[Federal Register Volume 77, Number 4 (Friday, January 6, 2012)]
[Rules and Regulations]
[Pages 735-745]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2012-35]


=======================================================================
-----------------------------------------------------------------------

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.

-----------------------------------------------------------------------

SUMMARY: The Food and Drug Administration (FDA, the Agency) is issuing 
an order prohibiting certain extralabel uses of cephalosporin 
antimicrobial drugs in certain food-producing animals. We are issuing 
this order based on evidence that certain extralabel uses of these 
drugs in these animals will likely cause an adverse event in humans 
and, therefore, present a risk to the public health.

DATES: This rule becomes effective April 5, 2012. Submit either 
electronic or written comments on this document by March 6, 2012.

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:
    <bullet> Federal eRulemaking Portal: http://www.regulations.gov. 
Follow the instructions for submitting comments.

Written Submissions

    Submit written submissions in the following ways:
    <bullet> Fax: (301) 827-6870.
    <bullet> 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.
    Instructions: All submissions received must include the Agency name 
and Docket No. FDA-2008-N-0326 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, 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: Eric Nelson, Center for Veterinary 
Medicine (HFV-230), Food and Drug Administration, 7519 Standish Pl., 
Rockville, MD 20855, (240) 276-9201, email: <a href="/cdn-cgi/l/email-protection#10756279733e7e757c637f7e507674713e7878633e777f66"><span class="__cf_email__" data-cfemail="0366716a602d6d666f706c6d436567622d6b6b702d646c75">[email protected]</span></a>.

SUPPLEMENTARY INFORMATION:

I. Background

A. History

    In the Federal Register of July 3, 2008 (73 FR 38110), FDA 
published an order prohibiting the extralabel use of cephalosporin 
antimicrobial drugs in food-producing animals, with a 60-day comment 
period and a 90-day effective date for the final order. The order, 
which was to take effect as a final rule on October 1, 2008, would have 
resulted in a change to part 530 (21 CFR part 530) in Sec.  530.41 to 
list cephalosporins as prohibited from extralabel use in food-producing 
animals as provided for in Sec.  530.25(f).

[[Page 736]]

    In response to publication of this order, the Agency received 
requests for a 60-day extension of the comment period. The requests 
conveyed concern that the original 60-day comment period would not 
allow the requesters sufficient time to examine the available evidence, 
consider the impact of the order, and provide constructive comment.
    FDA considered the requests and, in the Federal Register of August 
18, 2008 (73 FR 48127), extended the comment period for the order for 
60 days, until November 1, 2008. Accordingly, FDA also delayed the 
effective date of the final rule 60 days, until November 30, 2008.
    The Agency received many substantive comments on the July 3, 2008, 
order of prohibition. Therefore, to allow more time to fully consider 
the comments, FDA decided to revoke the order so that it would not take 
effect November 30, 2008. Accordingly, in the Federal Register of 
November 26, 2008 (73 FR 71923), FDA withdrew the final rule and 
indicated that if, after considering the comments and other relevant 
information the Agency decided to issue another order of prohibition 
addressing this matter, FDA would follow the procedures in Sec.  530.25 
that provide for a public comment period prior to implementing the new 
order.

B. Comments on the July 3, 2008, Order of Prohibition

    The Agency received comments from approximately 170 organizations 
and individuals on the July 3, 2008, order of prohibition. Comments 
were received from a trade organization representing new animal drug 
manufacturers, several trade organizations representing food animal 
producers, several professional associations representing 
veterinarians, a consumer protection organization, several new animal 
drug manufacturers, and many individuals including food animal 
veterinarians, farmers, and ranchers. Only two of the commenters 
supported the July 3, 2008, order of prohibition as written. All others 
felt that the prohibition should be revised in some manner before 
enactment or that it was unnecessary and should not be enacted in any 
form. These comments can be summarized into two general categories:
    (1) The scope of the order was too broad in that it unnecessarily 
prohibited certain extralabel uses that do not significantly contribute 
to the problem of cephalosporin resistance. Many of these commenters 
were concerned about the unintended negative consequences on animal 
health that would result from such action; and
    (2) FDA failed to meet the legal standard for issuing a prohibition 
order. Some of these comments alleged that FDA appeared to have applied 
the ``precautionary principle'' rather than basing its decision on 
sound scientific evidence.
    Although FDA does not agree with comments alleging that the Agency 
did not meet the legal standard for issuing an order of prohibition, 
the Agency does agree with comments that the scope of the original 
order of prohibition could have been more targeted. After considering 
the comments and information submitted in response to the July 2008 
order of prohibition, FDA has re-examined the basis for the original 
order. Based on this re-examination, FDA has determined that there is 
sufficient basis for prohibiting certain extralabel uses of 
cephalosporin drugs in food-producing major animal species. 
Specifically, as explained in detail later in this document, FDA is 
prohibiting the extralabel use of cephalosporin antimicrobial drugs 
(not including cephapirin) in cattle, swine, chickens, and turkeys: (1) 
For disease prevention purposes; (2) at unapproved doses, frequencies, 
durations, or routes of administration; and (3) if the drug is not 
approved for that species and production class.
    Thus, with the exception of extralabel uses of cephapirin, the 
final effect of this order will be to prohibit many extralabel uses of 
cephalosporin drugs in food-producing major animal species (cattle, 
swine, chickens, and turkeys) including:
    (1) Use for disease prevention purposes;
    (2) Use at unapproved dose levels, frequencies, durations, or 
routes of administration (e.g., Biobullets in cattle and injection or 
dipping of poultry eggs); and
    (3) Use of products not approved in the major food species (e.g., 
use of human or companion animal cephalosporin drugs).
    The extralabel uses that are not prohibited by this order include:
    (1) Use of approved cephapirin products in food-producing animals;
    (2) Use to treat or control an extralabel disease indication as 
long as such use adheres to a labeled dosage regimen (i.e., dose, 
route, frequency, and duration of administration) approved for that 
species and production class; and
    (3) Use in food-producing minor species.
    The Agency is prohibiting these extralabel uses in food-producing 
major species because we believe such uses in these animals will likely 
cause an adverse event in humans and, therefore, present a risk to the 
public health. FDA may further restrict extralabel use of cephalosporin 
antimicrobial drugs in animals in the future if it has evidence that 
demonstrates that such use has caused or likely will cause an adverse 
event.

II. Basis for Prohibiting the Extralabel Use of Cephalosporins With 
Certain Exceptions

A. AMDUCA and Cephalosporins

    The Animal Medicinal Drug Use Clarification Act of 1994 (AMDUCA) 
(Public Law 103-396) was signed into law October 22, 1994. It amended 
the Federal Food, Drug, and Cosmetic Act (the FD&C Act) to permit 
licensed veterinarians to prescribe extralabel uses of approved human 
and animal drugs in animals. In the Federal Register of November 7, 
1996 (61 FR 57732), FDA published the implementing regulations 
(codified at part 530) for AMDUCA that include, among other things, a 
definition for the term ``extralabel use'' as well as provisions for 
prohibiting extralabel uses.
    Section 530.3 states that extralabel use means actual use or 
intended use of a drug in an animal in a manner that is not in 
accordance with the approved labeling. This includes, but is not 
limited to:
    (1) Use in species not listed in the labeling;
    (2) Use for indications (disease or other conditions) not listed in 
the labeling;
    (3) Use at dose levels, frequencies, or routes of administration 
other than those stated in the labeling; and
    (4) Deviation from the labeled withdrawal time based on these 
different uses.
    The sections in FDA's implementing regulations governing the 
prohibition of extralabel use of drugs in animals include 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 such an order. FDA may issue a 
prohibition order if it finds that extralabel use of a drug in animals 
presents a risk to the public health. Under Sec.  530.3(e), this means 
that FDA has evidence demonstrating that the use of the drug has 
caused, or likely will cause, an adverse event. Furthermore, as 
discussed in section III.B of this document, the regulations permit a 
prohibition order to be either a general ban on the extralabel use of 
the drug or

[[Page 737]]

class of drugs, or a ban limited to one or more of the uses described 
in the definition of extralabel use cited previously.
    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 FDA revokes or 
modifies the order, or extends the period of public comment. The list 
of drugs prohibited from extralabel use is found in Sec.  530.41.
    At this time, FDA is concerned that certain extralabel uses of 
cephalosporins in food-producing major species are likely to lead to 
the emergence and dissemination 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. The Agency is 
particularly concerned about the extralabel use of cephalosporin drugs 
that are not approved for use in food-producing major species because 
very little is known about their microbiological or toxicological 
effects when used in food-producing animals. Therefore, FDA is issuing 
an order prohibiting, with limited exceptions, the extralabel use of 
cephalosporins in food-producing major species because, as discussed in 
this document, the Agency has determined that such extralabel use 
likely will cause an adverse event and, therefore, presents a risk to 
the public health.

B. Importance of Cephalosporins in Veterinary and Human Medicine

    Cephalosporins are members of the beta-lactam ([beta]-lactam) class 
of antimicrobials. Members of the cephalosporin class have a [beta]-
lactam ring fused to a sulfur-containing ring-expanded system (Ref. 1). 
These antimicrobials work by targeting synthesis of the bacterial cell 
wall, resulting in increased permeability and eventual hydrolysis of 
the cell.
    Introduced into clinical use in 1964, cephalosporins are widely 
used antimicrobial agents in human medicine. Beta-lactams make up 40 
percent of total prescriptions in the outpatient setting, and 
cephalosporins contribute 14 percent of the total outpatient antibiotic 
prescriptions. This use accounts for over 50 million prescriptions per 
year (Ref. 2). In the inpatient setting, cephalosporins are most 
commonly used to treat pneumonia. Older cephalosporins 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. Approved 
indications for newer cephalosporins include the treatment of lower 
respiratory tract infections, acute bacterial otitis media, skin and 
skin structure infections, urinary tract infections (complicated and 
uncomplicated), uncomplicated gonorrhea, pneumonia (moderate to 
severe), empiric therapy for febrile neutropenic patients, complicated 
intra-abdominal infections, pelvic inflammatory disease, septicemia, 
bone and joint infections, meningitis, and surgical prophylaxis. 
Indicated pathogens include, but are not limited to, Acinetobacter 
calcoaceticus, Bacteroides fragilis, Enterobacter agglomerans, 
Escherichia coli, Haemophilus influenzae (including [beta]-lactamase 
producing strains), Klebsiella oxytoca, Klebsiella pneumoniae, 
Moraxella catarrhalis, Morganella morganii, Proteus mirabilis, 
Pseudomonas aeruginosa, Serratia marcescens, Staphylococcus aureus, 
Streptococcus pneumoniae, and Streptococcus pyogenes (Ref. 3). Newer 
cephalosporins (for example, third generation cephalosporins such as 
ceftriaxone) are used in the hospital setting to treat seriously ill 
patients with life-threatening disease, many of which are due to 
organisms that reside in the gastrointestinal tract. These newer 
cephalosporins are the antibiotics of choice in the treatment of 
serious Salmonella and Shigella infections, particularly in children 
where fluoroquinolones may be avoided due to potential for toxicity 
(Ref. 4).
    Two cephalosporin drugs are currently approved for use in food-
producing animal species: Ceftiofur and cephapirin. Injectable 
ceftiofur products are approved for the treatment and control of 
certain diseases, including: (1) The treatment of respiratory disease 
in cattle, swine, sheep, and goats; (2) the treatment of acute bovine 
interdigital necrobacillosis (foot rot) and acute bovine metritis; (3) 
the control of bovine respiratory disease; and (4) the control of early 
mortality associated with E. coli infections in day-old chicks and 
poults. In addition, ceftiofur is approved as an intramammary infusion 
for the treatment of clinical mastitis in lactating dairy cattle 
associated with coagulase-negative staphylococci, Streptococcus 
dysgalactiae, and E. coli. Cephapirin is only approved as an 
intramammary infusion for the treatment of lactating cows having bovine 
mastitis caused by susceptible strains of Streptococcus agalactiae and 
Staphylococcus aureus.

C. Mechanism of Cephalosporin Resistance

    In general, there are three major 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. 5).
    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). CMY-2 (a type of AmpC) 
enzymes are found on the chromosome of most Enterobacteriaceae, and are 
also currently found on promiscuous plasmids in Salmonella, E. coli, 
and other members of the Enterobacteriaceae. These enzymes provide 
resistance to first, second, and third generation cephalosporins. CMY-2 
is currently the predominant [beta]-lactamase associated with 
Salmonella collected from animals and humans in the United States 
displaying resistance to ceftiofur and decreased susceptibility or 
resistance to ceftriaxone (Refs. 6-8), both third generation 
cephalosporins.
    ``Fourth generation'' cephalosporins are active in vitro against 
bacteria producing AmpC type [beta]-lactamases, but there is some 
disagreement as to the clinical significance of that activity. 
Recently, three E. coli producing variant CMY-2 [beta]-lactamases were 
isolated from patients in Pennsylvania. Two of the three patients from 
whom these isolates were obtained had undergone treatment with 
cefepime, a fourth generation cephalosporin, within the 2 months 
preceding isolation of the organisms. These isolates were shown to have 
reduced susceptibility to fourth generation cephalosporins, suggesting 
that CMY-2 has the potential to evolve to provide resistance to fourth 
generation cephalosporins when exposed to selective pressure (Ref. 9).
    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 cephalosporins. 
Different ESBLs hydrolyze different cephalosporins at different 
efficiencies and rates, thus leading to varying patterns of in vitro 
susceptibility. In 2010, the CLSI revised

[[Page 738]]

the cephalosporin resistance breakpoints to more accurately reflect in 
vivo susceptibility. Prior to this time, a particular ESBL strain that 
might not raise the minimum inhibitory concentration (MIC) for a given 
cephalosporin to a level above the breakpoint for resistance would 
commonly prove to be resistant in vivo (Ref. 5). Therefore, there were 
specific guidelines for screening bacterial isolates for the presence 
of ESBLs when MICs fell in the susceptible range. Any bacterial isolate 
which produced either an AmpC enzyme or an ESBL was reported to 
clinicians as resistant to all cephalosporins even though 
susceptibility testing may have shown in vitro susceptibility to some 
of the cephalosporins (Ref. 10).
    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 caused by Salmonella serovar 
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 the United 
States do TEM and SHV still predominate, although CTX-M enzymes are now 
rising in prevalence (Refs. 12-19). 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.
    Serious infections caused by cephalosporin-resistant bacteria may 
be empirically treated with ineffective antibacterial regimens, 
significantly increasing the likelihood of death. Urinary tract 
infections caused by community-acquired cephalosporin-resistant E. coli 
may be associated with bloodstream infections, and these infections may 
also be resistant to most or all antibiotics commonly used to treat 
such infections. Empirical treatment of such infections is often with a 
fluoroquinolone, amoxicillin-clavulanate, or a cephalosporin; however, 
these E. coli are likely to be resistant to all of these agents, making 
treatment of these infections more difficult (Ref. 11).

D. Cephalosporin-Resistant Zoonotic Foodborne Bacteria

    In regard to antimicrobial drug use in animals, the Agency 
considers the most significant risk to the public health associated 
with antimicrobial resistance to be human exposure to food containing 
antimicrobial-resistant bacteria resulting from the exposure of food-
producing animals to antimicrobials, including cephalosporins. 
Resistance to certain cephalosporins is of particular public health 
concern in light of the evidence of cross-resistance among drugs in the 
cephalosporin class. Importantly, resistance to ceftiofur compromises 
the efficacy of ceftriaxone, a first-line therapy for treating 
salmonellosis in humans. 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 CMY-2 and CTX-M [beta]-lactamases (Ref. 6), 
which confer cephalosporin resistance and are transmissible between 
enteric bacteria. Acquired resistance to [beta]-lactams in animal and 
human isolates has been observed in surveillance programs such as the 
U.S. National Antimicrobial Resistance Monitoring System (NARMS) and 
the Canadian Integrated Program for Antimicrobial Resistance 
Surveillance (CIPARS).
    Because food-producing animals are a known source of resistant 
Salmonella infections in humans (Ref. 20), the NARMS program has 
monitored ceftiofur resistance among Salmonella isolates from food-
producing animals at slaughter since 1997. In 1997, no Salmonella 
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 2009, the prevalence of 
ceftiofur resistance among Salmonella slaughter isolates increased to 
14.5 percent for cattle, 4.2 percent for swine, 12.7 percent for 
chickens, and 12.4 percent for turkeys (Ref. 21).
    Among food animal Salmonella isolates in NARMS, ceftiofur 
resistance has been identified in more than 20 different serotypes, and 
it has increased substantially in several serotypes commonly found in 
humans (Ref. 22). Ceftiofur resistance among all Salmonella Typhimurium 
isolates from chickens was 0.0 percent in 1997 and 33.3 percent in 
2009. Among all Salmonella Typhimurium isolates from cattle, ceftiofur 
resistance was 3.0 percent in 1998 and 27.8 percent in 2009. Ceftiofur 
resistance rose from 12.5 percent in 1998 to 58.8 percent in 2009 among 
Salmonella Newport isolates from cattle. There was no ceftiofur 
resistance among Salmonella Heidelberg isolates from poultry in 1997, 
but resistance rose to 17.6 percent in chicken isolates and 33.3 
percent in turkey isolates in 2009 (Refs. 22, 23).
    The NARMS program has also monitored ceftiofur resistance among 
Salmonella isolates from humans since 1996. Ceftiofur resistance among 
non-Typhi Salmonella isolates from humans rose from 0.2 percent in 1996 
to 3.4 percent in 2009. Resistance to ceftiofur also rose in several 
Salmonella serotypes commonly isolated from humans. In 1996, ceftiofur 
resistance among Salmonella isolates from humans was 0.0 percent, 0.0 
percent, and 1.4 percent for serotypes Typhimurium, Newport, and 
Heidelberg, respectively. In 2009, ceftiofur resistance among isolates 
from these serotypes was 6.5 percent, 6.4 percent, and 20.9 percent, 
respectively (Refs. 23, 24).
    The CIPARS program revealed an increase in Quebec of resistance to 
cephalosporins among Salmonella Heidelberg isolates from humans 
reaching a level of 36 percent of isolates in 2004. This increase was 
accompanied temporally by an increase in ceftiofur resistance in 
Salmonella Heidelberg isolates from retail chicken, which rose to 62 
percent in 2004. Hatcheries in Quebec voluntarily stopped the use of 
ceftiofur in eggs and day-old chicks in February 2005. This action was 
followed temporally by a dramatic decline in the prevalence of 
ceftiofur resistance in Salmonella Heidelberg isolates from humans and 
retail chicken in Quebec, which by 2008 had declined to 12 percent and 
18 percent, respectively. These trends in Salmonella Heidelberg were 
accompanied by similar trends in ceftiofur resistance in E. coli 
isolates from retail chicken (Ref. 25).
    Ceftiofur is not used in human medicine in the United States, but 
after the 2010 CLSI change in the cephalosporin breakpoint, resistance 
to this agent largely coincides with resistance to ceftriaxone, a third 
generation cephalosporin that is a critically important antimicrobial 
approved for use in humans (Ref. 23). As discussed earlier, this 
resistance trait conferred by the CMY-2 enzyme. CMY-2 provides 
resistance to first, second, and third generation cephalosporins. In 
addition to conferring ceftiofur and ceftriaxone resistance, CMY-2 also 
imparts resistance to several other [beta]-lactams, including 
ampicillin and amoxicillin/clavulanate (Ref. 26). The prevalence and 
spread of CMY-2 is reflected in the surveillance data on ceftriaxone 
and ceftiofur susceptibility

[[Page 739]]

(Ref. 27) and supports the finding that cephalosporin use in food-
producing animals is likely contributing to an increase in 
cephalosporin-resistant human pathogens.

E. Extralabel Uses of Greatest Concern

1. Dairy Cattle
    The U.S. Department of Agriculture (USDA) Food Safety and 
Inspection Service (FSIS) conducts both ante-mortem and post-mortem 
inspection of livestock and poultry presented for slaughter at each 
official establishment. As part of ante-mortem inspection, FSIS 
personnel inspect animals to determine whether they exhibit behaviors 
or conditions that are indicative of illegal chemical use. If such 
behaviors or symptoms are exhibited, the animals are tagged and further 
examined at post-mortem inspection. During post-mortem inspection, FSIS 
veterinarians examine carcasses and their organs to determine whether 
the animals they came from had pathological diseases or other 
conditions that could have warranted the use of drugs or other 
chemicals and whether there are any indications of illegal chemical 
use. In addition, FSIS conducts laboratory analysis of sample tissues 
that have been taken from carcasses that have pathologies or other 
conditions indicative of chemical use to determine whether they contain 
violative chemical residues. FSIS transmits to FDA information about 
the violative chemical residue found, including the name of the 
official establishment where the livestock or poultry was presented for 
slaughter.
    During the 1-year period ending June 25, 2009, FSIS reported 113 
instances of violative ceftiofur residues in dairy cows and an 
additional 22 instances of violative ceftiofur residues in other food-
producing animals, including beef cattle and veal calves. The FSIS 
reports include quantitative drug residue levels for each violation. In 
most instances, the violative residue levels of ceftiofur detected in 
dairy cows were significantly above the allowable tolerance of 0.4 ppm 
(kidney) in tested tissues and are summarized as follows:
    <bullet> Up to 2x above the tolerance = 12 violations
    <bullet> Between 2x and 5x above the tolerance = 17 violations
    <bullet> Between 5x and 10x above the tolerance = 16 violations
    <bullet> Between 10x and 20x above the tolerance = 30 violations
    <bullet> Over 20x above the tolerance = 38 violations
    An examination of 25 recent inspections of farms responsible for 
violative ceftiofur residues identified a number of factors that 
resulted in the misuse of ceftiofur animal drug products. These factors 
include, but were not limited to, the following: (1) Poor or 
nonexistent animal treatment records for adequately monitoring treated 
animals; (2) inadequate animal identification systems for monitoring 
treated animals; (3) animal owners' lack of knowledge regarding 
withdrawal times associated with the animal drug product; (4) the 
animal drug product was administered by a route not included in the 
approved labeling; (5) the animal drug product was administered at a 
dose higher than stated in the approved labeling; and (6) the animal 
drug product was administered to a type of animal (e.g., veal calves) 
not listed in the approved labeling. Most of the violations involved 
culled dairy cows. More than half of the violations involved ceftiofur 
residue levels more than 10 times the established tolerance level.
    Based on investigations conducted by FDA, the majority of residue 
violations were the result of poor recordkeeping and other management 
practices. Among the provisions required for extralabel drug use in 
animals under 21 CFR part 530, the client (the owner of the animal or 
animals or other caretaker) must agree to follow the instructions of 
the veterinarian, the veterinarian must institute procedures to assure 
that the identity of the treated animal or animals is carefully 
maintained, and the veterinarian must take appropriate measures to 
assure that assigned timeframes for withdrawal are met and no illegal 
drug residues occur in any food-producing animal subjected to 
extralabel treatment.
    Adhering to the ELU requirements is particularly important for 
extralabel drug use in dairy cattle because treatment often occurs in 
sick adult dairy cows close to the time of potential slaughter and 
introduction into the food supply. Evidence of this practice is the 
fact that 67 percent of all tissue residue violations reported by FSIS 
at slaughter are attributed to adult dairy cattle. In comparison, 
antimicrobial drug treatment in swine and beef cattle more often occurs 
earlier in the life of the animal, typically at some transition point 
that is well before slaughter. This aspect of dairy husbandry is not 
only a concern regarding violative drug residues, it is also a concern 
in the context of antimicrobial resistance. Recent evidence suggests 
that administration of ceftiofur crystalline-free acid (CCFA) in cattle 
will cause a transient increase in the population of ceftiofur-
resistant isolates in gut bacteria that lasts approximately two weeks 
before a return to more normal susceptibility patterns (Ref. 28). 
Because of this, the Agency is concerned that improper extralabel use 
of ceftiofur in culled dairy cows just prior to slaughter could result 
in increased levels of cephalosporin resistance in carcass bacteria.
    Ceftiofur use in dairy herds has been shown to increase herd 
prevalence of ceftriaxone resistant E. coli over that in herds without 
ceftiofur use. Herds reporting ceftiofur use were 25 times more likely 
to have cows from which ceftriaxone resistant E. coli were isolated 
than those that did not use ceftiofur (Ref. 29). In addition, a 
ceftiofur-resistant fecal E. coli isolate expressing CTX-M-type 
extended-spectrum [beta]-lactamase was recovered from a sick dairy calf 
that was treated in an extralabel manner for diarrhea with ceftiofur 
(Ref 17). Escherichia coli are considered good indicators of the 
selective pressure imposed by antimicrobial use in food-producing 
animals and, as such, may reflect what might occur in Salmonella spp. 
under the same conditions (Ref. 30). Salmonella Newport has been shown 
to be the predominant serotype among cases of clinical salmonellosis in 
dairy cattle, followed by S. Typhimurium, including the S. Typhimurium 
variant, 4,5,12:i:- (Refs. 31, 32). Over 68 percent of all isolates 
were resistant to five or more antimicrobials in these studies. In one 
study, 97 percent of S. Newport isolates were multi-drug resistant 
(MDR), exhibiting an MDR-AmpC phenotype (Ref. 31). The proportion of 
multi-drug resistance was significantly higher (p < 0.0001) among S. 
Newport and S. Typhimurium, both serotypes of human importance, than 
among all other serotypes. MDR-AmpC S. Newport resistant to third 
generation cephalosporins has also been shown to persist in the dairy 
environment and can be shed from individual cows for up to 190 days 
(Ref. 33). Studies have also shown that recent antimicrobial treatment, 
including ceftiofur, can increase the probability of isolating 
Salmonella in calves, heifers, and cows (Refs. 34, 35).
    It is estimated that just over one million cases of human 
salmonellosis occur every year in the United States (Ref 36). 
Salmonella serovars Typhimurium and Newport are often multi-drug 
resistant and appear to be associated with more severe human disease 
than other serovars (Refs. 37, 38). These infections can lead to 
treatment failures, greater hospitalization or death rates, and higher 
costs than infections with susceptible strains. Consumption of

[[Page 740]]

dairy products, as well as dairy farm contact, represents important 
risk factors for human S. Newport MDR-AmpC infection (Ref. 39). 
Additionally, a number of outbreaks of S. Newport MDR-AmpC have been 
linked to dairy product consumption (Refs. 40, 41). NARMS data indicate 
that in 2006, 42.6 percent of diagnostic Salmonella isolates from 
cattle were ceftiofur resistant. S. Typhimurium and S. Newport were the 
second and third most frequently isolated serovars from human 
infections in that year, and S. Newport was the third most frequently 
isolated serovar from cattle. Thirty-four percent of S. Newport 
isolated from humans and 32 percent of S. Newport isolated from cattle 
were resistant to ceftiofur, making this serovar the leading source of 
ceftiofur-resistant isolates for both hosts.
2. Poultry
    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. 42). For example, ceftiofur was being 
administered at unapproved dosing levels or via unapproved methods of 
administration. In particular, ceftiofur was being administered via egg 
injection, rather than by the approved method of administering the drug 
to day-old chicks. The Agency is concerned that this extralabel use, 
particularly when employed in conjunction with automated technology, 
could result in levels of cephalosporin exposure in food-producing 
animals that are significantly higher than exposure levels from the 
approved uses. As a result, FDA believes human exposure to food 
containing cephalosporin-resistant bacteria would be significantly 
higher as well. Therefore, considering the large amount of food 
produced by the poultry industry each year, the Agency believes such 
extralabel use presents a risk to the public health.
3. Other Extralabel Uses That Increase Drug Exposure
    One of the goals of this order of prohibition is to reduce the 
amount of cephalosporins used in food-producing animals for uses that 
have not been evaluated for safety and approved by FDA. This is 
particularly important for uses that result in significant increases in 
cephalosporin drug exposure such as the injection of chick eggs 
previously noted. Other extralabel uses that significantly increase 
drug exposure include certain deviations from an approved dosage 
regimen. This would include higher doses and longer durations of 
administration than approved and extralabel routes of administration 
that facilitate mass dosing of large numbers of animals, such as 
through drinking water. A similar concern is the use of a cephalosporin 
drugs to prevent an extralabel disease or condition, particularly when 
such use involves entire flocks or herds of animals. FDA believes that 
exposing large numbers of animals to cephalosporin drugs when such use 
has been neither evaluated nor approved by FDA presents a risk to the 
public health.
4. Biobullets
    The Agency received 35 comments on the July 3, 2008, order of 
prohibition that documented the extralabel use of ceftiofur in a 
compounded new animal drug product known as Biobullets. According to 
the manufacturer's Web site, Biobullets deliver a solid pellet of 
ceftiofur sodium (NADA 140-338) encased in a biodegradable bullet 
propelled by an air rifle into the muscle of cattle. Such use clearly 
represents an extralabel use because ceftiofur sodium is only approved 
for injection in liquid form by hypodermic needle. Since the rate and 
extent of dissolution and distribution of ceftiofur sodium in solid 
form delivered as an implant has not been established, the 
microbiological and toxicological profile of this extralabel use is 
unknown; thus, the safety of human food derived from animals treated in 
this manner is also unknown. Furthermore, based on these comments, and 
on past regulatory actions regarding Biobullets (Ref. 43), FDA 
continues to have concerns that the manufacture, distribution, and use 
of this product may violate the compounding and valid veterinary-
client-patient-relationship provisions of AMDUCA and 21 CFR part 530.
5. Human Cephalosporins
    Another concern is the extralabel use in food-producing animals of 
cephalosporin drugs that are only approved for use in humans. The use 
of these human drug products in food-producing animals presents a risk 
to public health because, like Biobullets, the microbiological and 
toxicological profile of this extralabel use is unknown; thus, the 
safety of human food derived from animals treated with these drugs is 
also unknown. Also, since none of these drugs are approved for use in 
food-producing animals, there are no approved labels to guide the use 
of these drugs regarding, for example, dosing regimen or withdrawal 
period.
    FDA has evidence of the extralabel use of human cephalosporins 
(cephalexin) by veterinarians for the treatment of cattle. This 
evidence was obtained during inspections of farms and veterinary 
hospitals by FDA investigators. Furthermore, one of the comments on the 
July 3, 2008, order of prohibition reported that cephalosporin drugs 
that are either being researched or approved for human use are being 
administered to food-producing animals, including via drinking water.

III. Response to Comments

A. Revised Scope of the Order

    Many of the comments received on the July 3, 2008, order of 
prohibition said the scope of the original order was too broad in that 
it unnecessarily prohibited certain extralabel uses that do not 
significantly contribute to the development of antimicrobial 
resistance.
    As is recognized for the use of antimicrobial drugs in general, the 
use of cephalosporins provides selection pressure that favors expansion 
of resistant variants of bacteria. 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, as stated in the July 2008 order of prohibition, FDA 
believes that it is necessary to take action to limit the extent to 
which extralabel use of cephalosporins in food-producing animals may be 
contributing to the emergence and dissemination of resistant variants. 
However, as noted earlier, FDA also agrees with many of the comments 
received on the July 3, 2008, order of prohibition that said the scope 
of the original order was too broad in that it unnecessarily prohibited 
certain extralabel uses that are not likely to cause an adverse event 
and present a risk to the public health. As discussed below, based on 
the comments and additional information submitted in response to the 
July 3 order, the Agency has reconsidered its position on the following 
three specific areas: extralabel use of cephapirin, extralabel use for 
unapproved indications, and extralabel use in food-producing minor 
species.
1. Cephapirin
    FDA considered the possibility of limiting the order of prohibition 
to certain generations of cephalosporins, or to certain individual 
cephalosporin drugs. FDA recognized that not all cephalosporin drugs 
necessarily posed the same level of risk. But given the

[[Page 741]]

potential for confusion regarding the classification of individual 
cephalosporin drugs into various generations, FDA concluded in the July 
3, 2008, final rule, that it would be problematic to define the scope 
of the prohibition based on cephalosporin ``generation.'' Although FDA 
continues to believe that a ``generation-based'' prohibition would be 
problematic, the Agency has given further consideration to excluding 
certain cephalosporin drugs from the order of prohibition. Therefore, 
based on the comments received on the July 3, 2008, order of 
prohibition, the Agency now believes that it is not necessary to 
prohibit the extralabel use of approved cephapirin drug products in 
food-producing animals.
    Several factors contribute to cephapirin drug products being of a 
lesser concern for promoting antimicrobial resistance in bacteria of 
significant public health concern. First, there are currently no 
cephapirin drug products approved for use in humans and, since 
cephapirin has such a narrow spectrum of activity compared to newer 
cephalosporins like ceftiofur, it is less likely to cause cross-
resistance to drugs in other cephalosporin classes (Refs. 26, 28). 
Furthermore, target organisms for approved uses of cephapirin include 
those not normally considered to cause serious human infections through 
the foodborne route.
    Second, cephapirin is currently only approved for use in food-
producing animals as intramammary infusion drug products for dairy 
cattle. These products are formulated and dispensed in a manner that 
limits their suitability for other uses or routes of administration, 
thus restricting their potential for extralabel use significantly.
    Therefore, because the impact of cephapirin on antimicrobial 
resistance among bacteria of public health concern is substantially 
less than other, newer cephalosporins, and its unique dosage form 
restricts the extent of its extralabel use significantly, the Agency 
believes that it is appropriate to exclude cephapirin drug products 
from the prohibition order.
2. Extralabel Indications for Use
    People often think of extralabel use only in terms of unapproved 
indications for use, that is, diseases or conditions not included in 
the approved labeling. However, as noted earlier, the definition of 
``extralabel use'' includes several aspects of drug use not described 
in the approved labeling including, but not limited to:
    (1) Use in species not listed in the labeling;
    (2) Use for indications (disease or other conditions) not listed in 
the labeling;
    (3) Use at dose levels, frequencies, or routes of administration 
other than those stated in the labeling; and
    (4) Deviation from the labeled withdrawal time based on these 
different uses.
    For example, if a veterinarian uses a drug for an approved 
therapeutic indication, but administers it at twice the labeled dose, 
such use would represent an extralabel use. Alternatively, if a 
veterinarian uses a drug for an approved therapeutic indication, and 
administers the drug at the approved dosage regimen for that 
indication, but there is a failure to observe the labeled withdrawal 
time before the treated animal is sent to slaughter, such use would 
also represent an extralabel use. It is important to understand that 
there are many ways to use an approved drug in an extralabel fashion.
    As noted earlier, a prohibition order can be either a general ban 
on all extralabel use of a drug or class of drugs, or a lesser ban 
limited to one or more of the individual extralabel uses. Many 
commenters were concerned that a blanket prohibition of all extralabel 
use of cephalosporins would have a negative impact on animal health and 
welfare because, by prohibiting all extralabel use, therapeutic use for 
unapproved indications would also be prohibited, thereby eliminating 
effective treatment options for many life-threatening diseases for 
which there are limited or no approved therapies. However, while the 
vast majority of the comments objected to a blanket prohibition, few 
expressed an objection to prohibiting extralabel dosage regimens. Only 
those comments regarding intramammary use of cephalosporins expressed a 
need for extralabel dosage regimens. In fact, several comments 
explicitly suggested FDA narrow the order to only allow extralabel use 
for unapproved therapeutic indications, but still prohibit most other 
extralabel use, including modifications to approved dosage regimens.
    An important tenet of the Agency's microbial food safety assessment 
for antimicrobial drugs in food-producing animals is its focus on 
conditions of use. When the microbial food safety hazard associated 
with the use of an antimicrobial drug in food-producing animals is 
evaluated as part of the new animal drug approval process, the 
evaluation takes into consideration the proposed conditions of use, 
including:
    (1) Dosage regimen (dose level, frequency of administration, 
duration, and route of administration), and
    (2) Indications for use (purpose of treatment, species, class or 
age of the target animal, and the number of animals likely to be 
treated).
    As such, it is the approved conditions of use that help mitigate 
antimicrobial resistance risks associated with a particular drug's use 
by controlling the overall drug exposure in treated animals. Although 
all aspects of the conditions of use contribute to some extent to drug 
exposure, FDA believes, after re-examining the basis for this order of 
prohibition, that extralabel uses of cephalosporins that involve 
modifications of the approved dosage regimen are likely to pose the 
greatest risk of increasing the extent to which animals are exposed to 
the drug. Such extralabel uses allow for greater exposure of individual 
animals through modification of dose levels, duration of 
administration, and/or frequency of administration. Furthermore, using 
the drug by unapproved routes of administration (e.g., via drinking 
water) can also increase exposure levels by facilitating administration 
of the drug to a significantly larger number of animals.
    It is in this context that FDA concluded that extralabel uses that 
conform to the approved dosage regimen, but involve use for unapproved 
therapeutic indications, pose a significantly lower risk with respect 
to increasing overall drug exposure than uses at unapproved dose 
levels, unapproved duration and/or frequency of administration, or 
unapproved routes of administration. Accordingly, the Agency also 
concluded that an exception to the order of prohibition could be made 
on this basis. However, FDA also took into account the extralabel uses 
of cephalosporin drugs in food-producing animals of greatest concern 
(see discussion in section II.E of this document regarding prevention 
use) and concluded that this exception to the prohibition should only 
be for the treatment and control of disease.
    Therefore, the Agency thinks it is appropriate to narrow the scope 
of the prohibition order somewhat by only allowing extralabel use in 
food-producing major species for treatment or control of unapproved 
disease indications, but continuing to prohibit most other extralabel 
use in these species including unapproved dosage regimens and use to 
prevent extralabel disease indications.
    For the reasons described previously, FDA does not at this time 
believe that extralabel use in food-producing major

[[Page 742]]

species to treat or control an unapproved disease indication presents a 
risk to the public health as long as the drug is used at a labeled 
dose, frequency, duration, and route of administration approved for 
that species and production class.
3. Food-Producing Minor Species
    In accordance with the act, minor species means animals other than 
cattle, swine, chickens, turkeys, horses, dogs, cats, and humans. Many 
comments requested that food-producing minor species, particularly 
small ruminants, be excluded from the order of prohibition. Most of 
these comments cited the limited availability of approved animal drug 
products for these species and several comments also noted that small 
ruminants represent only very limited uses of cephalosporin drug 
products compared to cattle, swine, and poultry. Based on these 
comments, the Agency reconsidered the decision to include food-
producing minor species in the prohibition on the extralabel use of 
cephalosporin drugs in food-producing animals.
    As noted earlier, in regard to the use of antimicrobial drugs in 
animals, the Agency considers the most significant risk to the public 
health associated with antimicrobial resistance to be human exposure to 
food containing antimicrobial-resistant bacteria resulting from the 
exposure of food-producing animals to antimicrobials. However, when 
considering the foodborne pathway, the potential for human exposure to 
antimicrobial-resistant pathogens is significantly less for food 
derived from minor species than it is for food derived from the food-
producing major species. The exposure potential is less in part because 
the amount of food derived from cattle, swine, and poultry is much 
greater than the amount of food derived from sheep, goats, and 
aquaculture, the minor species from which the most food is derived. 
Furthermore, the amount of food derived from any of the other food-
producing minor species, such as deer, bison, elk, rabbit, duck, goose, 
quail, pheasant, partridge, pigeon, ostrich, or emu is considerably 
less than the amount of food derived from sheep, goats, and 
aquaculture. In addition, cephalosporins are approved for use in sheep 
and goats, thereby reducing the potential for extralabel use in these 
species, and there is little or no practical use for cephalosporin 
drugs in aquaculture.
    Therefore, for the reasons described previously, FDA does not at 
this time believe that extralabel use in food-producing minor species 
presents a risk to the public health.
    Please note that all the provisions of AMDUCA remain applicable to 
the exceptions noted above. This includes provisions making it unlawful 
for the permitted extralabel use of a cephalosporin drug to result in a 
residue above an established tolerance or safe level. See 21 U.S.C. 
360b(a)(4)(B) and FDA regulations at 21 CFR 530.11.

B. Legal Standard

    Several comments questioned the legal standard applied by FDA in 
implementing the order of prohibition. Some comments referred to the 
Agency's approach as involving the ``precautionary principle,'' an 
apparent reference to a principle used in the European Union in some 
environmental and regulatory decision-making. Two comments suggested 
that, in order to support an order of prohibition, it would be 
necessary for FDA to demonstrate ``either a demonstrative negative 
impact on human health or an imminent danger to human health.'' Some 
comments suggested that FDA must perform a risk assessment that would 
characterize the hazard, evaluate the risk, and ascertain the impact of 
any risk management recommendations associated with the order.
    One comment suggested that a link between the use of cephalosporins 
in the treatment of animals and the development of bacterial resistance 
in humans would not meet the criterion of the AMDUCA implementing 
regulation that the extralabel use of cephalosporins has caused or will 
likely cause an adverse event. That comment appears to make a technical 
argument that an adverse event in the context of the regulation can 
only be an adverse event in animals, as opposed to humans. (The 
commenter acknowledged that the lack of drug efficacy when used for a 
labeled pathogen in target animals would be considered an adverse 
event.)
    AMDUCA was enacted in 1994, and its provisions became effective 
upon FDA's issuance of final regulations implementing those provisions 
in 1996. Prior to the passage of AMDUCA, Federal law prohibited the use 
of a new animal drug in a manner other than in accordance with the 
approved label directions, i.e., extralabel use. Recognizing the 
reality that veterinarians are often confronted with situations in 
which there are no approved drugs for the species of animal that they 
are treating, or for particular diseases or conditions afflicting those 
animals, Congress enacted AMDUCA to allow licensed veterinarians to 
prescribe extralabel uses of approved animal drugs and approved human 
drugs for animals without violating the law.
    The provisions of AMDUCA relating to extralabel use in animals of 
approved new animal drugs and approved human drugs, sections 512(a)(4) 
and 512(a)(5) of the FD&C Act, respectively, provide that such 
extralabel use must be in compliance with conditions specified in 
implementing regulations promulgated by FDA. (21 U.S.C. 360b(a)(4) and 
360b(a)(5)). Section 512(a)(4) further provides that if FDA finds, 
after extending an opportunity for public comment, that the extralabel 
use of a new animal drug ``presents a risk to the public health * * * 
[FDA] may, by order, prohibit any such use.'' (Section 512(a)(4)(D) (21 
U.S.C. 360b(a)(4)(D)).
    Although the express language relating to prohibiting extralabel 
use appears in the provisions of AMDUCA that deal with extralabel use 
of approved new animal drugs, in its implementing regulations at part 
530, FDA has interpreted the statute as applying the same standard to 
extralabel use of approved human drugs in food-producing animals. FDA's 
implementing regulations state that a prohibition may occur if FDA 
determines that ``[t]he extralabel use of the drug or class of drugs 
presents a risk to the public health.'' 21 CFR 530.21(a)(2). See also 
21 CFR 530.25(a)(2). The regulations permit a prohibition to be either 
a general ban on the extralabel use of the drug or class of drugs, or a 
ban limited to particular species, indications for use, dosage forms, 
routes of administration, or a combination of those factors. 21 CFR 
530.21(b).
    The regulations further define the phrase ``use of a drug presents 
a risk to the public health'' to mean that ``FDA has evidence that 
demonstrates that the use of the drug has caused or likely will cause 
an adverse event.'' 21 CFR 530.3(e). FDA has thus, by regulation, 
imposed upon itself the requirement that it have some evidence that 
demonstrates either that a drug has caused an adverse event or that it 
likely will cause an adverse event. FDA believes that, when the issue 
is, as with cephalosporins, a question of the development of 
antibacterial resistance in animals that may affect human health, an 
order of prohibition may be based on evidence that such development of 
antibacterial resistance--which could lead to serious adverse events in 
humans--is ``likely'' as a result of the extralabel animal drug use. 
The regulation is clear that there need not be evidence that such an 
event has actually occurred.

[[Page 743]]

    FDA rejects the apparent suggestion of one commenter, noted above, 
that an order of prohibition cannot be based on an adverse event in 
humans. Such a reading would be squarely inconsistent with the 
statutory provisions authorizing FDA to ban extralabel uses that 
present a risk to the public health. FDA addressed this issue in the 
preamble to the final AMDUCA implementing regulations, clarifying that 
``[t]he agency did not intend for the term `adverse event' to be 
interpreted as related only to animal `adverse drug reactions.' '' (61 
FR 57732 at 57737, November 7, 1996). Also, as made clear by the 
preamble, ``* * * the primary focus will be on human health.'' (61 FR 
at 57732 at 57737).
    FDA also rejects the assertion by some commenters that FDA relied 
on the ``precautionary principle.'' As previously noted, the standard 
in the regulation does require the existence of evidence. In the 
preamble to the final rule, FDA addressed the question of what type of 
evidence would be necessary by saying that the risk determinations that 
would lead to prohibition of an extralabel use ``typically will involve 
documented scientific information. However, the Agency believes that it 
is not limited to making risk determinations based solely on documented 
scientific information, but may use other suitable information as 
appropriate.'' (61 FR 57732 and 57738; November 7, 1996). In other 
sections of this preamble, FDA provides a detailed description of the 
evidence supporting its conclusion that the extralabel use that is 
being prohibited by this revised order does in fact present a risk to 
the public health, including a likelihood that the use would, if not 
prohibited, ultimately lead to adverse events in humans resulting from 
the development of resistance to antibiotic drugs needed to treat human 
infections.

IV. Conclusions

    Based on information regarding cephalosporin resistance as 
discussed previously, FDA continues to believe, as it did in July of 
2008, that it is likely that the extralabel use of cephalosporins in 
certain food-producing animal species is contributing to the emergence 
of cephalosporin-resistant zoonotic foodborne bacteria. Therefore, FDA 
has determined in accordance with the relevant provisions of 21 CFR 
part 530 that, with some exceptions, such extralabel use likely will 
cause an adverse event and, as such, presents a risk to the public 
health. As also noted earlier, FDA agrees with many of the comments 
received on the July 3, 2008, order of prohibition that said the scope 
of the original order was too broad and, in response, has narrowed the 
scope of this order accordingly. Specifically, this order prohibits all 
extralabel use of cephalosporin drugs in food-producing animals except 
for the following uses, provided they comply with AMDUCA and FDA's 
regulations implementing AMDUCA at 21 CFR part 530:
    (1) Cephapirin: Extralabel uses of approved cephapirin products are 
excluded from the prohibition.
    (2) Extralabel Indications for Use: Extralabel uses to treat or 
control an extralabel disease indication in food-producing major 
species when used at a labeled dose, frequency, duration, and route of 
administration approved for that species and production class, are 
excluded from the prohibition.
    (3) Food-Producing Minor Species: Extralabel uses in food-producing 
minor species are excluded from the prohibition.
    To restate in more practical terms, after this order becomes 
effective, the following extralabel use restrictions will apply to all 
cephalosporin drug products, except approved cephapirin products, when 
used in food-producing animals:
    Major Species: Extralabel use of a cephalosporin drug product is 
permitted in food-producing major species to treat or control an 
extralabel disease indication, but only when it is approved and labeled 
for use in that particular species and production class, and only when 
the product is administered at dose levels, frequencies, durations, and 
routes of administration stated on the approved labeling for that 
particular species and production class. However, extralabel use for 
disease prevention purposes is prohibited.
    Minor Species: All extralabel use of a cephalosporin drug product 
is permitted in food-producing minor species provided such use complies 
with the requirements of AMDUCA and 21 CFR part 530.

V. Comments

    FDA is providing 60 days from the date of this publication for the 
public to comment on this document. For the effective date of the 
order, see the DATES section of this document, unless the Agency 
revokes or modifies the order, or extends the comment period. 
Interested persons may submit to the Division of Dockets Management 
(see ADDRESSES) either electronic or written comments regarding this 
document. It is only necessary to send one set of comments. It is no 
longer necessary to send two copies of mailed comments. Identify 
comments 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.

VI. Order of Prohibition

    Therefore, I hereby issue the following order under 21 CFR 530.21 
and 530.25. FDA finds that certain 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, the 
Agency is prohibiting the extralabel use of the cephalosporin class of 
antimicrobial drugs as follows:
    Cephalosporins (not including cephapirin) are prohibited from 
extralabel use in cattle, swine, chickens, or turkeys as follows: (1) 
For disease prevention purposes; (2) at unapproved doses, frequencies, 
durations, or routes of administration; and (3) if the drug is not 
approved for that species and production class.

VII. References

    The following references have been placed on display in the Dockets 
Management Branch (see ADDRESSES). You may view them between 9 a.m. and 
4 p.m., Monday through Friday. FDA has verified the Web site addresses, 
but FDA is not responsible for any subsequent changes to the Web site 
after this document publishes in the Federal Register.

1. Livermore, D.M. and L.D. Williams. [beta]-Lactams: Mode of Action 
and Mechanisms of Resistance. In Antibiotics in Laboratory Medicine; 
Victor Lorian (ed.); Williams & Wilkins, Baltimore, pp. 502-578, 
1991.
2. John H. Powers, M.D., Transcript--Official Meeting of the 
Veterinary Medicine Advisory Committee, New Drug Microbial Safety 
Review Under Guidance <greek-i>152, http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/VeterinaryMedicineAdvisoryCommittee/ucm126971.htm (accessed January 
6, 2011), September 25, 2006.
3. U.S. Food and Drug Administration, MAXIPIME (cefepime 
hydrochloride) for Injection, NDA 50-679/S-021, http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/050679s028lbl.pdf 
(accessed January 6, 2011).
4. Biedenbach, D.J. et al. Analysis of Salmonella spp. with 
resistance to extended-spectrum cephalosporins and fluoroquinolones 
isolated in North America and Latin America: report from the SENTRY 
Antimicrobial Surveillance Program (1997-2004). Diagnostic 
Microbiology and Infectious Disease 54:13-21, 2006.
5. Livermore, D.M. Beta-Lactamases in Laboratory and Clinical 
Resistance.

[[Page 744]]

Clinical Microbiology Review 8:557-584, 1995.
6. Li, X.Z. et al. [beta]-Lactam Resistance and [beta]-lactamases in 
Bacteria of Animal Origin. Veterinary Microbiology 121:197-214, 
2007.
7. Centers for Disease Control and Prevention (CDC), National 
Antimicrobial Resistance Monitoring System for Enteric Bacteria 
(NARMS): Human Isolates Final Report, 2008. Atlanta, Georgia: U.S. 
Department of Health and Human Services, CDC, 2010.
8. Glenn, L.M. et al. Analysis of Antimicrobial Resistance Genes 
Detected in Multidrug-Resistant Salmonella enterica Serovar 
Typhimurium Isolated from Food Animals. Microbial Drug Resistance 
17:407-418, 2011.
9. Doi, Y. et al. Reduced Susceptibility to Cefepime among 
Escherichia coli Clinical Isolates Producing Novel Variants of CMY-2 
[beta]-Lactamase. Antimicrobial Agents and Chemotherapy 53:3159-
3161, 2009.
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. et al. CTX-M: Changing the Face of ESBLs in 
Europe. J. Antimicrobial Chemotherapy 59:165-174, 2007.
12. Lewis, J.S. et al. First Report of the Emergence of CTX-M-Type 
Extended-Spectrum [szlig]-Lactamases (ESBLs) as the Predominant ESBL 
Isolated in a U.S. Health Care System. Antimicrobial Agents and 
Chemotherapy 51:4015-4021, 2007.
13. Castanheira, M. et al. Rapid Emergence of blaCTX-M Among 
Enterobacteriaceae in U.S. Medical Centers: Molecular Evaluation 
From the MYSTIC Program (2007). Microbial Drug Resistance 14:211-
216, 2008.
14. Sj[ouml]lund-Karlsson, M. et al. Human Salmonella Infection 
Yielding CTX-M [beta]-Lactamase, United States. Emerging Infectious 
Diseases 14:1957-1959, 2008.
15. McGettigan, SE. et al. Prevalence of CTX-M [beta]-Lactamases in 
Philadelphia, Pennsylvania. Journal of Clinical Microbiology 
47:2970-2974, 2009.
16. Sj[ouml]lund-Karlsson, M. et al. Salmonella Isolates with 
Decreased Susceptibility to Extended-Spectrum Cephalosporins in the 
United States. Foodborne Pathogens and Disease 7:1503-1509, 2010.
17. Wittum, T.E. et al. CTX-M-Type Extended-Spectrum [szlig]-
Lactamases Present in Escherichia coli from the Feces of Cattle in 
Ohio, United States. Foodborne Pathogens and Disease 7:1575-1579, 
2010.
18. Naseer, U. and A. Sundsfjord. The CTX-M Conundrum: Dissemination 
of Plasmids and Escherichia coli Clones. Microbial Drug Resistance 
17:83-97, 2011.
19. Sj[ouml]lund-Karlsson, M. et al. CTX-M-producing Non-Typhi 
Salmonella spp. Isolated from Humans, United States. Emerging 
Infectious Diseases 17:97-99, 2011.
20. M[oslash]lbak, K. Spread of Resistant Bacteria and Resistance 
Genes from Animal to Humans--The Public Health Consequence. Journal 
of Veterinary Medicine B51:364-369, 2004.
21. USDA, ``National Antimicrobial Resistance Monitoring System for 
Enteric Bacteria (NARMS): Animal Arm Annual Report, 2009,'' Athens, 
Georgia, U.S. Department of Agriculture, USDA, 2011.
22. FDA, ``National Antimicrobial Resistance Monitoring System-
Enteric Bacteria (NARMS): 2009 Executive Report,'' Rockville, MD, 
U.S. Department of Health and Human Services, Food and Drug 
Administration, 2011.
23. FDA, ``National Antimicrobial Resistance Monitoring System-
Enteric Bacteria (NARMS): 2007 Executive Report,'' Rockville, MD, 
U.S. Department of Health and Human Services, FDA, 2010.
24. CDC, ``National Antimicrobial Resistance Monitoring System for 
Enteric Bacteria (NARMS): Human Isolates Final Report, 2009,'' 
Atlanta, Georgia, U.S. Department of Health and Human Services, CDC, 
2011.
25. Dutil, L. et al. Ceftiofur resistance in Salmonella enterica 
serovar Heidelberg in chicken meat and humans, Canada. Emerging 
Infectious Diseases 16:1, 2010.
26. Zhao, S. et al. Beta-Lactam Resistance in Salmonella Isolated 
From Retail Meats in the United States: National Antimicrobial 
Resistance Monitoring System (NARMS): 2002-2006. Applied and 
Environmental Microbiology Oct. 23, 2009.
27. Zhao, S. et al. Identification and expression of cephamycinase 
blaCMY genes in Escherichia coli and Salmonella isolates from food 
animals and ground meat. Antimicrobial Agents and Chemotherapy 
45:3647-50, 2001.
28. Lowrance, T.C. et al. Changes in antimicrobial susceptibility in 
a population of Escherichia coli isolated from feedlot cattle 
administered ceftiofur crystalline-free acid. American Journal of 
Veterinary Research 68:501-507, 2007.
29. Tragesser, L.A. et al. Association between ceftiofur use and 
isolation of Escherichia coli with reduced susceptibility to 
ceftriaxone from fecal samples of dairy cows. American Journal of 
Veterinary Research 67:1696-1700, 2006.
30. van den Bogaard, A.E. and E.E. Stobberingh. Epidemiology of 
resistance to antibiotics. Links between animals and humans. 
International Journal of Antimicrobial Agents 14:327-335, 2000.
31. Cummings, K.J. et al. The incidence of salmonellosis among dairy 
herds in the northeastern United States. Journal of Dairy Science 
92:3766-3774, 2009.
32. Cummings, K.J. et al. The duration of fecal Salmonella shedding 
following clinical disease among dairy cattle in the northeastern 
USA. Preventive Veterinary Medicine 92:134-139, 2009.
33. Cobbold, R.N. et al. Long-term persistence of multi-drug-
resistant Salmonella enterica serovar Newport in two dairy herds. 
Journal of the American Veterinary Medical Association 228:585-591, 
2006.
34. Warnick, L.D. et al. Effect of previous antimicrobial treatment 
on fecal shedding of Salmonella enterica subsp. enterica serogroup B 
in New York dairy herds with recent clinical salmonellosis. 
Preventive Veterinary Medicine 56:285-297, 2003.
35. Berge, A.C., D.A. Moore, and W.M. Sischo. Prevalence and 
antimicrobial resistance patterns of Salmonella enterica in 
preweaned calves from dairies and calf ranches. American Journal of 
Veterinary Research 67:1580-1588, 2006.
36. Scallan, E. et al. Foodborne Illness Acquired in the United 
States--Major Pathogens. Emerging Infectious Diseases January 2011.
37. Varma, J.K. et al. Antimicrobial-resistant nontyphoidal 
Salmonella is associated with excess bloodstream infections and 
hospitalizations. Journal of Infectious Diseases 191:554-561, 2005.
38. Varma, J.K. et al. Hospitalization and antimicrobial resistance 
in Salmonella outbreaks, 1984-2002. Emerging Infectious Diseases 
11:943-946, 2005.
39. Varma, J.K., et al. Highly Resistant Salmonella Newport-MDRAmpC 
Transmitted through the Domestic US Food Supply: A FoodNet Case-
Control Study of Sporadic Salmonella Newport Infections, 2002-2003. 
Journal of Infectious Diseases 194:222-230, 2006.
40. Centers for Disease Control and Prevention. Outbreak of 
multidrug-resistant Salmonella Newport--United States, January-April 
2002. Morbidity and Mortality Weekly Report 51:545-548, 2002.
41. CDC, Outbreak of multidrug-resistant Salmonella enterica 
serotype Newport infections associated with consumption of 
unpasteurized Mexican-style aged cheese--Illinois, March 2006-April 
2007. Morbidity and Mortality Weekly Report 57:432-435, 2008.
42. 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.
43. U.S. Food and Drug Administration, Dallas District, Warning 
Letter: The Veterinary Pharmacy, Inc. REF-2004-DAL-WL-29, August 6, 
2004. http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2004/ucm146544.htm (accessed January 6, 2011).

List of Subjects in 21 CFR Part 530

    Administrative practice and procedure, Advertising, Animal drugs, 
Labeling, Reporting and recordkeeping requirements.

    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:

[[Page 745]]

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 (not including cephapirin) in cattle, swine, 
chickens, or turkeys:
    (i) For disease prevention purposes;
    (ii) At unapproved doses, frequencies, durations, or routes of 
administration; or
    (iii) If the drug is not approved for that species and production 
class.
* * * * *

    Dated: November 23, 2011.
 Bernadette Dunham,
 Director, Center for Veterinary Medicine.
[FR Doc. 2012-35 Filed 1-4-12; 11:15 am]
BILLING CODE 4160-01-P


</pre><script data-cfasync="false" src="/cdn-cgi/scripts/5c5dd728/cloudflare-static/email-decode.min.js"></script></body>
</html>