the Test Methods

Table 6-1 shows the reported frequency of use of

the various test methods in a survey of American

laboratories, and table 6-2 provides information

about the relative costs of the most commonly

used methods. None of the methods differs very

much in labor costs. Based on the costs of equipment and supplies, the disk diffusion method is

the least costly. O’Brien (1994) argues that it can

also be the most informative under most conditions because the sizes of the zones of inhibition

(see photograph) provide raw data that have not

been subject to interpretation, and zone of inhibition information is more quantitative than broth

dilution tests that are sometimes based on only

one or two dilutions.

Will Faster Tests Make a Difference?

A test result that shows that bacteria are resistant

to the empirically chosen antibiotic will certainly

cause the physician to substitute another antibi-
134 | Impacts of Antibiotic-Resistant Bacteria TABLE 6-2: Principal Features of Presently Available Manual and Automated Antimicrobial Susceptibility Testing Systems Method or instrument Test format Means of growth detection/ endpoint determination/time Equipment required Approximate cost of equipment Approximate cost/test* Broth microdilution (prepared in-laboratory) 96-well plastic microtiter trays Visual determination of MICs by turbidity; 18–24 hours Tray dispenser, manual reader $35,000 $6–7 Broth microdilution (commercial frozen or dried trays) 96-well plastic microtiter trays Visual determination or automated reader interpretation of MICs; 18–24 hours Choice of manual reader or auto-reader $500 $50,000 $7–9 Disk diffusion 6–12 disks on 100–150 mm petri plates Visual measurement of zones of inhibition; suscept. categories; 16–18 hours None (only standard lab incubator) None $1.50–4 Etest 1–5 strips on 100–150 mm petri plates Visual determination of MICs; 16–18 hours None (only standard lab incubator) None $3–11 Dade MicroScan WalkAway 96-well plastic microtiter trays Fluorogenic substrate auto-incubator/ reader MICs; 3.5–15 hours Auto-incubator/reader $85,000 $125,000 $10–12

bioMerieuxVitek

30–45-well plastic cards Kinetic turbidimetric MICs or 

categories; 4–15 hours

Auto-inoculator/ incubator/reader $40,000 $152,000 $4–6

* Includes cost of consumable supplies only; labor requirements do not differ substantially between methods.SOURCE: J.H. Jorgensen. March 1995. Current and future phenotypic methods for detection of resistant bacteria. Report prepared for the U.S. Congress, Office of Technology Assessment.
Chapter 6 New Technologies for Infection Diagnosis and Control | 135

otic if the patient is not improving. Sometimes,

however, the patient improves despite the presence of apparently resistant bacteria. This can

occur because the patient’s immune system is

successfully controlling the bacteria, or because

the antibiotic reached a higher concentration in

the patient’s body than in the laboratory test, so

that the bacteria were killed or inhibited.

Up to 40 percent of antibiotic therapy was

inappropriate as judged by a comparison of physicians’ prescriptions to an analysis of the laboratory results for bacterial identification and

antibiotic susceptibility tests (see, for example,

Jorgensen and Matsen, 1987). While older

reports in the literature (see Edwards, Levin,

Balogtas, et al., 1973) indicated that physicians

pay little attention to microbiology test results,

more recent publications (Doern, Scott, and

Rashad, 1982; Weinstein, Murphy, Reller, et al.,

1983; Jorgensen and Matsen, 1987) indicate that

some physicians do modify their prescriptions

upon receiving additional laboratory information. In particular, rapid susceptibility tests,

which can be completed in four to 10 hours,

resulted in more appropriate therapy, and Doern,

Vautour, Gaudet, et al. (1994) found that rapid

tests resulted in fewer additional laboratory tests,

fewer invasive procedures, shortened time in

intensive care, and reduced mortality.

Physicians typically receive the results of antibiotic susceptibility tests on the morning of the

second or third day after specimens are submitted to the laboratory. The faster methods produce

the results more quickly, but unless the physicians and nursing staff are prepared to use the

information at the earlier time, it will not be considered until the next morning. In this case, technological improvements can only be useful if

accompanied by changes in habits.

Jorgensen (1995) discusses another obstacle to

the use of rapid methods. Laboratory managers

often confirm the results of the faster methods

with backup tests using the older, slower methods. However, this requires performing the tests

more than once and therefore increases costs.

Trade-offs must be made among the objectives

of speeding up the process, ensuring accuracy by

performing backup tests, and saving money.

❚ New Technologies for Identifying 

Bacteria

Antigen Tests

Antigen tests use antibodies to recognize specific

molecules on or in bacterial or other cells. For

instance, the home pregnancy test detects antigens that are produced only during pregnancy.

There are many versions of antigen tests to

detect the presence of strep A bacteria in sore

throats, but the usefulness of these tests is limited

by low sensitivity. Traditional cultures are still

recommended when tests are negative. Antigen

tests are also available to detect Clostridium dificile in patients with diarrhea and to determine the

bacterial cause of meningitis.

Methicillin-resistant Staphylococcus aureus

(MRSA) presents identification problems

because it and all other S. aureus grow slowly.

Further, its identification is usually accomplished

by a specific test for protein antigens on its surface, and these tests failed to identify between 1

and 25 percent of S. aureus. Kuusela, Hilden,

Savolainen, et al. (1994) discovered another protein on the surface of S. aureus and developed a

test for it that detects both methicillin-susceptible

S. aureus and MRSA.

Tests which Directly Measure the Presence of 

a Bacterial or Antibiotic Resistance Gene

Tests which directly measure the presence of a

bacterial gene (discussion of tests for antibiotic

resistance genes follows) are fundamentally different from the traditional tests, which measure a

property of an organism such as its ability to

grow in the presence of a certain concentration of

antibiotic. The new gene tests bring with them a

new set of considerations: A bacterium might

contain a gene for resistance, but not “express” it

under the conditions of the traditional diagnostic

tests, or a resistance gene may have undergone a

mutation that does not affect its function but that

makes its presence undetectable, or the genes of

dead bacteria may be detected with DNA tests.
136 | Impacts of Antibiotic-Resistant Bacteria

For example, samples from a patient who is

being successfully treated with anti-TB drugs

often test positive in DNA tests, but negative in

culture-based tests that rely on growing the

organism. These are problems that must be considered in designing new genetic tests and using

them in clinical practice.

One huge advantage of tests that measure the

presence of a bacterial gene is that they are

quick; many tests take only a few hours or less.

Another advantage is that they generally have

much higher sensitivity than the antigen and

other enzymatic tests described above, although

in some cases the sensitivity is not as high as that

of traditional culture methods. The speed combined with the sensitivity is very useful. However, some tests require culturing, i.e., the

growing of bacteria from the clinical samples,

before the genetic test can be performed. The

culturing requirement adds time to the process.

To date there exists no test so rapid that it will

confirm bacterial identification and susceptibility

before a patient leaves a physician’s office. The

development of faster and more susceptible

genetically based tests for bacteria started in the

early 1980s, but most are still not available for

routine use. Nevertheless, some of these tests,

such as those that are able to diagnose tuberculosis in a few hours instead of a few weeks, represent a significant technological advancement that

has improved clinical practice.

DNA probe assays

Single-stranded fragments of DNA or RNA that

are complementary to a target DNA or RNA

sequence will form a double-stranded molecule,

known as a “stable hybrid,” under certain reaction conditions. Diagnostic fragments, or probes,

which will bind to target DNAs or RNAs, are

labeled with enzymes or dyes so that the binding

of the probe to the target can be detected.

At the present time, several commercial DNA

probe tests in clinical use are manufactured by

Gen-Probe, Inc. (San Diego, California), GeneTrak (Framingham, Massachusetts), Ortho Diagnostic Systems (Raritan, New Jersey), and

others. Some of these tests are designed to confirm the identification of cultivated colonies,

such as tests for M. tuberculosis, M. avium (an

important pathogen in patients with AIDS), and

Neisseria gonorrheae (the agent of gonorrhea).

Other tests can be used for the direct detection of

bacteria in clinical samples, such as Neisseria,

Chlamydia trachomatis (an agent of urethritis,

cervicitis, and pelvic inflammatory disease) and

S. pyogenes (a cause of suppurative tonsillitis or

“strep throat”). These are organisms that for the

most part are difficult or slow to cultivate and

identify in the laboratory. The tests require

approximately two to four hours to complete and

cost the patient approximately $20–40 per test.

One important disadvantage of probe-based

methods to date has been their low sensitivity

compared to culture-based methods. Probe

assays for M. pneumoniae (an agent of atypical

or “walking” pneumonia) and Legionella pneumophilia (the agent of Legionnaire’s Disease)

are no longer much used, primarily because of

this problem. New technologies in development,

which provide the ability to amplify probe or

probe-linked signals after binding to the target,

may help increase the sensitivity of these tests.

One promising probe-based test that does

have adequate sensitivity is a rapid direct DNA

probe test from Gen-Probe that can identify

Group A Streptococcus directly from throat

swabs. In comparative studies, test results agreed

closely with those from older and slower tests

(see, for example, Rippin, et al., 1994; Heiter and

Bourbeau, 1993), unlike the quick antigen strep

tests described above. However, Heiter and

Bourbeau conclude that because this test requires

several instruments not routinely found in doctors’ offices and because it still requires two

hours, the test will not be useful for point-of-care

testing in doctors’ offices or emergency room

clinics.

Target amplification methods

One of the most promising approaches for

increasing the sensitivity of probe-based DNA

tests is to amplify the target DNA sequence

through such methods as polymerase chain reaction (PCR), which can rapidly generate millions
Chapter 6 New Technologies for Infection Diagnosis and Control | 137

of copies of bacterial or resistance gene DNA or

RNA sequences. PCR requires identifying and

synthesizing short sequences complementary to

the target gene that act as “primers” for the synthesis of the DNA. It is relatively easy to synthesize millions of these short sequences, but it

would be difficult to synthesize larger pieces of

DNA. Starting with as little as one strand of

DNA from the sample, PCR uses enzymes to

elongate the “primers” into full copies of the

DNA. PCR can generate millions of copies of a

particular DNA in hours.

Species-specific PCR detection assays have

been developed for at least 50 different bacterial

pathogens, and specific sequences are available

from a much larger number of species, for which

PCR primers can be designed. However, only a

few standardized kits for performing these tests

on specific bacterial species are commercially

available in the U.S. Among those kits that either

have been cleared, or are nearing clearance, by

the Food and Drug Administration are PCR

assays for C. trachomatis, N. gonorrheae, and M.

tuberculosis. Even without a commercially available standardized kit, the tests can still be set up

individually by service labs. However, there are

several disadvantages to performing these tests

without using a standard kit. First, most of these

assays do not perform as well in detecting bacteria in clinical samples as they do in purified cultures; suboptimal sample preparation procedures

and reaction conditions are probably to blame.

Second, unless physical, chemical, or enzymatic

precautions are in place, PCR and other target

amplification methods are easily jeopardized by

contaminating nucleic acid, either from prior

amplification reactions or from positive clinical

samples. Third, there is dramatic interlaboratory

variability in the test results for the same group

of clinical samples. Many of these problems may

be solved by the availability of standardized

commercial kits.

After the nucleic acid is isolated and amplified

by a technique such as PCR, the nucleic acid can

be sequenced to identify the organism. Automated sequencers marketed by Applied Biosystems can determine 48 independent DNA

sequences of 400–500 nucleotides in length in

approximately 8 hours, and speed and sequence

length capabilities are continually being

improved. Automated sequencing systems

require an initial investment of approximately

$55,000 (Molecular Dynamics) to $125,000

(Applied Biosystems, including sequence analysis software). It is estimated that identification of

a single bacterial isolate with an automated procedure will cost approximately $75.

Another way to identify the organism is to

bind the nucleic acid to probes that recognize

specific sequences. Currently, sequences prepared from specific reference strains of bacteria

are used. New strategies are expected to use random sequences of nucleic acid bound in orderly

arrays on micro-scale photolithographic silicon

chips, and the nucleic acid can be identified by

determining which probes bind to it. Because of

the microscopic scale of these tests, the bound

nucleic acid must be detected with a laser confocal microscope. This approach has already been

shown to be useful for the detection of single

base pair mutations in the human immunodeficiency virus. This technology offers significant

potential for rapid sequence determination of

specific gene targets and for the detection of

specific identifying signature sequences or antibiotic-resistance-associated sequences. Firstgeneration chip-based sequencing systems may

be available for research by 1996.

Using rapid DNA tests to 

diagnose tuberculosis

Diagnosing tuberculosis is difficult because it

has many different clinical manifestations. Moreover, many physicians were not trained to recognize tuberculosis because its prevalence was

decreasing until about 10 years ago. The recent

resurgence of this disease is a huge problem,

both in the United States and around the world,

and rapid diagnosis is critical so that patients can

be treated before they pass this highly infectious

disease to others. Quick determination of the susceptibility of the infecting organism is also

becoming increasingly important because many
138 | Impacts of Antibiotic-Resistant Bacteria

drugs are inactive against some of the multiresistant strains of tuberculosis.

The tuberculin skin test is often used as the

first diagnostic indication that a person has been

infected with tuberculosis. A positive tuberculin

skin test does not mean that the person has active

disease, only that the person has been exposed to

tuberculosis. Haas and Des Prez (1995) review

studies of the interpretation of positive tuberculin

skin tests in nursing homes which show that

3.8 percent of men who were tuberculin-positive

on admission to nursing homes subsequently

developed active disease, and that 11.6 percent

of men who became positive while in the nursing

home later developed the disease. The percentage developing active disease could be reduced

to 0.2–0.3 percent with the prophylactic use of

the antibiotic INH. However, the level of hepatic

toxicity from INH was 3–4 percent, and there

were other side effects. Deciding when to prescribe antibiotics for a patient with a positive

skin test but no other symptoms is very complicated because the toxicity of the drug must be

weighed against the probability that the patient

will develop tuberculosis. The same considerations apply to new diagnostic tests based on the

detection of the DNA of M. tuberculosis.

Isolating the mycobacteria causing tuberculosis requires from three to eight weeks, and susceptibility testing by agar dilution methods

requires another three to six weeks. Highly variable results have been observed between two different clinical laboratories using culture methods

(Hewlett, Horn, and Alfalla, 1995). The identification and susceptibility testing of drug-resistant

TB can be significantly hastened by using the

BACTEC radiometric method, but the time

required is still 20 days or more. Recent data on

the Etest for susceptibility testing of mycobacteria suggest that MIC values can be obtained in

five to 10 days, a significant improvement over

current methods (Wanger and Mills, 1995).

With PCR and probe-based DNA tests, physicians will have the ability to identify mycobacteria in the sputum of patients within a few hours

to a few days. All tests that are currently cleared

by the FDA require some culturing of the clinical

sample, but newer tests in development will

allow identification of mycobacteria directly

from clinical samples. These tests are used in

many other countries, including much of Europe.

Some laboratories are promoting clinical use of

PCR tests in the U.S. Macher and Goosby (1995)

document a difficulty in interpretation of PCR

tests in the absence of other clinical signs of

tuberculosis. On the basis of two (out of three)

positive PCR tests, the patient received antituberculosis chemotherapy and was placed in isolation. Later, six cultures turned out to be negative

for tuberculosis, and the patient was taken off

drugs for active tuberculosis and placed on INH

alone for preventive therapy. This case study

indicates that the DNA probe tests might be too

sensitive: they might detect non-viable mycobacteria from a previous exposure. This result is

comparable to a positive tuberculin skin test,

which, as discussed above, indicates past exposure to mycobacteria but does not necessarily

signify active tuberculosis.

❚ New Technologies for Detecting 

Antibiotic Resistance

The increasing prevalence of antibiotic-resistant

bacteria is leading manufacturers to develop tests

specifically to identify resistant strains. In general, these tests are designed to produce results in

a few hours. Discrepancies may arise between

the results of old and new methods. The older

methods directly measure whether an organism

expresses resistance and can grow in the presence of an antibiotic. Some of the newer methods

indicate whether an organism has a gene encoding for resistance. However, the organism may

not “express” this resistance even if it has the

gene. In some cases, it is unknown whether the

presence of the gene or the expression of the

gene under laboratory conditions is the more

important predictor of clinical outcome.

Enzymatic Tests

Enzymatic tests can directly measure the presence of an enzyme that confers antibiotic resistance, such as β-lactamases that inactivate
Chapter 6 New Technologies for Infection Diagnosis and Control | 139

penicillins and other β-lactam antibiotics and the

enzyme that inactivates chloramphenicol. The

detection of the β-lactamases requires only a few

minutes (Stratton and Cooksey, 1990), but it is

limited to only a few bacterial species. Moreover, it does not detect penicillin resistance

caused by other mechanisms, such as the production of modified penicillin binding proteins. The

test for the chloramphenicol inactivating enzyme

requires one to two hours and can be used to

detect the most common form of chloramphenicol resistance, but it has decreasing utility

because of the declining use of this antibiotic.

Tests Based on Indicator Dyes or 

Light-Producing Enzymes

Some tests add indicator dyes to a bacterial culture and then detect the presence of living organisms by a color change in the indicator dye. An

example is the Crystal MRSA Rapid ID test from

Beckton Dickinson. This test, which can detect

MRSA in four hours in cultured bacteria, uses an

indicator dye that can be observed under an ultraviolet light source in the absence of oxygen. In

this test, three samples of bacteria are incubated

with the indicator dye. In addition, one of the

samples is incubated with oxacillin (a semi-synthetic penicillin similar to methicillin) and one of

the samples is incubated with vancomycin. If the

bacteria survive, they will use the oxygen in the

samples and the dye changes color. If the sample

contains MRSA, the organism will survive in the

presence of oxacillin but not in the presence of

vancomycin. If the organism is susceptible to

oxacillin, it will not survive either antibiotic. The

test, which costs about five dollars, does not

require expensive instrumentation. Kohner, Kolbert, Geha, et al. (1994) found that this system is

an effective rapid screening method for MRSA

but has poor performance for coagulase-negative

Staphylococci, which often present a greater

diagnostic dilemma.

A more complicated test for multiresistant

tuberculosis is currently in very early development (Jacobs, Barletta, Udani, et al., 1993). In

this test, the gene for the light-producing enzyme

from fireflies was cloned into a virus that infects

M. tuberculosis. The virus is added to a sample

of sputum from the patient. The virus will infect

any mycobacteria that are present. If the virus

infects living mycobacteria, the viral DNA is

activated, and the firefly enzyme will cause the

culture to give off light. When antibiotics are

added to the test, only resistant mycobacteria will

support viral growth; susceptible ones will not,

and susceptible cultures will not light up. Thus

susceptibility can be determined. Research is

currently underway to determine if this test can

measure as few as 100 live M. tuberculosis bacteria, and would therefore work directly on

patient samples in a few hours (Jacobs, NIH

Grant R01AI27235). However, this sensitivity

may be difficult or impossible to achieve because

of background signals in the sample.2

DNA-Based Methods for Testing 

Antibiotic Resistance

Current susceptibility patterns suggest that

rifampin resistance in M. tuberculosis can be

used as a predictive marker of multidrug resistance. In general, surveillance indicates that

resistance to rifampin correlates well with resistance to three or more antituberculosis drugs.

Furthermore, virtually all of the highly resistant

mycobacterial strains (resistant to greater than

five drugs) are rifampin-resistant. However, this

may change in the future if M. tuberculosis

undergoes further genetic mutation.

PCR tests are in development to detect

rifampin resistance in M. tuberculosis caused by

the rpoB gene. The use of the signature

sequences in the rpoB gene assumes that there

are not significant numbers of rifampin-resistant

M. tuberculosis strains in the community with

other, uncharacterized rpoB mutations in the

gene.

2 All samples “glow in the dark”—some background signals are detected. This test will only achieve high sensitivity if the signal from the

firefly enzyme is significantly larger than the background signal.
140 | Impacts of Antibiotic-Resistant Bacteria

MRSAs are currently identified by using the

traditional tests discussed in the first part of this

chapter. The performance of these tests may be

variable. Factors such as the inoculum size, incubation time and temperature, pH of the medium,

salt concentration of the medium, and prior exposure to β-lactam antibiotics all influence the

expression of resistance. To complicate matters

further, only some bacteria in a culture may

express methicillin resistance, even if all have

the gene. Taking into account these factors, the

National Committee for Clinical Laboratory

Standards (NCCLS) has recommended guidelines to optimize the detection of resistance.

However, occasional organisms have been isolated that are difficult to characterize by these

methods. The results produced by various methods of disk diffusion and those from agar dilution

methods are often not consistent. In addition, it is

difficult to separate organisms that are highly

resistant due to overproduction of β-lactamase

from organisms that have the mecA gene encoding for an altered penicillin binding protein.

Organisms resistant due to the mecA gene often

require vancomycin therapy, while organisms

resistant due to overproduction of β-lactamase

might actually respond better to treatment with

β-lactam antibiotic/β-lactamase inhibitor combinations than vancomycin.

PCR and DNA-probe techniques have now

been developed to identify the mecA gene. In

general, the studies to date show a high degree of

correlation between traditional and DNA-based

tests and allow accurate classification of highly

resistant and borderline resistant strains.

Guidelines for interpretation of the mecA

detection result will need to be formally

addressed as more laboratories begin to use this

and other genetic methods. Proposals have been

made to regard mecA-positive organisms (both

coagulase-negative staphylococci and S. aureus)

as intrinsically resistant to all antibiotics except

vancomycin and to report immediately all mecApositive results, which can be available well

before results from traditional methods. There

are situations where the mecA-positive organism

does not express resistance clinically and may

respond to β-lactam therapy. It is important to

document these cases carefully to avoid unnecessary use or overuse of vancomycin. Nevertheless, all mecA-positive organisms may be highly

resistant if the organism expresses the mecA

gene. This may lead to treatment failures if β-lactam antibiotics are chosen.

Surveillance and DNA-based diagnostics

Surveillance of genetic mutations in bacteria will

be essential in the use of new DNA diagnostics,

which measure the presence of specific genetic

sequences. Mutations might alter these

sequences, or new genes conferring resistance

may spread. For example, widespread surveillance efforts are necessary to insure that signature sequences represent the majority of

mutations in the rpoB gene that confer rifampin

resistance in M. tuberculosis.

❚ Regulation of Diagnostic Tests

The Clinical Laboratory Improvement Amendments (CLIA ’88) were passed by Congress to

regulate the quality of diagnostic testing. Regulations under CLIA, which became effective in

September of 1992, require all clinical laboratories that perform certain diagnostic tests to register with the federal government and perform

quality control tests and document quality assurance. However, certain tests are “waived” under

CLIA; this means that the test can be performed

in any physician’s office, whether or not the

office is registered under CLIA. Other tests, generally the more complex ones, can be performed

only in offices that comply with the CLIA regulations for laboratories.

The CLIA regulations may be a disincentive

to performing tests. Complying with them

increases the cost of testing and may delay

results. For example, physicians may choose not

to register their offices under CLIA and will

therefore be compelled to send out numerous

tests that they formerly performed. This may

result in the performance of fewer diagnostic

tests, which could contribute to the overuse of

antibiotics. A physician might decide that it is
Chapter 6 New Technologies for Infection Diagnosis and Control | 141

easier and more cost-effective to prescribe antibiotics for all sore throats rather than perform

throat cultures. However, this negative potential

consequence of the CLIA regulations must be

weighed against whatever positive effects they

have had on the quality and consistency of testing that is done in the clinical laboratories that

meet CLIA standards.

❚ Getting New Tests to Market

The worst outcome for a sensitivity test is to

indicate that bacteria are susceptible to an antibiotic when the antibiotic has no effect against that

strain. Such an error, which can result in a

patient’s death, is called a “very major error” in

testing. The second worst outcome is to report

that bacteria are resistant to an antibiotic that is

in fact effective against them. That error, which

could result in treatment with a more toxic, more

expensive antibiotic than necessary, is termed a

“major error” (Jorgensen 1995).

It is impossible to design and perform tests

that are completely error free. The manufacturers, the FDA, health care providers, and the public have to decide what levels of errors are

acceptable. Often, new tests are compared with a

“gold standard”—an older test that has been

proved to be reliable. However, the “gold standard” is also not completely error free. Therefore

it is sometimes difficult to interpret differences

between a new test and a “gold standard.” For

example, culturing M. tuberculosis is considered

the “gold standard” for the diagnosis of tuberculosis. However, Abe, et al. (1993) found that

some patient samples were positive for M. tuberculosis by DNA-based techniques but negative

when cultured; these patients had clinical signs

of tuberculosis, including characteristic radiographs, clinical manifestations of the disease

and/or clinical response to antituberculosis chemotherapy.

Two FDA centers are involved in approving

test methods for antibiotic susceptibility. The

FDA Center for Drug Evaluation and Research

certifies that disks are available for each antibiotic on the market in the United States, and it

assures the potency of the disks and that criteria

for interpretation of the disk assays are available

when an antibiotic goes on the market. The FDA

Center for Devices and Radiological Health has

responsibility for determining the safety and

effectiveness of other devices and materials,

including computer software, for susceptibility

testing.

A new diagnostic device can be reviewed by

FDA under two different procedures. A device or

method that employs principles similar to those

used by products already on the market and that

requires an incubation period of 16 hours or

more is reviewed under the “510(k) clearance”

process. The performance of the new device or

method is compared to the performance of the

product already marketed to determine whether

the two are “substantially equivalent.” If they

are, the new device or method is cleared for marketing without undergoing the more extensive

procedures, known as “pre-market approval.”

The 510(k) process is also used when a manufacturer wants to add a new antibiotic to the battery

of antibiotics already included in a test kit.

New diagnostic tests that are not “substantially equivalent” to any product on the market

must submit an application for “pre-market

approval” (PMA) to the FDA. Because the

approval process under the PMA review is substantially more difficult, manufacturers have a

disincentive to develop novel products.

Any device that requires less than 16 hours’

incubation is required to undergo the pre-market

approval process, which takes longer and is substantially more difficult to complete than the

510(k) clearance process. Jorgensen (1995)

claims that there is no clear justification for the

16-hour incubation period serving as the cutoff

between a 510(k) review and a PMA review

because there is no indication that more rapid

devices are inherently less accurate than others.

The difference in the time required to obtain a

510(k) clearance, as opposed to a pre-market

approval, is a matter of contention. According to

Jorgensen (1995), the requirements for a 510(k)

clearance have grown since 1990, and they are

now approaching those required for a PMA. On
142 | Impacts of Antibiotic-Resistant Bacteria

the other hand, FDA (1995) asserts that there

have been marked improvements in the processing of 510(k) applications.

VACCINES

Perhaps the ultimate weapon against antibioticresistant bacteria is the development of vaccines

and pre-emptive immunization. In concept, vaccines are simple. When a person receives an

inoculation of a preparation of killed or attenuated (“weakened”) disease-causing bacteria or

virus, a component of such an agent, or a related

organism that does not cause disease, the inoculated person’s immune system will respond and

produce antibodies to antigens on the injected

materials. The immune system has a “memory.”

As a result, if the person is subsequently infected

by the organism for which the vaccine was prepared, he or she will produce antibodies that can

inactivate the agent and remove it from the body.

“Natural immunity” is produced in a similar

way; once a person has had a disease, the

immune system recognizes the organism that

caused it and eliminates it from the body.

In practice, preparation of the specific material for the inoculation—the antigen—can be difficult. Preparing it so that the production of

antibody is stimulated without objectionable toxicity, either at the time of inoculation or later,

may not be simple.

The success of Haemophilus influenzae

type B (Hib) vaccines, which were introduced in

1988, demonstrates that antibacterial vaccines

can be quite successful. Countering that great

success is the more than 75 years’ experience

with an antituberculosis vaccine.

❚ Hib Vaccines, a Success Story

Before the introduction of vaccines against it,

Hib (Haemophilus influenzae type B) was the

leading cause of invasive bacterial disease in

children under five years of age, and it caused

about 20,000 cases of meningitis and another

3,000 to 5,000 cases of invasive Hib disease

annually. The mortality rate was 3 to 5 percent;

moreover, up to 20 percent of the survivors of

meningitis suffered hearing loss or mental retardation, and resistance to ampicillin was increasing (Adams, Deaver, Cochi, et al. 1993).

In 1993, five years after the introduction of

Hib vaccines, a number of researchers published

reports about the incidence of Hib diseases in

children up to five years old. Those vaccinated

with Hib vaccine generally had disease rates 80

to 90 percent below the rates seen in unvaccinated children (Wenger 1994). The rates of Hib

meningitis began to fall in 1989, after the introduction of the vaccine, and they continued to fall

through 1991 (the last year for which data were

available). In contrast, the rates of meningitis

from Neisseria meningitidis and Streptococcus

pneumonia remained unchanged, ruling out a

general decline in meningitis as the explanation

for the Hib results. An unexpected result of the

Hib vaccination program was a reduction in the

number of children who carry Hib in their upper

airways. That, in turn, reduced the number of

children who could infect others, and the rates of

Hib disease have fallen in both vaccinated and

unvaccinated children.

A polysaccharide (a polymer of sugar molecules that is unique to the Hib bacteria) vaccine

licensed in 1985 had no effect on the occurrence

of invasive Hib disease in Los Angeles County

(see figure 6-4) and, in fact, it was of little value

in disease prevention. Three years later, a conjugate vaccine, prepared by chemically joining the

polysaccharide to a protein that was known to

stimulate antibody production, was licensed.

This vaccine was very successful. Even when use

of this vaccine was restricted to children older

than 18 months (from 1988 through 1990), there

was a drop in the Hib invasive disease rate in

younger children. Vaccination of the older children had reduced infections of the younger ones,

due to reduced transmission of the bacteria.

Licensing of a vaccine for 2-month-old children

in 1990 led to great reductions in the disease in

Los Angeles County by 1992.
I

I

1 1

1983 1984 1985 1986 1987 1988 1989 1990 1991 1992

SOURCE: Division of Microbiology and Infectious Diseases, National

Institute of Allergy and Infectious Diseases. 1994. Annual Report,

p. 1

❚ BCG Vaccine, 75 Years’ Experience

Albert Calmette and Camille Guerin at the Pasteur Institute in Paris first produced BCG as a

vaccine for the prevention of TB. BCG is made

from preparations of a live, attenuated strain of

M. bovis, which is closely related to M. tuberculosis, and over 70 percent of children worldwide

now receive the vaccine. It is compulsory in 64

countries and recommended in 118 others (OTA,

1993). People who have received this vaccine

typically show a positive response to tuberculin

skin tests. This is considered a great disadvantage in the U. S., where tuberculin skin tests are

used to screen for exposure to tuberculosis.

Colditz, Brewer, Berkey, et al. (1994) reported

the most thorough review of the efficacy of BCG

vaccine. Their meta-analysis of the worldwide

literature led to the conclusion that BCG reduced

the risk of TB by about 50 percent, but the success rate vanes from batch to batch of the vaccine, which is prepared in different laboratories

under different conditions around the world. The

50 percent effectiveness conclusion was chal

ce because oquestos about ts ecacy ad

its usefulness in a population with a low incidence of TB. In 1979 the Centers for Disease

Control and Prevention (CDC) recommended the

vaccine for health care workers in contact with

TB patients, but CDC’s 1988 policy statement

reversed that recommendation because of the

lack of evidence for increased TB among health

care workers (OTA, 1993). CDC recommend

BCG for members of high risk groups who have

limited access to health care. However, the CDC

believes that the rate of tuberculosis is so low in

the general population of the U.S. that the advantages conferred by vaccination are outweighed

by the disadvantage of being unable to screen the

population by using the tuberculin skin test.

❚ Vaccine Research

Successful vaccines are available for use against

viral diseases such as measles, mumps, and

rubella, and against bacterial diseases such as

diphtheria, tetanus, and pertussis (whooping

cough). Currently, researchers are pursuing new

vaccines against bacterial pathogens, such as the

Streptococcus species, Staph. aureus a n d

Helicobacter pylori, which are common problems, in part because of high rates of antibiotic

resistance.

Active Systemic Immunization

Active immunization is the process of administering specific microbial antigens that stimulate

the host’s immune system to produce protective

antibodies. Active immunization can be

systemic-the traditional method—or mucosal

(discussed below). Systemic immunity is accomplished by injection, the result being long-lived

production of circulating immunoglobulin G
144 | Impacts of Antibiotic-Resistant Bacteria

(IgG) antibodies. For bacterial vaccines, polysaccharides from the outside capsule of the bacteria

are generally employed, but as was seen with the

Hib vaccines (Wenger, 1994), capsular polysaccharides alone do not always stimulate sufficient

antibody production. To raise sufficient levels of

antibodies, the polysaccharides may have to be

conjugated with “carrier proteins,” potent immunogens that provoke an immune system response

to the entire complex (i.e., to polysaccharide

antigen and protein carrier). The combination of

polysaccharide and protein is called a “conjugate

vaccine.” Finding the proper carrier is one of the

more difficult aspects of vaccine development,

but four different proteins—all of bacterial origin—work well in Hib vaccines.

Streptococcus pneumoniae vaccines

Vaccine development is further complicated

because different strains of the same bacteria

have different polysaccharide antigens. For

instance, Streptococcus pneumoniae has 84 distinct capsular polysaccharides. A vaccine that

contains 23 different polysaccharides provides

protection against 90 percent of invasive pneumococcal strains (Siber, 1994). That vaccine is

75 percent effective when administered to immunocompetent adults, and its wider use might prevent half of the 80,000 annual pneumococcal

pneumonia deaths among older people (Medical

World News, 1993). It is not, however, reliable

in children under two years of age. For the vaccination of children, several companies are developing conjugated vaccines against the

polysaccharides of the seven strains of pneumococcus that most commonly infect children, and

these are currently undergoing human trials. In

addition, researchers are investigating the possibility of using a polysaccharide that is common

to all pneumococcus conjugated to one or more

of several proteins that are common to all pneumococcus as vaccines, but there is no definitive

evidence for their usefulness (Siber 1994).

Vaccines against otitis media

S. pneumonia is one of several bacteria that cause

otitis media. That illness is so notorious that physicians who surveyed parents about their willingness to have their children immunized against the

disease titled their report “The Surprisingly High

Acceptability of Low-Efficacy Vaccines for Otitis Media...” (Wischnack, Jacobson, Poland, et

al., 1995). Although no such vaccine is now in

use, the interviewers asked about five hypothetical vaccines that had different efficiencies in disease prevention, and side effects that ranged

from the temporary discomfort of a “shot” in all

children to a few days of flu-like symptoms in up

to half of vaccinated children. About half of the

601 interviewed parents would accept any vaccine if it would prevent three or more infections

in the next six months. Parents were less accepting of vaccines with lower efficiencies and worse

side effects. The authors of the study conclude

that parents, even of children who have not had

otitis media, are willing to accept some discomfort in their children to obtain protection against

the disease and that parents’ willingness is

greater than the medical establishment’s or

FDA’s.

A biotech firm, MicroCarb (Bethesda, Maryland), has licensed one vaccine against Haemophilus influenza, another cause of otitis media, to

Pasteur Merieux Serums et Vaccines S.A. If this

vaccine proves successful, it will be of value

against both antibiotic susceptible and resistant

H. influenza, which are increasingly common.

Staphylococcus aureus vaccines

Vaccines against Staph. aureus, which is often

antibiotic resistant, would be helpful to patients

at high risk for infection with this organism,

including renal dialysis patients, or patients

receiving prosthetic devices like hips or vascular

grafts, which act as sites for infection (Univax,

1994). Researchers are pursuing vaccines made

of capsular polysaccharide types 5 and 8, which

would encompass 90 percent of Staphylococcus

systemic infections. Recent research has shown

that high levels of biologically active antibodies

against Staph. aureus types 5 and 8 can be stimulated in human subjects when the antigens are

combined with a protein from P. aeruginosa as
Chapter 6 New Technologies for Infection Diagnosis and Control | 145

the carrier (Fatton, et al., 1990; Fatton, et al.,

1993).

Active Mucosal Immunization

The second approach to active immunization is

to stimulate the immune defenses of the mucosal

linings of the gastrointestinal, respiratory and

urogenital tracts, the nasal passages, and the

inner ear. These mucosal linings produce immunoglobulin A (IgA). IgA diminishes microbial

virulence by preventing microbial adherence to

host cells. It also coats the surface of the antigen,

making an antigen/IgA complex that stimulates

white blood cells to recognize, engulf, and

destroy any pathogen expressing that antigen.

Mucosal lymphocytes also trigger production of

circulating IgG antibodies. Current targets for

mucosal immunity include Helicobacter pylori,

Clostridium difficile, Shigella flexneri, Campylobacter strains, and certain strains of Escherichia

coli.

Mucosal vaccines are immunogenic only if

they reach specific immune response tissues

beyond the stomach, which requires their surviving passage through stomach acid and enzymes.

Some researchers are testing synthetic polymers

to protect their vaccines. Another strategy is to

use liposomes, lipid-containing vesicles made

from the same natural materials that compose

mammalian cell membranes.

Helicobacter pylori vaccines

The discovery by Marchetti, Arico, Burroni, et

al. (1995) that bacteria isolated from humans

with ulcers could infect mice and cause disease

processes that mimic those seen in humans has

spurred progress toward a vaccine against H.

pylori, the causative organism. Those researchers

found that mice were protected from infection

after administration of disrupted H. pylori bacteria. This finding, characterized as “of extreme

practical importance” (Tompkins and Falkow

1995) may lead to a vaccine to protect the

50 percent of the world’s population that are currently infected by H. pylori. While H. pylori is

most often associated with gastritis and ulcers in

the United States, elsewhere in the world it is

also a common cause of stomach cancers.

Campylobacter vaccines

Campylobacter strains have recently emerged as

one of the common causes of diarrhea and may

cause 2.5 million cases annually in the United

States. Treatment is increasingly complicated by

antibiotic resistance. In 1994, the U.S. Navy

signed a Cooperative Research and Development

Agreement (CRADA) with MicroCarb Inc. for

clinical trials of a vaccine against Campylobacter.

Passive immunization

Passive immunization involves administering

antibodies directed against specific pathogens to

individuals who have not developed such antibodies on their own but who are at risk for infection. This may be due to lack of prior exposure to

the pathogen, or due to immunosuppression,

which renders the individual’s immune system

unable to produce antibodies. The antibodies are

purified from the blood of healthy donors whose

antibody levels are raised by active immunization. The most common example of passive

immunization is the administration of Hepatitis

B virus-specific gamma-globulin to travelers.

Researchers are currently focusing efforts to

develop antibodies against Staph. aureus and P.

aeruginosa, both of which are often antibiotic

resistant, as well as against other bacteria.

Passive immunization does not always work.

Low birthweight babies are at high risk of nosocomial infections because of long hospitalizations and immature immune systems. Injections

of pooled human antibodies (“immune globulin”) into very low birthweight babies did not

reduce the incidence of nosocomial infections

compared to the incidence in very low birthweight babies who did not receive the immune

globulin (Fanaroff, Korones, Wright, et al.,

1994). This failure does not invalidate the idea of

passive immunization, even in low birthweight

babies, but it underlines the importance of trials

of the efficacy of interventions before they are

introduced widely into practice.
146 | Impacts of Antibiotic-Resistant Bacteria

Vaccine Summary

Vaccines are not high-profit items. UNICEF estimates that the entire global vaccine market is

about $3 billion, which can be compared to the

$3.5 billion market for a single ulcer drug. While

vaccine development against bacteria that have

high frequencies of antibiotic-resistant strains,

such as Staph. aureus or S. pneumonia, would

reduce infections by those bacteria, few vaccines

will be developed for bacteria solely because of

the problems raised by antibiotic resistance.

Instead, the general problems raised by the bacteria may lead to development of a vaccine that

will protect against both antibiotic susceptible

and resistant strains.

STIMULATING THE IMMUNE SYSTEM

Granulocyte colony-stimulating factor (G-CSF)

is a growth factor that stimulates the proliferation

of neutrophil cells, important components of the

immune system. Crawford, Ozer, Stoller, et al.

(1991) have shown that the administration of GCSF to cancer patients on chemotherapy led to a

51 percent reduction in culture-confirmed infections, a 47 percent reduction in the mean number

of days of antibiotic use, and a 45 percent reduction in the mean number of days of hospitalization. G-CSF in the form of filgrastim (Amgen,

Thousand Oaks, California) has been approved

by the FDA and is clinically available.

TARGETED DELIVERY OF ANTIBIOTICS

Some sites of infection or potential infection are

localized, such as wounds or the area around a

joint replacement. Delivery of antibiotics directly

to those sites may stop the growth of susceptible

bacteria, and if the concentration can be raised

high enough, it may even stop the growth of

many resistant bacteria. Direct delivery of antibiotics in this way has the additional advantage of

producing only very low levels of circulating

antibiotics, thus reducing pressure for the selection of resistant bacteria elsewhere in the body.

❚ Microencapsulation

Entry into the body, whether surgical or traumatic, opens pathways for infection. Surgical

patients who develop wound infections spent, on

average, 14.3 days longer in the hospital than

uninfected matched controls (Maderazo, Judson,

and Pasternak, 1988), at an increased cost of

$36,000 to $45,000 per patient (Cohen, 1994;

Daly, Eliopoulos, Reiszner, et al., 1988).

Twenty-four percent of United States servicemen

who sustained open fracture wounds in Panama

during Operation “Just Cause” developed wound

infections (Jacob, Erpelding, and Murphy, 1992),

and 48 percent of wounded United States soldiers in the Persian Gulf conflict who sustained

open fractures developed postoperative infections (Travis and Cosio, 1993). Gustilo, Mendoza, and Williams (1984) report similar

infection rates in civilians with severe open fractures of the tibia. Many of these infections occur

in patients who receive very large doses of systemic antibiotics.

Researchers at the Walter Reed Army Institute

of Research (WRAIR) have developed a novel

biodegradable local antibiotic delivery system

that promises to decrease infections in wounds.

They encapsulate an antibiotic in a copolymer of

poly (DL-lactide-coglycolide) to produce microspheres 50 to 250 micrometers (μm) in diameter.

Dusted into wounds after surgery, these microspheres provide an initial burst of the antibiotic

within the first few hours and prolonged drug

release over a period of up to 21 days. After 2 to

3 months, the microspheres completely degrade.

As of March 1995, the WRAIR researchers had

constructed microspheres containing ampicillin,

cefazolin, cefamandole, and tobramycin.

Cefazolin-containing microspheres were used

to treat wounds in rats that had been intentionally

infected with cefazolin-resistant MRSA, and

they were as effective as free cefazolin powder in

eliminating MRSA. Systemic administration of

cefazolin, on the other hand, had no effect on the

MRSA infections. In a similar experiment

involving ampicillin-resistant MRSA, microspheres containing ampicillin were more effec-
Chapter 6 New Technologies for Infection Diagnosis and Control | 147

tive than free ampicillin powder, and systemic

ampicillin had no effect.

The United States Army, which developed

this technique (Setterstrom, Tice, and Myers,

1994; Jacob, Setterstrom, Bach, et al., 1991;

Jacob, Cierny, Fallon, et al., 1993), has a patent

pending on it. Further development will require

private funding to take the research from the preclinical stage to trials in humans.

❚ Antibiotic-Impregnated Cement

Bone infections and infections of joint prostheses

are hard to treat with systemic antibiotics, partially because limited blood flow to the skeletal

tissues does not allow high concentrations of the

drug to reach the area of infection. An antibioticimpregnated polymer, poly (methyl-methacrylate) (PMMA), has been used to cement bone

fractures and prostheses in place, and has shown

clinical success, but its usefulness is limited by

the toxicity of the material and shrinkage which

leaves marginal mechanical support for the

remaining bone. Yu, et al. (1992) described

hydroxyapatite (HAP) cement, which has the

same chemical composition as bone mineral.

This material can be molded to fill the space left

by the absence of bone, and Yu, et al. demonstrated that antibiotics impregnated in this material are slowly released. They concluded that this

material is very promising for preventing infections in bone fractures and in joining prostheses,

and they propose future in vivo experiments.

❚ Biological Substances to Facilitate the 

Entry of Antibiotics into Bacteria

One mechanism of resistance involves bacterial

cell walls in excluding antibiotics from the bacterial cell. Research is underway on biological substances that allow antibiotics to penetrate into

such bacteria. For example, because iron is insoluble but necessary for bacterial metabolism, bacteria synthesize and excrete compounds that can

bind iron ions, called “siderophores.” These

compounds scavenge iron outside the cell, and

the cell then transports the iron-siderophore compound back inside the cell. Inside the cell, the

iron-siderophore complex is metabolized by the

bacteria, releasing iron for bacterial use. Siderophores may be modified to carry antibiotics into

the bacteria. These may be especially useful in

the treatment of Gram-negative bacterial infections. Although the outer cell membrane channels (“porins”) of Gram-negative bacteria are too

small to accommodate many antibiotics, siderophores enter the cell via a non-porin route, and

researchers reason that antibiotics attached to

siderophores might be “dragged” inside.

Over 200 siderophore molecular structures are

known. Often, only portions of the siderophores

are required to penetrate the cell. One goal of

current research is to optimize synthetic siderophores in order to make their transport into

bacterial cells more efficient. Synthetic siderophores, when conjugated with beta-lactam antibiotics or erythromycin, can carry the antibiotic

across bacterial cell membranes with high efficiency. These antibiotics kill bacteria when

delivered inside the cell in this manner (Miller,

1989; McKee, Sharma, and Miller, 1991).

Siderophores are also being explored for their

potential to transport vancomycins. Although

siderophore/antibiotic conjugates have thus far

been used only as antibacterials, researchers are

currently attempting to apply the same methodology to antifungal/siderophore conjugates.

REDUCING INFECTIONS BY 

MODIFYING DEVICES

Several hundred thousand cases of hospital

acquired infection per year are related to the use

of medical devices such as catheters, endotracheal tubes and mechanical ventilators (IOM,

1992). These devices provide extra opportunities

for bacteria to enter the body. Experience with

dialysis, the filtering of the blood of patients with

kidney disease, indicates that changing the

design and materials of medical devices can minimize infections.

❚ Infections in Dialysis Patients

In 1991, there were approximately 120,000

patients on maintenance dialysis (Favero, Alter,
148 | Impacts of Antibiotic-Resistant Bacteria

and Bland, 1992) with 45,000 new patients

added per year. Infections are the cause of death

in 15 to 30 percent of dialysis patients.

The technique called hemodialysis is used to

treat approximately 85 percent of dialysis

patients. Simulating the function normally performed by the kidney, it filters the patient’s

blood through a membrane which separates out

unwanted components and adds needed components. Cupraphane membranes, the most commonly used filtration membrane in hemodialysis,

are made from cotton fibers dissolved in an

ammonia solution of cupric oxide. Recently,

membranes made of synthetic polymers such as

polysulfone (PS), polymethylmethacrylate

(PMMA) and polyacrylonitirile (PAN) have

been developed. A recent review of the properties of hemodialysis membrane (Hakim, 1993)

describes how the interaction of blood with cotton fiber membranes such as Cupraphane produces a decrease in the immune functions in the

blood, leaving the patient more susceptible to

infection. The membranes made of synthetic

polymers do not seem to decrease the immune

functions in the blood. Retrospective studies

showed that replacing a Cupraphane membrane

with a polysulfone membrane eliminated

50 percent of the infections.

Another 15 percent of patients are on peritoneal dialysis. In this technique, fluid is pumped

into the patient’s abdomen, allowing exchange of

blood components through the peritoneal lining

of the abdomen. A recent review (Diaz-Buxo,

1993) shows that the incidence of peritonitis

(peritoneal infection) was twice as high when

older CAPD (continuous ambulatory peritoneal

dialysis) machines were used than when new

dialysis machines of different design, such as

CCPD (continuous cyclic peritoneal dialysis)

machines and Y-set connections for CAPD, were

used. This may be because the order of flow is

reversed in CCPD and Y-set CAPD compared to

other forms of CAPD, so that the connections

(and contaminating bacteria) are washed out

before fluid is pumped into the body. Diaz-Buxo

comments that CAPD machines are more common than CCPD machines, partially because of

the lower cost of the machine itself. When the

total costs of the two systems were calculated,

including the cost of the machine and the cost of

hospitalization for peritoneal infections, the total

costs were the same (King, et al., 1992).

Analyzing the costs of dialysis for kidney

patients is especially interesting because dialysis

patients have been covered by Medicare since

1973 regardless of their age. Medicare pays a set

amount per patient for dialysis and pays separately for any hospitalization necessitated by

complications. Under this system, physicians

have a financial incentive to use the least expensive equipment. However, it would be beneficial

to the patients, and probably cheaper for Medicare, to use the more expensive equipment and

prevent infections that may require hospitalization. Outpatient costs, primarily dialysis,

accounted for 33 percent of total costs compared

with 44 percent of total costs attributable to hospitalizations (Smits, 1995). (The remainder of the

costs were for physician services, skilled nursing

care, and home health care.) This demonstrates

that investing in new technologies that prevent

infections and hospitalizations can be cost-effective. These investments would also reduce antibiotic resistance by preventing infections and thus

reducing the use of antibiotics.

❚ Infections from Sutures and Catheters

Improvements in the materials used for other

medical devices such as sutures and catheters

could also greatly reduce the rate of infection. In

particular, sutures made of synthetic materials

such as dacron and nylon have lower infection

rates compared to natural sutures such as cotton,

silk and catgut, and monofilament sutures have

lower infection rates compared to polyfilament

sutures.

Studies of the colonization of medical devices

by coagulase-negative staphylococci (Christensen, Baldassarri, and Simpson, 1994) provides

some insight into why some suture materials are

associated with infections more than others. The

process of colonization of non-biological surfaces by coagulase-negative staphylococci is
py, 

surprising that the natural materials and polyfilaments are more often associated with infections

than the synthetic materials and monofilaments.

Knowledge about the colonization and infection

process for non-biological materials will help

guide new designs of medical devices that may

minimize infections and reduce the need for antibiotics.

Maki (1 994) reviewed innovative designs that

help prevent infections in intravascular catheters

used for infusion therapy. Some catheters have a

new design that creates mechanical barriers

against infection at the entrance of the catheter to

Like the microencapsulated antibiotics and antibiotic-impregnated cement, these coated catheters may have the advantage of delivering high

concentrations of antibiotics to the site of potential infection with much lower systemic antibiotic concentrations. In one system, the catheters

are coated or impregnated with silver ions, which

are bactericidal but non-toxic to humans. (Manufacturers include Arrow International and C.R.

Bard Urological Division; Maki, et al., 1991;

Stamm, 1991). In another system, catheters are

coated with materials bearing positively charged

chemicals, to which negatively charged antibiotSeries of four microphotograph demonstrating the colonization of a non-biological surface.

Courtesy of Meryl E. Olson, University of Calgary, Calgary, Canada

4
150 | Impacts of Antibiotic-Resistant Bacteria

ics are bound (Cook Bio-Guard AB coated catheters, Cook Critical Care). A trial with these

catheters coated with cefazolin showed a sevenfold decrease in the infection rate (Kamal,

Pfaller, Rempe, et al., 1991). Further, a reduction

in the infection rate was seen even if the catheters were changed only once every seven days

(compared to once every four days for standard

catheters; Kamal, Divishek, Adams, et al., 1994).

The longer life of the coated catheter compensates for its higher cost (about $4.50 more per

catheter).

OLD THERAPIES

In the pre-antibiotic era, scientists and physicians

tried different methods to treat bacterial infections. Two of those methods, “phage therapy”

and “serum therapy,” are now mentioned as possible treatments in a post-antibiotic era.

❚ Phage Therapy

While most people may not recognize the term

“phage therapy,” many people read about it in

Arrowsmith. The hero of that novel tried to treat

bacterial infections by the use of viruses that

would specifically attack the bacteria, and in real

life, many physicians tried the same method in

the early part of this century. Because viruses

that infect bacteria are called “bacteriophages”

(literally, eaters of bacteria) or “phages” for

short, the treatment is called “phage therapy.”

Phage therapy has remained outside the mainstream of medicine because of doubts about its

efficacy and the success of antibiotics.

Phages recognize specific binding sites on the

bacteria. Therefore, phages that infect E. coli

generally do not infect other bacteria, and, in

fact, sometimes will only recognize a single

strain of bacteria. This specificity offers the

promise of being able to prepare phages to attack

particular bacteria.

Levin and Bull (1995) and Levin, DeRouin,

Moore, et al. (1995) review the literature about

phage therapy. They focus on some recent experiments with systems that involve mice infected

with E. coli and argue that phage therapy is

worth renewed investigation. While they do not

think that it will replace antibiotics, they believe

that it may have some future use in treating antibiotic-resistant bacteria. They also argue that the

time to develop alternatives to antibiotic therapy

is now, when antibiotics remain effective against

most diseases.

❚ Serum Therapy

Textbooks of medicine and of microbiology published before 1940 are filled with instructions for

serum therapy. In some respects similar to passive immunization, serum therapy involves taking blood serum from horses or rabbits that have

survived an intentional bacterial infection and

injecting it into a patient suffering from an infection by the same organism.

Serum is still used in the treatment of some

diseases that involve bacterial toxins; in particular, tetanus and botulism are treated with horse

serum. Serum for the treatment of botulism is

kept at several major airports around the country,

ready for shipment to hospitals that diagnose the

rare disease. (According to the CDC [1979],

there were about 10 outbreaks of botulism,

involving about 2.5 people per outbreak, each

year in the period 1899 through 1977.) For other

infections, serum therapy was replaced as antibiotics became available. A patient’s possible anaphylactic response to chemical substances in the

animal serum is the chief danger.

Serum therapy may have application in treating Escherichia coli O157:H7, which became

famous as the cause of more than 500 cases of

disease and perhaps four deaths in people who

ate under-cooked fast-food hamburgers in the

Pacific Northwest in early 1993. The usual treatment for the disease does not include antibiotics

(Salyers and Whitt, 1994). Antibiotics have not

been shown to shorten the course of the disease

or to reduce the occurrence of kidney complication. Further, antibiotic treatment may cause the

bacteria to increase the production of the bacterial toxin that causes the disease. The cause of

disease in E. coli O157:H7 infections is a toxin

that resembles the Shigella toxin that causes dys-
Chapter 6 New Technologies for Infection Diagnosis and Control | 151

entery. That toxin has been isolated and purified.

Antibodies generated against the toxin have

potential in treating E. coli O157:H7-caused diseases, but the market for such a drug is small,

and no trials are in progress.

SUMMARY

This chapter reviews some new technologies that

will help health care providers use antibiotics

more effectively. Diagnostic technologies help

the clinician identify the specific bacteria causing the infection and its susceptibility to antibiotics. This information is critical for choosing the

most appropriate antibiotic. New technologies,

such as DNA identification of antibiotic resistance genes, have the potential to provide this

information more quickly than is possible with

traditional diagnostic tests, which require growing the bacteria in cultures. These new diagnostic

technologies have already proven useful in diagnosing tuberculosis. Many companies are rapidly

developing additional tests for TB and other bacteria. There are unresolved issues with respect to

the accuracy, sensitivity, and reproducibility of

these tests. These issues may not be resolved

until the tests have received FDA review and are

widely used in clinical settings. This chapter discusses some of these issues.

Preventing infections is another way to slow

the increase of antibiotic-resistant bacteria

because prevention will reduce the total use of

antibiotics. Methods of preventing infection

include vaccines and changes in the design and

composition of medical devices to prevent the

growth of bacteria. The recent introduction of a

vaccine against Hemophilus influenza B resulted

in a dramatic reduction in the incidence of childhood diseases caused by this bacteria. A number

of other vaccines are under development, including those for Staphylococcus aureus, as well as

better vaccines for Streptococcus pneumoniae.

Indwelling devices and sutures are often ports of

entry for bacteria into the body, and improved

devices and materials have been shown to reduce

infection rates. Further research and application

could produce further reductions.

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| 155

7

Antibiotics in

Animal

Husbandry

hat effect does the use of antibiotics

in food production have on the

occurrence of antibiotic-resistant

bacteria? Everyone concerned with

that question agrees about a few things: About

half of the antibiotics (by weight) used in the

United States are used in the production of food

animals, much smaller amounts are used to control bacterial diseases in plants and in fish farming, and some proportion of the bacteria that are

present in and on food may survive cooking or

other preparation in the food eaten by humans.

Beyond such small areas of agreement, there is

widespread disagreement, or so it would seem. In

fact, the real questions about the transfer of antibiotic-resistant bacteria from foods to humans

are how often does it happen and what are its

consequences, rather than does it happen at all.

The chairman of a National Research Council

(NRC) advisory panel that looked at the question

neatly posed a scenario for the risks from use of

antibiotics in farm animals:

...a beef producer feeds tetracycline in low

doses to his calves to encourage rapid weight

gain; nonpathogenic Escherichia coli in the guts

of the calves acquire antibiotic resistance.

Somewhere along the chain from feedlot to

dinner table, the E. coli may come into close

association with some salmonella, and the salmonella may acquire resistance to antibiotics by

plasmid transfer. The meat eater becomes

infected, develops Salmonella septicemia and

dies while his physicians are treating him with

an inadequate antibiotic (Stallones, 1982).

The scenario is clearly stated, but how often

does it occur? That question could be answered

by identifying people who harbor antibioticresistant bacteria and linking those bacteria to

meat that was derived from antibiotic-treated

animals. That has proved impossible to do; there

are many possible sources for bacteria, each one

would have to be eliminated, and it is difficult to

trace the origins of “meat” as it arrives at a

butcher shop or supermarket. “[S]ome studies

can be conceived but cannot be delivered” (Stallones, 1982). 

In the absence of definitive information, disagreements about the significance of antibiotic

use in agriculture on the emergence of antibioticresistant human pathogens have fostered several

reviews and analyses of the data about animal to

human transfer of antibiotic-resistant bacteria.

Congress requested an Office of Technology

Assessment (OTA) study, Drugs in Livestock

Feed, that reviewed risks and benefits of antibiotic (and other drug) use in agriculture including

W
156 | Impacts of Antibiotic-Resistant Bacteria

the risks of increasing the prevalence of antibiotic-resistant bacteria in humans (OTA 1979).

OTA did not reach a hard and fast conclusion

about the magnitude of the risk. Instead, it put

that risk in context by comparing it to the risk of

antibiotic resistance developing as a result of

antibiotic use in medicine, and concluded that the

risk exists, but that it is less than the risk from

uses of antibiotics in humans: 

The risk from resistant plasmids of animal

origin is not quantifiable....The majority of

resistance in human bacterial populations is

probably caused by widespread use of antibacterials in humans (some of which are unnecessary), but the enormous pool of R-plasmids that

now exist in animals, together with the ability

of an R-plasmid to be promiscuously transferred among bacterial species, must be

regarded as a threat to the therapeutic value of

antibacterials in the treatment of both human

and animal diseases. (U.S. Congress, Office of

Technology Assessment 1979, p. 7)

A year later, an NRC committee (1980)

reached a similar conclusion, and painted a bleak

picture about the possibility of learning more:

After reviewing the evidence, the committee

concluded that the postulations concerning the

hazards to human health that might result from

the addition of subtherapeutic antimicrobials to

foods have been neither proven nor disproven.

The lack of data linking human illness with subtherapeutic levels of antimicrobials must not be

equated with proof that the proposed hazards do

not exist. The research necessary to establish

and measure a definite risk has not been conducted, and, indeed may not be possible.

In contrast to the report’s conclusion that suggests the possibility of a link between uses of

antibiotics in animals and human health, the

chairman of the NRC committee, in a later publication, downplayed any risk: “If the decision

were mine, the hog farmers could use all the antibiotic drugs they wish to make the pigs grow.

The risk to humans looks to me to be vanishingly

small” (Stallones, 1982). Not everyone shared

that opinion, and studies and reviews have continued to the present time.

Almost a decade later, the Institute of Medicine (IOM) issued a report that dealt with the

risks from subtherapeutic use of two common

antibiotics—penicillin and two kinds of tetracyclines (oxytetracycline and chlortetracycline)—

in animal feeds (IOM, 1989). Its authors further

narrowed the focus of the report to the risks of

antibiotic-resistant Salmonella from animal

sources causing human deaths. The authors calculated that, 

“The likeliest estimate of excess deaths attributable to subtherapeutic uses of penicillin and/or

the tetracylines...is in the range of 6 per year.”

The committee also considered the difficulties

that might arise in treating antibiotic-resistant

Salmonella infections in humans and calculated

that,

“The likeliest estimate of deaths...arising

because of ‘increased difficulty of disease treatment’ is 20 per year.”

At the same time, the committee acknowledged

that it

“was unable to find a substantial body of direct

evidence that established the existence of a definite human health hazard in the use of subtherapeutic concentrations of penicillin and the

tetracyclines in animal feeds.”

The controversy over the health effects of

antibiotic use in animal husbandy has spawned

several expert committee reviews that have clarified the issue somewhat (see table 7-1 for a listing of review bodies other than the three

mentioned above). There is no doubt that risk

exists. There is also no doubt that direct evidence, in the form of studies that show a direct

connection between agricultural use of antibiotics and human illness or death, is sparse and

difficult to obtain. Moreover, if the IOM committee’s estimate of the number of deaths caused

by antibiotic-resistant Salmonella of agricultural

origin is in the right range, determining what proportion of the 40,000 cases of reported Salmonella infection each year is related to agricultural

use of antibiotics is probably impossible.
Chapter 7 Antibiotics in Animal Husbandry | 157

Levy (1992, pp. 136–157) summarizes studies

that show that bacteria are transferred from farm

animals to farm workers, as well as a few studies

that show transfer of bacteria to the human community beyond the farm. These studies, however,

leave unanswered questions about the quantitative importance of such transfer in the spread

of antibiotic-resistant bacteria and, especially,

how important such transfer is in comparison to

medical use (and overuse) of antibiotics. 

OTA does not, in this single chapter of a general report about antibiotic-resistant bacteria,

attempt to resolve an issue which has persisted

for more than two decades. This report does,

however, contain a description of antibiotic uses

in animal husbandry and some other aspects of

agriculture, an update of some research findings

since the release of the 1989 IOM study, and a

discussion of a current regulatory proceeding

TABLE 7–1: Reviews—Antibiotics in Animal Feeds

1968 Netherthorpe Committee.

1969 British Government Joint Committee (“Swann Report”).a

1970–1977 FDA makes several reviews of antibiotic use in animal feeds.

1977 FDA directs its Center for Veterinary Medicine to prepare notice of withdrawal of penicillin and 

tetracyclines from subtherapeutic uses.

FDA publishes proposals to restrict subtherapeutic uses. Proposals criticized because of reported 

inadequate evidence for adverse effects from such uses.

1978 Congressional request to the National Academy of Sciences (NAS) for a study by the National Research 

Council (NRC) of the effects of subtherapeutic uses.

FDA Draft Environmental Impact Statement on the Banning of Penicillin and Tetracycline from Animals 

Feeds.b

1979 OTA Report on Drugs in Livestock Feed.c

1980 NRCd reports that data neither prove nor disprove human health effects from subtherapeutic uses.

1981 House Appropriations Committee provides funds to FDA to study antibiotic in feed issue.

1984 FDA-sponsored study completed. No regulatory action taken.

The Natural Resources Defense Council (NRDC) petitions the Secretary for Health and Human Services 

(HHS) for suspension of subtherapeutic uses because such uses pose an “imminent hazard.”

House Committee on Science and Technology holds hearings on the NRDC petition and results of FDAsponsored study.

FDA Commissioner holds hearings on same subjects.

1985 Secretary of HHS denies NRDC petition.

1987 FDA makes request to the NAS for a quantitative assessment of the risks from subtherapeutic uses. 

NAS assigns study to the Institute of Medicine (IOM) 

1989 IOMe concludes that there is no definitive evidence of adverse effects although such effects may exist.

Council for Agricultural Science and Technology (CAST) report.f

1994 FDA review of fluoroquinolone use.

a A subcommittee of the Netherthorpe Committee. Its recommendation results in the United Kingdom forbidding the agricultural use of 

antibiotics used in human medicine.

b Feinman, S.E. and J.C. Matheson, 1978.

c OTA, 1979. 

d National Research Council, 1980.

e Institute of Medicine, 1989.

f Hays and Black, 1989.

SOURCE: Adapted from U.S. Food and Drug Administration. 1993. Information for Consumers: Antibiotics in Animals Feeds. Photocopied 

typescript and other sources.
158 | Impacts of Antibiotic-Resistant Bacteria

about approving of fluoroquinolone antibiotics

for use in food animals.

ANTIBIOTIC USE IN FOOD PRODUCTION

Everyone, whether a city dweller or farmer,

knows about antibiotic uses in medicine. Doctors

prescribe antibiotics to treat diseases, in advance

of certain surgical procedures to prevent infection, and, sometimes, as prophylaxis during dental procedures to prevent infections in people

with heart valve abnormalities. In all these cases

the administration of the antibiotic is overseen by

a physician.

Paralleling physicians’ practice in humans,

veterinarians use antibiotics to treat infectious

diseases in food (and companion) animals.1 But

from there on, things are different on the farm.

There are differences in medical and veterinarian

diagnostic laboratories, and veterinarian diagnostic laboratories reportedly do not meet the same

standards for accuracy and reliability as do medical laboratories (Walker, 1994). Currently, however, practices are changing in veterinary

laboratories, and the National Commission for

Clinical Laboratory Standards has recently published the first guideline document for detecting

antibiotic sensitivity in animal pathogens. Lack

of laboratory quality assurance is not, however,

the major difference between uses of antibiotics

in animals and humans.

The major difference is that about 90 percent

of all the antibiotics used in food animals is used

in subtherapeutic doses and not for the treatment

of sick animals. For instance, in 1985, veterinarians used about 1 million kilograms (about 2.2

million pounds or 1,100 tons) of antibiotics to

treat diseases in cattle, swine, and poultry. During the same year, farmers fed about 5 million

kilograms of antibiotics to cattle, swine, and

poultry for “disease prevention,” and another 2

million kilograms for “growth promotion” (table

7-2). The estimated total of all antibiotics used in

1 “In fact, it has been said that the definition of a physician is a veterinarian with a limited knowledge that restricts his practice to a single

species.” (Walker, R. 1994. Remarks at U.S. Food and Drug Administration, Part 15 Hearing: Surveillance Systems for Antibacterial Resistance, Rockville Civic Center, Rockville, MD, November 10.)

cattle, swine, and poultry in that year was 8 million kilograms, or 18 million pounds.

“Disease prevention” describes prophylactic

actions taken to stave off the spread of a disease.

If a poultry producer notices that a few chickens

are ill and he suspects that the illness is caused

by bacteria, he could add antibiotics to the feed

or water in an effort to stop the spread of the disease. These decisions can be made by the poultry

producer acting alone without any involvement

of a veterinarian.

“Growth promotion” is a little-understood

effect from feeding low levels of antibiotics, generally at a rate of 200 grams or less of antibiotic

in each ton of feed. How such levels of antibiotics affect growth is not clear; they may ward off

undetectable but consequential, minor infections,

or they may have other effects. 

Both disease prevention and growth promotion are long-term uses, and the U.S. Food and

Drug Administration (FDA) uses 14 days as the

threshold for long-term use. When a company

requests approval for longer-than-14-day use,

FDA requires the company to demonstrate that

such use will not increase the shedding of Salmonella (through feces) that might infect humans

and that it will not increase the number of antibiotic-resistant bacteria that contaminate carcasses.

FDA (1995) has stated that submissions of

requests for approval of long-term uses of antibiotics are decreasing, being replaced, in part, by

requests for approval of somatotropins and other

growth-promoting substances. More specifically,

R.H. Teske of FDA (1995) has stated that, “It is

not likely that FDA will see applications for

long-term use of antibiotics that have therapeutic

uses.” 

There is so much overlap between prophylactic uses and doses and growth-promotion uses

and doses that the division between the two

applications that is shown in table 7-2 must be

regarded as uncertain. Furthermore, the estimates
Chapter 7 Antibiotics in Animal Husbandry | 159

of agricultural use shown in table 7-2 are some

30 percent higher than the estimates produced by

the Animal Health Institute for the same year

(IOM, 1989, p. 74).

The data in table 7-2 are from 1985, and OTA

looked for newer data as part of this report. The

only source was a commercial firm that requires

purchases of data to join a syndicate, and, as a

condition of membership in the syndicate, the

purchaser is not allowed to publish the data.

OTA did not purchase those data, but experts in

the Center for Veterinary Medicine of FDA

assert that agricultural uses of antibiotics continue to decline (FDA, 1995).

Most of the antibiotics used in subtherapeutic

applications were “old” antibiotics, and penicillins and tetracyclines accounted for 84 percent of

antibiotics sold for use in animal feeds in 1985.

Some other antibiotics are used only in animals

and not in human medicine. These uses make the

development of resistance to an antibiotic that is

currently used in human medicine less likely.

They do not, however, guard against the possibility that a drug closely related to one used in animals will be developed for human use. In that

case, resistance to the animal drug, if transferred

to bacteria that infect humans, might be crossresistant to the human drug and reduce its efficacy.

There is an example of possible cross resistance in Europe. In the United States vancomycin-resistant Enterococci (VRE) are found

largely, if not exclusively, in large hospitals. In

Europe, they are also found in the feces of nonhopitalized patients and of healthy persons, as

well as in waste waters, farm animals, and some

food products. A glycopeptide called “avoparcin,” which is chemically related to vancomycin,

has been used as a growth promoter in animal

feeds in Europe since the mid-1970s. Bates et al.

(1994) reported that VRE were present in fecal

materials from farm animals on German farms

where avoparcin was used and not present on

farms that did not use avoparcin, suggesting that

use of the growth promoter was selecting for

vancomycin-resistance in Enterococci. Moreover, VRE of the species that infect humans were

found in poultry sold in retail markets (Bates et

al., 1994; Klare et al., 1995).

Acting on reports of VRE in chickens that had

been fed avoparcin, Denmark has banned the use

of the drug, and it is now petitioning the European Union to ban it also. Sweden banned use of

all growth-promoting antibiotics several years

ago. To reduce the emergence and spread of

VRE, Murray (1995) urges decreasing use of

glycopeptides in animal husbandry and restricting vancomycin use to essential applications in

medical practice. 

ANTIBIOTIC-RESISTANT 

BACTERIA IN HUMANS

“While the number and types vary from day-today, at any moment in time over 40 percent of

people have some antibiotic-resistant bacteria in

their colon” (Gorbach, 1993). In the vast majority of cases, these antibiotic-resistant bacteria

appear to cause no harm, and they usually constitute a minute proportion of the total bacteria in

the intestines, probably one antibiotic-resistant

TABLE 7–2: Estimated Annual Use of Antibiotics in Livestock, 1985

All Antibiotics (thousands of kilograms)

Therapeutic Use Subtherapeutic Use

Disease Prevention Growth Promotion Total

Cattle 458 1100 340 1898

Swine 250 3578 1391 5219

Poultry 304 580 315 1199

Total 1112 5258 2046 8316

SOURCE: IOM, 1989, p. 75.
intestine, and that their numbers fluctuate as a

result of the opposing effects of ingestion and

elimination. That benign situation can be

changed by antibiotics, of course. If a person taking an antibiotic ingests Salmonella that are

resistant to that antibiotic, the ingested bacteria

will have a growth advantage over the other bacteria. In that case, they may multiply to become a

major component of the intestinal flora and cause

disease.

Figure 7-1 shows the numbers of tetracyclinesensitive and tetracycline-resistant Escherichia

coli in feces collected from a volunteer over a

41-day period. During the first 21 days, the volunteer ate a regular diet, and the number of sensitive and resistant bacteria fluctuated daily. For

instance, the number of tetracycline-resistant E.

coli dropped from 107 (10 million) bacteria per

gram of stool on day 7 to a low of about 2X101

(20) per gram on day 13. Although the fluctuations in the number of total E. coli (susceptible as

well as resistant) were not so great, they still varied from about 104 (10,000) per gram on day 4 to

over 108 (100 million) per gram on day 10.

These variations are interpreted to reflect, in part,

differences in the numbers of E. coli ingested

daily.

Beginning on day 21, the volunteer ate only

sterilized food. The number of tetracyclineresistant E. coli dropped to about 20 or less two

days later and remained there. The number of tetracycline-sensitive E. coli may also have

dropped, but not much below the numbers seen

on some days when non-sterile food was consumed (days 1 to 8).

Elder et al. (1 993) examined fecal samples

from two groups of non-vegetarians and two

groups of vegetarians over a 12-month period.

.

0

3

2

1

1 6 11 16 21 26 31 36

Time (days)

SOURCE: Corpet, 1993

There were no differences in the prevalence of

antibiotic-resistant bacteria in the two groups,

and there was a slightly increased frequency of

multiply-resistant bacteria in the vegetarians.

These results are consistent with the conclusion

that meat is not the only source of antibioticresistant bacteria, and the authors suggest that

restrictions on antibiotic use in animals would

have little effect on antibiotic-resistant bacteria

in humans. They do not show, however, that

meat is unimportant as a source of antibioticresistant bacteria, nor do they pinpoint other

sources of antibiotic-resistant bacteria in the diet.

Corpet (1993), who carried out the experiment

summarized in figure 7-1, concluded that

humans’ primary source of antibiotic-resistant

bacteria is their food, which is consistent with the

knowledge that food is a common source of bacterial infections in humans. For instance, Murray

(1995) concluded that more than half of Campylobacter infections in humans arise from

ingestion of contaminated poultry, and studies of

the same organisms, in particular Campylobacter

jejuni in Washington State, showed that antibiotic resistance patterns were similar in infected

humans and in poultry purchased from retail

markets (U.S. House of Representatives, 1984).
Chapter 7 Antibiotics in Animal Husbandry | 161

It is important in this context that both antibioticsensitive and antibiotic-resistant C. jejuni caused

human disease, underlining the importance of

other factors in whether or not ingested bacteria

will cause illness. 

Virulent, antibiotic-resistant Salmonella

caused an outbreak of lethal diseases in cattle in

England that infected as many as 500 humans

and might have contributed to the deaths of 6

individuals (Anderson, 1968). [The closing down

of one farm which was in the business of buying

and reselling calves apparently stopped that epidemic (Bywater, 1995).] Furthermore, there is no

doubt that farmers and others who are around

and care for antibiotic-treated livestock can

become carriers of bacteria with the same kinds

of antibiotic-resistant bacteria as are found in the

animals (Levy, 1978, 1983, 1992 and Levy et al.,

1976). 

Antibiotic-resistant bacteria in food are

ingested by humans along with other bacteria,

and antibiotic-resistant bacteria can be passed

from animals to humans. Questions remain about

how often these transmissions cause disease in

human beings or promote the flow of genetic

information for antibiotic resistance from bacteria of animal origin to bacteria that can cause

human disease. 

❚ Antibiotic Residues in Food

FDA, in approving uses of an antibiotic in food

animals, specifies a “withdrawal period” following the administration of the antibiotic to allow

time for the antibiotic “residue” concentration to

fall to a level that is of no concern to the agency.

When the withdrawal period is observed, and the

residue level falls appropriately, the concentration of antibiotics in meat, according to FDA,

should have no effect on the bacterial flora in

humans. Any meat that has a higher concentration violates the law. 

If, however, residue concentrations were high

enough, they could have the same effect on

humans as ingesting antibiotics directly. Corpet

(1993) summarizes a number of experiments that

indicate that the concentrations of antibiotics in

meats may rarely be sufficient to have an effect

on human bacterial flora. He emphasizes, however, that those effects are less important to

human health than the ingestion of antibioticresistant bacteria. 

A number of papers printed in two special

issues of journals about veterinary microbiology

reached similar conclusions: Veterinary and

Human Toxicology 35 (supplement 1), 1993, and

Veterinary Microbiology 35 (no. 3,4), 1993.

Kidd (1994), in a report prepared for the Fédération Européenne de la Santé Animale, comes to a

similar conclusion, but cautions that the lack of

evidence for any effect of antibiotics in meat

may reflect an absence of investigations of the

possibility. While there may remain some lingering suspicions that antibiotic residues in meats

can affect the micro-organisms in human beings,

the remainder of this chapter will focus on the

risks of antibiotic-resistant bacteria from food

that was treated with antibiotics.

Antibiotics on Plants and Vegetables

Levy (1992, p. 159–167) estimates that 40,000 to

50,000 pounds of antibiotics are used on fruit

trees in the United States each year. While that

amount is small in comparison to the 18 million

pounds of antibiotics used in animals, some of it

is sprayed onto fruit trees and other crops,

spreading it into the environment, and some of it

could be ingested by humans when they consume

fruits and vegetables. Oxytetracycline and streptomycin are used to treat various “rots,” “molds,”

and “spots” on fruits and vegetables, and some of

the plant pathogens that cause those diseases

have developed resistance to the antibiotics.

Levy (1992, pp. 163–165) points to the possibility that the bacteria that infect plants serve as a

reservoir for antibiotic-resistant genes that can be

transferred to other bacteria that infect humans,

but this possibility has not been researched.

Antibiotics in Fish

Commercial fish farming is a fast-growing enterprise, and oxytetracycline, a sulfa drug, and a

derivative of trimethoprim are used to control
162 | Impacts of Antibiotic-Resistant Bacteria

diseases. FDA requires that the antibiotics be

withdrawn from the fish for a specified number

of days before the fish are sold to reduce transmission of antibiotics to humans, but bacteria can

be carried along with the fish when they go to

market.

Catfish, raised in ponds, are the primary commercially farmed fish in the United States. Trout

are raised in enclosed raceways, and some

salmon are raised in ocean netpens in Puget

Sound, Washington, and off the Maine coast.

Farmed fish, when treated with antibiotics, are

fed medicated feeds. Thus, antibiotics enter the

environment either in fish feces or uneaten food.

In catfish farming, antibiotics in feces or food

drop to the bottom of the pond and are subject to

biological binding or degradation in the sediment. When catfish ponds are drained, the sediment is generally placed on the pond levee,

restricting movement of the antibiotics into the

general environment.

These U.S. practices differ from those elsewhere. In Norway, antibiotics are sometimes

sprayed onto the surface of bodies of water and

the antibiotic can then spread throughout the

water and possibly cause disturbances in the ecosystem. In that country, quinolones, as well as

oxytetracycline, are used to treat diseases in

farm-grown fish, and Ervik et al. (1994) showed

that detectable residues of antibiotics in the flesh

of wild fish and mussels in sprayed water bodies

were more common than in fish and mussels

taken from waters not known to be treated with

antibiotics. The frequency of antibiotic-resistant

bacteria in fish and mussels near the fish farms

was also higher, but the frequency of such bacteria was not zero, even in fish and mussels from

untreated waters. This study demonstrates that

antibiotics can move through the aquatic environment and affect the flora of wild fish. Its

implications for human health are unknown, and

not generally applicable to the United States. In

particular, no quinolones are approved for use in

aquaculture in the United States, and, according

to the Animal Health Institute (1995), no such

use is contemplated.

CONTROVERSY ABOUT ANTIBIOTIC USE 

IN RAISING LIVESTOCK

There is little controversy about the desirability

of using antibiotics to treat sick animals. More

controversy arises about the subtherapeutic uses

in prophylaxis and growth promotion, and the

possible diversion of antibiotics licensed only for

therapeutic purposes to other uses. Whatever the

reason for the use of the antibiotic, treatment of

animals can result in contamination of meat by

antibiotic-resistant bacteria. Three things can

happen as a result. The first is that antibioticresistant pathogenic bacteria might be transferred

to humans. The second is that antibiotic-resistance genes, although present in non-pathogenic

bacteria in the animal, may be transferred to

pathogenic organisms in humans. The third is

that antibiotic-resistant bacteria that do not normally infect humans will be ingested by people

on antibiotic therapy, that the therapy will have

altered the human flora, and that the alteration

will favor the growth of bacteria that pose a risk

to human health.

Any of these effects is a risk to human health.

Why would anyone subject himself or herself,

his or her family, and his or her customers to a

risk? Clearly, if there were no apparent gain from

using subtherapeutic doses of antibiotics in animals, no one would do it. The manufacturers of

antibiotics gain, of course, because such uses

increase their sales. But farmers would not be

expected to buy the antibiotics if they did not

profit from them. 

Discussions about subtherapeutic uses have

been dominated by concerns about risks, but the

fact that the uses continue and are sanctioned by

the federal government is convincing evidence of

the received benefits. Whatever the risks may be,

any decision about subtherapeutic uses will

involve considerations of both risks and benefits,

and continued focus on efforts to better pin down

estimates of risks to the exclusion of benefits

may have little effect on the decisions. In any

case, as can be seen from the earlier reviews of

this issue, determining actual risk is not simple.
Chapter 7 Antibiotics in Animal Husbandry | 163

❚ How Well Do Subtherapeutic 

Doses Work?

A measure of the success of subtherapeutic uses

of antibiotics in increasing meat production

would be provided by information about the

amounts of antibiotics that meat producers buy

over time. From the limited information available it appears that success varies from animal to

animal and from time to time. As discussed

below, a major chicken producer uses the same

kinds and amounts of subtherapeutic antibiotics

as were used years ago, and large-scale pork producers are reducing their use. In addition, small

“niche” markets have been developed for meats

from drug-free animals, and some producers do

not use antibiotics in order to participate in these

markets.

While OTA has not carried out any original

research or analysis on this issue, it appears that

answers to the question of how well subtherapeutic antibiotics work to promote growth depends

on the particulars of the application. Unsatisfying

as it may be, the answer appears to be, “It

depends.”

Chickens—Constant Use and 

Constant Benefits

Chickens are archetypal food animals (see box

7-1). Because of selection for faster growing

chickens and attention to animal husbandry,

farmers can now produce a 6-pound chicken in

56 days. Thirty years ago, a chicken of the same

age weighed two pounds.

Viral infections, against which antibiotics

have no effect, are a far greater threat to chickens

than are bacterial infections, and they are controlled by hygiene, vaccination, and isolation of

chickens from possible human and animal

sources of contamination (Dekich, 1994). A few

“old” antibiotics, including tetracyclines, are

available for treating bacterial infections, but

such actions are uncommon. A large east coast

producer treated less than 2 percent of its 7,500

flocks in 1994.

Two antibiotics—virginamycin and bambermicin—are used to promote growth in chickens.

Neither is used in human medicine. The dose for

growth promotion has remained constant at 1 to

2 grams per ton of feed for 10 years, and the

increased growth rate has remained constant.

According to a chicken-producing company, the

company would discontinue growth promotion

use if it did not contribute to profits.

Pigs—Decreasing Use with Increasing 

Concentration of Production

The number of pork producers is decreasing and

the number of pigs sold by each producer is

increasing (National Pork Producers Council,

1994), and antibiotic use appears to decrease

with increasing size of pork production operations (Sundberg, 1994). The reasons for the trend

are not well known, but better hygiene is

believed to account for part of the decrease in

subtherapeutic antibiotic use. More generally,

larger operations mean that the producer’s

income is more dependent on pork production,

rather than being drawn from several products,

say, corn and pigs, and management probably

becomes more focused on the animals.

The National Pork Producers Council has produced a Quality Assurance Program (National

Pork Producers Council, 1994) that includes

guidelines for the use of all drugs, including antibiotics. Those guidelines are intended to prevent

the appearance of levels of drugs that exceed federal limits in finished meat products. According

to the pork producers council, the percentage of

BOX 7–1: Chickens in the United States

The chicken—not the sparrow, pigeon, or starling—is the most common bird on the planet. The

United States produces 7 billion chickens annually, or about 29 chickens for every one of the 240

million Americans.

About 20,000 farm families contract with large

chicken producers and packers, and the average

farm has two chicken houses. Each house produces all of the chicken consumed by 15,000

Americans annually. Production has doubled

since 1978, and increases 4 to 5 percent annually.
164 | Impacts of Antibiotic-Resistant Bacteria

violations for all drug residues in pork dropped

from 10 percent in the mid-1980s to less than 1

percent in 1994. 

Trends in Some Other Sectors of 

Meat Production

During the early 1980s, sales of tetracyclines and

penicillin for use in animal feeds slowly declined

from 2.9 million kilograms of tetracyclines in

1980 to 2.4 million in 1985 and from 400,000

kilograms of penicillin in 1980 to 300,000 in

1984 (IOM, 1989, chap. IV). No more recent

data are readily available.

Levy (1992, p. 142) states that tetracyclines

were added to animal feeds for growth promotion at levels of 5 to 10 parts per million in the

1950s (roughly 5 to 10 grams of antibiotic per

ton of feed). Currently, concentrations of 50 to

200 parts per million are commonly used. The

higher rates of use have not substantially

increased production costs because the cost of

antibiotics on a weight basis has decreased over

the same period. Because of the slim profit margin in meat production, decreased growth promotion effects, coupled with increased costs, could

lead to a reduction in subtherapeutic uses of antibiotics as the costs of the drugs approach or

exceed the benefits from faster growth.

❚ Summary of Comments on 

Subtherapeutic Uses of Antibiotics

Levy (1992, p. 156) suggests that several factors

are reducing the agricultural uses of antibiotics:

increased concerns about drugs of all kinds in

food; greater appreciation of the threat of antibiotic-resistant bacteria and the contribution that

agricultural use of antibiotics may make to it;

better animal husbandry that reduces the need for

antibiotics; and legislative and regulatory initiatives. Indeed, FDA experts report that they see

few applications for the subtherapeutic uses of

new antibiotics (FDA, 1995). While Levy’s

impressions may be accurate, and decreases in

such uses were reported over a decade ago, the

phasing out of subtherapeutic uses would not

necessarily end the controversy about antibiotic

use in animals.

CONTROVERSY OVER FLUOROQUINOLONES IN FOOD PRODUCTION

Just as physicians need new antibiotics to treat

human diseases, veterinarians see needs for the

use of new antibiotics in their practices. FDA has

approved the use of one fluoroquinolone in the

treatment of diseases in companion animals, and

several manufacturers have requested approvals

for the use of fluoroquinolones in the treatment

of diseases in food animals. Fluoroquinolone use

in animals has been more widespread in Europe,

and resistance to the drugs has been reported in

bacteria isolated from treated animals. 

Because of the importance of fluoroquinolones in medicine, the American Society for

Microbiology, the Infectious Diseases Society of

America, and officials of the Centers for Disease

Control and Prevention have advised FDA to

restrict the use of fluoroquinolones in food

animals. In particular, the Infectious Diseases

Society requested that no formulations of fluoroquinolones in animal feeds be allowed. That

request, if honored, would allow veterinarians to

treat individual animals, but prevent treatment of

herds or flocks. It is opposed by some veterinarians who maintain that using the antibiotic in feed

is necessary to treat animals.

FDA has received no applications for the

long-term use of fluoroquinolones in agriculture

and does not expect to (FDA Veterinarian,

1994), but it held public hearings in May 1994

on possible therapeutic uses. At that meeting

FDA announced that it was considering a new

policy that would restrict approval of new antibiotics to prescription uses in disease treatment and

prevention. The consensus of the advisory panel

convened for that study was that the benefits of

restricted short-term therapeutic use of fluoroquinolones in food animals outweighed the

potential human health risk due to resistant

organisms, but that strict controls on usage and

improved surveillance were warranted (FDA

1995a).
Chapter 7 Antibiotics in Animal Husbandry | 165

As therapeutic agents, fluoroquinolones could

be used to prevent disease in herds or flocks that

are known to contain infected animals. Such preventive use requires formulations of antibiotics

that can be incorporated into water or feed, leading to concern that those formulations will find

widespread use in growth promotion, exerting

heavy selection pressure for the emergence of

fluoroquinolone-resistant bacteria. There is a historical base for this concern. Chloramphenicol

(CAP) was licensed for therapeutic use in livestock but never for subtherapeutic uses. Nevertheless, veterinarian and husbandry experts

published articles that gave details about the use

of CAP for growth promotion. As sales soared

for such unapproved use, FDA intervened and

banned the marketing of oral solutions of CAP

that were convenient for treating farm animals.

Unlike most antibiotics, CAP causes severe anemias and other diseases of the blood in some

humans, increasing concern that any residual

CAP in meat might directly harm humans. 

At the May 1994 meeting, FDA considered

opinions from private organizations and professional societies and other federal agencies that

ranged from urging that the fluoroquinolones be

completely restricted from agricultural use to

arguments that they were necessary for the care

of animals and that the risk of resistance from

agricultural use paled beside the risk from medical uses. Currently (July 1995) FDA is preparing

its policy statement for agricultural uses of fluoroquinolones. 

In November 1994, FDA held another meeting about the possible use of surveillance systems to keep track of the emergence of

antibiotic-resistant bacteria, including the emergence of fluoroquinolone-resistant bacteria in

animals if agricultural uses of those drugs are

permitted. FDA is also drafting a statement on

surveillance that will consider the questions

raised by antibiotic resistance.

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this report. 30 May.

Bates, J., J.Z. Jordens, and D.T. Griffiths. 1994.

Farm animals as a putative reservoir for vancomycin-resistant enterococcal infection in

man. Journal of Antibiotics and Chemotherapy 34:507–516.

Bywater, R.J., SmithKline Beecham Animal

Health, Surrey, United Kingdom. 1995. Personal communication; telephone conversation with M. Gough, OTA. April 20.

Corpet, D.E. 1993. An evaluation of methods to

assess the effect of antimicrobial residues on

the human gut flora. Veterinary Microbiology 35:199–212.

Dekich, M., Purdue Farms, Salisbury, Maryland.

1994. Remarks at U.S. Food and Drug

Administration “Part 15 Hearing: Surveillance Systems for Antibacterial Resistance.” Rockville Civic Center, Rockville,

MD. November 9.

Elder, H.A., I. Roy, S. Lehman, et al. 1993.

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Ervik, A., B. Thorsen, V. Eriksen, et al. 1994.

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on wild fish and blue mussels Mytilus edulis

in the vicinity of fish farms. Diseases of

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Environmental Impact Statement. Subtherapeutic Antibacterial Agents in Animal Feeds.

U.S. Food and Drug Administration: Rockville, MD. 

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discuss fluoroquinolones. July/August

issue, pp. 2–5.

Gorbach, S.L. 1993. Perturbation of intestinal

microflora. Veterinary and Human Toxicology 35 (Supplement 1):15–23.
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Animals: The Antibiotic Resistance Issue.

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Agricultural Science and Technology:

Ames, IA.

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with the Subtherapeutic Use of Penicillin or

Tetracyclines in Animal Feed. National

Academy Press: Washington, DC.

Kidd, A.R.M. 1994. The Potential Risk of Effects

of Antimicrobial Residues on Human

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Européenne de la Santé Animale: Brussels,

Belgium. 

Klare, I., H. Heier, H. Claus, R. Reissbrodt, and

W. Witte. 1995. vanA mediated high level

glycopeptide resistance in Streptococcus

faecium from animal husbandry. FEMS

Microbiology Letters 125:165–172.

Levy, S.B. 1978. Emergence of antibiotic-resistant bacteria in the intestinal flora of farm

inhabitants. Journal of Infectious Diseases

137:688–690.

Levy, S.B. 1983. Antibiotic-resistant bacteria in

food of man and animals. In Woodbine, M.

(ed.) Antimicrobials and Agriculture. Butterworth: London, pp. 43–61.

Levy, S.B. 1992. The Antibiotic Paradox. Plenum Press: New York.

Levy, S.B., G.G. Fitzgerald, and A.B. Macone.

1976. Changes in intestinal flora of farm

personnel after introductions of tetracyclines-supplemented feed on a farm. New

England Journal of Medicine 295:583–588.

Murray, B.E. 1995. Editorial response: What can

we do about vancomycin-resistant enterococci? Clinical Infectious Diseases

20:1134–1136.

National Pork Producers Council. 1994. Pork

Facts. National Pork Producers Council:

Des Moines, IA.

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Human Health of Subtherapeutic Use of

Antimicrobials in Animal Feeds. National

Academy Press: Washington, DC.

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policy: Pro- and anti-biotic. American Journal of Epidemiology 115:485–491.

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Des Moines, IA. 1994. Remarks at U.S.

Food and Drug Administration “Part 15

Hearing: Surveillance Systems for Antibacterial Resistance.” Rockville Civic Center,

Rockville, MD. November 9.

Teske, R.H., Center for Veterinary Medicine,

U.S. Food and Drug Administration. 1995.

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Office. [OTA-F-91.]

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Memorandum from Lois Adams, U.S. Food

and Drug Administration, to M. Gough,

OTA. April 10.

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report. Memorandum from Associate Commissioner for Legislative Affairs, U.S. Food

and Drug Administration to Office of Technology Assessment. June 16.

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Science and Technology, Subcommittee on

Investigations and Oversight. 1984. Hearing:

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| 167

A

Appendix A:

Coverage of Antibiotic

Resistance in the

Popular Literature,

1950 to 1994

he substance and tone of articles about

antibiotic resistance in the popular literature have changed over time (Rosenkrantz, 1995).1

 In the 1950s sobering

cautions about the dangers of antibiotic overuse

accompanied announcements from medical and

scientific experts celebrating reduced mortality

from specific diseases. The articles were recast

by the mid 1980s. The public was faced with

new warnings that bacteria are “winning the

race” because they are “smarter” than men.

These conclusions are illuminated through the

decade-by-decade analysis that follows.

❚ 1950 to 1959

In the late 1940s and early 1950s scientific and

popular periodicals were generally enthusiastic

about the benefits that antibiotics would provide

for human health and well-being through better

medicine, agriculture, and even home gardening.

Public interest can partly be gauged by the range

of journals and articles. The Saturday Evening

Post, as well as Science, published articles on

streptomycin and tuberculosis; Reader’s Digest

1 Rosenkrantz, B.G. 1995. Historical Review: Responses to Antibiotic Resistance. Contract Report to the Office of Technology Assessment. Photocopied transcript.

(June 1955) excerpted an article, “Bringing the

Antibiotics Up To Date,” by Paul DeKruif, a

popular science writer and author of The

Microbe Hunters. But there were also many

warnings against false confidence in the continuing usefulness of antibiotics.

Literature is this decade included feature articles about the problems of resistance. The New

York Times (May 2, 1953) quoted Sir Alexander

Fleming, who discounted reports that germs were

becoming penicillin resistant and suggested that

indiscriminate use led to patient sensitivity.

Howard Florey, the English scientist who developed methods for producing penicillin, was

quoted in Newsweek (Oct. 20, 1958) explaining

that Staphylococcus aureus itself is not resistant;

only certain strains that develop in hospitals produce an enzyme called penicillinase that destroys

penicillin.

A reporter covering a U.S. Public Health Service conference on hospital infections wrote that

“ . . . every week in the year at least one hospital

in the cleanest country on earth is threatened

with an outbreak of serious ‘staph’ infections”

(Newsweek, Sept. 29, 1958). In the same year,

T
168 | Impacts of Antibiotic-Resistant Bacteria

the U.S. Surgeon General announced that overreliance on antibiotics had led to inroads by the

“golden staph” [Staph. aureus]. The public

learned that these germs could be found everywhere. The recommended response for control

was hospital hygiene and asepsis, not more antibiotics (Time, Mar. 24, 1958).

The popular press pondered the cause of this

growing problem. Was it the unjustified or unscientific use of antibiotics, or were medical practitioners taking a “shotgun” approach to therapy?

An unnamed surgeon reflected that in his field

penicillin was used casually, “like water.” An

article in Science News Letter (1953) was titled

“Fear Man-made Epidemics.” Scientists were

cited explaining that antibiotics should not be

used prophylactically in attempts to ward off

infection.

At the same time, scientists informed the public about research on the causes of bacterial resistance. Time (Mar. 24, 1958; Nov. 17, 1958)

reported that microbiologists were divided about

whether Staphylococcus develops resistance to

antibiotics or whether antibiotics eliminate susceptible Staphylococci, leaving behind the most

virulent strains. Although antibiotics might have

falsely raised expectations, by the end of the

decade most of the popular press did not question

the authority of scientists or the capability of science and medicine to continue to make progress

in fighting disease.

❚ 1960 to 1969

During the 1960s new questions surfaced about

the responsibility of government in ensuring the

safety and efficacy of pharmaceuticals, and

increasing concern about the dangers of bacterial

resistance furthered public interest in the development of new antibiotics. In this decade the

U.S. Food and Drug Administration (FDA)

became more visible to the public; first through

Senator Estes Kefauver’s hearings on the drug

industry, but even more so when the tragedy of

thalidomide was narrowly averted in the United

States.

For the more informed reader, Science

(May 26, 1967) explained how “R factors” (now

called plasmids) mediated resistance, and Newsweek (Aug. 22, 1966) introduced scientific language to explain that “resistant bacteria can pass

their R factors along to bacteria of other strains,”

emphasizing the specific dangers posed by

mutant Escherichia coli from cattle fed antibiotic-laced feed. Perhaps to appear evenhanded,

the same article implied that an editorial in the

New England Journal of Medicine warning about

the dangers of indiscriminate antibiotic use

might be overdramatic. Good Housekeeping

(August 1961; January 1964) warned that antibiotics were never to be used casually for minor

ailments. In the early 1960s, the New York Times

published reports of a steady increase in antibiotic-resistant hospital infections (Mar. 12, 1961;

Feb. 25, 1962; Sept. 28, 1962).

Despite the introduction of new antibiotics,

and the promise of more yet to be identified, the

popular press cautioned that specific criteria

should be used to determine which drugs are

effective in treating each disease. The science

editor and editorial board of the New York Times

(Sept. 9, 12, 14, 1966; Nov. 21, 23, 1969) produced a series on the transmission of antibiotic

resistance among bacteria. Resistance was

described as a widespread peril that could be

spread by “mating” among different bacteria.

In 1967 the New York Times reported that, in

comparison to Great Britain, the United States

was slow to control use of antibiotics in agriculture, a lapse that could exacerbate resistance

(New York Times, June 11, 1967). Newspapers

covered the tensions in the debate among interested parties, including: recommendations generated by FDA and the National Research Council

of the National Academy of Sciences regarding

limiting antibiotics in animal feed; skepticism

registered by pharmaceutical firms about the significance of antibiotic resistance; and warnings

by the meat industry about potential price

increases should antibiotic protection of herds be

prohibited (New York Times, Sept. 22, 1966;

June 11, 1967).
Appendix A: Coverage of Antibiotic Resistance in the Popular Literature, 1950 to 1994 | 169

❚ 1970 to 1979

In the 1970s the periodical press turned sympathetically to physicians for their perspectives on

the conflicting benefits and dangers of antibiotics. McCalls’ (October 1976) regular physician

columnist Dr. William Nolen authored “Antibiotics: What They Will and Won’t Cure,” and

focused on the therapeutic limitations of antibiotics, but he did not raise the complications of antibiotic resistance. Other periodicals focused on

the fundamentals of bacterial genetics. Newsweek (June 19, 1978), in its regular coverage of

medical news, directed attention to hospital

“mini-epidemics” and the new medical specialty,

infection control, that brought doctors, nurses,

technicians and epidemiologists to the scene.

Attention to antibiotic resistance was also more

frequent in articles on agriculture, and in these

reports both pharmaceutical and agricultural

interests were identified as enemies of regulation.

Accounts of bacterial resistance available to

the general reader varied, sometimes framed in

dramatic language that emphasized the emergence of “super bugs” like the “Andromeda

strain,” and at other times presenting detailed

reports of scientific meetings (New York Times,

Oct. 15, 18, 1970; Feb. 6, 1972; Mar. 3, 1975).

Concerns about the consequences of indiscriminate use of antibiotics were reflected in a Senate

Health Subcommittee finding “that drug companies over-promote antibiotics to physicians and

physicians overprescribe them, especially for

colds and other viral infections that antibiotics

can’t counter” (Science News, May 27, 1972).

Information on the basic mechanics of “Transmissible Multiple Drug Resistance” (Science,

May 19, 1972) became increasingly sophisticated in Science, Scientific American, and Science News. Good Housekeeping (March 1975)

reported that the American Medical Association

had discovered that resistant organisms, once

largely confined to hospitals, were now also

found in the community.

Reflecting a general frustration, the New York

Times (July 16, 1971) reported on a 25-year survey of health care that found despite “spectacular

scientific advances. . .many diseases that should

no longer exist, such as TB, still do.” Data from

the CDC reported pneumonia and gonorrhea

resistance to antibiotics. A CDC research team

estimated that 22 percent of antibiotic use in the

hospital was unnecessary and led to “superinfection” (New York Times, Jan. 28, 1976; Nov. 10,

1976).

The FDA proposed policies (congruent with

Britain and other European countries) to limit

antibiotics in animal feed and reported that animals consumed more than 40 percent of the antibiotics produced. In a replay of an article that had

appeared in the late 1960s, Time (Sept. 10, 1979)

reported that the FDA-proposed limits were

opposed “by a coalition of pharmaceutical manufacturers and farming interests.” Congress agreed

“to stay any action pending further studies.”

❚ 1980 to 1994

Reports of emergent and re-emergent diseases

have often implicated antibiotic resistance.

Tuberculosis, once slated for virtual eradication

in the United States by the early 21st century,

proved impossible to eliminate, and its persistence was linked to premature budget cuts in the

nation’s public health efforts. But the blame for

the re-emergence of tuberculosis was spread

broadly. New cases of tuberculosis were often

associated with homeless populations or with

immigrants from areas of the world where the

disease was endemic (New York Times, July 26,

1980, June 18, 1985); reportedly, attempts to

control tuberculosis were exacerbated by

patients’ failure to comply with extended treatment, which could lead to multi-drug-resistant

disease.

In the 1980s epidemiologic and comparative

international perspectives on antibiotic resistance

became prominent for the first time. In 1981 doctors in medical teaching centers called for international controls “to halt ‘indiscriminate’ use of

antibiotics” (New York Times, Aug. 6, 1981).

Broader concern was reflected in reports from

prominent spokespersons for the international
170 | Impacts of Antibiotic-Resistant Bacteria

scientific and medical communities, as well as in

reports of the dangers to Americans from multiple-drug-resistant organisms imported as a result

of increased world travel, and via immigrants

(often illegal) from developing countries.

Some diseases once treated by antibiotics

were reportedly now out of control. CDC reports

on the rise of antibiotic-resistant gonorrhea,

streptococci, and hemophilus infections brought

the danger closer to home when they were connected to children’s ear infections and to the

overwhelming (not antibiotic-resistant) infection

that killed the Muppets creator, Jim Henson

(New York Times, Feb. 23, 1989; May 8, 18,

1990; Jan. 28, 1992). The emphasis and tone of

reporting on antibiotic-resistant bacteria shifted,

markedly influenced by accounts of how infectious disease strikes back in the war between pestilence and people (Time, Sept. 12, 1994).

Time reported that the rising tide of antibiotic

resistance affected “nearly every disease organism known to medicine”; the “microbe’s extraordinary ability to adapt” was “a fact of life.” The

magazine reported that adaptation was “written

into evolution,” but few anxieties were relieved

by reassurances that microorganisms were only

“trying to. . . survive and reproduce, just as we

are” (Time, Sept. 12, 1994).

Readers of popular magazines were challenged by articles such as “Are you overdosing

on antibiotics?” (Redbook, December 1991).

There was mounting tension between warnings

of dangers from “the ghost of scourges from the

past” (U.S. News and World Report, Oct. 26,

1992) and reports of FDA approvals of new antibiotics. As in the 19th century, doctors cautioned

that “A Hospital is No Place for a Sick Person To

Be” (Discover, October 1985), and patients

feared that “Hospitals May Be Breeding

Grounds” (USA Today, February 1991), as evidence mounted that “Hospitals Can Make You

Sick” (World Press Review, August 1988).

Scientists and physicians were quoted in desperate moments as they drew dire conclusions

for the future. A feature article, “The End of

Antibiotics,” quoted one physician’s explanation

that “microorganisms are winning” because

“they are so much older than we are . . . and

wiser” (Newsweek, Mar. 28, 1994). With no new

antibiotics ready for introduction and evidence of

the existence of “smart bugs” that carry information in resistance genes, attention to misuse of

antibiotics in medicine and agriculture competed

for blame with human populations which were

likened to hothouses for breeding of germs.

Some reports downplayed professional accountability, shifting responsibility to social changes

that included the spread of AIDS, the rise in

homelessness, the proliferation of child care centers, the influx of immigrants, increases in international travel, and the disturbance of

ecosystems in both economic development and

recreation (U.S. News and World Report, Oct.

26, 1992).

A change of tone and target appeared in the

1980s. Partly as a consequence of lessons in

immunology that accompanied publicity on

AIDS, but also because bacterial genetics had

become a growth industry, reports of new evidence on antibiotic resistance used adaptations of

everyday language and diagrams to explain resistance genes to the public. Bacteria acquired identities of their own. They were pictured or

perceived as willful beings governing their own

mutations and transferring resistance genes to

other bacteria in conscious efforts to outwit

humans and their antibiotics. Journalists quoted

scientists describing “bugs” with a crafty intelligence capable of becoming relentless demons.

❚ Comments on the Popular Literature

Penicillin marked the beginning of a new era for

most Americans and a majority of people around

the world. However, from its very beginning the

triumph of antibiotics was accompanied by fear

that resistance might reverse the advantages

gained over infections. Anxiety was expressed as

concern that ordinary germs would take revenge,

that miracle drugs were a two-edged sword,

eliminating some bacteria and favoring others.

Over time the early warnings transformed into

forecasts of apocalypse. Penicillin had not banished hospital infections as had once been
Appendix A: Coverage of Antibiotic Resistance in the Popular Literature, 1950 to 1994 | 171

dreamed; instead, first “staph” and then other

organisms became resistant. Unexpected disease

and death spread among patients despite the

efforts of infectious disease experts. Scientists

discovered that bacterial resistance to antibiotics

was transmitted among disease-bearing organisms in ways that were unimaginable before the

availability of the tools of molecular biology.

Scientists collaborated with journalists to instruct

the public in the new language of resistance

genes, and the American public read about unexpected outbreaks of untreatable mysterious infections in the 1960s and 1970s. But the 1980s

appeared more dangerous yet. AIDS laid the

groundwork for new fears, and fatal multipledrug-resistant tuberculosis and streptococcal

pneumonia put medical news and the terms

“emergent” and “re-emergent” disease on the

front page of newspapers and on bestseller lists.

According to Rosenkrantz (1995), the emergence or control of antibiotic resistance was

posed first as a contest between knowledge and

ignorance, then between control and irresponsibility, and ultimately between good and evil. The

1990s saw the stream of scientific and medical

information merge with fears about social disorder and political corruption. The bearers of the

new threat were often immigrants from Asia,

Africa, and South America, where AIDS, tuberculosis, and other infectious diseases were prevalent and where antibiotics were unavailable or

improperly used. The homeless, who failed to

comply with treatment plans, were blamed for

the spread of antibiotic-resistant tuberculosis.

Child-care centers and hospitals were singled out

as places that spawn antibiotic resistance. But

blame was not restricted to the powerless. Pharmaceutical firms and agribusiness were also

incriminated on the basis of alleged irresponsibility and greed. Attributing the spread of antibiotic resistance to victims of disease as well as to

representatives of corporate power accentuated

public anxiety and seemingly placed control outside the realm of science. Meanwhile, it appears

that fear of antibiotic-resistant disease has not

eroded public demand for antibiotics. The placing of blame on the most vulnerable and the most

powerful may have compromised the impetus for

controlling patients’ inappropriate requests for

antibiotic prophylaxis and therapy.

The problems with antibiotic-resistant bacteria

are not new to this decade or even to this generation. Such bacteria were identified soon after the

first use of antibiotics, and the technical and popular press has reported on them and the problems

with which they are associated. Over the last

50 years, warnings have been voiced about inappropriate antibiotic use—too frequently

demanded by patients, too heavily prescribed by

physicians, too heavily used in agriculture, and

too often used when they have no effect. The

variety of possible explanations for the emergence of this public health problem highlights

the complexity of the issues and also provides a

number of approaches to control the problem,

which are discussed elsewhere in this OTA

report.
| 173

B

Appendix B:

Glossary

Active Efflux: a major mechanism of bacterial

resistance in which an antibiotic is pumped

out of the bacterial cell.

Active Immunization: the process of administering specific microbial antigens that stimulate the host’s immune system to produce

protective antibodies, “vaccination.”

Agar Dilution Test: one of four diagnostic

methods currently used to determine the

antibiotic susceptibility or resistance of bacteria. See also agar gradient test, broth dilution test, and disk diffusion test.

Agar Gradient Test: one of four diagnostic

methods currently used to determine the

antibiotic susceptibility or resistance of bacteria. See also agar dilution test, broth dilution test, and disk diffusion test.

Aminoglycosides: a family of bactericidal antibiotics that block bacterial protein synthesis

by binding to the small subunit of the bacterial ribosome; examples are streptomycin,

kanamycin, neomycin, gentamicin, amikacin, and tobramycin.

Amoxicillin: a broad-spectrum β-lactam antibiotic drug.

Antibacterial: a drug that kills or inhibits the

growth of bacteria.

Antibiogram: a guide produced by a microbiology laboratory for physicians’ use that profiles the susceptibility of commonly

encountered bacteria to various antibiotics.

Antibiotics: a class of substances that can kill or

inhibit the growth of some groups of microorganisms. Used in this report to refer to

chemicals active against bacteria. Examples

are penicillin, tetracycline, erythromycin,

and cephalosporins. Originally antibiotics

were derived from natural sources, e.g., penicillin from molds, but many currently used

antibiotics are semi-synthetic and modified

with additions of man-made chemical components. See antimicrobials.

Antibiotic Resistance: a property of bacteria

that confers the capacity to inactivate or

exclude antibiotics or a mechanism that

blocks the inhibitory or killing effects of

antibiotics.

Antibiotic Susceptibility: the opposite of resistance and applies to bacteria that are killed

or inhibited by an antibiotic. Susceptibility

to a particular antibiotic does not mean that

the bacteria are susceptible to all antibiotics.

Antigen: a chemical structure on or in a cell that

is recognized by the immune system. The
174 | Impacts of Antibiotic-Resistant Bacteria

immune system produces antibodies that

react with the antigens.

Antigen Test: a diagnostic method for detecting

the presence of a specific chemical structure.

As used here, it is a test for detecting the

presence of specific bacteria.

Antimicrobials: a class of substances that can

destroy or inhibit the growth of bacteria;

examples are sulfonamides. See antibiotics.

Anti-Sense: DNA is a helical molecule with two

strands. One strand, the “sense” strand, is

used in the synthesis of RNA and protein;

the other strand, the “anti-sense” strand,

serves a structural purpose in DNA but not

in RNA synthesis.

Anti-Sense Oligonucleotide: a length of the

anti-sense strand of DNA prepared to bind

specifically to a target stretch of DNA.

Bacteremia: a pathologic state characterized by

the presence of bacteria in the blood.

Bacteria: microscopic, single-celled organisms

that have some biochemical and structural

features different from animal and plant

cells.

Bactericidal: a term for agents that kill bacteria.

Bacteriophage: see phage.

Bacteriostatic: a term for agents that inhibit bacterial growth.

Beta-Lactam Antibiotics: the most widely used

class of antibiotics which includes penicillins, cephalosporins including ceftriaxone

and ceftazidime, carbapenems, monobactams, and imipenem. β-lactam antibiotics act

by inhibiting the synthesis of peptidoglycan—the major component of a bacterial cell

wall.

Beta-Lactamase: an enzyme produced by some

bacteria that degrades beta-lactam antibiotics. See penicillinase.

Breakpoint: a concentration of antibiotic that

marks the division either between the resistant and intermediate response or between

the intermediate and susceptible response

using antibiotic susceptibility tests.

Broad-Spectrum Antibiotic: an antibiotic

effective against a large number of bacterial

species; generally describes antibiotics

effective against both Gram-positive and

Gram-negative bacteria.

Broth: a sterile nutrient growth medium used to

grow bacteria.

Broth Dilution Test: one of four diagnostic

methods currently used to determine the

antibiotic susceptibility or resistance of bacteria. See also agar dilution test, agar gradient test, and disk diffusion test.

Broth Microdilution Test: a miniaturized version of the broth dilution test that uses a test

plate with small-sized wells that hold a small

volume (about 0.1 milliliters) of broth.

Cecropin: a peptide from the North American

silk moth Hyalophora cecropia that

increases bacterial permeability and can

cause bacterial death.

Cell Culture: propagation of cells in a laboratory environment.

Chromosome: used in this report to refer to the

circular DNA that contains the genes for the

functioning of a bacterium.

Clinical Trial: used in this report to refer to

research to establish the safety and efficacy

of a drug such as an antibiotic.

Colonization: capacity of a bacterium to remain

at a particular site and multiply there.

Commensals: bacteria that live on the skin, in

body orifices, or the intestines, and do not

usually cause disease, and may be beneficial

to the host organism.

Conjugation: the process by which DNA is

transferred from one bacterium to another

that involves cell-to-cell contact.

Defensin: a peptide from mammalian cells

including epithelial cells lining the human

small intestine that increases bacterial permeability and can cause bacterial death.

Deletion Mutation: a mutation that results in

loss of a length of DNA from the chromosome.

Disk Diffusion Test: one of four diagnostic

methods currently used to determine the

antibiotic susceptibility or resistance of bacteria. See also agar dilution test, agar gradient test, and broth dilution test.
Appendix B: Glossary | 175

DNA (deoxyribonucleic acid): the substance of

heredity; a nucleic acid that is found in the

cell nucleus that carries the genetic information necessary for all cellular functions.

DNA Probe Assay: a new diagnostic method for

identifying the presence of bacteria by using

fragments of DNA or RNA (probes) that

bind to target bacterial or resistance gene

DNA or RNA sequences.

Efficacy: used in this report to refer to the probability of benefit to individuals in a defined

population from a medical technology

applied for a given medical problem under

defined conditions of use.

Empiric Therapy: used in this report to describe

antibiotic treatment based on signs and

symptoms of disease and in absence of

knowledge of the causative agent of infection.

Enterococcus: bacteria normally found in the

intestinal tract and genitourinary tract. Some

strains are pathogenic and a few are resistant

to all available antibiotics, including vancomycin.

Enzymatic Test: a diagnostic method of testing

for antibiotic resistance that directly measures the presence of an enzyme that confers

resistance in a bacterium.

Escherichia coli: a commensal bacterium that

lives in the intestine, a workhorse of biotechnology, and sometimes a cause of opportunistic infections.

Eukaryote: a cell or organism with membranebound, structurally discrete nuclei, and welldeveloped cell organelles. Eukaryotes

include all plants, animals, and fungi. Compare prokaryote.

Expression: functioning of a gene, generally

measured by the amount of gene product

(usually a protein or nucleic acid) made by

the cell. See gene expression.

Flora: the populations of commensal bacteria

normally present in the intestine, body orifices, and on the skin.

Fluorometer: an optical device more sensitive

than the human eye to detect the presence or

absence of growth of bacteria in microdilution tubes. See broth microdilution test.

Formularies: a listing of approved drugs for

various medical indications originally created as a cost-controlling measure, but used

more recently to guide use of antibiotics

based on information about resistance patterns.

Fungus: member of a class of relatively primitive organisms; includes mushrooms, yeasts,

rusts, molds, and smuts.

Gene: a unit of heredity; a segment of the DNA

molecule that carries the directions for the

structure of a given protein.

Gene Expression: activity of a gene measured

by the amount of gene product (usually a

protein or nucleic acid) made by the cell.

Genetic Recombination: the process by which

separate lengths of DNA from different

sources are chemically joined to produce

new genetic combinations.

Glycopeptides: compounds made up of amino

acids and sugars that may have antibacterial

activity; vancomycin and teichoplanin are

glycopeptide antibiotics.

Gram’s Stain: a bacteriological stain used to

determine a major division between bacterial

species; the reaction depends on the complexity of the cell wall. Bacteria that retain

the gram stain (blue) are Gram-positive; bacteria that lose the gram stain but stain with a

counterstain (red) are Gram-negative.

Haemophilus influenzae: a commensal bacterium commonly found in the upper respiratory tract capable of causing infections such

as otitis media, sinusitis, conjunctivitis,

bronchopneumonia and type b meningitis.

Immunosuppression: inhibition or suppression

of the normal immune response, as a result

of giving drugs to prevent transplant rejection, of irradiation or chemotherapy, or of

some infections as in AIDS.

Incidence: the frequency of new occurrences of

disease within a defined time interval. Incidence rate is the number of new cases of a

specified disease divided by the number of
176 | Impacts of Antibiotic-Resistant Bacteria

people in a population over a specified

period of time, usually one year.

Infection: successful colonization on a site of

the body by a microorganism capable of

causing damage to the body.

Insertion Mutation: a mutation that adds a

length of DNA to an existing DNA molecule.

Integron: DNA segment that can carry multiple

antibiotic resistance genes and that can insert

in plasmid and chromosomal locations.

Intermediate Resistance: In some cases, resistance to an antibiotic emerges in incremental

steps, so some bacteria have “intermediate”

resistance and can survive and grow in low

concentrations but not higher concentrations

of an antibiotic.

Invasive: of a bacterium, (1) capable of penetrating the host’s defenses; (2) capable of entering host cells or passing through mucosal

surfaces and spreading in the body.

In-vitro Tests: techniques that use cells, tissues,

or explants grown in a nutritive medium

rather than using living animals or human

subjects.

In-vivo Expression Technology (IVET): techniques that identify bacterial genes that are

expressed only when the bacteria are in the

host.

Isolate: to establish a pure culture of a microorganism.

Lactoferrin: the second most abundant protein

in human milk; found to have antibacterial

activity.

Macrolides: a family of bacteriostatic antibiotics

that inhibit protein synthesis by binding to

the large subunit of the bacterial ribosome;

include erythromycin, clindamycin, chloramphenicol (rarely used because of adverse

side effects), and the new drugs clarithromycin and azithromycin.

Magainins: short peptides, taken from the skin

cells of frogs, that increase bacterial permeability by inserting into the bacterial cell

membrane that can lead to death of the bacterial cells.

MDR-TB: multi-drug-resistant tuberculosis.

Methicillin-Resistant Staphylococcus aureus

(MRSA): strictly speaking, a bacterial strain

resistant to methicillin. In practice, MRSAs

are generally resistant to many antibiotics

and some are resistant to all but vancomycin.

Microorganism: minute, microscopic or submicroscopic living organisms; includes bacteria, fungi, and protozoa. Viruses are often

included in this category, but they are incapable of growth and reproduction outside of

host cells, and some experts insist they

should not be classified as organisms.

Minimum Inhibitory Concentration (MIC):

the lowest concentration of antibiotic that

prevents growth of a bacterium.

MRSA: See methicillin-resistant Staphyloccus

aureus.

Multiple Resistance or Multiple Drug Resistance: applies to bacteria that are resistant to

more than one antibiotic.

Mutation: a genetic change; can occur either

randomly or at an accelerated rate through

exposure to radiation or certain chemicals

(mutagens); may lead to a change in the

structure of the protein coded by the mutated

gene.

Mycobacteria: bacteria that have cell wall structures different from other bacteria. Mycobacterium tuberculosis is the cause of

tuberculosis.

Narrow-Spectrum Antibiotic: an antibiotic

effective against a limited number of microorganisms; often applied to an antibiotic

active against either Gram-positive or Gramnegative bacteria.

Natural Selection: process by which ancestral

species of animals and plants evolve into

new species.

Nosocomial Infection: infection acquired during

hospitalization that is neither present nor

incubating at the time of hospital admission

unless related to prior hospitalization and

that may become clinically manifest after

discharge from the hospital.

Notifiable Disease: a disease that physicians are

required to report to State health departments.
Appendix B: Glossary | 177

Oligosaccharides: (“oligo,” a few; “saccharides,” sugars). Specific oligosaccharides are

present on the surfaces of cells in different

organs and tissues.

Opportunistic Infection: an infection caused by

an organism that does not usually trouble

people, such as a commensal bacterium.

Oxacillin: a semi-synthetic penicillin similar to

methicillin.

Parasite: an organism living in or on an organism of another species (its host), obtaining

part or all of its subsistence from it without

rendering any service in return.

Pathogen: an organism that is capable of causing disease.

Pathogenicity: capacity to cause disease.

Penicillin: the first true antibiotic.

Penicillinase: an enzyme which degrades penicillin so that it has no effect on bacteria. See

beta-lactamase.

Peptides: small protein molecules. Most of interest in this report are peptides from bacteria

and from human, frog, shark, rabbit, and

moth cells that have been shown to inhibit

the growth of or kill some bacteria by

breaking down their permeability barriers to

the entry of antibiotics. See magainins,

cecropin, and defensin.

Peptidoglycan: a complex polymer of sugars

and amino acids that form the major component of the bacterial cell wall.

Phage: a virus that infects bacteria.

Phage Therapy: the use of viruses that attack

bacteria to treat disease; an “old” and currently unused therapy.

Plasmid: a circular piece of DNA not associated

with the chromosome found in the cytoplasm and capable of replicating and segregating independently. Many plasmids can be

spread through bacterial populations by conjugation, and many of the antibiotic-resistance genes of clinical significance are

carried by plasmids.

Point Mutation: a “single letter” mutation consisting of an alteration in a single nucleotide

in DNA.

Polymerase Chain Reaction (PCR): a laboratory procedure that produces millions of

copies of DNA from one or a few molecules.

Preclinical Test: animal studies of drugs before

they are tested in human beings.

Prevalence: refers to the total number of cases

(new as well as previous cases) of a disease

during a designated time period.

Prokaryote: an organism lacking cell organelles

and whose DNA is not enclosed within a

membrane-bound, structurally discrete

nucleus. Bacteria and blue-green algae are

prokaryotes. (Some experts consider “bluegreen algae” to be better classified as “bluegreen bacteria.”) Compare eukaryote.

Prophylactic Antibiotic Therapy: the administration of antibiotics before evidence of

infection and intended to ward off disease.

Protozoa: single-celled animals with membranebound organelles.

Quinolones: a class of purely synthetic antibiotics that inhibit the replication of bacterial

DNA; includes ciprofloxacin and fluoroquinoline.

Resistance: see antibiotic resistance.

Rifampin: an antibiotic that blocks transcription,

e.g. synthesis of RNA; its principal use is in

treatment of tuberculosis.

Selective Pressure: used in this report to refer to

the selection of antibiotic-resistant bacteria

through the use of antibiotics. Susceptible

bacteria are killed or inhibited, and resistant

ones are selected.

Self-Limiting: of an infection, one that proceeds

to a point and no further.

Semi-Synthetic Antibiotics: antibiotics derived

in part from natural products produced by an

organism and in part from synthetic components. Examples are methicillin, nafcillin

and cloxacillin.

Sepsis: a state characterized by the presence of

pathogenic microorganisms and their products into the bloodstream.

Serum Therapy: the use of fractions of blood

from infected animals to treat human disease; an “old” therapy with limited use. Cur-
178 | Impacts of Antibiotic-Resistant Bacteria

rently used for the treatment of tetanus and

botulism (and snakebites).

Service Laboratory: a commercial microbiology laboratory to which physicians send

clinical specimens for analysis.

Squalamine: a steroid compound, closely

related to cholesterol, with antibacterial

activity. Testing of squalamine is at the preclinical stage.

Staphylococcus aureus: Normally commensal

bacteria on the skin that can cause nosocomial infections when they penetrate into

body tissues and organs as a result of

wounds and surgery. See MRSA.

Steroids: natural compounds; the best known is

cholesterol. Some steroids isolated from various organs of sharks have been shown to

have antibacterial characteristics.

Streptococcus pneumoniae or “Pneumococcus” bacteria: the most common cause of

bacterial infection in the United States.

Streptogramin: a new antibiotic, now in phase

III clinical trials, effective against some antibiotic-resistant bacteria, including some

strains of VRE.

Structure-Based Drug Design: a method of

antibiotic research that focuses on an understanding of the ligand:receptor interaction

that occurs at the “active site” where the

“ligand,” in this case the antibiotic, binds to

some structure, the “receptor” in the bacteria. Research tools such as X-ray crystallography, nuclear magnetic resonance

spectroscopy, and supercomputer combinatorial chemistry are used to design new compounds that will bind more tightly to the

“active site.”

Sulfa Drugs: a group of synthetic chemicals that

inhibit bacterial growth and metabolism. See

sulfonamide.

Sulfonamide: the first antibacterial drug that

was not overly toxic to humans. It is a synthetic, antimicrobial (rather than antibiotic)

drug.

Surveillance Systems: used in this report to

refer to data collection and record keeping to

track the emergence and spread of diseasecausing organisms such as antibiotic-resistant bacteria.

Susceptibility Test: any of a large number of

tests used to determine if bacteria are susceptible or resistant to an antibiotic.

Systemic: pertaining to or affecting the body as a

whole; frequently applied to bloodstream

infections.

Target Amplification Method: methods to

increase the number of target DNA

sequences through such methods as polymerase chain reaction (PCR). See polymerase chain reaction.

Tetracyclines: a family of broad-spectrum antibiotics used in the therapy of infections

caused by Gram-positive and Gram-negative

bacteria.

Toxicity: the quality of being poisonous. Referring to antibiotics, the degree to which they

produce unwanted, adverse effects.

Transcription: synthesis of RNA from a DNA

template.

Transduction: transfer of bacterial genes from

one bacterium to another by a bacterial virus

(called a phage).

Transformation: uptake by a bacterium of DNA

from a ruptured cell and incorporation of

genes from the DNA into the bacterial chromosome.

Transposons: small, mobile DNA sequences

that can move around chromosomes and

plasmids. Often they carry genes specifying

antibiotic resistance.

Treponema pallidum: bacteria that cause syphilis.

Trimethoprim: an antibiotic administered in

combination with a sulfonamide in the treatment of urinary tract infections.

Vaccine: a preparation of living, attenuated, or

killed bacteria or viruses, fractions thereof,

or synthesized antigens identical or similar

to those found in the disease-causing organisms, that is administered to raise immunity

to a particular microorganism.

Vancomycin: a widely used glycopeptide antibiotic, particularly important for treatment of

infections caused by strains of Staphylococ-
Appendix B: Glossary | 179

cus aureus some of which are resistant to all

other antibiotics.

Vancomycin-Resistant Enterococcus (VRE): a

bacterial strain. Some VREs are resistant to

all commercially available antibiotics.

Virulence: a measure of the degree and severity

of pathogenicity of a disease-causing organism.

Virus: submicroscopic pieces of genetic material

(RNA or DNA) enclosed in a protein coat

that cause infectious disease. Viruses are

obligate parasites that can reproduce only in

living cells.

Zone of Inhibition: area of no bacterial growth

around a disk containing antibiotic; used to

measure the antibiotic susceptibility or resistance of bacteria. See disk diffusion test.
| 181

C

Appendix C:

Acknowledgments

OTA wishes to thank the Impacts of AntibioticResistant Bacteria advisory panel and the following individuals and organizations for their

contributions of materials and advice to this

OTA report. In addition, several unnamed individuals at the Food and Drug Administration

contributed to the review of drafts of this report.

Lois Adams

Food and Drug Administration

Association of Practitioners of Infection Control 

and Epidemiology

Washington, DC

Karen Bush

Lederle Laboratories

Jose Diaz Buxo

Metrolina Nephrology Associates, P.A.

Marty Cetron

The Centers for Disease Control and Prevention

Mitchell Cohen

The Centers for Disease Control and Prevention

N. Cary Engleberg

University of Michigan Medical School

Victor Esposito

Microcarb, Inc.

Scott Evans

Latter-Day Saints Hospital

Gerard Fergerson

New York University

Robert Gaynes

The Centers for Disease Control and Prevention

Donald Goldman

Children’s Hospital, Boston

Gregory J. Gosch

Bio-Rad Laboratories

John H. Griffin

Stanford University

Richard Gustafson

Lawrenceville, NJ
182 | Impacts of Antibiotic-Resistant Bacteria

George Habel

Food and Drug Administration

Raymond M. Hakim

Vanderbilt University Medical Center

David Hooper

Massachusetts General Hospital

Tom Isett

Becton Dickinson Microbiology Systems

Daniel Kacian

Gen-Probe Inc.

Gagan Kamal

University of Iowa Hospital

Gordon Kemp

Animal Health Institute

Bruce Kreter

Rhone-Poulenc Rorer

Elliot Jacobs

Walter Reed Army Medical Center

Richard Lenski

University of Michigan

Bruce R. Levin

Emory University

Robert Linnabary

University of Tennessee

William Maise

Lederle Laboratories

Tom McDaniels

Washington, DC

John E. McGowan, Jr.

The Centers for Disease Control and Prevention

George Miller

Schering-Plough Research Laboratory

National Pork Producers Council

Des Moines, IA

Michael O’Connell

Miles Inc.

Brian O’Malley

U.S. House of Representatives

Sindy Paul

New Jersey Department of Health

Elaine Power

Office of Technology Assessment

Issam Raad

M.D. Anderson Cancer Center

Linda Rayford

Office of Technology Assessment

Eric Robinson

McNeil Pharmaceutical

Susan Rose

Department of Energy

Daniel Sahm

Washington University Medical Center

David R. Scott

Kaiser Permanente

Jean A. Setterstrom

Walter Reed Army Medical Center

Rodney Sobin

Office of Technology Assessment

P. Frederick Sparling

University of North Carolina School of Medicine

Morton Swarz

Massachusetts General Hospital

Robert V. Tauxe

The Centers for Disease Control and Prevention
Appendix C: Acknowledgments | 183

Fred Tenover

The Centers for Disease Control and Prevention

Martin Terry

Animal Health Institute

Steve Teutsch

The Centers for Disease Control and Prevention

Judith Wagner

Office of Technology Assessment

Robert A. Weinstein

Cook County Hospital

Thomas White

Roche Molecular Systems

Maureen Wirth

Middle Village, NY

Leah Wolfe

Cleveland Heights, OH