Federation ofVeterinarians of Europe

Antibiotic Resistance& Prudent use ofAntibiotics in Veterinary Medicine

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The word antibioticis used throughoutthe document; it isintended to cover allantimicrobial agentsadministered orally,topically or parente-rally to animals toproduce a curativeor protective effect.It includes antibio-tics produced by fermentation of livemicro-organisms aswell as chemicallysynthesised com-pounds with antibio-tic activity such assulphonamides, tri-methoprim and qui-nolones. It does notinclude disinfectantsand coccidiostats.

Antibiotic Resistance& Prudent use ofAntibiotics inVeterinary Medecine

AbstractTherapeutic antibiotics are used in the treat-ment and control of many types of infectionsin a wide variety of animal species.

This use can lead to the selection of resis-tant forms of micro-organisms to antibio-tics, which is a natural and unavoidable phenomenon. It is an inherent risk associa-ted with the use of antibiotics in any species, including man.

The appearance in human pathogens of mul-tiple resistance to antibiotics has focusedattention on both human and veterinary useof these valuable medicines. However, thedegree to which usage of antibiotics in veterinary medicine contributes to this problem is yet to be fully understood.

The development of resistance can be minimised provided that a number of measures are observed to prolong the usefullife of all antibiotics in both human and vete-rinary medicine. Antibiotic use should belimited to situations where they are needed and the selection of the right anti-biotic should take a number of factors intoaccount.

The purpose of this paper is to increase theawareness of prescribing and supervisingveterinary surgeons to the problem of anti-biotic resistance and to review the basic prin-ciples on the prudent use of antibiotics.

Antibiotic use should not, however, be seenin isolation from the disciplines of animalmanagement, animal welfare, husbandry,hygiene, nutrition, immunology and vaccina-tion. Diseases must be controlled to reducethe need for antibiotic use and they can onlybe controlled successfully by an holisticapproach.

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kanamycin), but may also exist betweenunrelated chemicals (e.g. erythromycin-lin-comycin).

Micro-organisms may be resistant to severalunrelated antibiotics. Use of one such anti-biotic will therefore also select for resistanceto the other antibiotics.

Epidemiology of ResistanceResistance patternsResistance patterns observed in animals arelikely to be affected by antibiotic exposure,but they will also vary according to:

• the size of the population of micro-organisms;

• pre-exposure prevalence of resistance genes;

• the fitness of the selected population ofmicro-organisms in competition withother micro-organisms present in theenvironment which have not been expo-sed to antibiotics.

Resistance transferThere are multiple sources of resistantmicro-organisms, both commensal andpathogenic:

• Animals and their faeces;

• Food of animal origin that may havebeen contaminated during processing;

• Fruits or vegetables that may come froma contaminated environment;

• Contaminated water;

• Humans.

Whenever an animal or human host is exposed toantibiotics, there will be some degree of selectionfor resistant bacterial population. Selection will depend upon the type of antibiotic used, the number of individuals treated, the dosageregimen and the duration of treatment. Therefore,it is vital to limit therapeutic antibiotic use tothose situations where they are needed.

Antibiotic Resistance:OverviewResistance to antibiotics existed even before antibiotics were used throughoutthe world. However, this intrinsic form ofresistance is not a major source of concernfor human and animal health. The vastmajority of drug-resistant organisms haveinstead emerged as a result of geneticchanges, acquired through mutation ortransfer of genetic material during the lifeof the micro-organisms, and subsequentselection processes.

Acquired Resistance: mutational vs. transferableresistanceMutational resistance develops as a result ofspontaneous mutation in a locus on themicrobial chromosome that controls susceptibility to a given antibiotic. The pre-sence of the drug serves as a selectingmechanism to suppress susceptible micro-organisms and promote the growth of resis-tant mutants. Spontaneous mutations aretransmissible vertically.

Resistance can also develop as a result oftransfer of genetic material between bacteria. Plasmids, which are small extra-chromosal DNA molecules, transposons andintegrons, which are short DNA sequences,can be transmitted both vertically and hori-zontally and can code for multi-resistance.

It is estimated that the major part of acquiredresistance is plasmid-mediated.

Multiple ResistanceResistance depends on different mecha-nisms and more than one mechanism mayoperate for the same antibiotic.

Micro-organisms resistant to a certain anti-biotic may also be resistant to other anti-biotics that share a mechanism of action orattachment. Such relationships, known ascross-resistance exist mainly betweenagents that are closely related chemically(e.g. polymyxin B and colistin, neomycin and

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The relative contribution of each of thesesources as well as the different routes oftransfer remain to be fully understood.

However, if the use of antibiotics in humanmedicine is the main source of resistance inthe human population, direct contact withanimals and the consumption of contami-nated food of animal origin are recognisedto be the main routes of transfer of resis-tance from animals to humans.

In addition, while much attention has focu-sed on transfer of resistant bacteria fromfood animals to man it must be kept inmind that human and animal populationsconstitute overlapping reservoirs of anti-biotic resistance, as shown in the figureabove.

Veterinarians therefore need to educatetheir clients on the hazards involved. This istrue for farmers but also for pet owners,when medicating companion animalsknown or suspected to be infected withzoonotic organisms, as these animals mayshare living accommodation with young

Hospitals Community

Househould wasteHousehold

Surface water

Waste water

Faeces

Animal FeedPet Animals

Farm Animals

Farmers

Fruits & Vegetables

Meat & Dairy Products

Antibioticexposure

Antibioticexposure

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Known products approved for the species and the indicationNo medicinal product can be placed on the market unless its quality, safety andefficacy have been demonstrated. There-fore, the first line of choice should be basedon the products approved for the speciesand the indication concerned.

Known efficacy established inwell performed field trialsWhen no suitable product is licensed for aspecific condition or species, the choice ofan alternative product should be based,whenever possible, on the results of wellperformed field trials and a proven efficacy for the condition or speciesconcerned. Indiscriminate off-label useshould be avoided.

children, the elderly, immunocompromisedpatients or caretakers of food animals.

Finally, given that it will rarely be possibleto establish with certainty where the resis-tance was originally acquired and given thegeneral complexity of the subject, it isimportant that both medical doctors andveterinarians work together to address theissues.

Prudent use ofAntibiotics: PrinciplesPrudent use of antibiotics is an integral partof good veterinary practices. It is an attitu-de to maximise therapeutic efficacy andminimise selection of resistant micro-orga-nisms.

Prudent use principles are a guide for opti-mal use of antibiotics. They should not beinterpreted so restrictively as to replaceprofessional judgement of practitioners orto compromise animal health or welfare.

In all cases, animals should receive promptand effective treatment as deemed necessa-ry by the prescribing or supervising veteri-narian.

Choice of the right antibioticThe choice of the right antibiotic should bebased on:

Accurate diagnosisThe use of antibiotics should be based onthe clinical evaluation of the animals underthe care of the prescribing veterinary sur-geon and on the judgement that antibiotictherapy will have a beneficial effect.

When it is not possible to make a direct cli-nical evaluation, the diagnosis should bebased on past experience, on knowledge ofthe farm epidemiological status and on on-going sensitivity testing.

Antibiotic therapy should help to containand limit further extension of the infection,shorten duration of the infection anddisease, or reduce risks of systemic compli-cations.

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Known or predictable sensitivities of possible micro-organism involvedAntibiotics should only be used when it isknown or suspected that an infectious agent,that will be susceptible to the therapy, is pre-sent. When treating a disease, the sensitivityof the causal organism should ideally be ascer-tained before therapy is started. In certainsituation such as disease outbreaks involvinghigh mortality or where there are signs ofrapid spread of disease among contact ani-mals, treatment may be started on the basis ofclinical diagnosis. Even so, the sensitivity ofthe suspected causal organism, should, wherepossible, be determined so that if treatmentfails, it can be changed in the light of theresults of sensitivity testing. Antibiotic sensiti-vity trends should be monitored over time,and such monitoring used to guide clinicaljudgement on antibiotic usage.

Susceptibility testing can only give an indica-tion of what the clinical activity of the drugwill be. The effect of the drug in vivo dependson its ability to reach the site of infection in ahigh enough concentration, the nature of thepathological process and the immune respon-se of the host.

Known pharmacokinetics /tissue distribution The choice of the right antibiotic also need totake into account pharmacokinetics para-meters, such as bioavailability, tissue distribu-tion, half-life, tissue kinetics to ensure theselected therapeutic agent reaches the site ofinfection. Duration of withdrawal periods maybe a factor in choosing suitable products.

Considerations must also be given to theavailable pharmaceutical forms and to theroute of administration. Prolonged oral useshould be avoided as most of the concernswith regard to resistance is associated withthe selection and transfer of resistant bacteriathat inhabit the gut.

Susceptibility tests are intended to be a guide for the clinician, not a gua-rantee that an antibiotic will be effecti-ve in therapy.

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Known status of immunocompetenceWhen treating animals with immuno-sup-pression or life-threatening infections thenbactericidal substances should be preferred,as successful use of bacteriostatic antibioticsrely on an active immune system to controlthe infection.

Appropriate spectrum of activityThe choice of antibiotic should take the sus-ceptibility of the demonstrated or suspec-ted micro-organism into account, whileaiming for a minimal effect on other micro-organisms.

The risk for development of resistance inmicro-organisms of the individual animal,the population of animals and the risk fortransfer to other populations should beconsidered. Generally, antibiotics with abroad spectrum of activity lead to develop-ment of resistance in non-target micro-organisms more rapidly that those withnarrow spectrum, because they exert aselection pressure on a greater number ofmicro-organisms.

Therefore, in order to minimise the likeli-hood of broad antibiotic resistance develop-ing, where an appropriate narrow spectrumagent is available, it should be selected inpreference to a broad spectrum agent.

Consideration should also be given topotential consequences of resistance to thespecific substance in question. Selection ofantibiotics that are used for animals or manin special, critical, situations where few or noother antibiotics are available, should becarefully justified.

Known antibiotic combinationsThe indiscriminate use of antibiotic com-binations should be avoided because of thepotential for increased toxicity, pharmaco-logical antagonism, and the selection ofresistant organisms.

However, the use of multiple antibiotics toprovide broader coverage may be justifiedwhen failure to initiate effective antibiotictherapy will significantly increase mortalityor morbidity or in seriously ill patientswhen the identity of an infecting organismis not apparent.

Therapy may failbecause the causativemicro-organisms are orbecome resistant to thechosen antibiotic.However, there are othercauses of failure unrela-ted to acquisition ofresistance. Therapy mayalso fail because:

• The animal ownerdoes not comply with the prescription;

• The dose prescribed is insufficient or admi-nistered for an insuffi-cient duration;

• An inappropriate anti-biotic is prescribed;

• The antibiotic fails to reach the infected site;

• Poor host response isencountered due to a systemicdisease;

• Inactivation of theantibiotic by feedingredients, mineralsalts in water.

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Use of the right antibioticLabel instructions should be carefully follo-wed and due attention paid to species anddisease indications and contra-indications,dosage regimen, withdrawal periods, andstorage conditions. Off-label use of antibio-tics should be limited to cases where noother suitable product is available and care-fully justified, for instance as part of thewritten prescription.

Dosage regimenIt is essential to administer the selectedantibimicrobial agent in accordance withthe recommended dosage regimen andrecommended route to avoid administra-tion of sub-therapeutic doses, which canlead to a lack of efficacy and, in some cases,may increase the risk of resistance. Correctadministration will minimise therapy fai-lures and exploit fully the efficacy potentialof the product.

Each antibiotic has its own unique pharma-codynamic properties, which are expressedfully when the recommended dosage regi-men is applied.

Duration of treatmentGenerally the duration of the treatmentshould be as indicated on the label.Insufficient duration of administration canlead to recrudescence of the infection. Thismay also increase the likelihood of selec-ting organisms with reduced sensitivity.

On the other hand, antibiotic use should bestopped as soon as the animal’s own hostdefence system can control the infectionitself. Limiting the duration of use to onlythat required for therapeutic effect willminimise the exposure of the bacterialpopulation to the antibiotic. Thus, theadverse effects on the surviving micro-orga-nisms are minimised.

Group medicationIn some classes of livestock, like fish, pigs orpoultry, if a number of animals in a grouphave overt signs of disease, both sick andhealthy animals will usually need to betreated with therapeutic levels of an anti-biotic. This is intended to cure the clinically

Antibiotic use shouldnot, however, beseen in isolationfrom the disciplinesof animal manage-ment, animal welfa-re, husbandry,hygiene, nutrition,immunology andvaccination.Diseases must becontrolled to reducethe need for antibio-tic use and they canonly be controlledsuccessfully by anholistic approach.

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affected animals, reduce the spread of thedisease and prevent clinical signs appearingin the remainder.

Strategic medication

It is recognised that strategic medication maybe appropriate in certain precisely definedcircumstances. However, this should be partof an integrated disease control programmeand the need for such medication should beregularly re-ascertained.

The use of antibiotics in the absence of clini-cal disease or pathogenic infections shouldbe restricted to situations where past expe-rience indicates that the group of animalsmay develop the disease if not treated ishigh. In addition, long-term administrationto prevent disease should not be practicedwithout a clear medical justification.

Each practice should develop a written policyor protocol covering the circumstances inwhich this is considered appropriate.

Prescribing, delivering and record keeping

All prescribing of antibiotics should be foranimals under the care of the prescribingveterinarian.

All therapeutic antibiotics should be suppliedby, or with a prescription from a veterinarysurgeon. Records of all antibiotics suppliedand administered should be kept by the pres-criber, the supplier and the end-user.

If part of the treatment regimen is to beundertaken by the animal caretaker, he/sheshould be given written instructions ondosage, duration of treatment and if appro-priate, withdrawal period. The veterinarianshould ensure that the animal caretaker hasunderstood fully the instructions. Quantitiesof antibiotic left with the animal caretakershould correctly reflect the needs, to avoidan oversupply.

Veterinarians should advise the animal care-taker about the disposal of unused antibio-tics and containers, in accordance with localrequirements.

Errors in antibiotic usage:

• Incorrect diagnosis• Ineffective levels of the

appropriate products areadministered

• A product that has no esta-blished specific effective-ness is prescribed

• Treatment of uncomplicatedviral infections

• Antibiotic therapy is chan-ged too rapidly and incor-rectly, assuming therapeutic failure prior tocorrecting all contributingfactors

• Non compliance with labelor written instructions

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Final ConsiderationsIt is difficult, if not impossible, to have a setof guidelines, which could be applied uni-versally. These general principles thereforeonly cover the basic principles on the pru-dent use of antibiotics and have beendrawn up in the light of the current state ofknowledge. Further work is now requiredto transform these basic principles intonational, local or practice guidelines.

However, when developing such guidelines,species-specific guidelines or formularies,caution should be made not to interpretthese principles too restrictively. Prescribingand supervising veterinary surgeons mustretain a reasonable freedom of professionaljudgement.

In addition, it will also be necessary to dis-cuss further a number of items to betterunderstand the problem of antibiotic resis-tance and of its impact on human and ani-mal health. More data must be generatedto fully appreciate the risk associated withthe use of antibiotics and to develop appro-priate risk management strategies.

Co-ordinated susceptibilitysurveillanceGood data on antibiotic resistance are lac-king. Furthermore, when data are avai-lable, they are difficult to compare becauseof the different methods and differentbreakpoints used.

Surveillance should target micro-organismsof both veterinary and public health impor-tance. Data from diagnostic laboratories,with collection of samples from pathogenicspecimens, have an inherent bias towards ahigher percentage of resistant strains thanspecimens collected prior treatment.Therefore, it is encouraged to also gatherdata from samples collected at randomfrom farms, slaughterhouses, or food inorder to investigate the prevalence of resis-tance in veterinary pathogens, zoonotic

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pathogens and sentinel organisms.

The results of such surveillance schemesshould be provided to the prescribing andthe supervising veterinary surgeons, whichwill allow the modification of antibioticusage whenever necessary.

Monitoring of antibiotic usageIt is also necessary to collect data on consump-tion of antibiotics to establish:

• Whether links between antibioticconsumption and resistance trends canbe made;

• Whether guidelines on the prudent useof antibiotics are correctly implementedand effective.

The sources and classification of the rawdata should be considered and standardi-sed. Technical units of measurement allo-wing the safe comparisons of incidence ofuse over time and per animal species needto be developed.

Alternatives to antibioticsand integrated diseasecontrol programmeFinally, the importance to develop systema-tic preventive measures to reduce the needto use antibiotics must be stressed again.Prevention is better than cure.

In food animals, antibiotic use should alwaysbe part of, and not a replacement for, inte-grated disease control programmes, such asHealth Heard Surveillance Programmes.These programmes are likely to involvehygiene and disinfection procedures, biose-curity measures, management alterations,changes in stocking rates, vaccination, etc…

Continued antibiotic use in such controlprogramme should be regularly assessed asto effectiveness and whether their use canbe reduced or stopped.

Antibiotics need to be used withcare to maintaintheir efficacy.

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