[Federal Register Volume 73, Number 129 (Thursday, July 3, 2008)]
[Rules and Regulations]
[Pages 38110-38113]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: E8-15052]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Part 530
[Docket No. FDA-2008-N-0326]
New Animal Drugs; Cephalosporin Drugs; Extralabel Animal Drug
Use; Order of Prohibition
AGENCY: Food and Drug Administration, HHS.
ACTION: Final rule.
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SUMMARY: The Food and Drug Administration (FDA) is issuing an order
prohibiting the extralabel use of cephalosporin antimicrobial drugs in
food-producing animals. We are issuing this order based on evidence
that extralabel use of these drugs in food-producing animals will
likely cause an adverse event in humans and, as such, presents a risk
to the public health.
DATES: This rule becomes effective October 1, 2008. Submit written or
electronic comments on this document by September 2, 2008.
ADDRESSES: You may submit comments, identified by [Docket No. FDA-2008-
N-0326], by any of the following methods:
Electronic Submissions
Submit electronic comments in the following way:
Federal eRulemaking Portal: http://www.regulations.gov.
Follow the instructions for submitting comments.
Written Submissions
Submit written submissions in the following ways:
FAX: 301-827-6870.
Mail/Hand delivery/Courier [For paper, disk, or CD-ROM
submissions]: Division of Dockets Management (HFA-305), Food and Drug
Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852.
To ensure more timely processing of comments, FDA is no longer
accepting comments submitted to the agency by e-mail. FDA encourages
you to continue to submit electronic comments by using the Federal
eRulemaking Portal, as described previously, in the ADDRESSES portion
of this document under Electronic Submissions.
Instructions: All submissions received must include the agency name
and Docket No(s). and Regulatory Information Number (RIN) (if a RIN
number has been assigned) for this rulemaking. All comments received
may be posted without change to http://www.regulations.gov, including
any personal information provided. For additional information on
submitting comments, see the ``Comments'' heading of the SUPPLEMENTARY
INFORMATION section of this document.
Docket: For access to the docket to read background documents or
comments received, go to http://www.regulations.gov and insert the
docket number(s), found in brackets in the heading of this document,
into the ``Search'' box and follow the prompts and/or go to the
Division of Dockets Management, 5630 Fishers Lane, rm. 1061, Rockville,
MD 20852.
FOR FURTHER INFORMATION CONTACT: Neal Bataller, Center for Veterinary
Medicine (HFV-230), Food and Drug Administration, 7519 Standish Pl.,
Rockville, MD, 20855, 240-276-9200, e-mail: [email protected].
SUPPLEMENTARY INFORMATION:
I. Background
A. AMDUCA
The Animal Medicinal Drug Use Clarification Act of 1994 (AMDUCA)
(Public Law 103-396) was signed into law on October 22, 1994. It
amended the Federal Food, Drug, and Cosmetic Act (the act) to permit
licensed veterinarians to prescribe extralabel uses of approved animal
and human drugs in animals. In the Federal Register of November 7, 1996
(61 FR 57732), we published the implementing regulations (codified at
part 530 (21 CFR part 530)) for AMDUCA. The sections regarding
prohibition of extralabel use of drugs in animals are Sec. Sec.
530.21, 530.25, and 530.30. These sections describe the basis for
issuing an order prohibiting an extralabel drug use in animals and the
procedure to be followed in issuing an order of prohibition.
We may issue a prohibition order if we find that extralabel use of
a drug in animals presents a risk to the public health. Under Sec.
530.3(e), this means that we have evidence demonstrating that the use
of the drug has caused, or likely will cause an adverse event.
Section 530.25 provides for a public comment period of not less
than 60 days. It also provides that the order of prohibition become
effective 90 days after the date of publication, unless we revoke or
modify the order, or extend the period of public comment. The list of
drugs prohibited from extralabel use is found in Sec. 530.41.
B. Cephalosporins
Cephalosporins are members of the [beta]-lactam class of
antimicrobials. These antimicrobials work by targeting synthesis of the
bacterial cell wall, resulting in increased permeability and eventual
hydrolysis of the cell. Members of the cephalosporin class have a
[beta]-lactam ring fused to a sulfur-containing ring-expanded system
(Ref. 1).
Certain cephalosporins are currently approved for use in a number
of animal species. These approved uses include the treatment of
respiratory disease in cattle, swine, sheep, and goats, as well as
acute bovine interdigital necrobacillosis, acute metritis, and clinical
and sub-clinical mastitis in cattle. They are also approved for the
control of bovine respiratory disease, and the control of early
mortality associated with Escherichia coli infections in day-old chicks
and poults. Furthermore, approved animal uses of cephalosporins include
the treatment of skin and soft tissue infections in dogs and cats,
genitourinary tract infections (cystitis) in dogs, and respiratory
tract infections in horses.
Cephalosporins are also some of the most widely used antimicrobial
agents in human medicine. Older agents are widely used as therapy for
skin and soft tissue infections caused by Staphylococcus aureus and
Streptococcus pyogenes, as well as treatment of upper respiratory tract
infections, intra-abdominal infections, pelvic inflammatory disease,
and diabetic foot infections. Newer cephalosporins, with or without
aminoglycosides, have been considered drugs of choice for serious
infections caused by Klebsiella, Enterobacter, Proteus, Providencia,
Serratia, and Haemophilus spp. These cephalosporins are also used to
treat systemic salmonellosis, although not specifically approved for
this purpose. Fourth
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generation cephalosporins are indicated for treatment of urinary tract
infections, febrile neutropenia, intra-abdominal infections, pneumonia,
and skin and skin structure infections (Ref. 2).
FDA is concerned that the extralabel use of cephalosporins in food-
producing animals is likely to lead to the emergence of cephalosporin-
resistant strains of foodborne bacterial pathogens. If these drug-
resistant bacterial strains infect humans, it is likely that
cephalosporins will no longer be effective for treating disease in
those people. Therefore, FDA is issuing an order prohibiting the
extralabel use of cephalosporins because, as discussed in section II of
this document, the agency has determined that such extralabel use will
likely cause an adverse event and as such presents a risk to the public
health.
II. Basis for Prohibiting the Extralabel Use of Cephalosporins
A. Cephalosporin-Resistant Zoonotic Foodborne Bacteria
A recent review of [beta]-lactam resistance in bacteria of animal
origin states that an emerging issue of concern is the increase in
reports of broad-spectrum [beta]-lactamases (CMY-2 and CTX-M) (Ref. 3).
Acquired resistance to [beta]-lactams in animal isolates has been
observed in surveillance programs such as the Canadian Integrated
Program for Antimicrobial Resistance Surveillance (CIPARS), Danish
Integrated Antimicrobial Resistance Monitoring and Research Programme
(DANMAP), and the U.S. National Antimicrobial Resistance Monitoring
System (NARMS).
The 2005 European Antimicrobial Resistance Surveillance System
(EARSS) report indicated that most European countries reported less
than 5 percent resistance to third generation cephalosporins in
foodborne pathogens including Enterococcus faecalis, E. faecium, and E.
coli. However, the report noted that resistance was rising in 23 of 28
countries, with significant trends identified for 15 countries. The
EARSS report states that third generation cephalosporin resistance
appears to be increasing rapidly, even in countries with formerly very
low levels of resistance (Ref. 4).
Ceftiofur is a third generation cephalosporin approved for certain
uses in animals. Since 1997, the NARMS program has monitored ceftiofur
resistance in Salmonella isolated from food-producing animals at
slaughter. In 1997, no isolates from cattle or swine were resistant to
ceftiofur, while ceftiofur resistance among isolates from chickens and
turkeys was 0.5 percent and 3.7 percent, respectively. By 2006, the
prevalence of ceftiofur resistance among Salmonella slaughter isolates
increased to 18.8 percent for cattle, 2.0 percent for swine, 12.8
percent for chickens, and 5.3 percent for turkeys (Ref. 5).
Food-producing animals have been shown to be a source of resistant
Salmonella infections in humans (Ref. 6). Data collected as part of
NARMS have shown an increase in multi-drug resistance among Salmonella
isolates from humans, including resistance to third generation
cephalosporins. The prevalence of ceftiofur resistance among non-Typhi
Salmonella isolates from humans rose from 0.2 percent in 1996 to 3.4
percent in 2004. A similar trend was observed over this same period
(i.e., 1996 to 2004) for decreased susceptibility to ceftriaxone, a
third generation cephalosporin approved for use in humans (Ref. 7).
Although ceftiofur is not used in human medicine, the observed
trend of increasing resistance to this drug in human isolates
highlights concerns about the movement of foodborne bacterial pathogens
between animals and humans. In particular, as discussed in more detail
in this document, resistance to certain cephalosporins is of public
health concern in light of the evidence of cross-resistance among drugs
in the cephalosporin class. Expanded-spectrum cephalosporins (e.g.,
ceftriaxone and cefotaxime) are the antimicrobial agents of choice for
invasive Salmonella infections of pediatric patients (Ref. 8). FDA
believes that the surveillance data cited supports the finding that
certain cephalosporin use in animals is likely contributing to an
increase in cephalosporin-resistant human pathogens.
B. Scope of Order of Prohibition
The cephalosporins are one of the most diverse classes of
antimicrobials, and have been subject to several different
classification schemes, including those using chemical structure,
microbial activity, pharmacokinetics, or marketing date to divide the
various molecular entities into distinct groups. While there is
considerable overlap among proposed schemes, individual cephalosporin
drugs do not always fall into the same groups in all classifications.
For example, a commonly used scheme that classifies cephalosporins into
``generations'' provides some general idea of the first marketing date
for the various cephalosporins. However, classification by generation
does not necessarily group together cephalosporins with similar
microbiological or pharmacokinetic characteristics. Therefore, because
classification into ``generations'' is not based on specific properties
of individual cephalosporins, there can be disagreement on which drugs
belong in which generation.
FDA considered the possibility of limiting the order of prohibition
to certain individual cephalosporin drugs or to certain generations of
cephalosporins. However, given the potential for confusion regarding
the classification of individual cephalosporin drugs into various
generations, FDA concluded that it would be problematic to define the
scope of the prohibition based on cephalosporin ``generation.''
Furthermore, as discussed in more detail in this document, data
regarding mechanisms by which bacteria become resistant to
cephalosporins have demonstrated cross-resistance among various
individual cephalosporin drugs and among various generations of
cephalosporin drugs.
In general, there are three mechanisms by which bacteria become
resistant to antimicrobial agents: (1) Alteration of the antimicrobial
target, (2) efflux of the antimicrobial or changes in permeability of
the bacterial cell, and (3) inactivation of the antimicrobial agent
itself. Gram negative bacterial resistance to cephalosporins occurs
mainly through inactivation of the cephalosporin by [beta]-lactamases.
These enzymes can be both innate and acquired (Ref. 9).
Among bacteria of human health concern, the two most important
classes of [beta]-lactamase enzymes are the AmpC cephalosporinases and
the extended-spectrum [beta]-lactamases (ESBL). AmpC enzymes are found
on the chromosome of most Enterobacteriaceae, and are also currently
found on promiscuous plasmids in Salmonella and E. coli. These enzymes
provide resistance to first, second, and third generation
cephalosporins. ``Fourth generation'' cephalosporins are active in
vitro against AmpC producing bacteria, but there is some disagreement
as to the clinical significance of that activity. The AmpC enzymes are
currently the predominant [beta]-lactamases associated with Salmonella
collected from animals and humans in the United States displaying
resistance to ceftiofur and decreased susceptibility to ceftriaxone
(Ref. 3).
ESBLs present in bacteria of human health concern include members
of the TEM, SHV, and CTX-M families. These enzymes are plasmid mediated
and have the potential to provide resistance to all
[[Page 38112]]
cephalosporins. Different ESBLs hydrolyze different cephalosporins at
different efficiencies and rates, thus leading to varying patterns of
in vitro susceptibility. However, although a particular ESBL may not
raise the minimum inhibitory concentration (MIC) for a given
cephalosporin to a level above the breakpoint for resistance, these
strains commonly prove to be resistant in vivo (Ref. 9). Therefore,
there are specific guidelines for screening bacterial isolates for the
presence of ESBLs when MIC's fall in the susceptible range. Any
bacterial isolate which produces either an AmpC enzyme or an ESBL is
reported to clinicians as resistant to all cephalosporins even though
susceptibility testing may show in vitro susceptibility to some of the
cephalosporins (Ref. 10). Thus, regardless of in vitro susceptibility
results, the effect of resistance mediated by an AmpC enzyme or ESBL is
that the organism is treated as if it is cross-resistant to all
cephalosporins.
In a review of the CTX-M family of ESBLs, Livermore et al. (Ref.
11) noted that until the late 1990s, European surveys found the TEM and
SHV families of ESBLs almost exclusively. CTX-M enzymes were recorded
rarely, although large outbreaks of Salmonella Typhimurium with CTX-M-4
and CTX-M-5 were reported in Latvia, Russia, and Belarus in the mid
1990s. However, CTX-M enzymes are now the predominant ESBLs in many
European countries, and E. coli has joined Klebsiella pneumoniae as a
major host. CTX-M enzymes are supplanting TEM and SHV in East Asia as
well as in Europe. Only in North America do TEM and SHV still
predominate, although CTX-M enzymes have been occasionally detected.
Once mobilized, CTX-M enzymes can be hosted by many different genetic
elements, but are most often found on large multi-drug resistance
plasmids. Therefore, FDA is concerned that if CTM-X becomes prevalent
in the United States, as has occurred in other countries, cephalosporin
resistance may escalate.
Given that [beta]-lactamases have been identified in zoonotic
bacteria of human health concern, and given that [beta]-lactamases can
impart cross-resistance among cephalosporins (Ref. 12), FDA concluded
that measures to prohibit extralabel use should be directed at the
entire cephalosporin class of drugs.
C. Extralabel Use of Cephalosporins in Animals
As summarized previously, certain cephalosporins are currently
approved for use in a number of animal species for a variety of
indications. However, under the provisions of AMDUCA, cephalosporins
that are approved for use in animals or humans may be used in an
extralabel manner in animals provided certain conditions are met.
Although few data are available regarding the extent to which such
extralabel use currently occurs in the various food-producing animal
species, evidence exists that extralabel use is occurring. FDA
conducted inspections at U.S. poultry hatcheries in 2001 and examined
records relating to the hatcheries' antimicrobial use during the 30-day
period prior to inspection. FDA found that six of the eight hatcheries
inspected that used ceftiofur during that period were doing so in an
extralabel manner (Ref. 13). For example, ceftiofur was being
administered at unapproved dosing levels or by unapproved methods of
administration. In particular, ceftiofur was being administered by egg
injection, rather than by the approved method of administering the drug
to day-old chicks.
As is recognized for the use of antimicrobial drugs in general, the
use of cephalosporins provides selection pressure that favors expansion
of resistant variants. FDA believes the extralabel use of
cephalosporins likely will contribute to the emergence of resistance
and compromise human therapy. Given the importance of the cephalosporin
class of drugs for treating disease in humans, FDA believes that
preserving the effectiveness of such drugs is critical. Therefore, FDA
believes it is necessary to take action to limit the extent to which
extralabel use of cephalosporin in animals may be contributing to the
emergence of resistant variants.
FDA is particularly concerned about the extralabel use of
cephalosporins in food-producing animals given that such animals are
known reservoirs of foodborne bacterial pathogens such as Salmonella.
Based on information regarding cephalosporin resistance as discussed
previously, FDA believes it is likely that the extralabel use of
cephalosporins in food-producing animals is contributing to the
emergence of cephalosporin-resistant zoonotic foodborne bacteria.
Therefore, FDA has determined that such extralabel use likely will
cause an adverse event and, as such, presents a risk to the public
health.
III. Comments
Interested persons may submit to the Division of Dockets Management
(see ADDRESSES) written or electronic comments regarding this document.
Submit a single copy of electronic comments or two paper copies of any
mailed comments, except that individuals may submit one paper copy.
Comments are to be identified with the docket number found in brackets
in the heading of this document. Received comments may be seen in the
Division of Dockets Management between 9 a.m. and 4 p.m., Monday
through Friday.
Please note that on January 15, 2008, the FDA Division of Dockets
Management Web site transitioned to the Federal Dockets Management
System (FDMS). FDMS is a Government-wide, electronic docket management
system. Electronic comments or submissions will be accepted by FDA only
through FDMS at http://www.regulations.gov.
IV. Order of Prohibition
Therefore, I hereby issue the following order under Sec. Sec.
530.21 and 530.25. We find that extralabel use of the cephalosporin
class of antimicrobial drugs in food-producing animals likely will
cause an adverse event, which constitutes a finding that extralabel use
of these drugs presents a risk to the public health. Therefore, we are
prohibiting the extralabel use of the cephalosporin class of
antimicrobial drugs in food-producing animals.
V. References
The following references have been placed on display in the
Division of Dockets Management (see ADDRESSES) and may be seen by
interested persons between 9 a.m. and 4 p.m., Monday through Friday.
1. Livermore, D. M. and L. D. Williams, ``[beta]-Lactams: Mode
of Action and Mechanisms of Resistance,'' pp. 502-578, Victor Lorian
(ed.), Antibiotics in Laboratory Medicine, Williams & Wilkins,
Baltimore, 1991.
2. U.S. Food and Drug Administration, Maxipime (cefepime
hydrochloride) for injection, NDA 50-679/S-021, http://www.fda.gov/medwatch/SAFETY/2003/03MAR_PI/Maxipime_PI.pdf (accessed March 13,
2007).
3. Li, X. Z., M. Mehrotra, S. Ghimire, and L. Adewoye, ``[beta]-
Lactam Resistance and [beta]-Lactamases in Bacteria of Animal
Origin,'' Veterinary Microbiology, 121:197-214, 2007.
4. European Antimicrobial Resistance Surveillance System, EARSS
Annual Report 2005, pp. 1-147, Bilthoven, The Netherlands, 2006.
5. U.S. Department of Health and Human Services, National
Antimicrobial Resistance Monitoring System/Enteric Bacteria (NARMS/
EB) Salmonella Annual Veterinary Isolates Data, U.S. Department of
Agriculture, http://www.ars.usda.gov/Main/docs.htm?docid=6750&page=4, 2006.
6. Holmberg, S. D., J. G. Wells, and M. L. Cohen, ``Animal-to-
Man Transmission of Antimicrobial-Resistant Salmonella:
Investigations of U.S. Outbreaks, 1971-1983,'' Science, 225:833-835,
1984.
[[Page 38113]]
7. CDC, ``National Antimicrobial Resistance Monitoring System
for Enteric Bacteria (NARMS): Human Isolates Final Report,'' 2004,
Atlanta, GA, U.S. Department of Health and Human Services, CDC,
2007.
8. Giles, W.P. , A. K. Benson, M. E. Olson, R. W. Hutkins, J. M.
Whichard, P. L. Winokur, and P. D. Fey, ``DNA Sequence Analysis of
Regions Surrounding blaCMY-2 From Multiple Salmonella Plasmid
Backbones,'' Antimicrobial Agents and Chemotherapy, 48:2845-2852,
2004.
9. Livermore, D. M., ``Beta-Lactamases in Laboratory and
Clinical Resistance,'' Clinical Microbiology Review, 8:557-584,
1995.
10. Clinical and Laboratory Standards Institute, Performance
Standards for Antimicrobial Susceptibility Testing: Sixteenth
Informational Supplement, M100-S16, Wayne, PA, USA: CLSI, 2006.
11. Livermore, D. M., R. Canton, M. Gniadkowski, P. Nordmann, G.
M. Rossolini, G. Arlet, J. Ayala, T. M. Coque, I. Kern-Zdanowicz, F.
Luzzaro, L. Poirel, and N. Woodford, ``CTX-M: Changing the Face of
ESBLs in Europe,'' Journal of Antimicrobial Chemotherapy, 59:165-
174, 2007.
12. Jacoby, G. A. and L. S. Munoz-Price, ``The New B-
Lactamases,'' New England Journal of Medicine, 352:380-391, 2005.
13. U.S. Food and Drug Administration, Center for Veterinary
Medicine, unpublished report, Summary of Data From Hatchery
Inspections Conducted September-October 2001, April 15, 2002.
List of Subjects in 21 CFR Part 530
Administrative practice and procedure, Advertising, Animal drugs,
Labeling, Reporting and recordkeeping requirements.
0
Therefore, under the Federal Food, Drug, and Cosmetic Act and under
authority delegated to the Commissioner of Food and Drugs and
redelegated to the Director of the Center for Veterinary Medicine, 21
CFR part 530 is amended as follows:
PART 530--EXTRALABEL DRUG USE IN ANIMALS
0
1. The authority citation for 21 CFR part 530 continues to read as
follows:
Authority: 15 U.S.C. 1453, 1454, 1455; 21 U.S.C. 321, 331, 351,
352, 353, 355, 357, 360b, 371, 379e.
0
2. In Sec. 530.41, add paragraph (a)(13) to read as follows:
Sec. 530.41 Drugs prohibited for extralabel use in animals.
(a) * * *
(13) Cephalosporins.
* * * * *
Dated: June 24, 2008.
Bernadette Dunham,
Director, Center for Veterinary Medicine.
[FR Doc. E8-15052 Filed 7-2-08; 8:45 am]
BILLING CODE 4160-01-S