The rationale for prudent use of antimicrobial agents is to maximize therapeutic success and at the same time minimize development of antimicrobial resistance, thereby safeguarding antimicrobials for future veterinary and human use. This is done by optimizing drug choice, drug dose and dosing regimens, in addition to reducing unnecessary use of antimicrobial agents.

Resistance
Antimicrobials do not make organisms resistant but they do create selective pressure on a population of organisms. Those that are resistant flourish. If the resistant population is of a pathogen, then this may have serious implications for animal and human health, and for disease control.

Phenotypically, resistance may manifest in a wide variety of ways, including:

• Production of enzymes that destroy the antimicrobial agent
• Production of efflux pumps, which prevent adequate accumulation of the antimicrobial agent inside the bacterial cell
• Mutation of the target site so that it is no longer recognized by the antimicrobial agent.

Veterinary antimicrobials are the same as, or closely related to, antimicrobials used in human medicine. In the past this had led to the suggestion that emerging resistance to antimicrobials in human pathogens was associated with the overuse and misuse of antimicrobials in veterinary medicine.

It now seems most likely that resistance in human pathogens is more closely associated with patterns of antimicrobial use by the medical profession; nevertheless, it is vitally important that the veterinary profession uses antimicrobials prudently in order to:

• Minimize selection of resistant veterinary pathogens and therefore safeguard animal health
• Minimize possible resistance transfer to human pathogens
• Retain the right to prescribe certain antimicrobials that are important in human medicine, e.g. the fluoroquinolones and third generation cephalosporins.

The conceptual hurdle
It is natural for veterinary surgeons to judge the appropriateness or success of therapy by clinical response; in the case of antimicrobials, does the infection resolve? There are several criteria used to assess therapeutic success, including:

• Is the antimicrobial effective against the causal organism?
• Has resistance to the antimicrobial agent developed?
• Individual animal factors
• Will the antimicrobial reach the site of infection in sufficient concentration?
• Size of the inoculum and other local factors.

Although some of these criteria may also help reduce the development of resistance, there are other important considerations. In order to include these it is necessary to shift from thinking about the individual animal(s) requiring treatment to the population as a whole. Treatment with a broad-spectrum, highly potent, relatively new antimicrobial may be highly effective in the short term, but overuse will select for resistance and reduce usefulness in
the medium to long term. It is easy to realise this but harder to have the confidence to act upon it.

Guidelines to good antimicrobial stewardship
In the UK all antimicrobials are prescription-only medicines (POM-V), therefore the responsibility and control of use rests solely with the prescribing veterinary surgeon.

1. Veterinary surgeons should arm themselves with a working knowledge of commonly used antimicrobials.
2. If possible, a narrow-spectrum antimicrobial should be chosen.

• Many drug formularies (including the BSAVA Small Animal Formulary) provide information on suggested antimicrobials for infections involving particular pathogens and organ systems. These can be helpful, although ultimately it is important that choices are tailored to the individual. Recently, the BSAVA in conjunction with the Small Animal Medicine Society (SAMSoc) have issued the PROTECT poster. In addition to providing some good general guidelines, specific suggestions of appropriate antimicrobials for selected bacterial diseases are detailed. This provides the ideal opportunity for practice members to discuss and decide on practice policy in relation to antimicrobial choices. 
• In reality the majority of authorized veterinary antimicrobials are broad-spectrum, increasing the challenge.
• Veterinary surgeons need to have a good idea of the likely pathogen involved and/or results from culture and sensitivity tests to be able to make a choice about which antimicrobial to use.

3. Prophylactic use should generally be avoided. However, there are some situations where prophylactic use may be merited, including:

• High-risk immunosuppressed patients
• Surgical prophylaxis. The aim of surgical prophylaxis is to reduce the incidence of infection following a surgical procedure. However, information on the incidence of surgical site infection in veterinary practice is limited. Key considerations include:
  • The goal in surgical prophylaxis is to have tissue levels of an appropriate antimicrobial present at the time of surgery (i.e. at the time of bacterial contamination risk)
  • There would seem to be little benefit in the continuation of antimicrobial therapy beyond several hours after the time of bacterial contamination (i.e. postoperatively) and, in fact, it is likely that this increases the emergence of resistant organisms, which would be detrimental
  • Ideally, prophylactic antimicrobials should be administered prior to the induction of anaesthesia. A soluble intravenous preparation is optimal
  • A potentiated amoxicillin or a first-generation cephalosporin is a good choice for surgical prophylaxis
  • If there is likely to be involvement of anaerobic organisms, metronidazole or clindamycin should be considered in addition or instead
  • Where contamination with gut contents is possible, using a combination of a beta-lactam and an aminoglycoside should be considered. A fluoroquinolone could replace this if aminoglycoside toxicity is of concern. Veterinary surgeons must be aware that most fluoroquinolones are not especially good in terms of anaerobic spectrum. The third-generation fluoroquinolones (e.g. pradofloxacin) do not have this limitation
  • If a pre-existing infection exists, then therapeutic rather than prophylactic antimicrobials are required
  •  Procedures of short duration and elective procedures on otherwise healthy animals should not require surgical prophylaxis.

4. If use of an antimicrobial is justified, the correct dose, dose frequency and duration of treatment should be used.

• Too much or too little antimicrobial is equally bad in terms of resistance development.
• Sub-therapeutic dosing is more of a risk for in-feed or in-water medication.
• Environmental contamination with antimicrobials should be avoided.
• Optimal dosing regimes maximize bacterial killing and minimize the window for resistance development to occur.
• Time- and concentration-dependent killing should be taken into consideration.
• The client should be educated in terms of the correct use of the antimicrobials prescribed.
• Topical or local use should be considered (if appropriate) as this will, for example, reduce selective pressure on gastrointestinal flora.

5. If combinations of antimicrobials are considered necessary, care should be taken to choose rational combinations.

6. Routine use of antimicrobials considered to be important in treating resistant infections in human and veterinary medicine (e.g. fluoroquinolones, third- and fourth-generation cephalosporins and amikacin) should be absolutely avoided. In reality there are few, if any, options for treating organisms that are or have become resistant to these antimicrobials so they must be safeguarded. 

• The European Medicines Agency (EMA, formerly EMEA) has a Committee for Medicinal Products for Veterinary Use (CVMP), which makes recommendations for action (www.ema.europa.eu/htms/general/contacts/CVMP/CVMP.html).
• In food-producing species the CVMP has specifically advised that third- and fourth-generation cephalosporins for systemic administration should be reserved for those conditions that have responded poorly or are likely to respond poorly to other antimicrobials. Use in groups or flocks of animals (as opposed to treatment of individuals) is strongly discouraged as is ‘off-label’ use. Ceftiofur and cefquinome are examples of such antimicrobials currently authorized in the United Kingdom. The same guidelines should also be applied to the fluoroquinolones.
• In all species fluoroquinolones and third- and fourth-generation cephalosporins should be used judiciously and never considered as first-choice options.
• Failure to adopt these prudent measures is likely to be countered with restrictions on veterinary use being placed on these antimicrobial classes.
• There is also a strong argument that ‘last resort’ antimicrobials, such as imipenem and vancomycin, should not be used for veterinary patients.

7. Taking time to institute practice-based guidelines for therapeutic antimicrobial use should be considered.

• For example, it is feasible to work out appropriate first option antimicrobials for uncomplicated urinary tract infections, pyoderma and surgical prophylaxis, which should then be used by all practice members.
• Creating a table of first-, second- and third-choice antimicrobials to be considered.
  • First-choice antimicrobials would comprise agents appropriate for initial treatment, not necessarily based on culture and sensitivity information.
  • Second-choice antimicrobials should be prescribed based on culture and sensitivity data, provided that no first-choice agents
    are appropriate.
  • Third-choice antimicrobials should only be prescribed for serious and life-threatening infections, based on culture and sensitivity data, and only where no first- or second-choice agents are appropriate.
• The key considerations are that all guidelines should be reviewed regularly and be flexible so that change could easily be adopted should inadequacies arise or new information become available.
• Many human hospitals have adopted such guidelines with positive outcomes. The Infectious Disease Society of America together with the Society for Health Care Epidemiology have put together a guidelines document; some of the guidelines suggested could be adapted and applied to veterinary practice situations.

8. Report treatment failures. This is a vital part of monitoring for developing and emerging resistance.

• Reports should be made to the Veterinary Medicines Directorate (VMD) using the Suspected Adverse Reaction Surveillance Scheme (SARSS) forms. These forms are available to download from the VMD website.
• Situations where this would be appropriate include:
  • Treatment failure despite culture and sensitivity results indicating that an appropriate antimicrobial class had been used
  • Treatment failure where a particular antimicrobial product is authorized for the specific condition and species, and where the clinician’s experience would suggest that a positive response should have occurred.

Further information
American Society of Health-System Pharmacists (1999) ASHP therapeutic guidelines on antimicrobial prophylaxis in surgery. American Journal Health-System Pharmacy 56, 1839–1888
Giguere S, Prescott JF, Baggot JD, Walker RD and Dowling PM (2006) Antimicrobial Therapy in Veterinary Medicine, 4th edition. Wiley-Blackwell, Oxford
Ramsey I (2011) BSAVA Small Animal Formulary, 7th edition. BSAVA Publications, Gloucester

Useful websites
Defra antimicrobial resistance coordination group (DARC)
Health Protection Agency (HPA)
National Office of Animal Health (NOAH)
Responsible use of medicines in animals (RUMA)
(this website relates only to food-producing animals)
Veterinary Medicines Directorate (VMD)
Of specific interest are the antibiotic-related publicaitons