[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 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
[[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 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, 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 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,
J. H. Wicklund, B. P. Johnson, K. A. Moore, and M. Osterholm,
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[FR Doc. 00-27832 Filed 10-26-00; 10:43 am]
BILLING CODE 4160-01-F