64954 Federal Register / Vol. 65, No. 211 / Tuesday, October 31, 2000 / Notices

Dated: October 25, 2000.

Carolyn J. Russell,

Director, Management Analysis and Services

Office, Centers for Disease Control and

Prevention.

[FR Doc. 00–27871 Filed 10–30–00; 8:45 am]

BILLING CODE 4163–70–P

DEPARTMENT OF HEALTH AND

HUMAN SERVICES

Food and Drug Administration

[Docket No. 00N–1571]

Enrofloxacin for Poultry; Opportunity

For Hearing

AGENCY: Food and Drug Administration,

HHS.

ACTION: Notice.

SUMMARY: The Food and Drug

Administration (FDA), Center for

Veterinary Medicine (CVM), is

proposing to withdraw approval of the

new animal drug application (NADA)

for use of the fluoroquinolone

enrofloxacin in poultry. This action is

based on CVM’s determinations that the

use of fluoroquinolones in poultry

causes the development of

fluoroquinolone-resistant

Campylobacter, a human pathogen, in

poultry; this resistant Campylobacter is

transferred to humans and is a

significant cause of the development of

resistant Campylobacter infections in

humans; and resistant Campylobacter

infections are a human health hazard.

Therefore, CVM is proposing to

withdraw the approval of the new

animal drug application for use of

enrofloxacin in poultry on the grounds

that new evidence shows that the

product has not been shown to be safe

as provided for in the Federal Food,

Drug, and Cosmetic Act (the act).

DATES: Submit written appearances and

a request for a hearing by November 30,

2000. Submit all data and analysis upon

which a request for a hearing relies by

January 2, 2001.

ADDRESSES: Written appearances,

requests for a hearing, data and analysis,

and other comments are to be identified

with Docket No. 00N–1571 and must be

submitted to the Dockets Management

Branch (HFA–305), Food and Drug

Administration, 5630 Fishers Lane, rm.

1061, Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT:

Linda R. Tollefson, Center for

Veterinary Medicine (HFV–200), Food

and Drug Administration, 7500 Standish

Pl., Rockville, MD 20855, 301–827–

6647.

SUPPLEMENTARY INFORMATION:

I. Fluoroquinolones Approved for

Poultry Use

The following are approved uses for

fluoroquinolones in poultry:

A. Sarafloxacin Hydrochloride

NADA 141–017, SaraFlox WSP,

approved August 18, 1995, for the

control of mortality in growing turkeys

and broiler chickens associated with

Escherichia coli organisms, Abbott

Laboratories, 1401 Sheridan Rd., North

Chicago, IL 60064.

NADA 141–018, SaraFlox Injection,

approved October 12, 1995, for the

control of early chick mortality

associated with E. coli organisms in

chickens and turkeys, Abbott

Laboratories, 1401 Sheridan Rd., North

Chicago, IL 60064.

B. Enrofloxacin

NADA 140–828, Baytril 3.23%

Concentrate Antimicrobial Solution,

approved October 4, 1996, for the

control of mortality in chickens

associated with E. coli organisms and

control of mortality in turkeys

associated with E. coli and Pasteurella

multocida organisms, Bayer Corp.,

Agriculture Division, Animal Health,

Shawnee Mission, KS 66201.

Abbott Laboratories has requested

withdrawal of NADA’s 141–017 and

141–018 for use of sarafloxacin

hydrochloride in poultry. By doing so,

the company has waived its right to a

hearing. Therefore, only NADA 140–828

is covered by this notice.

II. Summary of the Bases for

Withdrawing the Approval

CVM is providing notice of an

opportunity for a hearing on a proposal

to withdraw approval of the NADA for

enrofloxacin for use in poultry and to

revoke the new animal drug regulations

reflecting the approval of the NADA (21

CFR 520.813). Enrofloxacin belongs to

the class of antimicrobial drugs called

fluoroquinolones. Fluoroquinolones

also are approved for use in humans.

Fluoroquinolones are considered to be

one of the most valuable antimicrobial

drug classes available to treat human

infections because of their spectrum of

activity, pharmacodynamics, safety and

ease of administration. This class of

drugs is effective against a wide range

of human diseases and is used both in

treatment and prophylaxis of bacterial

infections in the community and in

hospitals. Fluoroquinolones are

essential to the treatment of foodborne

diseases. These diseases have a major

public health impact in the United

States.

Enrofloxacin oral solution for each of

its uses in poultry is a new animal drug

as defined in section 201(v) of the act

(21 U.S.C. 321(v)). As such, the drug

cannot be legally marketed in interstate

commerce in the absence of an

approved NADA (sections 301, 501, and

512 of the act (21 U.S.C. 331, 351, and

360b)). The requirements for approval of

NADA’s are set out in section 512 of the

act. Section 512 of the act requires that

a new animal drug must be shown to be

safe and effective for its intended uses.

Section 201(u) of the act provides that

‘‘safe’’ as used in section 512 ‘‘has

reference to the health of man or

animal.’’ The determination of safety

requires CVM to consider, among other

relevant factors, ‘‘the probable

consumption of such drug and of any

substance formed in or on food because

of the use of such drug’’ (section

512(d)(2)(A)). Accordingly, CVM must

consider not only safety of the new

animal drug to the target animal but also

safety to humans of substances formed

in or on food as a result of the use of

the new animal drug.

FDA approved the NADA’s for

fluoroquinolones for use in poultry in

1995 and 1996 (see section V.A.3 of this

document). After the approvals, CVM

instituted several strategies intended to

prevent or mitigate the development of

resistance (see section V.A.4 of this

document). However, resistance still

quickly developed to the

fluoroquinolones among the human

foodborne pathogen, Campylobacter

(see section V.B of this document). The

resistance developed from use of

fluoroquinolones in poultry under the

approved, labeled conditions of use (see

section V.B.1 of this document).

By 1998, Centers for Disease Control

and Prevention (CDC) testing found that

13.6 percent of Campylobacter human

isolates were resistant to

fluoroquinolones. Fluoroquinolone

resistance rose to 17.6 percent among

Campylobacter jejuni and 30 percent

among Campylobacter coli isolated from

ill humans in 1999. In 1998, testing

established that approximately 9.4

percent of the C. jejuni isolated from

chicken carcasses at federally inspected

slaughter plants in the United States

were fluoroquinolone resistant. Higher

levels of fluoroquinolone resistance are

observed in retail chicken (see section

V.B of this document).

After thoroughly analyzing all the

data and evidence, CVM has determined

the following: The primary cause of the

emergence of domestically-acquired

fluoroquinolone-resistant

Campylobacter infections in humans is

the consumption of or contact with

contaminated food (see section IV.B of

this document). Moreover, poultry is the

most likely source of campylobacteriosis

Federal Register / Vol. 65, No. 211 / Tuesday, October 31, 2000 / Notices 64955

in humans (see section V.C.2 of this

document), poultry is also a source of

fluroquinolone-resistant Campylobacter

(see sections V.B.3 and V.B.4 of this

document), and administration of

fluoroquinolones to chickens leads to

development of fluoroquinoloneresistant Campylobacter in chickens.

CVM has concluded, based on data

from surveillance programs, published

literature and other sources, that the use

of fluoroquinolones in poultry is a

significant cause of fluoroquinoloneresistant Campylobacter on poultry

carcasses, and therefore a significant

cause of fluoroquinolone-resistant

Campylobacter infections in humans.

CVM’s conclusion is supported by data

establishing a temporal association

between the approvals of these drugs for

use in poultry in the United States and

the increase in resistant Campylobacter

infections in humans. Fluoroquinolones

have been available for human use since

1986 and are commonly prescribed for

persons with gastrointestinal illness. Yet

resistance to fluoroquinolones did not

increase among Campylobacter

organisms above a very low level until

1996 or 1997, or soon after the approval

and use of these drugs in poultry (see

section V.B.5 of this document).

CVM’s conclusion is also supported

by comparison of fluoroquinolone use

in poultry with the two most likely

other possible causes of

fluoroquinolone-resistant human

infections—exposure to resistant

Campylobacter during foreign travel,

and direct use of fluoroquinolones in

humans. People are exposed to

fluoroquinolone-resistant

Campylobacter during travel to

developing countries (Ref. 1). However,

a risk assessment conducted by CVM

(see section V.C.3 of this document)

demonstrates an unacceptable human

health impact from domesticallyacquired Campylobacter infections from

use of fluoroquinolones in chickens

(Ref. 2). These domestically acquired

infections are much more likely to come

from exposure to resistant

Campylobacter through food than as a

result of direct treatment with

fluoroquinolones in humans (see section

IV.B of this document). This is due in

part to the fact that even if

fluoroquinolone treatment results in

resistant Campylobacter in an

individual, the resistant organisms are

unlikely to be transmitted to other

people in the United States because

generally the numbers of organisms

present are low and fecal-oral

transmission is required (Ref. 3).

Therefore, the level of fluoroquinoloneresistant Campylobacter now seen in

human isolates in the United States is

not plausibly due to fluoroquinolone

use in humans or the spread of resistant

Campylobacter from one human to

another.

Development of resistance to

fluoroquinolones among Campylobacter

has important consequences for human

health (see section V.C of this

document). Foodborne diseases have a

major public health impact in the

United States, and Campylobacter is the

most common known cause of

foodborne illness in the United States

(Ref. 3). Fluoroquinolones are

considered to be one of the most

valuable antimicrobial drug classes

available to treat a wide variety of

human infections, including infections

resistant to other drugs, and have been

particularly important in the treatment

of foodborne infections.

Patients with severe enteric disease

such as campylobacteriosis are usually

treated empirically. Therefore,

Campylobacter resistance presents a

dilemma for the physician. If

fluoroquinolone treatment is given

based on symptoms, and the patient is

infected with resistant Campylobacter,

there is a risk that the treatment will not

be effective or will be less effective and

valuable time will be lost. If treatment

is delayed until the causative organism

and susceptibility are confirmed by a

medical laboratory, again valuable time

will be lost. That is, the disease may be

prolonged or result in complications,

especially in vulnerable patients with

underlying health problems (Refs. 1 and

4). Use of an alternative drug to treat the

patient empirically may be less

desirable because that drug may have a

narrower spectrum of activity or greater

or more toxic side effects.

Isolation of fluoroquinolone-resistant

Campylobacter organisms from humans

means that fluoroquinolone therapy—if

administered—would be ineffective or

less effective in these humans. The

current level of resistance to

fluoroquinolones among human

Campylobacter isolates attributed to the

use of fluoroquinolones in poultry

represents a harm to human health.

Furthermore, a risk assessment

conducted by CVM demonstrated the

magnitude of the adverse impact that

the use of fluoroquinolones in chickens

has on human health. The risk

assessment determined that in 1999 a

mean estimate of 11,477 persons (5th

and 95th percentiles: 6,412 and 18,978)

infected with campylobacteriosis and

prescribed a fluoroquinolone would

have had a fluoroquinolone-resistant

illness due to the use of

fluoroquinolones in chickens. These

people are likely to have had prolonged

illnesses or complications. Furthermore,

CVM believes that the adverse human

health effects were underestimated due

to limitations in study methods and

data.

Finally, CVM is concerned that the

harm from fluoroquinolone-resistant

Campylobacter infections will continue

to increase such that more people will

be unable to be effectively treated with

fluoroquinolones when those drugs are

needed for foodborne illness. With

respect to the harm presented by

resistant foodborne pathogens, it is

especially important to take action as

soon as a problem is detected since the

nature of the problem is dynamic and

relatively large shifts in the prevalence

of resistance can occur within short

timeframes (Refs. 5 and 6).

III. Legal Context of the Proposed

Action

Section 512(e)(1)(B) of the act,

requires withdrawal of approval of an

NADA if:

* * * new evidence not contained in

[an approved] application or not

available to the Secretary until after

such application was approved, or tests

by new methods, or tests by methods

not deemed reasonably applicable when

such application was approved,

evaluated together with the evidence

available to the Secretary when the

application was approved, shows that

such drug is not shown to be safe for use

under the conditions of use upon the

basis of which the application was

approved * * *.

Under this clause, to meet its initial

burden to support withdrawal of an

approval CVM must provide ‘‘a

reasonable basis from which serious

questions about the ultimate safety of

[the drug] may be inferred.’’ See

Diethylstilbestrol: Withdrawal of

Approval of New Animal Drug

Applications; Commissioner’s Decision

(Commissioner’s DES Decision), 44 FR

54852 at 54861, September 21, 1979,

aff’d Rhone-Poulenc, Inc., Hess & Clark

Div. v. FDA, 636 F.2d 750 (D.C. Cir

1980). See also Nitrofurans: Withdrawal

of Approval of New Animal Drug

Applications; Final Rule; Final Decision

Following a Formal Evidentiary Public

Hearing, 56 FR 41902, August 23, 1991.

‘‘‘Serious questions’ can be raised where

the evidence is not conclusive, but

merely suggestive of an adverse effect’’

(44 FR 54861). Once this threshold

burden has been satisfied, the burden

passes to the sponsor to demonstrate

safety. Id.

Section 201(u) of the act provides that

for purposes of section 512 of the act,

‘‘safe’’ has ‘‘reference to the health of

man or animals.’’ In determining

whether a drug is ‘‘safe,’’ section

64956 Federal Register / Vol. 65, No. 211 / Tuesday, October 31, 2000 / Notices

512(d)(2)(A) of the act requires FDA to

consider ‘‘the probable consumption of

such drug and any substance formed in

or on food because of the use of such

drug.’’

‘‘Safe,’’ in the context of human food

safety, can be defined as ‘‘reasonable

certainty of no harm.’’ The definition is

derived from language in H. Rept. 2284,

85th Cong., 2d. sess. 4095, 1958,

defining the term ‘‘safe’’ as it appears in

section 409 of the act (21 U.S.C. 348),

which governs food additives.

Substances formed in or on food due to

the use of animal drugs were regulated

under the food additive provisions in

section 409 of the act until passage of

the Animal Drug Amendments in 1968

(the 1968 amendments). The 1968

amendments merely consolidated all of

the existing statutory authorities related

to animal drugs into section 512 of the

act, and the legislative history shows

that the consolidation in no way

changed the authorities with respect to

the regulation of new animal drugs (S.

Rept. 1308, 90th Cong., 2d. sess. 1,

1968). CVM has applied the ‘‘reasonable

certainty of no harm’’ standard in

determining the safety of substances

formed in or on food as a result of the

use of a new animal drug during the

new animal drug application review

process. CVM has done so by

determining the level at which a

substance formed in or on food as a

result of the use of a new animal drug

has no effect on humans (Ref. 75).

IV. Development of Antimicrobial

Resistance As a Result of Drug Use in

Animals

A. Development of Antimicrobial

Resistance That Can Compromise

Human Therapy

Antimicrobial drugs are products that

affect bacteria by inhibiting their growth

or by killing them outright.

Antimicrobial drugs are used to treat

bacterial disease in humans and since

their discovery have prevented

countless deaths worldwide. In animals,

these drugs are used to control, prevent,

and treat infection, and to enhance

animal growth and feed efficiency.

That antimicrobial agents could select

for resistant bacterial populations

became apparent soon after the first

antimicrobial drug, penicillin, was

discovered. Antimicrobial use promotes

antimicrobial resistance by selecting for

resistant bacteria (Refs. 7 and 8). When

an antimicrobial drug is used to treat an

infection, the bacteria most sensitive to

the drug die or are inhibited. Those

bacteria that have, or acquire, the ability

to resist the antimicrobial persist and

replace the sensitive bacteria. If these

bacteria that have developed resistance

are disease causing (pathogenic) in

humans, they may cause disease

resistant to treatment (Refs. 7 and 9).

Selective pressure resulting from the

use of antimicrobial drugs is the

underlying force in the development

and spread of resistant bacterial

populations. The association between

antimicrobial use and resistance has

been documented in various settings

(Ref. 7), for nosocomial infections (Ref.

10) as well as for community-acquired

infections (Ref. 11).

B. Antimicrobial Resistance in

Foodborne Pathogens of Animal Origin

In industrialized countries, the major

foodborne pathogens, Campylobacter

and Salmonella, are infrequently

transferred from person to person (Refs.

3 and 12). In these countries,

epidemiological data have demonstrated

that the primary source of antibiotic

resistant foodborne infections in

humans is the acquisition of resistant

bacteria from animals via food (Refs. 3,

13, and 14). This has been demonstrated

through several different types of

foodborne disease followup

investigations, including laboratory

surveillance, molecular subtyping,

outbreak investigations, and studies on

infectious dose and carriage rates (Refs.

15, 16, 17, and 18).

CDC published an extensive review of

epidemiological studies that focused on

human foodborne infections caused by

drug-resistant Salmonella and

concluded that the resistant infections

were acquired through contaminated

foods of animal origin (Refs. 12 and 19).

Transfer of Campylobacter from poultry

to humans through food was

demonstrated as early as 1984 (Ref. 15).

Recent emergence of a resistant

foodborne pathogen that has a foodproducing animal reservoir is illustrated

by Salmonella enterica serotype

Typhimurium Definitive Type 104

(DT104). DT104 is a multidrug resistant

pathogen that is currently epidemic in

human and food-producing animal

populations in the United Kingdom and

has been isolated in several countries in

Europe (Refs. 20, 21, and 22). This

organism has also been identified in

livestock and poultry in the United

States (Refs. 23, 24, and 25). Also, a

report from the United Kingdom

suggests that infections caused by

DT104 may be associated with greater

morbidity and mortality than infections

by less resistant serotypes of Salmonella

(Ref. 26).

C. Role of Animal Drug Use in the

Development of Resistant Foodborne

Pathogens

Scientific evidence demonstrates that

the use of antimicrobials in foodproducing animals can select for

resistant bacteria of human health

concern. Repeated dosing of foodproducing animals can also contribute

to the selection of resistant bacteria

(Refs. 27 and 28). When an

antimicrobial drug is administered to an

animal, the most susceptible bacteria

will be eliminated, while the least

susceptible organisms will survive.

These surviving bacteria will proliferate

and become the predominant

population. With additional exposure to

the drug, the resistant populations of

bacteria will expand and have an

increasing probability of survival and

dissemination.

The resistant bacteria that develop as

a result of antimicrobial drug use in

food-producing animals can then be

transferred to humans via food. The

contaminated food may cause disease in

persons handling or consuming the food

or in persons consuming food

contaminated from the animal-derived

food.

When antimicrobial drugs are

administered to food-producing

animals, they promote the emergence of

resistance in bacteria that may not be

pathogenic to the animal, but are

pathogenic to humans (Refs. 15, 29, 30,

31, and 32). For example, Salmonella

and Campylobacter are ubiquitous and

can exist in the intestinal flora of

various food-producing animals without

causing disease in the animals.

However, these bacteria can cause

severe, even fatal, foodborne illness in

humans. If using an antimicrobial in a

food-producing animal causes resistance

to occur in such bacteria, and the

resistant bacteria cause an illness in a

consumer who needs treatment, that

treatment may be compromised (Ref.9).

The link between antimicrobial

resistance in foodborne pathogenic

bacteria and use of antimicrobials in

food-producing animals has been

demonstrated in a number of studies

(Refs. 25, 33, 34, and 35). For example,

an association has been noted between

loss of susceptibility to

fluoroquinolones among Salmonella

enterica Typhimurium DT104 isolates

(see section IV.B of this document) and

the approval and use of a

fluoroquinolone for veterinary

therapeutic use in the United Kingdom

(Refs. 14, 30, and 36). Moreover,

fluoroquinolone administration to

chickens infected with fluoqouinolonesensitive C. jejuni has been shown to

Federal Register / Vol. 65, No. 211 / Tuesday, October 31, 2000 / Notices 64957

result in the development of

fluoroquinolone-resistant C. jejuni in

those chickens (Ref. 35).

Epidemiological evidence shows that

resistant foodborne pathogens are

present on or within animals as a result

of antimicrobial drug use in foodproducing animals and can result in

drug-resistant infections in humans

(Refs. 1, 16, 37, 38, and 39). Holmberg

et al. were the first to establish this by

documenting an outbreak of

salmonellosis in people caused by

multi-drug-resistant Salmonella from

eating hamburger originating from

South Dakota beef cattle fed the

antibiotic chlortetracycline for growth

promotion (Ref. 16). As explained more

fully in section V.B of this document,

researchers in Minnesota recently

reported on fluoroquinolone-resistant

Campylobacter infections in humans

acquired from poultry treated with

fluoroquinolones (Ref. 1).

V. Antimicrobial Resistance Resulting

From the Use of Fluoroquinolones in

Poultry

As discussed below, during its

evaluation of the NADA’s for use of

fluoroquinolones in poultry, CVM

carefully considered the issue of

potential resistance development due to

the use of the drugs in poultry. When

CVM approved the NADA’s for use of

fluoroquinolones in poultry, it believed

that the fluoroquinolones could be used

safely in poultry and that resistance

development could be limited by certain

restrictions placed on the use of the

drugs. Resistance, however, has

developed such that CVM now believes

that its only option to protect human

health is withdrawal of the approval of

the NADA’s for use of fluoroquinolones

in poultry.

A. Circumstances Surrounding the

Approval

1. Human Health Concern Related to

Fluoroquinolone Resistance

Prior to FDA’s approval of

fluoroquinolones for use in foodproducing animals, several scientific

organizations and individual scientists

expressed concern that the use of

fluoroquinolones in food-producing

animals would result in the selection of

fluoroquinolone-resistant foodborne

bacterial pathogens in humans (Refs. 7,

33, and 40). There were several reasons

for these concerns.

First, as explained more fully in

section V.C of this document,

fluoroquinolones are very important for

human therapy. Bacteria resistant to

veterinary fluoroquinolones exhibit

resistance to other compounds within

the class. Thus, resistance to a

fluoroquinolone used only in animals,

such as enrofloxacin, confers resistance

to all other fluoroquinolones, including

ciprofloxacin and other

fluoroquinolones used only in humans.

The veterinary fluoroquinolone

enrofloxacin is structurally similar to

ciprofloxacin and a portion of it is

metabolized to ciprofloxacin in the

animal (Ref. 41).

Second, reports of studies conducted

after approvals of fluoroquinolones for

poultry in other countries had shown a

relationship between the approval of

fluoroquinolones for therapeutic use in

food-producing animals and the

development of fluoroquinolone

resistance in Campylobacter in animals

and humans. For example, the approval

and use of these drugs in poultry in the

Netherlands (Refs. 33, 35, and 42), and

Spain (Refs. 43 and 44) preceded

increases in fluoroquinolone resistance

in Campylobacter isolates from treated

animals and ill humans. In the

Netherlands, Campylobacter isolates

from humans and poultry were

examined for resistance to the human

fluoroquinolone ciprofloxacin between

the years 1982 and 1989 to determine

the influence of licensing of

enrofloxacin for veterinary use in 1987

(Ref. 33). In 1982, none of the

Campylobacter isolates from either

human or poultry sources was resistant

to ciprofloxacin. In 1989,

fluoroquinolone resistance among the

Campylobacter isolates was 11 percent

in humans and 14 percent in poultry

(Ref. 33).

Third, there was a concern about use

of fluoroquinolones as water-soluble

products. This use raised the possibility

of development of resistant organisms in

greater numbers than if the drugs were

to be administered in an individually

administered injectable dosage form.

Due to the nature of animal production,

the most efficient way to treat herds or

flocks is to administer drugs through the

water supply or the feed. When disease

is detected in a herd of animals or a

flock of poultry, the product is put into

the animals’ water supply, thereby

exposing greater numbers of animals

than just the few with clinical signs of

the disease. The practice of treating an

entire herd or flock is more likely to

result in resistant pathogens than

individual animal treatment due to the

inability to control each animal’s dose

and the widespread contamination by

water leakage and animal waste that

occurs when large numbers of animals

are treated, which result in untreated

animals being exposed to the drug.

Selective pressure exerted by

fluoroquinolone use is the driving force

for the development and spread of the

genetic mutations in Campylobacter that

lead to fluoroquinolone resistance.

Administering fluoroquinolones to large

numbers of animals through water or

feed could substantially increase the

selective pressure on the organisms and

facilitate the spread of resistant

pathogens. An additional problem arises

when the dose administered to each

bird is variable, which is the case when

the antimicrobial is administered ad

libitum in the water. This practice may

result in ineffective dosing in some

animals and increase the probability of

selecting for resistant zoonotic bacteria

in both healthy and diseased animals.

2. Advisory Committee Review

Because of the concerns surrounding

the use of fluoroquinolones in foodproducing animals, CVM consulted with

a panel of experts comprised of its

Veterinary Medicine Advisory

Committee and FDA’s [Human] AntiInfective Drug Advisory Committee in

May 1994 to address the issue of use of

fluoroquinolones in food-producing

animals in light of concerns about

antimicrobial resistance. The panel

supported several restrictions on the use

of the drugs in food-producing animals

in order to minimize the human health

risks related to the development of

resistant bacteria in animals (Ref. 45).

Frequently expressed recommendations

of committee members included

approval for therapeutic use by

veterinary prescription only, prohibition

of extra-label use, and establishment of

a nationally representative surveillance

system to prospectively monitor

resistance trends of selected enteric

bacteria of animals that can cause

disease in humans (Ref. 45).

3. Approval of Enrofloxacin

The NADA for Baytril 3.23%

Concentrate Antimicrobial Solution

(enrofloxacin) was approved October 4,

1996, for broiler chickens and growing

turkeys. The approval is for therapeutic

use: Enrofloxacin is approved for the

control of mortality in chickens

associated with E. coli organisms and

control of mortality in turkeys

associated with E. coli and P. multocida

organisms.

At the time this drug was approved,

microbial safety studies were not

required for therapeutic uses of

antimicrobial new animal drugs in foodproducing animals. Thus, no studies

were required of the drug sponsor, and

none was performed, demonstrating the

safety of the use of fluoroquinolones in

poultry with respect to antimicrobial

resistance and the potential for resistant

pathogens to be transferred from poultry

64958 Federal Register / Vol. 65, No. 211 / Tuesday, October 31, 2000 / Notices

to humans. At that time, the agency

believed that such studies were

necessary only for certain

subtherapeutic feed uses in foodproducing animals (21 CFR 558.15).

However, increasing evidence that

therapeutic as well as subtherapeutic

use of antimicrobials in food-producing

animals may select for resistant bacteria

of human health concern led the agency

to issue final guidance addressing this

concern in December 1999 (Ref. 46). The

guidance addresses how FDA intends to

consider the potential human health

impact of all uses, therapeutic as well as

subtherapeutic, of all classes of

antimicrobial new animal drugs

intended for use in food-producing

animals. The guidance states that

preapproval studies to answer questions

regarding the human health impact of

the microbiological effects of an

antimicrobial product may be needed

for therapeutic as well as subtherapeutic

products (Ref. 46).

4. Approval Restrictions, Surveillance,

and Educational Activities

Certain actions were taken at or near

the time of approval of the

fluoroquinolones to help ensure that

resistance to fluoroquinolones did not

develop in bacteria that are transferred

from poultry to humans, and to detect

any trend towards the development of

resistance at an early stage. First, CVM

imposed two restrictions on the use of

the fluoroquinolones. CVM limited the

drugs to use by or on the order of a

licensed veterinarian. Also, FDA issued

an order to prohibit all extra-label uses

of fluoroquinolones in animals, which

became effective in August 1997 (21

CFR 530.41).

Second, the agency took steps to

gather surveillance data on the

development of antimicrobial resistance

among foodborne pathogens, including

resistance to fluoroquinolones. In 1996,

FDA, CDC, and the U.S. Department of

Agriculture (USDA) established the

National Antimicrobial Resistance

Monitoring System: Enteric Bacteria

(NARMS) to prospectively monitor

changes in antimicrobial susceptibilities

of selected zoonotic enteric pathogens

from human and animal clinical

specimens, from healthy farm animals,

and from carcasses of food-producing

animals at slaughter (Ref. 47).

Nontyphoid Salmonella was initially

selected as the sentinel organism and

the program has been expanded each

year since its inception. NARMS is

currently monitoring susceptibilities of

human and animal isolates of

Salmonella, E. coli, Campylobacter, and

Enterococcus. NARMS is set up as two

equal parts, human and animal, that use

the same methodology for isolating and

testing the organisms.

Animal isolate testing is conducted at

the USDA Agricultural Research Service

Russell Research Center. Human isolate

testing is conducted at the CDC National

Center for Infectious Diseases

Foodborne Disease Laboratory. Goals

and objectives of the monitoring

program include: Providing descriptive

data on the extent and temporal trends

of antimicrobial susceptibility in enteric

organisms from the human and animal

populations; providing information to

veterinarians, physicians, and public

health authorities so that timely action

can be taken; prolonging the life span of

approved drugs by promoting the

prudent use of antimicrobials;

identifying areas for more detailed

investigation; and guiding research on

antimicrobial resistance.

Third, CVM has supported efforts by

the American Veterinary Medical

Association (AVMA) and several

practitioner and producer groups to

define and promote the appropriate use

of antimicrobial drugs in foodproducing animals to try to minimize

the occurrence of resistant foodborne

pathogens that may be transferred to

humans through food. CVM is

supporting the development of printed

material and videotapes based on the

prudent use guidelines developed by

the AVMA to educate producers and

veterinarians about food-producing

animal drug use. CVM is also committed

to help develop other educational

strategies to be disseminated to

veterinarians and food-producing

animal producers via symposia and

exhibits at scientific meetings.

Veterinary medical schools may also use

these educational materials as part of a

food safety curriculum.

B. Development of Resistance After FDA

Approvals of Fluoroquinolones for Use

in Poultry

1. Overview

Despite the previously described

restrictions placed by FDA on the use of

the approved poultry fluoroquinolone

products, fluoroquinolone resistance

among Campylobacter developed and

increased after the 1996 approvals. CVM

believes, based on research, that prior to

1995, there was very little, if any,

fluoroquinolone-resistant

Campylobacter in the United States

among domestically acquired foodborne

disease (see section V.B.5 of this

document). After the approval, however,

fluoroquinolone resistance was

observed in Campylobacter from human

clinical cases, and in poultry isolates

taken from slaughter plants and retail

establishments. The results were

obtained from NARMS and a key study

by the Minnesota Department of Health.

In the 4 years since approval of the

fluoroquinolones, CVM has found very

little evidence of extra-label use of these

drugs in food-producing animals, based

on information derived from regulatory

inspections. Nor has CVM found

evidence of over-the-counter sales of the

poultry fluoroquinolones. Therefore, the

agency’s attempts to prevent the

development of fluoroquinoloneresistant human pathogens through

limiting these drugs to prescription use

and by prohibiting extra-label use have

not been sufficient.

2. Human Isolate Data from NARMS

CDC began routinely testing human

Campylobacter isolates for resistance to

fluoroquinolones in 1998, 2 years after

approval of enrofloxacin for use in

poultry. In 1998, CDC tested 346 human

Campylobacter isolates and found 13.6

percent of the Campylobacter isolates

were resistant to fluoroquinolones (Ref.

48). In 1999, CDC tested 315 human

isolates of Campylobacter;

fluoroquinolone resistance had risen to

17.6 percent among C. jejuni and 30

percent among C. coli, a statistically

significant increase (Ref. 49).

3. Poultry Isolate Data From NARMS

and Other Sources

Approximately 9.4 percent of the C.

jejuni isolated from chicken carcasses at

federally inspected slaughter plants in

1998 were fluoroquinolone resistant

(Ref. 50). The Campylobacter isolates

were collected in a pilot study during

the latter 3 months of the year. The 1999

data set, collected for the entire year,

shows that approximately 9.3 percent of

the C. jejuni were resistant to

fluoroquinolones (Ref. 51). However, the

1999 data when segregated by State

show that several areas of the country

had significantly higher than the 9.3

percent average level (Ref. 2). When the

isolate test results are weighted by the

level of chicken production in each

State, the level of resistance among C.

jejuni is approximately 12 percent for

1999 (Ref. 2).

Campylobacter isolates from retail

chicken products show even higher

levels of fluoroquinolone resistance. In

January-June 1999, public health

laboratories in Georgia, Maryland, and

Minnesota, under the direction of the

CDC, tested 180 chickens with 23

distinct brand names that were

purchased from 25 grocery stores (Ref.

52). Campylobacter were isolated from

80 (44 percent) of the chickens.

Nineteen (24 percent) of the samples

had Campylobacter isolates resistant to

Federal Register / Vol. 65, No. 211 / Tuesday, October 31, 2000 / Notices 64959

1 In two surveys encompassing 474 human

isolates from 1982 to 1992 in the United States,

only a single ciprofloxacin resistant isolate was

identified. This isolate was subsequently speciated

as C. lari, which is intrinsically resistant to

fluoroquinolones (Ref. 54).

fluoroquinolones and 25 (32 percent)

were resistant to nalidixic acid, a

quinolone antimicrobial drug that serves

as a precursor to fluoroquinolone

resistance development (Ref. 52). These

retail chicken findings are consistent

with those from an earlier, independent

study by the Minnesota Department of

Health, described in the next

subsection.

4. Human and Poultry Isolate Data From

the Minnesota Study

Researchers at the Minnesota

Department of Health studied quinolone

and fluoroquinolone resistance among

Minnesota residents, and evaluated

chicken as the source of the resistance.

They found that the proportion of

fluoroquinolone-resistant C. jejuni

isolates from humans increased from 1.3

percent in 1992 to 10.2 percent in 1998

(Ref. 1).

The proportion of resistant C. jejuni

collected from all reported cases of

illness increased only slightly from 1992

to 1994. Although researchers found

that increases between 1996 and 1998

were predominantly associated with

foreign travel, the percentage of resistant

infections that were acquired

domestically also increased from 0.3

percent to 3 percent between 1996 and

1998 (Ref. 1).

As part of the study, the Minnesota

Department of Health in cooperation

with the Minnesota Department of

Agriculture collected 20 different

brands of retail chicken products from

18 markets in the Twin Cities metro area

in 1997. Campylobacter were isolated

from 88 percent (80/91) of the samples;

20 percent of these were Campylobacter

resistant to fluoroquinolones. The

products with resistant strains had been

processed in five States (Ref. 1).

Molecular subtyping revealed a strong

association between resistant C. jejuni

strains from the retail chicken products

and C. jejuni strains from the

domestically acquired human cases of

campylobacteriosis. The study used

polymerase chain reaction with

restriction length polymorphism

flagellin gene typing to identify strains

of fluoroquinolone-resistant C. jejuni

among isolates from the domestically

acquired human cases and locally

available retail chicken products. The

investigators attributed the 1996 to 1998

increase in resistant domestic cases

among humans to poultry treated with

fluoroquinolones (Ref. 1). The

investigators concluded that ‘‘the use of

fluoroquinolones in poultry, which

began in the United States in 1995, has

created a reservoir of resistant C. jejuni’’

(Ref. 1).

5. Summary of Fluoroquinolone

Resistance Data

The most recent data on

fluoroquinolone resistance among

Campylobacter isolates (1999) show

17.6 percent resistance among C. jejuni

in humans, and 9.3 percent resistance

among C. jejuni on chickens sampled at

slaughter plants. Retail samples taken in

1999 indicate even higher levels of

fluoroquinolone-resistant

Campylobacter on chickens (Ref. 52).

After thoroughly analyzing all the

data and evidence, CVM has determined

that a significant cause of the emergence

of domestically-acquired

fluoroquinolone-resistant

Campylobacter infections in humans is

the consumption of, or contact with,

contaminated food (see section IV.B of

this document), that poultry is the most

likely source of campylobacteriosis in

humans (see section V.C.2 of this

document), and that poultry is also a

source of resistant Campylobacter (see

section V.B.3 and V.B.4 of this

document). CVM has also concluded

that the administration of

fluoroquinolones to chickens leads to

development of fluoroquinoloneresistant Campylobacter in the chickens

(see section IV.C of this document).

Fluoroquinolone-resistant

Campylobacter have been found in

broiler chicks that had been

administered fluoroquinolone drugs

(Ref. 35). Further, resistant

Campylobacter found on chicken

carcasses would not have resulted from

use of a nonfluoroquinolone drug

because fluoroquinolone resistance in

Campylobacter arises exclusively from

clonal expansion, rather than by the

transfer of plasmids or resistance

determinants (Ref. 53). Also, the

fluoroquinolone resistance results only

from drug use; that is, the resistance

could not have developed naturally

since fluoroquinolones are totally

synthetic antimicrobials with no known

natural analogues. (See also discussion

in section IV.A of this document.)

Consequently, CVM has concluded,

based on a careful study of all relevant

data and information, that use of

fluoroquinolones in poultry is a

significant cause of domestically

acquired resistant Campylobacter

infections in humans.

CVM’s conclusion is supported by the

establishment of a temporal association

between the approval of the

fluoroquinolones for poultry and the

emergence of fluoroquinolone-resistant

Campylobacter in humans. Although

most of the data cited above were

collected after the approval, CVM

believes that there was very little, if any,

fluoroquinolone-resistant

Campylobacter in the United States

among domestically acquired foodborne

disease cases before the approvals.

Fluoroquinolones have been available

for human use since 1986 when

ciprofloxacin was approved in the

United States (Refs. 1 and 54).

Ciprofloxacin soon was one of the most

commonly used antimicrobials to treat

infections caused by a variety of

bacterial infections in humans,

including Campylobacter infections.

However, emergence of domestically

acquired fluoroquinolone-resistant

human foodborne infections in numbers

large enough to be detected by national

surveillance systems did not occur until

sometime between 1996 and 1998

Ref. 1).

Only rare, sporadic, and isolated

incidents of fluoroquinolone-resistant

Campylobacter infections were reported

in humans prior to 1995.1 (NARMS was

not initiated until January 1996 and

Campylobacter were not tested until

1998.) In addition, as shown in section

V.B.4 of this document, only very low

levels of resistance were detected among

isolates from human Campylobacter

cases collected by the Minnesota

Department of Health from 1992 to 1994

(Ref. 1). Additional data from Minnesota

demonstrated an increase in

fluoroquinolone resistance among

Campylobacter collected from

domestically-acquired cases of human

illness after the approval of the poultry

fluoroquinolones (Refs. 1 and 54). The

researchers were able to conclude that

the 1996 to 1998 increases in domestic

cases were due to the use of

fluoroquinolones in poultry. That

conclusion is supported by the

association found between molecular

subtypes of resistant C. jejuni strains

that were acquired domestically in

humans and those found in chicken

products (Ref. 1). (See section V.B.4 of

this document.)

Because there was no food-producing

animal fluoroquinolone use other than

use in poultry until late 1998 (when

CVM approved fluoroquinolones for use

in cattle), CVM believes that the data

presented in this section V.B of the

document) provide strong evidence that

the increase in domestically acquired

fluoroquinolone resistance observed in

people since 1996 (Ref. 1) is largely

associated with the use of

fluoroquinolones in poultry. Data from

other countries, which showed

64960 Federal Register / Vol. 65, No. 211 / Tuesday, October 31, 2000 / Notices

increases in Campylobacter resistance

following approval of fluoroquinolones

for use in poultry, support this

conclusion as to temporal association

(Refs. 33, 43, and 55). (See section V.A.1

of this document.)

CVM’s conclusion is also supported

by an examination of the two most

likely other possible causes of

fluoroquinolone-resistant

Campylobacter in humans. One possible

cause is the direct use of

fluoroquinolones in humans. Although

fluoroquinolone-resistant

Campylobacter may develop in the

intestinal tract of persons with these

infections who are treated with

fluoroquinolones, spread of the

organisms to other persons is

uncommon because person-to-person

transmission of these organisms is rare

in developed countries (Ref. 3). As a

result, the resistance due to direct

human use is likely to be limited (Refs.

12 and 19). (See section IV.B of this

document.) The lack of an increase in

fluoroquinolone-resistant human cases

from the time when fluoroquinolones

were first used in human medicine, the

high level of human use since their

approval, and the emergence of

fluoroquinolone resistance in human

cases of Campylobacter infections soon

after the approval of fluoroquinolones

for poultry, all support the conclusion

that the resistance observed in humans

is due to the use of fluoroquinolones in

poultry.

Exposure to Campylobactercontaminated food can occur during

foreign travel and, indeed, some of the

fluoroquinolone resistance identified

among humans is due to acquiring an

illness while traveling outside the

United States. However, a risk

assessment conducted by CVM

demonstrates a significant human health

impact from domestically acquired

fluoroquinolone-resistant

Campylobacter infections due to the use

of fluoroquinolones in chickens (Ref. 2).

(See section V.C.3 of this document.)

CVM therefore believes that a

significant cause of the emergence of

fluoroquinolone-resistant

Campylobacter infections in humans is

the consumption of, or contact with,

contaminated poultry that had been

administered fluoroquinolones, had

contact with other poultry treated with

this drug, or had contact with the

environment contaminated directly or

indirectly with this drug.

C. Human Health Implications

1. Importance of Fluoroquinolines in

Human Medicine

Fluoroquinolones are considered to be

one of the most valuable antimicrobial

drug classes available to treat human

infections because of their broad

spectrum of activity, pharmacokinetics,

safety, and ease of administration (Ref.

56). This class of drugs is effective

against a wide range of human diseases

and is widely used both in treatment

and prophylaxis of bacterial infections

in the community and in hospitals (Ref.

56). Fluoroquinolones are important

because they are active against a variety

of organisms resistant to most other

classes of antibiotics or for which

alternative agents are more toxic and/or

not available for oral administration.

They have been very effective in treating

or preventing serious, often lifethreatening, infections in a number of

major areas of human medicine, both in

the hospital and in the community. In

the hospital setting, the

fluoroquinolones are very often lifesaving drugs of choice for a wide variety

of common resistant and serious

infections because of both their activity

and their favorable safety profiles.

Fluoroquinolones are particularly

important in the treatment of gram

negative infections, including those

caused by Campylobacter, but also

including Shigella, Salmonella, E. coli,

Klebsiella and other Enterobactericiae.

These type of enteric bacteria cause a

wide variety of infections and are

frequently resistant to agents such as

ampicillin, tetracycline, trimethoprimsulfa and many cephalosporins (Ref.

56). In addition, the fluoroquinolones

are often less toxic and more convenient

to administer than alternative

treatments that may be available for

resistant organisms.

Fluoroquinolones are the agents most

frequently used as the drugs of choice

in the empiric treatment of patients

presenting to a physician with serious

gastrointestinal symptoms such as acute

diarrhea or possible enteric fever (e.g.,

typhoid fever) because they traditionally

have exhibited a very high level of

clinical effectiveness against most

enteric pathogens (Refs. 4 and 57).

Severity of illness is one of the most

important criteria physicians use in

determining which patients require

immediate treatment for a presumed

infectious enteric illness. Other criteria

include having a complicating medical

condition and belonging to a high-risk

group such as persons who are

immunocompromised. Upon

presentation to the physician, the

patient is examined and if treatment is

deemed necessary, treatment is usually

prescribed empirically, that is, without

having the results of culture and

sensitivity testing available prior to the

selection of the treatment. Culture and

sensitivity testing of Campylobacter can

take 48 to 96 hours before results are

available to provide guidance to the

physician in selection of a treatment

regimen. Thus, the physician needs to

be able to confidently prescribe an agent

likely to be immediately effective

against the array of organisms most

likely to be causing the patient’s severe

symptoms.

Treatment of serious susceptible

enteric infections with an effective

fluoroquinolone (e.g., ciprofloxacin) can

reduce the duration of illness and most

likely prevent complications and

adverse outcomes, including

hospitalization (Refs. 19 and 58). The

magnitude of the benefit of antibiotic

treatment is directly related to the early

initiation of therapy (Refs. 19 and 58).

For example, effective treatment of

campylobacteriosis with

fluoroquinolones has been shown to

decrease the duration of illness from 10

days to 5 days and the mean duration

of diarrhea from 5 to 1.3 days (Refs. 7,

19, and 58).

2. Foodborne Diseases

a. Introduction. Foodborne diseases

have a major public health impact in the

United States. Recent estimates describe

5,000 deaths and 76 million foodborne

illnesses annually (Ref. 59). The causes

of foodborne illness are varied and

include bacteria, parasites, viruses,

toxins and novel agents. Clinical

severity of foodborne disease also varies

and ranges from mild gastroenteritis to

life-threatening neurologic, hepatic, and

renal syndromes as well as septicemia

(Ref. 59). Development of resistance in

foodborne bacterial pathogens to safe

and effective antimicrobials complicates

the medical and public health concern

as important treatment options are

compromised or lost (Refs. 7, 19, 61,

and 62).

b. Campylobacteriosis. The three

primary causes of bacterial foodborne

disease in the United States are

Campylobacter, Salmonella, and some

pathogenic strains of E. coli.

Campylobacter infections are

predominantly foodborne infections

associated with animal-derived food

products (Refs. 59, 63, and 64).

Campylobacter is the most common

known cause of foodborne illness in the

United States (Ref. 3), causing an

estimated 2 million cases every year

(Ref. 60). Compared to patients with

typical noninvasive salmonellosis,

patients with C. jejuni or Campylobacter

Federal Register / Vol. 65, No. 211 / Tuesday, October 31, 2000 / Notices 64961

coli gastroenteritis often experience

more severe illness and are ill longer.

Gastroenteritis caused by

Campylobacter commonly causes severe

diarrhea, often bloody, fever, severe

abdominal pain, and can mimic acute

appendicitis, which may result in

unnecessary surgery (Ref. 65). While

these symptoms usually improve within

several days, they persist or recur in 15

to 25 percent of patients and can be

confused with chronic bowel diseases

(Ref. 65). For example, among 460

sporadic (not associated with an

epidemic) cases of campylobacteriosis

recently reported in 19 representative

U.S. counties, the mean duration of

illness was 10 days, with 7 lost

workdays, and one-half hospitalization

day. Five patients (1 percent) died (Ref.

66). Effective treatment of

campylobacteriosis with

fluoroquinolones within the first 2 days

of illness decreased the duration of

illness from 10 days to 5 days (Refs. 7,

19, and 58).

Campylobacter species are often

found as commensal bacteria, which are

bacteria that exist in an animal without

causing harm to that animal. These

bacteria are carried in the intestinal tract

of food-producing animals and can

contaminate food during slaughter and

processing (Ref. 67). The USDA Food

Safety Inspection Service has recently

conducted surveys of recovery rates and

estimated the mean number per unit

(gram, cm3) of product for some of the

major foodborne pathogens found on

raw animal products at slaughter and

processing. Raw product isolation rates

vary by species, with turkeys and

chickens appearing to have the highest

rates of Campylobacter recovery (Refs.

68, 69, 70, and 71).

Broiler chickens carry the highest

carcass and ground product load of

Campylobacter when compared to other

food-producing animals at slaughter

(Refs. 70 and 71). These data are

consistent with the repeated

observations in epidemiological studies

of the increased risk of

campylobacteriosis associated with

exposure to poultry. In surveys of retail

food products conducted by other

organizations, Campylobacter was

isolated from: 2 to 20 percent of raw

beef, 40 percent of veal; up to 98 percent

of chicken meat; low proportions of

pork, mutton, and shellfish; 2 percent of

fresh produce from outdoor markets and

1.5 percent of mushrooms (Refs. 15 and

72).

The symptoms exhibited by persons

with an enteric foodborne illness

include vomiting, diarrhea, abdominal

pain, cramping, and fever. The causal

agent of an enteric illness is not easily

determined based upon symptoms

alone. Empiric treatment of patients

with serious enteric disease of

presumed bacterial etiology is usual

medical practice because when

treatment is delayed (e.g., until the

Campylobacter infection or another

etiologic agent is confirmed by a

medical laboratory), the therapy may be

ineffective or less effective, and the

illness is more likely to be prolonged or

result in complications (Ref. 4). Also,

the clinical signs of patients with

campylobacteriosis are

indistinguishable from enteric disease

caused by Salmonella, which also is

treated with fluoroquinolones. Relapses

occur in approximately 5 to 10 percent

of untreated patients with

campylobacteriosis (Ref. 4) and have

been associated with fluoroquinolone

resistance (Ref. 74).

Antibiotic therapy is always indicated

for patients who demonstrate symptoms

of high fever, bloody diarrhea, or more

than eight stools in 24 hours; who are

immunosuppressed; who have

bloodstream infections; or whose

symptoms worsen or persist for more

than 1 week (Ref. 4). More invasive

disease such as blood-borne infections

occur in less than 1 percent of patients

with C. jejuni infections and are more

common in the elderly or very young

individuals as well as those with

impaired immune systems (Ref. 65).

Rare manifestations of

campylobacteriosis can include

meningitis, endocarditis, and septic

abortion (Ref. 4).

Campylobacteriosis also carries the

potential for serious sequelae as a result

of immunologic reactions to the

infection. The disease has been linked

to reactive arthritis and Reiter’s

Syndrome as well as Guillain-Barre

Syndrome (Ref. 65). Guillain-Barre

Syndrome is an autoimmune-mediated

disorder of the peripheral nervous

system. Since the elimination of polio,

this syndrome is now the most common

cause of acute flaccid paralysis (Ref. 73).

Many studies have shown a link

between campylobacteriosis and

Guillain-Barre Syndrome. Culture and

serologic data indicate that 30 to 40

percent of patients with the syndrome

have evidence of a preceding

Campylobacter infection, but this may

be an underestimate (Ref. 73). C. jejuni

is the most common species identified

from patients with Guillain-Barre

Syndrome, but other species of

Campylobacter may be involved (Ref.

73). It is not known whether resistant

Campylobacter infections are more

susceptible to developing sequelae such

as Guillain-Barre Syndrome. There is

also evidence suggesting that GuillainBarre Syndrome may be more severe

following infection with Campylobacter

than other precipitating infections (Ref.

73).

3. Campylobacter Risk Assessment

The data on fluoroquinolone

resistance levels, and the evidence

leading to the conclusion that the use of

fluoroquinolones in chickens is a

significant cause of fluoroquinolone

resistance in humans, establish an

adverse effect on human health by

fluoroquinolones. To assist in

establishing the extent of the adverse

human health impact of

fluoroquinolone use in poultry, CVM

developed a risk assessment model. The

risk assessment estimates the extent of

the risk to human health from resistant

Campylobacter pathogens attributed to

the use of fluoroquinolones in chickens

in the United States. Specifically, the

risk assessment model relates the

prevalence of fluoroquinolone-resistant

Campylobacter infections in humans

associated with the consumption of

chicken to the prevalence of

fluoroquinolone-resistant

Campylobacter in chickens (Ref. 2). The

risk assessment addressed that portion

of the risk that was quantifiable, which

is the risk related to consumption of

chicken. The unquantifiable portion,

that portion due to spread of the

pathogen from chicken to other foods

through contamination during food

preparation or from secondary spread to

other animals, was not considered in the

risk assessment.

As explained in section V.B.5 of this

document, the presence of

fluoroquinolone-resistant

Campylobacter on chicken carcasses

results from the use of fluoroquinolones

in chickens. This conclusion was used

as a parameter in the risk assessment.

This does not mean, for purposes of the

risk assessment, that every chicken

carrying resistant Campylobacter had to

have been treated with a

fluoroquinolone. Resistant organisms

could have been acquired from a

contaminated environment due to

fluoroquinolone drug use in a previous

flock, through contact with other

chickens during transportation to the

slaughter plant and antemortem

processing, or through contamination in

the slaughter plant by other infected

chicken carcasses.

The number of Campylobacter culture

confirmed human cases in the U.S.

population was used to estimate the

total burden of campylobacteriosis.

These data are collected from State

public health laboratories that

participate in FoodNet, the CDC’s

Foodborne Disease Active Surveillance

64962 Federal Register / Vol. 65, No. 211 / Tuesday, October 31, 2000 / Notices

Network. FoodNet monitors the

incidence of foodborne disease in

humans and conducts studies to

identify the sources and consequences

of infection. Using the data on human

Campylobacter cases reported in

FoodNet, the risk assessment calculated

a mean estimate of 1.7 million cases of

campylobacteriosis (5th and 95th

percentiles: 1.1 million and 2.7 million)

for 1999 (Ref. 2).

The model also estimates the number

of fluoroquinolone-resistant

Campylobacter cases in humans

attributable to chickens. This estimate

excludes travelers to countries outside

the United States, those patients who

were prescribed a fluoroquinolone prior

to stool culture, and those patients who

were unsure of the timing of their

treatment in relation to stool culture.

For 1999, the mean estimate of the

domestically-acquired fluoroquinoloneresistant Campylobacter cases in

humans attributable to chickens is

190,421 (5th and 95th percentiles:

103,471 and 318,321) (Ref. 2). The

model also estimated the number of

humans with fluoroquinolone-resistant

campylobacteriosis due to chickens who

actually received a fluoroquinolone

drug for therapy.

For 1999, the estimated mean number

of people infected with

fluoroquinolone-resistant

Campylobacter from consuming or

handling chicken and who subsequently

received a fluoroquinolone as therapy is

11,477 (5th and 95th percentiles: 6,412

and 18,978) (Ref. 2). These people

received less effective or ineffective

therapy for their infections. Because

their therapy was less effective or

ineffective, these people would have

had adverse health effects. Since the

risk assessment was limited to

resistance development due to use of

fluoroquinolones in chickens only and

the impact is a mean estimate, the actual

risk to humans from fluoroquinoloneresistant Campylobacter infections from

all foodborne sources is likely to be

higher.

4. Summary of Human Health Impact

Foodborne diseases have a major

public health impact in the United

States, and Campylobacter is the most

common known cause of foodborne

illness. Fluoroquinolones are especially

important in the treatment of foodborne

diseases. Selection of Campylobacter

resistance to fluoroquinolones is

therefore a particular human health

concern. Fluoroquinolones used in

treating patients with enteritis are

typically prescribed empirically because

when treatment is delayed pending the

results of culture and sensitivity, the

illness may be extended or therapy may

be ineffective. Moreover,

fluoroquinolone resistance in

Campylobacter infections has been

associated with relapses (Ref. 74).

Campylobacter resistance therefore

presents a dilemma for the physician. If

fluoroquinolone treatment is given

based on symptoms, there is a risk that

the treatment will not be effective or

will be less effective and valuable time

will be lost. If the physician waits for a

culture to determine the organism and

its susceptibility to antimicrobials, again

valuable time will be lost. In either case,

the illness may be prolonged and result

in complications, including

hospitalization and deaths. The

physician could turn to another drug for

empiric treatment, but alternatives with

the spectrum of activity shown by the

fluoroquinolones are not available or

may be less desirable than the

fluoroquinolone due to greater side

effects associated with therapy or

increased cost of treatment. Even if an

acceptable alternative is available at the

time, the public health is diminished by

the loss of an effective drug from the

physician’s armamentarium. The

Campylobacter risk assessment provides

evidence of the extent of the adverse

impact of fluoroquinolone use in

poultry on human health. The risk

assessment determined in 1999 a mean

estimate of 11,477 people (5th and 95th

percentiles: 6,412 and 18,978) infected

with fluoroquinolone-resistant

Campylobacter from consuming or

handling chicken and who subsequently

received a fluoroquinolone as therapy.

The fact that fluoroquinolone use in

poultry has resulted in increased

resistance of Campylobacter infecting

humans is clear, as is the risk to human

health. Continued use will likely lead to

even higher levels of resistance and

additional adverse health effects.

VI. Other Considerations

Before issuing this notice of

opportunity for a hearing on the

withdrawal of the approval for use of

fluoroquinolones in poultry, CVM

considered requiring revisions to the

labeling of the fluoroquinolones to exert

more control over their use. Limiting

use to individual bird treatment and

requiring that the drugs not be used

more than once in any individual

animal in order to minimize the initial

development of resistant enteric

organisms were options considered.

CVM determined, however, that these

use limitations would be impractical for

both the veterinary practitioners and

poultry producers. The limitations

would necessitate mandatory animal

identification and maintenance of

extensive treatment records. Even if

feasible, due to poultry production and

processing practices, this approach

would not prevent untreated poultry

from picking up the resistant organism

from treated poultry or from the

environment, exposures that may be

substantial during transportation to

slaughter and antemortem containment.

CVM also considered establishing a

drug registry requiring that veterinarians

demonstrate the need for a

fluoroquinolone through culture and

antimicrobial susceptibility testing and

request permission to use the drug in

chickens or turkeys from CVM before

doing so. This approach would greatly

diminish the exposure of poultry to

fluoroquinolones and could also be used

to enforce a ‘‘single use’’ labeling

provision. The treated animals could be

tagged for followup testing at the

slaughter plant and if resistant

organisms were identified, the

contaminated carcasses could be

diverted to nonfood uses. CVM also

determined that this alternative was

impractical due to the cost of sampling,

process control problems with

accumulation of carcasses due to the

prohibitive amount of time required for

current resistance testing techniques,

and the public health risk associated

with the handling of contaminated

carcasses.

VII. Notice of Opportunity for a

Hearing

Therefore, notice is given to Bayer

Corp., Agriculture Division, Animal

Health, that CVM proposes to withdraw

the approval of the fluoroquinolone

enrofloxacin for use in poultry. This

action is based on section 512(e)(1)(B) of

the act in that new evidence not

contained in the NADA or not available

until after the application was

approved, evaluated together with the

evidence available when the application

was approved, shows that enrofloxacin

is not shown to be safe under the

conditions of use upon the basis of

which the application was approved.

In accordance with section 512 of the

act and part 514 (21 CFR part 514) and

under the authority delegated to the

Director of the Center for Veterinary

Medicine (21 CFR 5.84), CVM hereby

provides an opportunity for a hearing to

show why approval of the new animal

drug application for enrofloxacin for use

in poultry, NADA 141–828, should not

be withdrawn. Any hearing would be

subject to part 12 (21 CFR part 12).

If a sponsor decides to seek a hearing,

the sponsor must file: (1) On or before

November 30, 2000, a written notice of

appearance and request for a hearing,

and (2) on or before January 2, 2001, the

Federal Register / Vol. 65, No. 211 / Tuesday, October 31, 2000 / Notices 64963

data, information, and analyses relied

on to demonstrate that there is a

genuine and substantial issue of fact to

justify a hearing as specified in

§ 514.200.

Any other person may also submit

comment on this notice. Procedures and

requirements governing this notice of

opportunity for a hearing, a notice of

appearance and request for a hearing,

submission of data, information, and

analyses to justify a hearing, other

comments, and a grant or denial of a

hearing, are contained in § 514.200 and

part 12.

The failure of a holder of an approval

to file timely a written appearance and

request for hearing as required by

§ 514.200 constitutes an election not to

avail himself or herself of the

opportunity for a hearing, and the

Director of the Center for Veterinary

Medicine will summarily enter a final

order withdrawing the approvals.

A request for a hearing may not rest

upon mere allegations of denials, but

must set forth specific facts showing

that there is a genuine and substantial

issue of fact that requires a hearing. If

it conclusively appears from the face of

the data, information, and factual

analyses in the request for hearing that

there is no genuine and substantial issue

of fact that precludes the withdrawal of

approval of the applications, or when a

request for hearing is not made in the

required format or with the required

analyses, the Commissioner of Food and

Drugs will enter summary judgment

against the person who requests a

hearing, making findings and

conclusions, and denying a hearing.

If a hearing is requested and is

justified by the sponsor’s response to

this notice of opportunity for a hearing,

the issues will be defined, an

administrative law judge will be

assigned, and a written notice of the

time and place at which the hearing will

commence will be issued as soon as

practicable.

All submissions under this notice

must be filed in four copies. Except for

data and information prohibited from

public disclosure under 21 U.S.C. 331(j)

or 18 U.S.C. 1905, the submissions may

be seen in the Dockets Management

Branch (address above) between 9 a.m.

and 4 p.m. Monday through Friday.

This notice is issued under the

Federal Food, Drug, and Cosmetic Act

(section 512 (21 U.S.C. 360b)) and under

the authority delegated to the Director of

the Center for Veterinary Medicine (21

CFR 5.84).

VIII. Environmental Impact

The agency has determined under 21

CFR 25.33(g) that this action is of a type

that does not individually or

cumulatively have a significant effect on

the human environment. Therefore,

neither an environmental assessment

nor an environmental impact statement

is required.

IX. References

The following references have been

placed on display in the Dockets

Management Branch (address above)

and may be seen by interested persons

between 9 a.m. and 4 p.m., Monday

through Friday.

1. Smith, K., J. Besser, C. Hedberg, F. T.

Leano, J. B. Bender, J. H. Wicklund, B. P.

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Infections in Minnesota, 1992–1998,’’ New

England Journal of Medicine, 340(20), pp.

1525–1532, 1999.

2. FDA, ‘‘Human Health Impact of

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Attributed to the Consumption of Chicken,’’

October 18, 2000.

3. Tauxe, R. V., ‘‘Epidemiology of

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2000.

4. Blaser, M., ‘‘Campylobacter and Related

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1995.

8. Institute of Medicine, Committee on

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11. Baquero, F., J. Martinez-Beltran, and E.

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1991.

12. Angulo, F. J., R. V. Tauxe, and M. L.

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13. Harris, N., N. Weiss, and C. Nolan,

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17. Spika, J. S., S. H. Waterman, G. W. Soo

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1987.

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1985.

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22. Threlfall, E. J., J. A. Frost, L. R. Ward,

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25. Glynn, M. K., C. Bopp, W. Dewitt, P.

Dabney, M. Mokhtar, and F. J. Angulo,

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1333–1338, 1998.

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Ryan, M. Griffin, E. J. Threlfall, L. R. Ward,

and B. Rowe, a case control study of infection

with an epidemic strain of multiresistant

Salmonella typhimurium DT104 in England

and Wales, Communicable Disease Report,

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14, 1994.

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Tubau, M. A. Dominguez, and F. Gudiol,

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Escherichia coli in Fecal Flora of Cancer

Patients Receiving Norfloxacin Prophylaxis,’’

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40(2), pp. 503–505, 1996.

28. Pena, C., J. M. Albareda, R. Pallares, M.

Pujol, F. Tubau, and J. Ariza, ‘‘Relationship

Between Quinolone Use and Emergence of

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524, 1995.

29. Bates, J., J. Jordens, and D. Griffiths,

‘‘Farm Animals as a Putative Reservoir for

Vancomycin-resistant Enterococcal Infection

in Man,’’ Journal of Antimicrobial

Chemotherapy, vol. 34, pp. 507–516, 1994.

30. Piddock, L. J. V., ‘‘Does the Use of

Antimicrobial Agents in Veterinary Medicine

and Animal Husbandry Select for Antibiotic

Resistant Bacteria That Infect Man and

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2–5, 1998.

33. Endtz, H. P., G. J. Ruijs, B. van

Klingeren, W. H. Jansen, T. van der Reyden,

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27, pp. 199–208, 1991.

34. Helmuth, R. and D. Protz, ‘‘How to

Modify Conditions Limiting Resistance in

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1), pp. S136–138, 1997.

35. Jacobs-Reitsma, W. F., C. A. Kan, and

N. M. Boulder, ‘‘The Induction of Quinolone

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1994.

36. Rowe, B., Multiple Drug Resistance in

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37. Aarestrup, F. M., ‘‘Occurrence of

Glycopeptide Resistance Among

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1995.

38. Bager, F., M. Madsen, J. Christensen,

and F. M. Aarestrup, ‘‘Avoparcin Used as a

Growth Promoter is Associated With the

Occurrence of Vancomycin-resistant

Enterococcus faecium on Danish Poultry and

Pig Farms,’’ Preventive Veterinary Medicine,

vol. 31, pp. 95–112, 1997.

39. Kruse, H., B. K. Johansen, L. M. Rorvik,

and G. Schaller, ‘‘The Use of Avoparcin as a

Growth Promoter and the Occurrence of

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in Norwegian Poultry and Swine

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pp. 135–139, 1999.

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136, 1992.

41. Moellering Jr., R. C., ‘‘Quinolone

Antimicrobial Agents: Overview and

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J. S. Wolfson, American Society for

Microbiology, Washington, DC, pp. 527–535,

1993.

42. Piddock, L. J. V., ‘‘Quinolone

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891–898, 1995.

43. Perez-Tallero, E., F. Otero, C. LopezLopategui, et al., ‘‘High prevalence of

ciprofloxacin resistant Campylobacter jejuni/

coli in Spain,’’ Abstract C–21, p. 49. In:

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Interscience Conference on Antimicrobial

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of Microbiology, Washington, DC, 1997.

44. Velazquez, J. B., A. Jimenez, B.

Chomon, and T. G. Villa, ‘‘Incidence and

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Campylobacter Jejuni and Campylobacter

coli,’’ Journal of Antimicrobial

Chemotherapy, vol. 35, pp. 173–178, 1995.

45. FDA, transcript of the joint meeting of

the Veterinary Medicine Advisory Committee

and Anti-infective Drugs Advisory

Committee, Gaithersburg, MD, May 12, 1994.

46. FDA, ‘‘Guidance for Industry:

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the Microbial Effects of Antimicrobial New

Animal Drugs Intended for Use in FoodProducing Animals (GFI #78),’’ 64 FR 72083

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Pathogens,’’ In: Microbial Food Borne

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150, 1998.

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Prevention, 1999 Annual Report NARMS

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Agricultural Research Service, 1998

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51. U. S. Department of Agriculture,

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Dated: October 24, 2000.

Stephen F. Sundlof,

Director, Center for Veterinary Medicine.

[FR Doc. 00–27832 Filed 10–26–00; 10:43

am]

BILLING CODE 4160–01–F

DEPARTMENT OF HEALTH AND

HUMAN SERVICES

Food and Drug Administration

Advisory Committee; Renewals

AGENCY: Food and Drug Administration,

HHS.

ACTION: Notice.

SUMMARY: The Food and Drug

Administration (FDA) is announcing the

renewals of certain FDA advisory

committees by the Commissioner of

Food and Drugs (the Commissioner).

The Commissioner has determined that

it is in the public interest to renew the

charters of the committees listed below

for an additional 2 years beyond charter

expiration date. The new charters will

be in effect until the dates of expiration

listed below. This notice is issued under

the Federal Advisory Committee Act of

October 6, 1972 (Pubic Law 92–463 (5

U.S.C. app. 2)).

DATES: Authority for these committees

will expire on the dates indicated below

unless the Commissioner formally

determines that renewal is in the public

interest.

Name of committee Date of expiration

Gastrointestinal Drugs Advisory Committee March 3, 2002

Advisory Committee for Reproductive Health Drugs March 23, 2002

Arthritis Advisory Committee April 5, 2002

Veterinary Medicine Advisory Committee April 24, 2002

Anesthetic and Life Support Drugs Advisory Committee May 1, 2002

Blood Products Advisory Committee May 13, 2002

Pulmonary-Allergy Drugs Advisory Committee May 30, 2002

Drug Abuse Advisory Committee May 31, 2002

Science Advisory Board to the National Center for Toxicological ResearchJune 2, 2002

Peripheral and Central Nervous System Drugs Advisory Committee June 4, 2002

Psychopharmacologic Drugs Advisory Committee June 4, 2002

Transmissible Spongiform Encephalopathies Advisory Committee June 9, 2002

Science Board to the Food and Drug Administration June 26, 2002

Allergenic Products Advisory Committee July 9, 2002

Cardiovascular and Renal Drugs Advisory Committee August 27, 2002

Endocrinologic and Metabolic Drugs Advisory Committee August 27, 2002

Oncologic Drugs Advisory Committee September 1, 2002