[Federal Register Volume 77, Number 4 (Friday, January 6, 2012)]
[Rules and Regulations]
[Pages 735-745]
[FR Doc No: 2012-35]

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

Written Submissions

    Submit written submissions in the following ways:
     Fax:<PHONE_NUMBER>.
     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,<PHONE_NUMBER>, email<EMAIL_ADDRESS>
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).

    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

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

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

(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:
     Up to 2x above the tolerance = 12 violations
     Between 2x and 5x above the tolerance = 17 violations
     Between 5x and 10x above the tolerance = 16 violations
     Between 10x and 20x above the tolerance = 30 violations
     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

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

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

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.

    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.

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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:

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


[Federal Register Volume 76, Number 126 (Thursday, June 30, 2011)]
[Notices]
[Pages 38457-38458]
[FR Doc No: 2011-16374]

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DEPARTMENT OF TRANSPORTATION

National Highway Traffic Safety Administration

Reports, Forms and Record Keeping Requirements Agency Information
Collection Activity Under OMB Review

AGENCY: National Highway Traffic Safety Administration, DOT.

ACTION: Notice.

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SUMMARY: In compliance with the Paperwork Reduction Act of 1995 (44
U.S.C. 3501 et seq.), this notice announces that the Information
Collection Request (ICR) abstracted below has been forwarded to the
Office of Management and Budget (OMB) for review and comment. The ICR
describes the nature of the information collections and their expected
burden. The Federal Register Notice with a 60-day comment period was
published on March 30, 2011 [76 FR 17746].

DATES: Comments must be submitted on or before August 1, 2011.

FOR FURTHER INFORMATION CONTACT: Anetris Campbell at the National
Highway Traffic Safety Administration, Office of Rulemaking (NVS-100),
202-366-0933, 1200 New Jersey Avenue, SE., Room W43-331, Washington, DC
20590.

SUPPLEMENTARY INFORMATION:

National Highway Traffic Safety Administration

    Title: Replaceable Light Source Information Collection, 49 CFR part
564.
    OMB Number: 2127-0506.
    Type of Request: Extension of a currently approved collection.
    Affected Public: Business or other-for-profit organizations.
    Abstract: 49 U.S.C. 30111, 30112, and 30117 of the National Traffic
and Motor Vehicle Safety Act of 1996, authorizes the issuance of
Federal Motor Vehicle Safety Standards (FMVSS). The Secretary is
authorized to issue, amend, and revoke such rules and regulations as
she/he deems necessary.
    Using this authority, the agency issued FMVSS no. 125, ``Warning
Devices'', which applies to devices, without self contained energy
sources, that are designed to be carried mandatory in buses and trucks
that have a gross vehicle weight rating (GVWR) greater than 10,000
pounds and voluntarily in other vehicles. These devices are used to
warn approaching traffic of the presence of a stopped vehicle, except
for devices designed to be permanently affixed to the vehicles
    Estimated Total Annual Burden: 1 hour.

ADDRESSES: Send comments, within 30 days, to the Office of Information
and Regulatory Affairs, Office of Management and Budget, 725-17th
Street, NW., Washington, DC 20503, Attention NHTSA Desk Officer.
Comments are invited on: whether the proposed collection of information
is necessary for the proper performance of the functions of the
Department, including whether the information will have practical
utility; the accuracy of the Department's estimate of the burden of the
proposed information collected; ways to enhance the quality, utility
and clarity of the information to be collected; and ways to minimize
the burden of the collection of information on respondents, including
the use of automated collection techniques or other forms of
information technology. A comment to OMB is most effective if OMB
receives it within 30 days of publication.

    Issued: June 24, 2011.
Nathaniel Beuse,
Director, Office of Crash Avoidance Standards.
[FR Doc. 2011-16374 Filed 6-29-11; 8:45 am]
BILLING CODE 4910-59-P


[Federal Register Volume 87, Number 188 (Thursday, September 29, 2022)]
[Rules and Regulations]
[Page 58996]
[FR Doc No: 2022-21097]

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DEPARTMENT OF HOMELAND SECURITY

Coast Guard

33 CFR Part 165

[Docket No. USCG-2022-0794]

Safety Zone; Monte Foundation Fireworks, Capitola Pier, Capitola,
CA

AGENCY: Coast Guard, Department of Homeland Security (DHS).

ACTION: Notification of enforcement of regulation.

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SUMMARY: The Coast Guard will enforce the safety zone for the Monte
Foundation Fireworks Display in the Captain of the Port, San Francisco
area of responsibility during the dates and times noted below. This
action is necessary to protect life and property of the maritime public
from the hazards associated with the fireworks display. During the
enforcement period, unauthorized persons or vessels are prohibited from
entering into, transiting through, or anchoring in the safety zone,
unless authorized by the Patrol Commander (PATCOM) or other federal,
state, or local law enforcement agencies on scene to assist the Coast
Guard in enforcing the regulated area.

DATES: The regulations in 33 CFR 165.1191, will be enforced for the
location in Table 1 to Sec.  165.1191, Item number 22, from 8 p.m. to
8:20 p.m. on October 9, 2022.

FOR FURTHER INFORMATION CONTACT: If you have questions about this
notification of enforcement, call or email MST1 Shannon Curtaz-Milian,
Waterways Management, U.S. Coast Guard Sector San Francisco; telephone
(415) 399-7440, email [email protected].

SUPPLEMENTARY INFORMATION: The Coast Guard will enforce the safety zone
established in 33 CFR 165.1191, Table 1, Item number 22, for the Monte
Foundation Fireworks Display from 8 p.m. to 8:20 p.m. on October 9,
2022. The Captain of the Port has delegated the authority to issue the
notification of enforcement for this regulation to the Prevention
Department Head.
    The safety zone will extend to all navigable waters around the
land-based launch site at the Capitola Pier in Capitola, CA. During the
20-minute fireworks display, scheduled to begin at approximately 8 p.m.
on October 9, 2022, the safety zone will encompass navigable waters
around and under the fireworks launch site within a radius of 1,000
feet in approximate position 36[deg]58'09.92'' N, 121[deg]57'15.06'' W
(NAD 83) for the Monte Foundation Fireworks Display.
    This safety zone will be enforced from 8 p.m. until 8:20 p.m. on
October 9, 2022, or as announced via Broadcast Notice to Mariners. In
addition to this notification of enforcement in the Federal Register,
the Coast Guard plans to provide notification of this enforcement
period via the Local Notice to Mariners.
    Under the provisions of 33 CFR 165.1191, unauthorized persons or
vessels are prohibited from entering into, transiting through, or
anchoring in the safety zone during all applicable effective dates and
times, unless authorized to do so by the PATCOM or other Official
Patrol defined as a Federal, state, or local law enforcement agency on
scene to assist the Coast Guard in enforcing the regulated area.
Additionally, each person who receives notice of a lawful order or
direction issued by the PATCOM or Official Patrol shall obey the order
or direction. The PATCOM or Official Patrol may, upon request, allow
the transit of commercial vessels through regulated areas when it is
safe to do so.
    If the Captain of the Port determines that the regulated area need
not be enforced for the full duration stated in this notification, a
Broadcast Notice to Mariners may be used to grant general permission to
enter the regulated area.

    Dated: September 23, 2022.
Taylor Q. Lam,
Captain, U.S. Coast Guard, Captain of the Port, San Francisco.
[FR Doc. 2022-21097 Filed 9-28-22; 8:45 am]
BILLING CODE 9110-04-P


[Federal Register Volume 79, Number 139 (Monday, July 21, 2014)]
[Rules and Regulations]
[Page 42211]
[FR Doc No: 2014-17102]

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DEPARTMENT OF HOMELAND SECURITY

Coast Guard

33 CFR Part 165

[Docket No. USCG-2012-0730]
RIN 1625-AA00

Safety Zone; Annual Events Requiring Safety Zones in the Captain
of the Port Detroit Zone

AGENCY: Coast Guard, DHS.

ACTION: Notice of enforcement of regulation.

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SUMMARY: The Coast Guard will enforce the safety zone on Lake Erie in
Cedar Point, Ohio, for the Revolution 3 Triathlon in Cedar Point, Ohio.
This zone will be enforced from 6 a.m. until 10 a.m. on each day of
September 6 and 7, 2014. This action is necessary and intended to
ensure safety of life on navigable waters during the Revolution 3
Triathlon. During the aforementioned periods, the Coast Guard will
enforce restrictions upon, and control movement of, vessels in the
safety zone. No person or vessel may enter the safety zone while it is
being enforced without permission of the Captain of the Port Detroit.

DATES: The regulations in 33 CFR 165.941 will be enforced for safety
zone (a)(60) in Sec.  165.941, from 6 a.m. until 10 a.m. on each day of
September 6 and 7, 2014.

FOR FURTHER INFORMATION CONTACT: If you have questions on this
document, call or email MST2 Daniel O'Leary, Prevention Department,
Marine Safety Unit Toledo, 420 Madison Ave., Suite 700, Toledo, OH
43604; telephone<PHONE_NUMBER>; email<EMAIL_ADDRESS>
SUPPLEMENTARY INFORMATION: The Coast Guard will enforce the Revolution
3 Triathlon safety zone listed as item (a)(60) of 33 CFR 165.941.
Section 165.941 lists many annual events requiring safety zones in the
Captain of the Port Detroit zone. This Revolution 3 Triathlon zone
encompasses all waters and adjacent shoreline of Lake Erie located
within an area that is approximately 200 yards. The area is within
positions 41[deg]29'00.04'' N 082[deg]40'48.16'' W to 41[deg]29'19.28''
N 082[deg]40'38.97'' W to 41[deg]29'02.51'' N 082[deg]40'20.82'' W to
41[deg]28'45.52'' N 082[deg]40'35.75'' W then following the shoreline
to the point of origin on Lake Erie during the annual Revolution 3
Triathlon from 6 a.m. until 10 a.m. on September 6 and 7, 2014.
    All vessels must obtain permission from the Captain of the Port
Detroit, or his or her on-scene representative to enter, move within,
or exit the safety zone. Requests must be made in advance and approved
by the Captain of the Port before transits will be authorized.
Approvals will be granted on a case by case basis. Vessels and persons
granted permission to enter the safety zone must obey all lawful orders
or directions of the Captain of the Port Detroit, or his or her
designated representative.
    This document is issued under authority of 33 CFR 165.941, Safety
Zones; Annual events requiring safety zones in the Captain of the Port
Detroit zone, and 5 U.S.C. 552(a). In addition to this publication in
the Federal Register, the Coast Guard will provide the maritime
community with advance notification of this event via Broadcast Notice
to Mariners or Local Notice to Mariners. The Captain of the Port
Detroit, or his or her on-scene representative, may be contacted via
VHF Channel 16.

    Dated: July 3, 2014.
S. B. Lemasters,
Captain, U.S. Coast Guard, Captain of the Port Detroit.
[FR Doc. 2014-17102 Filed 7-18-14; 8:45 am]
BILLING CODE 9110-04-P


[Federal Register Volume 87, Number 93 (Friday, May 13, 2022)]
[Notices]
[Page 29417]
[FR Doc No: 2022-10256]

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SECURITIES AND EXCHANGE COMMISSION

[Release No. 34-94872; File No. SR-EMERALD-2022-15]

Self-Regulatory Organizations; MIAX Emerald, LLC; Notice of
Withdrawal of Proposed Rule Change To Amend the MIAX Emerald Fee
Schedule To Adopt a Tiered-Pricing Structure for Additional Limited
Service MIAX Emerald Express Interface Ports

May 9, 2022.
    On April 1, 2022, MIAX Emerald, LLC (``MIAX Emerald'' or
``Exchange'') filed with the Securities and Exchange Commission
(``Commission''), pursuant to Section 19(b)(1) of the Securities
Exchange Act of 1934 (``Act''),\1\ and Rule 19b-4 thereunder,\2\ a
proposed rule change to amend the Exchange's Fee Schedule to adopt a
tiered-pricing structure for additional limited service express
interface ports.
---------------------------------------------------------------------------

    \1\ 15 U.S.C. 78s(b)(1).
    \2\ 17 CFR 240.19b-4.
---------------------------------------------------------------------------

    The proposed rule change was immediately effective upon filing with
the Commission pursuant to Section 19(b)(3)(A) of the Act.\3\ On April
20, 2022, the proposed rule change was published for comment in the
Federal Register and, pursuant to Section 19(b)(3)(C) of the Act,\4\
the Commission: (1) Temporarily suspended the proposed rule change; and
(2) instituted proceedings under Section 19(b)(2)(B) of the Act \5\ to
determine whether to approve or disapprove the proposed rule change.\6\
On May 2, 2022, the Exchange withdrew the proposed rule change (SR-
EMERALD-2022-15).
---------------------------------------------------------------------------

    \3\ 15 U.S.C. 78s(b)(3)(A). A proposed rule change may take
effect upon filing with the Commission if it is designated by the
exchange as ``establishing or changing a due, fee, or other charge
imposed by the self-regulatory organization on any person, whether
or not the person is a member of the self-regulatory organization.''
15 U.S.C. 78s(b)(3)(A)(ii).
    \4\ 15 U.S.C. 78s(b)(3)(C).
    \5\ 15 U.S.C. 78s(b)(2)(B).
    \6\ See Securities Exchange Act Release No. 94718 (April 14,
2022), 87 FR 23633.

    For the Commission, by the Division of Trading and Markets,
pursuant to delegated authority.\7\
---------------------------------------------------------------------------

    \7\ 17 CFR 200.30-3(a)(12).
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J. Matthew DeLesDernier,
Assistant Secretary.
[FR Doc. 2022-10256 Filed 5-12-22; 8:45 am]
BILLING CODE 8011-01-P