Guidelines for the use of quinolones in veterinary medicine

G u i d e l i n e s
for the use of
q u i n o l o n e s
in veterinary medicine
Prudent therapeutic use of quinolones
in food-producing animals
Bayer`s position:
Expertise with responsibility
As one of the world's leading research-based chemical and pharmaceutical companies, Bayer's first concern is to ensure that its products offer the highest possible standards in terms With veterinary pharmaceutical products – as with any phar- maceutical product – this entails extensive efforts in research and development, utmost care throughout the production process and constant vigilance during marketing. In addition, prescribers and end users are expected to use the licensed products in a responsible way, according to the instructions provided by the regulatory agencies and Bayer. Only in this
way can maximum effectiveness with an optimal safety
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standard be achieved.
The Bayer Group is one of the major partners of the health care profession. In the area of antimicrobials, the Group's long history of expertise has resulted in the development of two categories of quinolone-based products: Cipro®/Ciproxin®/ Ciprobay® (active ingredient: ciprofloxacin) and Avelox®/Avalox® (active ingredient: moxifloxacin) for use in humans and Baytril ® (active ingredient: enrofloxacin) for use in animals. The use of antimicrobial agents such as quinolones can lead to the selection of resistant forms of bacteria. This is a naturally occurring biological phenomenon related to their application and is a feature common to all classes of antimicrobial agents. Generally, antimicrobial resistance is considered to be a major and complex problem which is of global concern. It is some- times postulated that the use of antibiotics in veterinary medi- cine may compromise human health if resistant bacteria develop in animals and are transferred to people via the food chain or the environment. This is of particular concern for
highly valuable classes of antibiotics such as the quin-
olones. The possible development of resistance to quin-
olones is constantly followed by the media with more than
usual interest. However, little evidence has been presented
indicating that the use of quinolones in veterinary medicine has adversely affected quinolone therapy in humans. This has been confirmed in the report of a WHO Meeting in June 1998 en- titled "Use of Quinolones in Food Animals and Potential Impact on Human Health”. Experts attending the meeting recognized that quinolones should have a place in the therapeutic arsenal of the veterinarian. To safeguard the efficacy of quinolones in the future, the WHO Meeting and more recently additional groups of experts made a number of recommendations, pri- 3
marily to develop strategies for prudent use and to establish susceptibility surveillance systems, the implementation and support of which Bayer began some years ago. It is Bayer's policy to sustain the benefits of its products by promoting product stewardship as stipulated in the chemical industry´s international "Responsible Care” program. Bayer is equally committed to protecting human health and to helping sick animals. As the issue of resistance in people is of
utmost importance and potential risks have not yet been
fully quantified, Bayer has established a clear framework of
precautions, extending the earlier "Bayer's guidelines” for
responsible use of quinolones. The principles, requirements
and recommendations outlined in this brochure aim to ensure that the use of quinolone-based antimicrobial products for food-producing animals will provide maximum benefit to ani- mal health and welfare without compromising human health. Quinolone use and emergence of resistance
It is Bayer's firm belief that there is a legitimate need in veteri- nary medicine for innovative agents such as fluoroquinolones.
Used properly, antimicrobials eliminate bacterial infections,
hasten recovery of infected animals and improve animal
welfare by alleviating pain, distress and lesions associat-
ed with disease. They can also prevent the spread of infec-
tion from animal to animal, as well as from animal to man, by reducing the bacterial burden in infected animals.
While quinolones play an important role in the therapy of
bacterial infections, their use – like the use of any other
antimicrobial agent – must be expected to encounter resist- ance or some degree of reduced susceptibility at some time.
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Any discussion on the use of quinolones and the resistance issue must take into account the following: ■ It is generally accepted that any treatment of infectionswith antimicrobials, including quinolones, may result in the emergence of resistant bacterial strains or strains with ■ There is a potential for pathogenic bacteria, including resistant strains, to be transferred from animals to humans ■ Whether or not resistant bacterial strains originate from the use of antimicrobials in food-producing animals and significantly impair the efficacy of antibiotics in people, is the subject of ongoing scientific debate and requires There are a number of possibilities to limit the development of resistance. They include research into the mechanisms of
resistance and the search for new drugs, proper attention
to preventive measures and commitment to prudent use.
A n t i m i c ro b i a l re s e a rc h
Knowledge is one of the cornerstones in the fight against antibiotic resistance. Fundamental research into the mech- anisms of resistance development is therefore one of the ways in which Bayer addresses the resistance issue. The under- standing of bacterial flora epidemiology has to be advanced and the evolution and persistence of resistance as well as the mechanism of transmission of resistant bacteria from animals to people, are being investigated. Also, treatment regimens for quinolones (based on current pharmacodynamic princi- ples) that would reduce the incidence of antimicrobial resist- 5
Concomitantly, Bayer is applying new technology in the
search for more potent antimicrobial drugs as well as for
new classes of antimicrobial drugs with novel modes of
action. It is, however, very important to recognize that over
the years it has become increasingly difficult to discover and to develop new classes of antimicrobial drugs. This underlines the necessity to take extensive measures to prolong the effect- ive life of existing antimicrobials.
A l t e r n a t i v e s t o a n t i m i c ro b i a l s
Priority should therefore be given not only to drug research
but, at the same time, to improving preventive veterinary
medicine. For example, Bayer addresses this by its research
into vaccine development and immune therapy. In addition, the company is developing a product which protects the natural intestinal flora from replacement by unwanted, poten- tially pathogenic bacteria including zoonotic enteropathogens Extensive farm hygiene programs, together with optimal nutri- tion and husbandry, are basic requirements to limit the risk of disease outbreaks and, through this, the need to use antimi- crobial drugs. Antimicrobials, including the highly valuable class of quinolones, should never be used as a substitute for good husbandry practices and should only be part of an integrated P r u d e n t u s e
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Prudent use of quinolones is important to reduce selection and dissemination of resistance and to ensure this class of antimicrobials remains effective. Bayer, therefore, goes to
great lengths to educate veterinary practitioners on the
appropriate and prudent use of quinolones. Together with
its partners within the animal health industry, the company provides ongoing education for the veterinary profession and in 1998 introduced a code of practice on when and how quin- olones should be prescribed and used. Also, Bayer is mon-
itoring bacterial resistance patterns in both human and
animal populations. These activities are primarily aimed at
preventing the risk of resistance caused by inappropriate usage, as well as timely detection of any emerging resistance. Bayer´s principles, requirements and recommendations
on the prudent use of quinolones are outlined on the fol-
lowing pages.
Guidelines on prudent use of quinolones
P r i n c i p l e s
Bayer is committed to serving the animal health industry with state-of-the-art medication, i.e., products comprising high quality and efficacy standards. At the same time, it is
Bayer's declared policy that product safety and environ-
mental compatibility have the same priority as quality and
efficacy. The following principles therefore govern Bayer's
● Quinolones are highly effective therapeutic drugs for bothhumans and animals and must be used in a responsible manner.
● Bayer strictly rejects any use of quinolones as performance 7
enhancers. Bayer has never sought nor will it ever seek ● Bayer does not support the use of enrofloxacin in aqua-culture.
● Bayer's quinolone products are not to be used routinely toprevent infection in healthy animals (prophylaxis). Bayer actively supports adherence to this principle.
● Concerns are being expressed about the illegal productionand distribution of counterfeit quinolones. Bayer supports all legal measures to combat product piracy at a national and ● To ensure environmental safety, Bayer conducts andendorses research on the degradability and bioavailability of R e q u i re m e n t s
In order to ensure efficacious treatment and, at the same time, minimize possible risks of resistance selection, the following guidelines govern the use of quinolones in animal health: Quinolones are to be available only on veterinary pre-
scription and should be used under the close supervision
of a licensed veterinarian. They are to be used for short-
term therapy only. They should only be used in cases of serious infections, and never used for viral or trivial bacterial infections.
Quinolone-based products, as they are prescription-only medicines, should be advertised only in veterinary profes- 8
sional journals or media, and not in the lay press. The market- ing behavior of the manufacturers and distributors must sup- Only fluoroquinolones approved for animal health are
to be used. These products are to be used only in strict accord-
ance with the terms of their market authorization, e.g., only for the species, indications and dosages specified. Bayer, therefore, opposes extra-label use of quinolones in food ani- mals. It should be noted that all antimicrobials must
undergo a very stringent regulatory review before they
are approved for marketing.
Wherever possible, administration of quinolones is, in
addition to an accurate clinical diagnosis, to be based on
bacterial culture diagnosis and susceptibility testing of
the causative pathogen(s) to ensure that quinolones are the
appropriate choice. In certain cases, however, it may be neces- sary to initiate therapy in the best interest of the patient, based on clinical diagnosis and experience of the veterinarian, before the results of susceptibility testing are available. To facil- itate the performance of susceptibility tests, validated enro- floxacin discs and E-test strips specific for enrofloxacin are avail- If Salmonella typhimurium DT 104 (a serotype prone to develop decreased susceptibility to antimicrobials) has been historically reported or is detected in a herd or flock, treatment with a quinolone is not recommended. Instead, an eradication program should be initiated. In general, livestock and poultry producers should take steps to intensify Salmonella control measures in order to reduce the persistence or spread of It is of utmost importance that records are kept of
antimicrobial usage. Generally, infectious diseases should be
documented and a record kept on the farm of the disease history, clinical diagnosis, bacteriological examination including susceptibility testing, antimicrobial treatment and therapeutic 9
outcome. All relevant information for a given farm should be consolidated into a single database and available to the pre- scribing veterinarian. Routine periodic review of this information can be used to reassess the efficacy of quinolone treatment.
Bacterial susceptibility testing on a regular basis, not only on the given farm but also of the local area or region, may help the practitioners to select the most appropriate and effective Special emphasis should be given to group therapy, prev- iously designated metaphylaxis, i.e. short-term treatment at therapeutic levels of a group of animals, some of which have acute infections, others which are subclinically diseased and still others which are incubating disease. Group therapy with
a quinolone is only appropriate if all the above preceding
requirements have been fulfilled. Medications to treat a group
of diseased animals can be added to the drinking water or the feed. In situations where it is essential to medicate a herd or a flock, this should encompass the smallest practical unit of ani- mals. As for individual treatments, an oversupply should be avoided by selecting a package size as close as possible to the required amount of drug to be prescribed. Do not share or use leftover antimicrobials.Unused product should be discarded R e c o m m e n d a t i o n s
In addition to the above requirements, the following recommen- dations are designed to safeguard product safety and efficacy: Bayer endorses professional education and information campaigns for veterinarians (including undergraduate and post- graduate level) and end users (all personnel involved in medica- tion of animals) as well as for policy-makers and scientific jour- nalists in order to ensure the rational use of quinolones. Bayer
veterinary staff must adhere to and promote the various
guidelines and codes of practice concerning the use of
therapeutic antibiotics in animals.
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Co-ordinated and standardized bacterial susceptibility
surveillance programs should be conducted over time to
increase the knowledge of resistance trends in relevant
bacteria. These programs should be based on standardized
laboratory techniques and on standardized veterinary break- points. Surveillance should target microorganisms of both vet- erinary and public health importance and samples should be collected at random from farms (pretreatment specimens), slaughterhouses and/or food of animal origin. A close collabor- ation with the authorities is required regarding the establish- ment of surveillance programs and analysis of results. Bayer veterinary staff should follow the programs and inform the vet- erinary practitioners of the outcome, enabling them to modify Bayer supports the implementation of quality assur-
ance programs such as HACCP (Hazard Analysis and
Critical Control Point system) and other hygiene systems
to reduce the level of bacterial contamination in animals
and animal products. Such public health safeguards mini-
mize the pathogen load and thereby any significant transfer of antimicrobial-resistant pathogens to humans through the food supply. Irrespective of the improvements made to reduce the levels of harmful bacteria in food, everyone needs to follow the established requirements for safe and careful handling of food, at home as well as in commercial kitchens.
In addition to improved management and hygiene,
alternative strategies aimed at reducing the need for anti-
biotics in disease control should be encouraged. This
includes disease eradication programs, vaccination, immuno- modulation, competitive exclusion and, in the long-term, selecting farm animals for increased disease resistance.
Attempts should be continued to achieve pathogen-free breeder stocks. This will ultimately significantly diminish the 11
overall use of antimicrobials. Bayer subsidiaries should explore ways to support pathogen eradication programs.
Collaboration among the major stakeholders (drug
manufacturers and suppliers, regulators, veterinarians
and end users) as well as with international (e.g., OIE,
WHO) and intergovernmental organizations is strongly
encouraged. Additionally, public health organizations as well
as the food processing industry should be involved. This col- laboration should focus on topics such as the development, distribution and implementation of guidelines for prudent use of antimicrobials, education programs and resistance surveillance.
International cooperation and agreements are needed to curb Research into the emergence and spread of antimicrobial resistance should be promoted. Also, it is essential to quantify the role of animals intended for food, as disseminators of antimicrobial resistant bacteria which can impact human health. This is necessary in order to define any risks to public health from the use of antimicrobials in food animals.
C o n t a c t s
International edition
Q u e s t i o n s and Answers
What is Bacteria can be destroyed by so the ability of certain bacteria, nor- antibiotic curately: antimicrobial drugs -, survive exposure to that antibiotic.
resistance? which are produced either by How does Acquired antimicrobial resis- antibiotic which is an inherent conse- resistance quence associated with any use occur? any species. In contrast, natural resistance can be transferred transfer directly to other strains).
Why do Antimicrobial drugs are used to animals need in a variety of companion and antibiotics? food-producing animals. In the Why use Medicines currently available a quinolone to some important bacterial dis- treat animals? eases of livestock and poultry Pasteurella, E. coli, Actinobacil- Widespread roquinolones in animals only antibiotic use can when microbiological diagnosis Are Bayer products to be the drug of choice. They contributing are available by prescription to a public health under the supervision of licensed problem? veterinarians. Moreover, the What is being Prescription and distribution of done to ensure ed when strictly necessary. To that the use of minimize the risk, Bayer sup- fluoroquinolones program for sales personnel in animals and veterinarians, as well as will not have an livestock and poultry producers impact on bacterial drugs. If the treatment public health? is to be undertaken by an ani- How does When poultry are infected and Bayer ensure that on an appropriate diagnosis), it to seven days. Once ample poultry is is necessary to treat the entire dosed effectively? contagious and spread rapidly mal´s body, processing for Which bacterial There are a number of bacteria pathogens in bacteria – which can cause dis- contact. With respect to quin- animals can cause eases in man. Well known disease in man? Campylobacter and some E. coli typhimurium DT 104 and on What is the Many strains of Salmonella, in- significance can be transmitted to humans, of salmonellosis in usually through the food supply, common Salmonella occurring in humans?What is of enteritis in man. Although the concern for this phage type be- meant by Salmo- great majority of Salmonella in- nella typhimurium fections in man result in self-lim- classes of antimicrobials (ampi- DT 104? fections may occur. Fluoroquin- olones and cephalosporins are the and may develop decreased sus- What is Bayer’s Decreased in vitro susceptibility of DT 104 to quinolones has been upsurge in the early 1990s.
understanding of noticed in some areas (e.g., Eng- Recent (Scottish) findings sug- Salmonella land) but not in others (e.g., Ire- gest that DT 104 bacteria with typhimurium minimum inhibitory concentration may not have originated from DT 104 and its (MIC) values are elevated but link to quinolone remain clearly below the clinical breakpoints for resistance of quin- cautionary measure is making susceptibility? olones used in human medicine, every effort to minimize potential What is Campylobacter, predominantly Campylobacter? the leading bacterial causes of Has Bayer seen It is well known that colonization erythromycin and azithromycin a rise in in poultry at an age of approx- Campylobacter imately 3 weeks. The degree of colonisation in 100% depending on the hygiene available to treat campylo- poultry or status of the farm. Resistance in resistant of Campylobacter against sev- Campylobacter? including quinolones, has been What is E. coli, the abbreviation for E. coli nantly aerobic bacterium found and what in the intestines of humans and significance has such as enterohemorrhagic E. coli 0157? E. coli (EHEC) can be a cause nificant representative is E. coli Can anything Yes. Since bacteria are naturally and washing hands and utensils be done to reduce to establish integrated hygiene meat and poultry can stop the the risk of management, including hus- foodborne age and consumer handling.
bacterial illness? Thorough cooking will eliminate Further information on Bayer's
Pirro, F., de Jong, A., Froyman, R. & van perspectives. Journal of the American Veteri- prudent use and monitoring pro-
Diest, J. (1998). Responsible use of anti- nary Medical Association, 212: 1209-1213.
microbial products in livestock production.
grams of therapeutic antibiotics
Antibiotic Resistance in the European Union in veterinary health
associated with Therapeutic Use of Veteri- Pirro, F., de Jong, A., Froyman, R., Greife, nary Medicines. Report and Qualitative Risk H.A. & Schmeer, N. (1999). Resistenz-Moni- Assessment by the Committee for Veterinary toring am Beispiel eines zugelassenen Fluo- Medicinal Products. July 1999.
rochinolons. Tierärztliche Praxis, 27: 329-334.
de Jong, A., & Mörner, A. (1999). Prudent use of fluoroquinolones in veterinary med- Scheer, M., Froyman, R., de Jong, A. & guidelines on the use of antimicrobials. The icine. Proceedings of Agriculture's Role in Altreuther, P. (1997). Antibacterial sensitivity Veterinary Record, 143: 565-566, 1998.
managing Antimicrobial Resistance Confer- monitoring of avian Escherichia coli isolates ence. Toronto, Canada. 24-26 October over 5 years. Journal of Veterinary Pharma- European Federation of Animal Health.
cology and Therapeutics 20 (Suppl. 1): 189.
Report on Responsible Use of Antimicrobialsto Control Disease in Farm Animals. 1996.
de Jong, A., Mörner, A. & Klostermann, L.
van Diest, J. (1998). The prudent use of anti- (2000). Prudent use of fluoroquinolones in biotics for therapy. World Poultry, 14: 54-55.
food animals. Proceedings of the 8th Inter- Report on Microbial Antibiotic Resistance in national Congress of the EAVPT. Jerusalem, van Diest, J. & de Jong, A. (1998). Over- Relation to Food Safety. Advisory Commit- Israel. July 30 - August 3, 2000. p. 126.
view of quinolone usage for food-producing tee on the Microbiological Safety of Food.
animals. Proceedings of WHO Meeting on London: The Stationary Office, August 1999.
Froyman, R., Scheer, M., de Jong, A. & the use of quinolones in food animals and Altreuther, P. (1994). Susceptibility to enro- potential impact on human health. Report World Health Organisation. Report on Use floxacin of avian Salmonellae collected in WHO/EMC/ZDI/98. 12, Geneva, Switzer- of Quinolones in Food Animals and Potenial Europe during 1992 and 1993. Proceed- land, 2-5 June 1998. pp. 97-102.
Impact on Human Health. Report WHO/ ings of Antimicrobials in Animal Intensive EMC/ZDI/98.10, Geneva, Switzerland.
Production. Zoopole, France. pp. 265-270.
Watson, P.M., Bell, G.D., Webster, C.M.M.
& Fitzgerald, R.A. (1998). Fluoroquinolone Froyman, R., Scheer, M., de Jong, A. & susceptibility of S. typhimurium DT 104.
Altreuther, P. (1997). Enrofloxacin sensitivity The Veterinary Record, 142: 374.
of avian Salmonella in the European Union.
microbial Resistance in Animals Intended for Proceedings of Salmonella and Salmonel- Food. Report WHO/CDS/CSR/APH/ 2000. losis. Ploufragan, France. pp. 455-458.
Background documents for gen-
4, Geneva, Switzerland. 5-9 June 2000. eral reading
Piddock, L.J.V. & de Jong, A. (1999).
World Organisation for Animal Health (OIE).
Implication of quinolone resistance in veteri- Use of antimicrobials and protection of pub- nary isolates of Salmonella. The Veterinary lic health. Second OIE international confer- ence on antimicrobial resistance. Paris, veterinary therapeutics in bacterial resist- ance development: animal and public health C o n t a c t s

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