[Federal Register Volume 65, Number 211 (Tuesday, October 31, 2000)]
[Notices]
[Pages 64954-64965]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 00-27832]


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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.

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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<Register> 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<Register> 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<Register> 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

[[Page 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 fluoroquinolone-resistant 
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 fluoroquinolone-
resistant 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 domestically-
acquired 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 fluoroquinolone-resistant 
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

[[Page 64956]]

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 food-
producing 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 
food-producing animals can select for resistant bacteria of human 
health concern. Repeated dosing of food-producing 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 fluoqouinolone-sensitive C. 
jejuni has been shown to

[[Page 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 food-producing 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 food-
producing 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 
food-producing animals, CVM consulted with a panel of experts comprised 
of its Veterinary Medicine Advisory Committee and FDA's [Human] Anti-
Infective 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<Register> 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 
food-producing 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

[[Page 64958]]

to humans. At that time, the agency believed that such studies were 
necessary only for certain subtherapeutic feed uses in food-producing 
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 food-
producing 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 
fluoroquinolone-resistant 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

[[Page 64959]]

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 
fluoroquinolone-resistant 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.)
---------------------------------------------------------------------------

    \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).
---------------------------------------------------------------------------

    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

[[Page 64960]]

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 Campylobacter-contaminated 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 life-threatening, 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 life-saving 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, trimethoprim-sulfa 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

[[Page 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, cm<SUP>3</SUP>) 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 Guillain-Barre 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

[[Page 64962]]

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 fluoroquinolone-resistant 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 fluoroquinolone-resistant 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

[[Page 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 Sec. 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 Sec. 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 Sec. 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, 
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[[Page 64964]]

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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