Natural Resources Defense Council, Inc. et al v. United States Food and Drug Administration et al

Filing 59

DECLARATION of Mitchell S. Bernard in Support re: 56 MOTION for Summary Judgment on Plaintiffs Third Claim for Relief.. Document filed by Center For Science In The Public Interest, Food Animal Concerns Trust, Natural Resources Defense Council, Inc., Public Citizen, Inc., Union Of Concerned Scientists, Inc.. (Attachments: # 1 Exhibit A, # 2 Exhibit B, # 3 Exhibit C, # 4 Exhibit D, # 5 Exhibit E)(Bernard, Mitchell)

EXHIBIT D
TO THE DECLARATION OF MITCHELL S. BERNARD

Alpharma, LLC
400 Crossing Boulevard
Bndgewater, NJ 08807

ALPHARMA ®

908.429.6000

Animal Health

August 25, 2010

www.alpharma.com

2010 AUG 2b A 8 : 00

Division of Dockets Management Branch (HFA-305)
Food and Drug Administration
5630 Fishers Lane, rm. 1061
Rockville, MD 20852
Docket No. FDA-2010—D-0094; Draft Guidance For Industry #209 (GFI
#209): The Judicious Use of Medically Important Antimicrobial Drugs in
Food-Producing Animals
Alpharma, LLC, a sponsor of over 100 new animal drug applications
(NADA) and abbreviated new animal drug applications (ANADA) potentially
affected by the proposed policy, is pleased to submit these comments on the
draft GFI #209.
SUMMARY
The Center for Veterinary Medicine's Draft GFI #20summarizes current
concerns regarding feed and water approved uses in food producing animals in
the U.S. relative to resistance concerns for drugs used in both animals and
people, and the agency's current thinking based on cited references. While
Alpharma understands the general concern and concepts presented in this Draft
Guidance, we believe that several underlying assumptions put forward deserve
additional discussion and critical analysis. Much of the scientific underpinning is
based on a limited set of publications which assert some overly-broad and in
some cases unsupported definitions and assumptions. While Alpharma
recognizes CVM's intended direction based on public health concerns related to
medically important antimicrobial drugs, we also believe additional discussions,
critical reviews of the science and, in particular, specifics on drug categorization
are needed prior to any subsequent regulatory initiatives. For example, bacitracin
products have only topical uses in humans and no cross resistance issues
versus other antimicrobials used in humans. Thus, there is no need to change or
restrict existing bacitracin indications for use in animals. Other antimicrobials
used mostly for therapeutic reasons in animals (e.g. chlortetracycline,
oxytetracycline, procaine penicillin, and sulfonamides), while related to older
human-use agents, have already been extensively scrutinized for potential
resistance impacts using microbiologically-specific, data-driven risk
assessments, Guidance for Industry #152 (GFI #152) reviews, and have been
tracked for resistance by NARMS and other surveillance programs for over a
decade. We maintain approved uses of our products--which help to safely and
efficiently provide high quality, affordable meat, milk and eggs for a growing
world population-- are in fact in the interest of protecting and promoting public

Fon-oolg -oory

GFI #209 Comments
August 25, 2010
Page 2 of 12

health; i.e., these are judicious uses. Alpharma intends to actively coordinate and
cooperate with the agency in developing sound, science-based and fair
regulatory policies. That having been said, Alpharma notes this proposed broad
policy statement does not indicate the current approved growth promotion uses
of antibiotics are unsafe within the meaning of section 512(e) of the Federal
Food, Drug and Cosmetic Act.
Comments Pertaining to Specific Sections of Draft GFI #209:
Executive Summary
P3. "Misuse and overuse of antimicrobial drugs creates selective evolutionary
pressure that enables antimicrobial resistant bacteria to increase in numbers ....."
Virtually all antimicrobial uses can create direct selective pressure that
allows resistant subpopulations to survive and grow, not just under supposed
conditions of "misuse and overuse", which is not well defined in this document
(other than strongly implying growth promotion claims fall into this category). As
pointed out below, therapeutic as well as subtherapeutic dosing regimens can
select for resistant bacteria. Our ongoing reviews of published experimental
studies directly related to subtherapeutic uses show that relative to current U.S.
approvals, there are no imminent or serious public health concerns that warrant
banning or taking more stringent risk management actions.
II Introduction, P4. "..key scientific reports.. "
The references cited include U.S. governmental summaries along with
selected international and other expert reviews and reports. While the citation list
covers much of recent current thinking by some governmental and international
expert bodies, there are numerous additional expert scientific reviews and
scientific organizations who have similarly and extensively reviewed this subject
matter; for example, the Institute of Food Technologists expert report on this
topic (IFT, 2006). It's clear that not all relevant sources agree with the implicit and
explicit conclusions put forward in this Guidance. Several of the international
reports cited were often comprised of the same limited set of individuals and
came to similar conclusions and recommendations in regard to growth promotion
uses. WHO expert groups are not, however, beyond criticism. For example,
Oxman et al. (2007) in a Lancet article investigated WHO recommendation
processes and concluded:
"systematic reviews and concise summaries of findings are rarely used for
developing recommendations. Instead, processes usually rely on experts in a
particular specialty, rather than representatives of those who will have to live with
the recommendations or on experts in particular methodological areas".
Specific to animal antimicrobials, Phillips (2007) described similar difficulties and
biases in the EU growth promoter debates. The limitations inherent in the papers

GFI #209 Comments
August 25, 2010
Page 3 of 12

cited likely biased CVM's 'weight of evidence' finding toward a particular point of
view favoring overly-precautionary actions rather than regulations based strictly
on scientific evidence and likely to effect actual improvements in public health.
We submit the FDA should more thoroughly review the broader set of
literature available on this topic. We question whether a truly scientifically
objective, conclusive "weight of evidence" finding can be made using such a
limited subset of cited references. The term 'weight of evidence' itself, is
imprecise in that it does not rely on any comprehensive or standardized criteria.
According to Weed (2005):
"Several problems are identified: the frequent lack of definition of the term
"weight of evidence," multiple uses of the term and a lack of consensus about its
meaning, and the many different kinds of weights, both qualitative and
quantitative, which can be used in RA."
We propose CVM should include a more comprehensive set of
publications from different disciplines when finalizing this Guidance. Further, any
kind of 'weight of evidence' analysis should be based on some type of objective,
preferably quantitative methodology (e.g., a meta-analysis), explaining how
literature sources are included and how their conclusions are integrated.
Page 4—Footnote and FAQ Question 6. Antimicrobial resistance was defined
as:
"the ability of bacteria or other microbes to resist the effects of a drug.
Antimicrobial resistance, as it relates to bacterial organisms, occurs when
bacteria change in some way that reduces or eliminates the effectiveness
of drugs, chemicals, or other agents designed to treat bacterial infections".
FDA should define resistance in a more accurate way and differentiate a
measurement (resistance) from subsequent risk impacts (loss of effectiveness in
treating bacterial infections). Raw resistance data by itself does not automatically
correlate to loss of medical effectiveness. The scientific definition of antimicrobial
resistance is the ability of a microorganism to grow in the presence of a drug
concentration that is normally inhibitory. This is the result of an in vitro test.
Vegetative bacteria may under certain conditions survive exposures to normally
inhibitory drug concentrations. The stated "ability to resist effects of a given
drug" can be caused by inoculum density or other conditions that temporarily halt
or slow bacterial growth. For example, the ability to resist cell wall inhibitor
antibiotics can be the result of limiting nutrients or other conditions preventing
rapid cell growth. The draft GFI and FAQ's proposed definition of antimicrobial
resistance should therefore be changed..
Changes in bacterial susceptibility related to the broader concept of "loss
of effectiveness" which the agency is concerned about from a public health
perspective, are usually attributed to "acquired resistance" due to a genetic
mutation or acquisition of a resistance determinant resulting in the ability of a
specific pathogen to grow in the presence of higher, clinically relevant
concentrations of a given drug used for the treatment of that pathogen. The

GFI #209 Comments
August 25, 2010
Page 4 of 12

medical "loss of effectiveness" of a given drug is best assessed by medical
surveillance programs and quantitative risk assessments, not just resistance data
by itself.
III "Key Scientific Reports"
Pages 4-5- 1969 Swann Report
This report is over 40 years old and was specific to the U.K.. While
historically interesting, the conclusion that subtherapeutic feeding posed a
hazard to human health was based on rudimentary and incomplete knowledge.
For example, it is well known that people may ingest resistant bacteria from a
variety of sources, not just undercooked meat. We question whether the
subsequent restrictions on feed antimicrobials in the U.K. resulting from this
report actually yielded meaningful reductions in resistance impacting humans in
that country.
We would also point out this early report recognized antibiotics used to
enhance production work in part through control of microorganisms, stating
"animals kept under commercial conditions are held back from their potential
growth rates by micro-organisms in the environment, and that antibiotics
somehow reduce this restraint'. The Swann Committee rejected as a
generalization the allegation the growth effect is a compensation for "deficiencies
in method of husbandry'.
Additionally, the report identifies three criteria for feed (production claim)
antibiotics to be used without veterinary prescription: "(a) that the proposed
'feed' antibiotic would have little or no applications as a therapeutic agent, (b)
that the efficacy of other prescribed therapeutics would not be impaired through
the development of strains of pathogens resistant to the proposed 'feed'
antibiotic, and (c) that the proposed feed' antibiotic would be of economic value
in livestock production...". Zinc bacitracin is identified in this report as one
antibiotic which could satisfy these criteria. Subsequent to this report, numerous
papers have affirmed the overall safety and beneficial effects of bacitracin used
in food production (Butaye et al., 2003, Phillips, 1999).
1970 FDA Task Force
The 1970 FDA Task Force report likewise needs to be taken in context of
the time; there were numerous initial findings of plasmid-encoded resistance in
enteric bacteria. These were relatively new findings at the time, therefore
regulations requiring the intentional feeding of resistant Salmonella strains (21
CFR 558.15) and following the shedding with and without fed antimicrobials was
conducted. These were to demonstrate that the agents did not promote bacterial
drug resistance. In most cases, there were insignificant differences found
between medicated and control feeds. If anything, these studies can now be

GFI #209 Comments
August 25, 2010
Page 5 of 12

seen as early evidence that low-level uses did not impose any unique level of
selection impact; to the contrary there was little selection found overall and in
some cases there was reduced shedding of resistant bacteria.
Page 6- 1977 Ban Initiative for Penicillin and Tetracyclines
We continue to agree with the (> 30 year old) decision to conduct further
studies and hold in abeyance the implementation of blanket withdrawal actions
for penicillins and tetracyclines. Numerous published in vitro, in vivo and risk
analysis studies following this action have shown a lack of data linking any actual
harm to human health due to approved feed and water animal usage of these
antimicrobials. While this does not prove that hazards do not exist (as stated in
the 1980 NAS report), subsequent surveillance data on sentinel bacteria
(Alpharma Comments, 2010), and more recent risk assessments continue to
show that such risks are extremely low (possibly zero) for all animal uses
regardless of route of administration of penicillin and tetracycline under current
conditions (Cox et al., 2009, Cox & Popken, 2010).
Page 7- 198810M Report
This report used a risk-analysis model using Salmonella infections causing
deaths. The Committee was unable to find a substantial body of direct evidence
demonstrating that the subtherapeutic use of penicillin or tetracycline in animal
feed posed a human health hazard. We believe this Committee accurately
determined that both subtherapeutic and therapeutic use of antimicrobials can
select for resistant bacteria that may be potential hazards.
Page 7- 1997 WHO Report
This expert group stated "low level, long-term exposure to antimicrobials
may have greater selective potential than short-term, full-dose therapeutic use"
(italics added). This very general and qualified assertion used to bolster the
group's recommendations, was not, however, backed up by experimental studies
on relevant individual drugs. To the contrary, we can cite numerous peerreviewed papers showing feed and water uses of approved antimicrobials do not
select for problematic resistance resulting in loss of effectiveness in
contemporary human medicine.
Pages 8-13.
Several studies mentioned (1999 EC Report, 2000 WHO Report, 2003
FA0/01C/WHO Expert Workshop, 200310M Report, 2004 FA0/01E/WHO
Expert Workshop, 2004 GAO Report, 2005 Codex Code of Practice).
These reports had overall general recommendations to conduct additional
studies. We note the sole U.S. government report in this set (GAO, 2004) stated
that researchers disagree about the extent of the human health risk caused by
the passive transfer of antibiotic resistant bacteria to humans. The GAO

GFI #209 Comments
August 25, 2010
Page 6 of 12

recommended advancing the risk assessment process, which in fact was
followed by FDA, industry, and Codex. We note that 2004 Codex Code of
Practice further specified responsible use of growth promoting agents did not
include drugs belonging to classes of antimicrobials used in humans in the
absence of appropriate risk analysis. We submit both FDA and industry have so
far successfully engaged and expanded the use of risk assessment approaches
for currently used subtherapeutic antimicrobials.
Additionally, Alpharma actively participates in and supports the efforts of
the Codex Ad Hoc Intergovernmental Task Force on Antimicrobial Resistance to
develop guidelines for risk analysis for minimization and containment of
foodborne antimicrobial resistant micro-organisms and resistance determinants
to protect consumers' health and ensure fair practices in food trade at the
national/regional level. While not intended for veterinary product registration
purposes, any FDA policies or regulations should take into account the principles
contained this Codex document, when adopted.
Pages 13-15.
IV. Strategies for Controlling Antimicrobial Resistance Are Needed
An important statement is made in this section that based on the previous
information presented in the Guidance: "FDA has reviewed the
recommendations provided by the various published reports and, based on this
review, believes the overall weight of evidence available to date supports the
conclusion that using medically important antimicrobial drugs for production
purposes is not in the interest of protecting and promoting the public health".
We noted in earlier comments for sections I and II that it's unlikely a truly
conclusive "weight of evidence" finding can be made using such a limited subset
of cited references; we therefore question it. We refer the authors of this
Guidance and statement to a contemporary article published in CVM Veterinarian
(Sechen, 2006), which summarized in detail how production animal health needs
are met while also protecting the public health. Providing high quality, affordable
protein in the form of meat, milk and eggs for a growing world population we
submit is in fact in the interest of protecting and promoting public health.
V. Current Regulatory Framework
We generally concur with this section, which describes the GFI#152
qualitative risk assessment paradigm. We also note the inherent limitations of
only using a qualitative process. We agree risk-related concerns associated with
approved NADAs can sometimes be better addressed through informal
processes and dialog with sponsors. We would, however, point out GFI #152 is
better suited to pre-approval evaluation of new antimicrobials than to assessing
the microbial safety of antimicrobials which have been used for decades in
animal feed or water and for which resistance rates and patterns remain stable.

GFI #209 Comments
August 25, 2010
Page 7 of 12

Page 1
,5-

VI. Status of FDA's Current Activities

We generally concur with statements in this section. We agree the
scientific understanding regarding antimicrobial resistance has advanced
significantly over time, and while some expert groups and governments have
raised public health concerns, it is also true the discipline of quantitative risk
assessment homing in on specific microbes and relevant drugs has also
advanced. Potential new regulatory initiatives should realize solely concern­
driven risk management has a high potential for unanticipated consequences; for
example, some EU countries which unilaterally banned production agents, even
those having "non important" or "low-level important" categorizations, ended up
using higher percentages and amounts of "highly important" and "critically
important" agents with potentially greater resistance risk to humans than those
banned .
The following figure shows an example of this for Denmark, subsequent to the
ban on growth promotion uses of antimicrobia'ls:

80 ,--------------------------------------------------------,
A.GP BANS
IMPLEME~_JTED

60

~
...

+--+-----~---------.----

0

.~

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ii

20

o
1990

200e

2002

2004

20m

20CO

-

- Ncnimportant.'lmpo1ant • Highly Im30rtant _ Critically Important

Changes in the amounts and types of antimicrobials used in food-producing animals in Denmark(DANMAP,
2008). Arrows show years where bans of growth promoters were implemented. Antimicrobials were grouped
as categOrized for their importance to human medicine by FAOMlHO/OIE (2007): "Critically Important:
G/ycopeptides, avi/amycin, penicillins, aminoglycosides, streptogramins, macrolides, fluoroquinolones and
cepha/osporinslother penicillins. Highly Important: TetraCYClines and sulfonamides. NonimportantJlmportant:
Flavofosfolipol, quinoxalines, coccidiostats and bacitracin".

GFI #209 Comments
August 25, 2010
Page 8 of 12

There have been no demonstrable improvements in human health or resistance
rates in major food borne pathogens in the EU following these AGP bans, and
there were notable deleterious effects on animal health. Moreover, the
prevalence of some foodborne bacteria such as Campylobacter increased after
bans were implemented across the EU. As summarized by Phillips (2007), "The
relentless increase in the prevalence of human campylobacteriosis in the EU is
so far unexplained, but we are not aware of any effort to investigate its potential
relationship to the cessation of use of growth-promoting antibiotics".
VII. Recommended Principles Regarding Judicious Use in Animals.
We agree with the statement: "The continued availability of effective
antimicrobial drugs is critically important for combating infectious disease
in both humans and animals. This Includes the continued availability of
feed and water uses of such drugs for managing disease in animal
agriculture". We also recognize that FDA believes additional steps are needed
in the area of judicious use guidance.
Pages 16-17. Commenting on the first stated Principle:
The use of medically important antimicrobial drugs in food-producing animals
should be limited to those uses that are considered necessary for assuring
animal health.
We believe this statement of principle needs to be addressed and mainly
accomplished by consulting expert sources in the field of veterinary
pharmacology, epidemiology, animal production science, and related agricultural
fields not just the cited sources or other individuals/organizations who believe
they can accurately estimate this parameter. The term "medically important"
needs to be further refined. Many categorization schemes have been developed
by expert groups, FDA and other countries. We submit that drugs having only
nominal human use should warrant less regulatory restrictions.
As a prime example, the narrow-spectrum peptide antibiotic bacitracin is
only used topically in humans and has been extensively documented as having
no important residues, resistance or cross-resistance impacts on pathogens
(Butaye et al., 2003, Jones, 2001, Jones, et al., 2006, Phillips, 1999). Though the
2007 WHO expert group had placed bacitracin into an 'Important' category based
on its limited topical human usage, bacitracin zinc or bacitracin methylene
disalicyclate products for feed use clearly warrant lower priority when considering
regulation of approved animal therapeutic or growth promotion uses. Indeed GFI
#152 in 2003 did not even list ionophores or bacitracin in the Appendix A list of
compounds of human medical importance, based on the collaborative expert
(CDER) review. Furthermore, bacitracin has subsequently been removed from
the NARMS surveillance drug testing panels for enterococci to allow space for
other drugs that are of greater human medical relevance. Medical experts in
infectious disease confirm since the bacitracin peptide is highly nephrotoxic when
injected, its human medical importance is inherently very minor (Jones, 2001,

GFI #209 Comments
August 25, 2010
Page 9 of 12

attached). We therefore submit bacitracin feed and water products as prime
examples of agents that should continue to be allowed as production
improvement tools in U.S. animal agriculture.
For several other older drug classes which are listed in GFI #152 (ag.,
natural penicillins, tetracyclines and sulfas), while they are still used in human
medicine thus medically important, in many cases are no longer preferred drugs
for human infection and have been shown by quantitative risk analyses to pose
extremely limited microbiological resistance risks (Cox et al., 2009, Cox &
Popken, 2010). Current NARMS data moreover shows resistance and multiresistance 11+ year patterns to be low, stable and even declining among human
Salmonella isolates (Alpharma Comments, 2010, attached). These facts plus a
long background of safe usage after over 5 decades in food-producing animals
should provide the proper context when proposing new policies or regulations for
feed and water applications of these agents.
We firmly agree with the statement "...FDA believes some prevention
indications are necessary and judicious". Judicious uses of feed and water
agents for prevention and control have long been recognized as appropriate tools
for keeping populations of domestic livestock and poultry healthy and thriving.
We believe there is good evidence that the five criteria specified in this section
have been addressed by numerous studies submitted to CVM, as well as in
published literature.
On page 17, a second Principle is stated: "The use of medically important
antimicrobial drugs in food-producing animals should be limited to those uses
that include veterinary oversight or consultation."
While many situations already involve such oversight, we believe label
indications have historically been safely and effectively used by responsible
parties. The shortage of veterinarians specializing in food production agriculture,
along with geographic distances and climates across our continent-spanning
nation suggests that reasonable accommodations on this principle could and
should be made. We are not aware of any recent cases of mis-application or
misuse of most feed and water products by farmers, ranchers, or animal nutrition
professionals resulting in problematic resistance outbreaks or residue violations.
Most of the violations involving residues are related to therapeutic
administrations. We note other uses of antimicrobials (e.g., antibacterial soaps,
some pet medications and fruit crop uses) often do not involve such oversight or
consultation. We question whether the paperwork, costs and administrative
burden of such requirements are justified given the extremely low-level risks
associated with mostly older-generation approved feed and water products being
reviewed in this Guidance.
VIII. Conclusion
Alpharma agrees with and supports FDA's commitment to working with
animal drug sponsors, the veterinary and public health communities, the animal
agriculture community and other interested stakeholders in developing a strategy

GFI #209 Comments
August 25, 2010
Page 10 of 12

to address resistance concerns in a manner protective of both human and animal
health. We believe reserving the formal regulatory authority for cases presenting
actual public health threats is the best policy. These can be better defined
through comprehensive and, wherever possible, quantitative risk assessments
and reviewing surveillance program findings. Working with drug sponsors and
professionals in the industry will help enable FDA to accomplish its mission of
minimizing adverse resistance impacts on animal and human health without
seriously disrupting U.S. animal agriculture.
Sincerely,

Sondra C. Flick
Director, Government & Industry Affairs

GFI #209 Comments
August 25, 2010
Page 11 of 12

REFERENCES
Alpharma, Inc. 2010. Comments to the 2010 NARMS Scientific Meeting
(attached).
Butaye P, Devriese LA, Haesebrouck F. 2003. Antimicrobial growth promoters
used in animal feed: effects of less well known antibiotics on gram-positive
bacteria. Clinical Microbiology Reviews 16(2):175-188
Cox, LA, Popken, DA, Mathers, JJ. 2009. Human health risk assessment of
penicillin/aminopenicillin resistance in enterococci due to penicillin use in food
animals. Risk Analysis 29(6):796-805.
Cox, LA, Popken, DA. 2010. Assessing potential human health hazards and
benefits from subtherapeutic antibiotics in the United States: tetracyclines as a
case study. Risk Analysis 30(3):432-457.
DANMAP, 2008. The Danish integrated antimicrobial resistance monitoring and
research programme. Report for 2008. www.danmap.orq
FAO/WHO/01E. 2007. Report of the joint FAO/WHO/01E meeting on critically
important antimicrobials.
www.who.int/foodborne disease/resources/Report%20ioint%2OCIA%20Meetinq.
pc1f)
1FT. 2006. Antimicrobial Resistance: Implications for the Food System
Comprehensive Reviews in Food Science and Food Safety 5(3) 71 - 137
Published Online: 2 Aug 2006
http://www.ift.oro/Knowledoe-Center/Read-IFT-Publications/ScienceReports/Expert-Reports/AntimicrobialResistance/-/media/Knowledqe/020Center/Science%20Reports/Expert/020Repo
rts/Antimicrobial%20Resistance/AntimicrobialResistance ExpertReport Full htm
Jones, RN. 2001. Human clinic role of bacitracin injectable in the USA. Letter,
June 28, 2001. The Jones Group, N. Liberty, IA, pp. 1-2.
Jones, RN et al. 2006. Contemporary antimicrobial activity of triple antibiotic
ointment. Diag. Microbiol. Infect. Dis. 54:63-71.
Oxman, AD, Levis, JN, Fretheim, A. 2007. Use of evidence in WHO
recommendations. The Lancet. Published online May 9, 2007.
DOI:10.1016/50140-6736(07)60676-X.
Phillips, I. 2007. Withdrawal of growth-promoting antibiotics in Europe and its
effects in relation to human health. Int. J. Antimicrob. Agents 30:101-107.

GFI #209 Comments
August 25, 2010
Page 12 of 12

Phillips, I. 1999. The use of bacitracin as a growth promoter in animals produces
no risk to human health. J. Antimicrob. Chemother. 44:725-728.
Sechen, S. 2006 The review of animal production drugs by FDA. FDA
Veterinarian 21(1) 8-11
http //www.fda ciov/downloads/AnimalVeterinary/NewsEvents/FDAVeterinarianNe
wsletter/UCM055697.pdf
Weed, DL. 2005. Weight of evidence: A review of concept and methods. Risk
Analysis 25(6):1545-.

Alpharma, LLC
400 Crossing Boulevard
Bridgewater, NJ 08807

ALPHARMA®
Animal Health

908.429.6000
www.alpharma.com

A Brief Review of U.S. NARMS Data Pertaining to
Relevant Feed and Water Antimicrobials used in Animal Agriculture
July 2, 2010
Alpharma, LLC, manufacturer and distributor of medicated feed and water
additives in the U.S. and worldwide, appreciates the opportunity to comment on
the U.S. National Antimicrobial Resistance Monitoring System (NARMS)
programs and data.
The primary stated objectives of NARMS include:
•

To provide descriptive data on the extent and temporal trends of
antimicrobial drug susceptibility in Salmonella and other enteric bacterial
organisms from human and animal populations, as well as retail meats.

•

To facilitate the identification of antimicrobial drug resistance in humans,
animals, and retail meats as it arises;

•

To provide timely information to veterinarians and physicians on
antimicrobial drug resistance patterns. (FDA NARMS, 2010)

Another goal of these activities is to have data available that will serve to help
inform national policy aimed at prolonging the lifespan of approved drugs by
promoting prudent and judicious use of antimicrobial drugs and to identify areas
needing more detailed investigation. The NARMS program is also an important
post-approval monitoring program for approved antimicrobials used in human
and animal sectors. The following review used data available from the most
recent NARMS annual reports from all three program arms. The review
emphasized trends and contrasts for multi-drug and single resistances among
older classes of antimicrobials relevant to feed and water uses in food-producing
animals.

Alpharma Comments
July 2, 1010
Page 2 of 13

Human NARMS Multidrud Resistance
For 2007 (most recent year having a final summarized report), 18.9%
(406/2144) of non-typhoidal Salmonella isolates from human clinical cases were
resistant to one or more CLSI antimicrobial classes (81.1% were therefore pansusceptible). Multidrug resistance is described in the NARMS program by both
number of antimicrobial classes and also by specific co-resistant phenotypes.
The penta-resistant ACSSuT phenotype (acronym for ampicillin,
chloramphenicol, streptomycin, sulfonamide, tetracycline co-linked resistance
markers), is commonly found among several Gram-negative bacterial types
including Salmonella and E. colt Of 239 non-typhoidal Salmonella resistant to
three or more classes, most were Salmonella Typhimurium (57.7%) serotype.
Some interesting observations on the individual drug resistances are also
discussed relative to hypotheses about antibiotics use in agriculture. From the
CDC 2007 report, the following highlights were reported:
• 6.3% (136/2144) of non-typhoidal Salmonella isolates had the pentaresistant
ACSSuT pattern.
• 1.7% (19/1100) of Campylobacter had resistance to three or more antibiotic
classes. None were reported with pentaresistance patterns.
• 2.1% (4/190) of E. colt 0157 isolates were resistant to three or more classes,
0.5% to five or more, and none (0%) were found with an ACSSuT phenotype.
• 33.2% (160/482) of Shigella isolates were resistant to three or more classes
and 3.7% (18/482) possessed the ACSSuT phenotype. (Note: Shigella only has
a human colonizing reservoir).

Trends: Figure 1 was taken directly from page 18 of the 2007 CDC NARMS
Summary Report. Overall, multidrug resistance patterns have shown an 11 year
downtrend since 1996.

2

3

Alpharma Comments
July2,1010
Page 3 of 13

Figure 1.07: Proportion of non-typhoidal Salmonella isolates resistant to 3 or more antimicrobial classes, by year,
1996-2007.
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Figure 1. Human NARMS overall multi drug resistance trend for Salmonella.

Comparison of Multi-Drug Resistant Salmonella from USDAIFSIS Slaughter,
FDA Retail, and CDC Human Clinical Sources
Non-Typhi Salmonella multiple drug resistance was compared by plotting
the weighted average resistance of four food-producing animal species
associated with USDA NARMS (FSIS slaughter carcass rinsates), along with the
resistance prevalence for all FDA retail meat and CDC human strains reported
through 2007 (Figure 2). The CDC human isolates have shown an 11-year
downtrend, with the USDA and FDA sets showing stable or declining patterns

4

Alpharma Comments

July2, 1010
Page 4 of 13

since 2000 and 2002, respectively. The overall multidrug resistance prevalence
levels are lower than 10%.

non-Typhi Salmonella , All ACSSuT Resistant Types

40 ~------------------------------------------------------,

30

a::
~
0

20

10

..

••

_ _ • _ _ ; . ' . .. -

, , , , . .. . - - .

:-~ : -_ " ~ ~ : - ­ - -

-

0
1996

, . .. . ;

_ • _ . 'T - ­

-tl

, 0 - , . - - 0 - . - - ' -0 ­ - - • - <l

1998

2000

2002

2004

2006

2008

Year

1
-...-

CDC (human) . - -. - - - USDA (weighted average) - - - 0 - - - FDA

~I r~tail) J

Figure 2. Overall multi-drug resistance trends as reported by three arms of the NARMS
program.

For animal carcass-sourced multi-drug resistant types (as measured by
the USDA NARMS program from associated slaughter carcasses) , there are
distinctive levels of resistance associated with animal species, with cattle and
swine recently having somewhat higher proportions of ACSSuT types . In Figure
3, the legend also lists the top 2 Salmonella serotypes in 2007 for each species.
It is known that different colonizing serotypes possess varying stable MDR
phenotypes , or alternatively virtually no resistance. An example from human

5

Alpharma Comments
July 2,1010
Page 5 of 13

source Salmonella; the second most prevalent non-Typhi Salmonella found in
human clinical cases (ser. Enteritidis) by NARMS has essentially no multiple drug
resistance, and very low single resistance levels yet has remained an important
disease causing pathogen in people.

non-Typhi Salmonella, ACSSuT Resistant

o
40
30 1 - - - - - - - - - - - - - - - - - - - - - - - - - - ­

a:: 20 -

- ' -'­- a

~
0

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10 .

.

0
1996

....-. . ,..

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.

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0

2000

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2002

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2004

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2006

2008

_.. - . . Cattle (Newport,Dublin)

. . -. ' .. Swine (Typhimurium . Agona)

. , .•. .. Turkey (Agona, Typhim urium)

.. · e· - - Chicken (Kentucky. Heidelberg)

----..- Human (Typhimurium . Newport)

-0-­

Retail Meat (Sefienberg. Typhimurium)

Figure 3. Specific animal-associated carcass isolate ACSSuT resistance prevalence
levels, as reported by USDA NARMS relative to CDC (human) and FDA (retail meat)
levels. Top two serotypes associated with MDR phenotypes in parentheses.

Other Enterics with Pentaresistant (ACSSuT) and MDR Phenotypes Reported by
NARMS
Campylobacter jejuni, although an important foodborne pathogen,
demonstrates relatively low levels of multi-drug resistance. The USDA NARMS
carcass C. jejuni showed <15% and CDC showed <3% resistance to three or

Alpharma Comments
July 2, 1010
Page 6 of 13

6

more drugs. Althougn non-Typhi Salmonella serovars can colonize animals and
thus serve as reservoirs for human infection, other enterics such as Shigella and
Salmonella Typhi only have known natural reservoirs in humans and other
primates (Tauxe, 2002). Salmonella Typhi causes typhoid fever and Shigella
spp. shigellosis; both acute human enteric diseases. Athough present at less
than 15% of total, the ACSSuT phenotype in both bacteria have been
consistently detected since 1998 from human clinical cases . The prevalence
levels of these phenotypes have been greater than for E. coli 0157: H7 (rare)
which may be carried in livestock (Figure 4), also greater than from generic E.
coli isolated from humans and chickens in CDC and USDA pilot projects . These
observations raise questions as to whether humans rather than food -producing
animals could be the most important reservoirs and/or sources of multi-drug
resistance determinants.

Other Enterics: ACSSuT Resistant Types
40 , - - - - - - -- - - - - -- - - -- - - - - -- - - - - -- - - -- - - - - -- - - - - -- - - -- - - .

30
0:::

~

20 +-- -- -- -- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -- - - -- -- - - - - -- -1

10 1 - - - - - -...-­
-

o

~------.---~--,_--~~~--~~~~~~~~~~----~

1996

1998

2000

2002

2004

2006

2008

Year
- - - ­ Salmonella Typhi

~

- ­ E.coli0157(CDC)

... ;(. .. E. coli (chicken)

Shigella

. . .. . .. E.coli (CDC Pilot)

-I

- - - ­ C. jejuni (>3 classes)

Fi gure 4. Pentaresistance (AC SSuT) trends for enterics other than nontyphoidal
Salmonella.

Alpharma Comments
July 2, 1010
Page 7 of 13

A popular hypothesis has been that commensal bacterial selected by
antimicrobials could be driving multi-drug resistance among foodborne
pathogens. The disparate animal and human resistance levels and trends
measured by the NARMS program, however, offer very limited empirical data
supporting this hypothesis.
Are older antimicrobials used in agriculture driving resistance in food-producing
animals and humans?
This question is one that NARMS can help answer, since single as well as
multiple drug resistance to relevant classes have been measured since 1996 and
1997 in both humans and from animal-associated carcass sources. Some
evidence can be found by looking at the prevalence trends, and also reviewing
which drug classes are/are not used in animal feeds and water. Figure 5 shows
the single-resistance trends for animal-associated slaughter types (USDA
NARMS) and human (CDC NARMS), for the older drugs streptomycin, ampicillin,
sulfonamide and tetracycline.
The resistance lines show slightly declining 11-year human-source trends
for all four antibiotic classes, with overall stable resistance levels for animalassociated slaughter (weighted averages shown). The average resistance levels
are plotted in the next graph (Figure 6) that for all four classes, human resistance
prevalence levels are essentially the same. Animal carcass-associated (USDA),
while showing relatively high tetracycline resistance also reveals there is also
significant resistance to streptomycin at a level higher than for ampicillin or sulfa.

7

8

Alpharma Comments
July2, 1010
Page8of13

non-Typhi Salmonella, Single- Drug Resistance
50 , - - - - ---------------------- - - -------------------------,

10

f - -- - -

o.

,
f - --

1996

- --

- - - - - - - - - - - - - - , - - - - - - - - - - - - - - - - - - - - - - - - ; - - - - - - '

1998

2000

20-=_______0
-,- 02
2 _04
2006
.. -. - - - CDC-Slr
_.. • - . - CDC-Amp
--<>-- USDA-Tel
... • - . - CDC-Tel
--+- US DA-Sulfa
. . . - - - CDC-Sulfa

2008

- - f : r - USDA-SIr
- 0 - - USDA-Amp

---

U

J

----

Figure 5. Single-drug resistance among carcass slaughter (USDA) and human source
(CDC) Salmonella as reported by NARMS.

Penicillin and su'lfas have some feed and water approved uses in U.S.
food producing animals, but at relatively low total volumes « 6.5 % of total for
both classes combined) in comparison to all antimicrobials sold each year
according to AHI sales statistics (AHI, 2007). Streptomycin, however, is only
used for mammary infusions and some injectable treatments for leptospirosis;
essentially having no feed or water approved uses. Among related
aminoglycosides (kanamycin, gentamycin and neomycin) there are some uses of
neomycin in livestock and poultry. All aminoglycosides make up < 0.8% of all
antimicrobials sold, however (AHI, 2007). The enteric bacterial exposure to these
antibiotics would thus be expected to be extremely low for streptomycin relative
to others. If drugs associated with oral administrations in agriculture were forcing
significant resistance levels among enteric Salmonella, we would predict
relatively low streptomycin resistance and a correlation among single-drug
resistances among Salmonella according to the relative amounts sold or used

9

Alpharma Comments
Ju'l y2,1010
Page 9 of 13

among classes used in feed and water mostly for disease prevention, control, or
therapy.

100

r-----------------------------------------------------,

80

- - - - - -.-

60

40

20

o
Streptomycin- NO oral
use

Penicillins(ampicillin)
LOW use
r---.­

Tetracyclines-HIGHER
use

Sulfa- lOW use

--­ --­

• USDA (11 Year A"9.) 0 CDC (11-year A"9.)

Figure 6. Lack of correlation of older antibiotic single-drug resistance levels and relative
amounts used in animal agriculture. Error bars, 95% confidence limits of prevalence
levels.

Except perhaps for some possible selection effects from tetracycline in
USDA (remembering that major colonizing serotypes heavily influence resistance
patterns and tetracycline being the most common resistance type), Figures 5 and
6 illustrate how little correlation there is between relative animal usage versus
single-drug resistance and 11-year trends in human (CDC) isolates.
Among the entire set of human clinical isolates reported by NARMS,
single resistance among older drugs are uniformly low and shows declining
trends over the 11 year period (Fig. 5). Salmonella and other enterics in people
likely have significant non-food animal reservoirs, but importantly the total
volumes used in food-producing animals are not good predictors of human
clinical resistance, when measured by isolates from associated slaughter animals

Alpharma Comments
July 2, 1010
Page 10 of 13

10

or from people. Another indication of this can be seen by looking at resistance
patterns for E. coli 0157 (Figure 4), which may be carried in livestock but which
still demonstrate very low resistance to single drugs, and virtually no
multiresistance despite potentially greater exposure to antimicrobials.
Another example of non-correlation with use, is chloramphenicol
resistance (the "C" of the ACSSuT phenotype), a commonly detected single and
multiple-associated resistance in many bacteria (6-10% prevalence level among
human NARMS Salmonella). This class is not approved for use in animal feeds
or water, however. If total agricultural use volumes were correlated with
resistance, one would predict this marker to have a very low prevalence among
sentinel bacteria such as those tracked in the NARMS program. This is shown to
not be the case.
NARMS Data and `PAMTA' Bills

To highlight the need for verifiable scientific information informing public
policy, House Bill H.R. 1549 (questionably titled "Preservation of Antibiotics for
Medical Treatment Act of 2009"), for example contains many scientifically
erroneous statements and assertions regarding antimicrobials used in foodproducing animals relative to human diseases, such as:
"An estimated 70 percent of the antibiotics and other antimicrobial drugs used in
the United States are fed to farm animals for nontherapeutic purposes, including
0 growth promotion; and ii) compensation for crowded, unsanitary, and stressful
farming and transportation conditions; ..."
The "70% nontherapeutic" and broad-brush value judgments on crowding
and sanitation conditions originate from non-peer reviewed advocacy group
sources that have overstated the total volumes of relevant antimicrobials (AVMA,
2009). Similarly, a Consumer Reports article, a 2001 editorial opinion in a
medical journal and similar "references" were used as the basis of the bill. After
mentioning specifically tetracyclines, macrolides, aminoglycosides, penicillins,
sulfonamides and others, the bill further states:

Alpharma Comments
July 2, 1010
Page 11 of 13

11

"these drugs are used in people to treat serious diseases such as scarlet fever,
rheumatic fever, venereal disease, skin infections, and even pandemics like
malaria and plague, as well as bioterrorism agents like smallpox and anthrax."
Several of the diseases specified in this bill (scarlet fever, rheumatic fever,
malaria, plague) are older (in some cases obsolete) diseases that have become
rare in the past 170 years in the United States (Quinn, 1989). Penicillin (either
oral penicillin V or injectable benzathine penicillin) remains the agent of choice for
preventing rheumatic and scarlet fever, because it is cost effective, has a narrow
spectrum of activity, has long-standing proven efficacy against pharyngeal
diseases, and group A streptococci resistant to penicillin have not been
documented (Dajani et al. 1995). Various macrolides, oral cephalosporins, and
other P-lactam agents are acceptable alternatives for rheumatic and scarlet
fevers, particularly in penicillin-allergic individuals, with no or very low resistances
reported for any of these older drugs.
Venereal diseases, skin diseases and anthrax are not foodborne
infections, malaria is a parasitic disease and smallpox is a virus that has been
eradicated worldwide (Henderson, 1980)—being a virus no animal feed related
antibiotic could treat it even if it were somehow resurrected as a bioterror agent.
These diseases were apparently listed in the bill either due to inadequate
literature review or perhaps for the ominous sounding impact achieved by listing
them. The list of diseases in H.R. 1549 is certainly not an accurate or realistic
representation of public health impacts that could be related to the targeted
drugs' resistance.
In contrast, data from NARMS show single resistance and multi-drug
resistance prevalence levels and 11-year trends among potentially relevant
foodborne bacteria remain low, stable, and even declining among human sentinel
and indicator isolates from 1996-2007. The actual data thus run contrary to
erroneous assertions made by advocacy groups and drafted into scientifically
misinformed legislative bills focusing on agricultural antibiotics uses. In addition
to this review's focus on NARMS data, microbiology-specific quantitative risk

Alpharma Comments
July 2, 1010
Page 12 of 13

assessments have been published in scientific journals and by governmental
sources for streptogramin, macrolide, penicillin and tetracycline classes; all
showing vanishingly low levels of potential resistance impacts.

Alpharma, LLC, as a responsible manufacturer and marketer of
antimicrobial products remains concerned about antimicrobial resistance.
Alpharma therefore supports continuing and improving the U.S. NARMS
surveillance programs as a source of relevant, timely, and science-based
antimicrobial resistance data.

Jeremy J. Mathers, MS, PhD
Senior Manager, Product Support-Microbiologist

12

Alpharma Comments
July 2, 1010
Page 13 of 13

13

References
USDA NARMS
http://www.ars.usda.gov/Main/docs.htm?docid=14491
FDA NARMS
http://wwwfda.qov/AnimalVeterinary/SafetyHealth/AntimicrobialResistance/Natio
nalAntimicrobialResistanceMonitoringSystem/default.htm
CDC NARMS
http://www.cdc.qov/narms/
2007 Annual Survey. Active Antibacterial Ingredients Sold by AHI Members:
http://www.ahi.org/files/Media%20Center/Antibiotic%20Use%202007.pdf
Tauxe RV. 2002. Emerging foodborne pathogens. Int. J. Food Microbiol 78:31.
Quinn, RW. 1989. Comprehensive review of morbidity and mortality trends for
rheumatic fever, streptococcal disease, and scarlet fever: The decline of
rheumatic fever. Rev. Infect. Dis. 11(6): 928.
Dajani, A. et al. 1995 (Oct.). Treatment of acute streptococcal pharyngitis and
prevention of rheumatic fever: A statement for health professionals
Pediatrics 96(4),758-764
http://pediatrics aappublications.orq/cqi/content/abstract/96/4/758
Henderson, DA. 1980. Smallpox eradication. Public Health Reports 95(5):422.
AVMA. 2009. Frequently Asked Questions about
Antimicrobial Use and Antimicrobial Resistance
http://www.avma.org/public health/antimicrobial use.asp

RR

DATE: June 28, 2001
TO:

The JONES Group, Inc.*
345 Seaver Kreek Centre, Suite A
North Liberty, Iowa 52317
Phone: [phone]
Fax: [phone]'

Eddy Piron
011-32-328-7! 8
41111.01
FROM: Ronald N. Jo
Director,
ratones
Professor o
cuic
Tuft's Univ. Se col of Medicine
RE:

Human Clinic Role of Bacitracin
Injectable in the USA

In response to your questions about the current use of Bacitracin for systemic
therapy in the United States, I doubt that this product ever will be used for the indication
listed in the approved package insert (PI). This compound by systemic mute is extremely
toxic as clearly outlined in the PI and numerous alternative agents of greater potency and
spectrum are available that carry more acceptable rates of toxic side effects. To my
knowledge in nearly 30 years of laboratory medicine and infectious disease practice, we
have never considered the use of this product for systemic use.
A query of the most recent edition (21 3t) of the USP-Drug Information publication
fails to show Bacitracin systemic in the "Advice of the Patient" volume. This agent only
appears in the "Dtug Information" volume (USP-DI, 2001, 20 edition) in the "Orphan
Product" list (page 3164) as an off-label treatment of antibiotic-associated enterocolitis.
This indication also seems to be of very limited value following preferred regimens with
vancomycin and/or metronidazole. This listing in the USP "Orphan Products" dates from
1984.
Furthermore, as the ehanhoider of the NCCLS Antimicre/oial Susceptibility Test
Subcommittee in the 1980's. I presided over the withdrawal of Bacitracin and other
topically used antimicrobials from the national standard methods. At that time (as now)
no significant use as systemic agents (toxic) was documented, and the reporting of in
vitro test results were not relevant to drug selection in human practice. In fact, current
national and international antimicrobial resistance surveillance programs (SENTRY,
Alexander, PROTEKT, MYSTIC, etc.) do not routinely monitor these agents because of
their limited or nil use in human medicine as systemic agents.

If I can be of assistance in this matter to a greater degree, please contact me at the
numbers on this letterhead. With best regards.
/Idm
Attachment: USP-DI Table (1)

Editorial Office for Diagnostic Microbiology and Infectious Disease
'Affiliated with The Jones Microbiology Institute ("Build it and they will

come")

•

3164..

Approved Drug Products with Tberapetuic Equivalence Evaluations -

LISP DI

USP DI

CUMULATIVE LIST OF ORPHAN'PRODUCT
DESIGNATIONS AND APPROVALS Nontiqueio
NAME
Gantmachanical
7W = Trade Name

INDICATION DESIGNATED

•

SPONSOR AND ADDRESS

= Marketing Approval

ARSENIC TRIOXIDE •

- TREATMENT OF ACUTE PROMYELOCYTIC LEUKEMIA.
NEW YORK, NY -• PHONE: [phone]
DO 03/03/1998

ARTESUNATE

TREATMENT OF MALARIA.

WORLD HEALTH ORGANISATION
SWITZERLAND CH
PHONE [phone]
DD OV19/1999

NAME

Gem
TN

EIA SILL

TN= Si

BECLC
DIPF

ATOVADUONE—
TN= MEPRON

TREATMENT OF AIDS ASSOCIATED PNEUMOCYSTIS CARINII
PNEUMONIA.

GLAXO WELLCOME INC.
RESEARCH TRIANGLE PARK, NC
PHONE [phone]

ATOVAOUONEm
TN= MEPRON

PREVENTION OF PNEUMOCYSTIS CARINII PNEUMONIA (PCP) IN
HIGH- RISK HIV-INFECTED PATIENTS DEFINED BY A HISTORY OF
ONE OR MORE EPISODES OF PCP AND/OR A PERIPHERAL C044.
(14 HELPERANDUCER) LYMPHOCYTE COUNT LESS THAN OR
EQUAL TO 200/11M3.

GLAXO WELLCOME RESEARCH AND
- DEVELOPMENT
RESEARCH TRIANGLE PARK NC
-PHONE [phone]
DD OS/14/1991

ATOVAOUONE
TN= MEPRON

TREATMENT AND SUPPRESSION OF TOXOPLASMA GONDII ENCEPHALITIS.

GLAXO WELLCOME INC.
RESEARCH TRIANGLE PARK, NC
PHONE: [phone]

ATOVAOUONE
TN= MEPRON

PRIMARY PROPHYLAXIS OF HIV-INFECTED PERSONSAT HIGH RISK FOR DEVELOPING TOXOPLASMA GONDII ENCEPHALITIS.

MAXI) WELLCOME INC.
RESEARCH TRIANGLE PARK. NC
PHONE: [phone]
DD 03/16/1993

AUTOLOGOUS DNP- CONJUGATED TUMOR
VACCINE
TN= hfrVAN

FOR ADJUVANT THERAPY IN MELANOMA PATIENTS WITH SURGICALLY RESECTABLE LYMPH NODE METASTASIS (STAGE III AND
LIMITED STAGE IV DISEASE).

AVAX TECHNOLOGIES, INC.
KANSAS CITY, MO
PHONE: [phone]

AUTOLYMPHOCYTE THERAPy

TREATMENT OF RENAL CELL CAROINOMA.

CYTOGEN CORPORATION
PRINCETON, NJ
PHONE [phone]
DD 07/12/1994

BEIRA
TNINT

.•

BENZC
PHE
TN= L

BENZ'
NYE
TN= BENZ'
BEI.
BEI
TN= z
SERA
TN=
NT
SUC
SERA
TN=
NT
Su

SU

AZATHIOPRINE
TN= IMURAN

TREATMENT OF ORAL MANIFESTATIONS OF GRAFT-VERSUSHOST DISEASE.

ORAL SOLUTIONS. INC.
NEW YORK, NY
PHONE: [phone]
DD 09/14/1999

SEW-

912036-PEG
TN= TROVERT

TREATMENT OF ACROMEGALY.

BET%
TN=

BACITRACIN
1/4= ALTRACIN

,• • ;
TREATMENT OF ANTIBIOTIC-ASSOCIATED PSEUDOMEMBRANOUS
• .. ENTEROCOUTS CAUSED BY TOXINS A AND 8 ELABORATED BY
CLOSTRIDIUM DIFFICILE
-

SENSUS CORPORATION
AUSTIN, TX
PHONE 5'2)47802712
DD 06/24/7997
A. L LABORATORIES, INC.
FORT LEE, NJ
PHONE: [phone]
DD 01(13/1984

BET.,
TN=

MEDTRONIC, INC.
MINNEAPOUS, MN
PHONE: [phone]
DO 11/10/1987

BET TN-,

TN= LIORESAL INTRATHECAL

_ 'TREATMENT OF INTRACTABLE SPASTICSFY CAUSED BY SPINAL
CORD INJURY MULTIPLE SCLEROSIS AND OTHER SPINAL DISEASES INCLuDING SPINAL ISCHStit& SPINAL TUMOR. TRANSVERSE MYELMS, CERVICAL SPONDYLOSIS. AND DEGENERATIVE MYELOPATHY)

BACLOFEN

TREATMENT OF INTRACTABLE SPASTCITY DUE TO MULTIPLE
SCLEROSIS OR SPINAL CORD INJURY.

INFLISAIO INC
NORWOOD. MA
PHONE [phone]
OD 12/16/1991

SEX-.
TN=

BACLOFEN
TN= LIORESAL INTRATHECAL

TREA IMENT OF SPASTICTTY ASSOCIATED WITH CEREBRAL
PALSY.

MEDTRONIC. INC
MINNEAPOIJS, MN
PHONE: [phone]
DD 09/26/1994

BINE

BIS Pr

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