Current controversies in equine antimicrobial therapy

Summary

Controversies exist regarding the use, misuse and potentialoveruse of antimicrobial treatments in foals and adults.When antimicrobials are required for treatment ofinfectious diseases, veterinarians should follow a logicalapproach and not simply reach for the newest drug.Targeted, single drug therapy is probably best, and cultureand sensitivity testing should be undertaken. The mostlikely infectious agent, potential drug toxicities, and age-appropriate dose and route should be considered. Thedevelopment of an increasing number of different multipledrug resistant pathogens requires that veterinarians useantimicrobial drugs responsibly to protect veterinarypatients and the public at large.

Introduction

Appropriate antimicrobial use in the equine patient posesmany specific challenges. Considerations prior toantimicrobial selection include poor oral absorption ofmany drugs, large total dosage (and therefore high cost)often required, and risk of adverse side-effects, the mostcommon of which is antimicrobial-associated enterocolitis.In addition, drug disposition in the foal may be verydifferent from that in the adult, with differences in oralabsorption, volume of distribution, metabolism andclearance of many drugs. Knowledge and understandingof basic pharmacokinetics and pharmacodynamics indifferent age groups is, therefore, essential to appropriateuse of antimicrobial agents. In addition, there is thequestion of development of antimicrobial resistance,which has important implications for both human andveterinary medicine. Many controversies exist regardingthe current use of antimicrobials, including appropriateantimicrobial selection, and use of antimicrobials in certainclinical situations.

Antimicrobial selection

There is little information available regarding appropriateantimicrobial selection in the horse. First line antimicrobialagents for suspected or proven infection should generallybe broad spectrum and have known efficacy against themost likely pathogens. First line antimicrobials are thosethat are appropriate for use in the absence of, or pending,culture and sensitivity results (Table 1). There are instancesin which a first line antimicrobial does not need to bebroad-spectrum, for example simple penicillin is anappropriate choice for treatment of suspectedStreptococcus equi ssp. equi infections, where treatment isdeemed necessary (Fig 1). Where possible, cultures shouldbe obtained prior to antimicrobial administration, allowingselection of further antimicrobial agents on the basis of the

216 EQUINE VETERINARY EDUCATIONEquine vet. Educ. (2009) 21 (4) 216-224

doi: 10.2746/095777308X321107

Tutorial ArticleCurrent controversies in equine antimicrobial therapyA. R. Hollis and P. A. Wilkins*

Sections of Medicine and Emergency, Critical Care and Anesthesia, Department of Clinical Studies,New Bolton Center, University of Pennsylvania School of Veterinary Medicine, 382 West Street Road,Kennett Square, Pennsylvania 19348, USA.

Keywords: horse; antibiotic; infection; antimicrobial resistance; nosocomial

Fig 1: Horse with nasal discharge (apparent in left nostril) due toinfection with Streptococcus equi var. equi or 'strangles'. While thisdisease seldom requires antimicrobials, horses with severesystemic illness may require treatment.*Author to whom correspondence should be addressed.

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A. R. Hollis and P. A. Wilkins 217

specific sensitivity pattern of the organism in question,should initial therapy be unsuccessful.

The American College of Veterinary Internal Medicine(ACVIM) has published a consensus statement onantimicrobial drug use in veterinary medicine (Morley et al.2005) recommending that veterinarians categoriseantimicrobials used in their practice into primary,secondary, and tertiary use categories. Drugs assigned to

the primary use category should include older drugs andthose with a narrower spectrum of activity, e.g. simplepenicillins, and these drugs should be used in the majorityof infections. Drugs assigned to the secondary usecategory include newer drugs with an extended spectrumof activity, and those with added importance in thetreatment of serious or frequently resistant infections inman. Drugs for which antimicrobial resistance appears todevelop relatively easily, e.g. rifampin, should also beassigned to this class. Secondary use drugs should bereserved for cases where culture and sensitivity resultsindicate primary use drugs are not appropriate. Tertiaryuse drugs are those particularly important for human andanimal health care, especially those most recentlydeveloped and those with extended spectra of coveragethat are useful against the most resistant bacteria (forexample methicillin resistant Staphylococcus aureus[MRSA]), with use limited to animals with clinicallyimportant infections caused by bacteria demonstratedresistant to all reasonable primary and secondary usedrugs (Morley et al. 2005). It is important that secondaryand tertiary category antimicrobial drugs are not usedwhen a primary category drug could be just as effective.

Decisions to advance from a primary to a secondary ortertiary category drug should be based on either cultureand sensitivity information, where available, or inadequateresponse to a lower category drug, after allowing sufficienttime to evaluate the response. In general, the authorsrecommend a period of at least 48 h with no clinical orclinicopathological improvement prior to deeming anantimicrobial agent ineffective. In addition, the use oftertiary antimicrobials should be restricted to animals with areasonable chance of survival. This consensus statement(Morley et al. 2005) should be studied in detail and used todevelop prescribing guidelines for each individualpractice. Guidelines for antimicrobial use in the authorshospital are included in Table 1. In addition to theseguidelines, directed antimicrobial therapy should be usedwhenever possible, using culture and sensitivity techniquesto target specific organisms. Further considerations forantimicrobial selection should include the availability of thedrugs and whether the antimicrobial is licensed for use inthe horse, or even any veterinary species. In addition,consideration should be given to the pharmacokinetic andpharmacodynamic profile of the drug, where known, asabsorption and distribution varies significantly both withinand between species. The authors are refraining fromcomment regarding the use of compounding pharmacies,as the controls and regulations of such pharmacies aredisparate between regulating agencies on variouscontinents and between countries on the same continent.

Association of antimicrobial drugs withenterocolitis and nephrotoxicity

There are many adverse drug reactions associated withantimicrobials, the most common of which is antimicrobial-

TABLE 1: Example antimicrobial use policy

Class 1: First choice antimicrobials in the absence of, or pendingculture and sensitivity results:

Primary use

Penicillins (sodium penicillin, potassium penicillin, ampicillin)Trimethoprim-sulphonamideFirst and second generation cephalosporinsGentamicin (reserve for serious infections)TetracyclinesMetronidazoleErythromycinRifampin (Never use as sole agent)

Class 2: First choice antimicrobial ONLY in emergent situations

Primary use (special circumstances)

Amikacin

Class 3: Antimicrobials to be used only when justified by cultureand sensitivity results AND lack of response to Class 1 or 2 drugs,contraindication to Class 1 or 2 drugs, or adverse response toClass 1 or 2 drugs:

Secondary use

Cefotaxime and other 3rd generation cephalosporinsEnrofloxacinTicarcillin + clavulanic acidChloramphenicolAzithromycinDoxycycline

Class 4: Last choice antimicrobials to be used only in very raresituations with documented resistance to all applicable Class 1, 2and 3 drugs, and disease. These drugs should only be used whenlocal therapy, or other alternatives are not an option, and wherethere is a chance of survival

Tertiary use

Imipenem4th generation cephalosporinsOther drugs used for the treatment of resistant bacteria, e.g.newer flouroquinolones

Class 5: Drugs prohibited for use without approval of designatedmembers of the Infection Control Committee

Tertiary use

Vancomycin


218 Current controversies in equine antimicrobial therapy

associated enterocolitis. Many clinicians hold very strongopinions on the association of certain antimicrobials withenterocolitis, but the fact remains that any antimicrobialdrug has the potential to cause enterocolitis. Horses areespecially prone to the development of antimicrobial-associated enterocolitis because of their poor oralabsorption of many drugs, leading to large concentrationsof active drug in the intestinal lumen (Papich 2003).However, drugs that are absorbed well orally oradministered i.v., have also been associated withdiarrhoea because of biliary excretion or enterohepaticrecycling, exposing the intestinal lumen to largeconcentration of the drug (Papich 2003). A decrease inanaerobic bacteria in the intestine leads to alteredcarbohydrate metabolism and the overgrowth of somepotentially pathogenic bacteria, both of which may leadto diarrhoea (Papich 2003). The most commonly implicatedantimicrobials are presented in Table 2; it is important tonote that, anecdotally, there appear to be geographicaldifferences in the antimicrobial drugs most likely to causeenterocolitis. Local knowledge of antimicrobials commonlyassociated with enterocolitis in a specific region is,therefore, helpful for antimicrobial selection.

The administration of potentially nephrotoxic drugs toazotaemic animals is another controversial topic. Many ofthese animals will have prerenal azotaemia secondary tohypovolaemia, rather than intrinsic renal disease, althoughoccult renal parenchymal disease may exist secondary tothat hypovolaemia. In most cases, administration ofnephrotoxic antimicrobial drugs (such as gentamicin andamikacin) can be avoided and other antimicrobial agentsused in preference; there are, however, clinical situationsin which complete nephrotoxic drug avoidance is notpossible. The prescribing veterinarian should consider thecost-benefit analysis of using such drugs in these animals;if the relative risk appears small, and the potential benefitgreat, potentially nephrotoxic drugs should be used withcaution and frequent monitoring of renal function(including urinalyses and serial, daily if necessary,creatinine concentration determinations) performed. Ifaminoglycosides are used in the azotaemic patient,therapeutic drug monitoring, with particular attention paidto the trough concentrations, should be carried out.

Guidelines for therapeutic drug monitoring are outside thescope of this article, and the reader is referred to othertexts (e.g. Dowling 2004).

One example of potential benefit outweighing anapparently small risk is administration of polymyxin B toendotoxaemic animals. Polymyxin B is an antimicrobialagent used at subantimicrobial doses for treatment ofendotoxaemia, and has proven to be efficacious, evenwhen given after administration of endotoxin (Barton et al.2004). Polymyxin B has potential nephrotoxic andneurotoxic effects (Raisbeck et al. 1989; MacKay et al.1999). Interestingly, despite its commonly statednephrotoxicity, this has not been demonstrated in the horseeven when very large doses have been experimentallyadministered (up to 36,000 iu/kg bwt) (Raisbeck et al. 1989;Durando et al. 1994; MacKay et al. 1999; Parviainen et al.2001; Morresey and MacKay 2006), and there are noreports of nephrotoxicity following polymyxin Badministration in the equine veterinary literature. In spite ofthis, it is commonly recommended that polymyxin B shouldbe used with care in azotaemic or hypovolaemic animals(Barton et al. 2004). Large doses have been associatedwith neurological side-effects, including ataxia,hypermetria and spasmodic coughing, seen at doses of18,000 iu/kg bwt and above (Raisbeck et al. 1989), but notat 10,000 iu/kg bwt or less (Durando et al. 1994; Barton et al.2004). Fortunately, polymyxin B binding of endotoxin occursat much lower doses, and the recommended dose rangeis 50006000 iu/kg bwt q. 812 h i.v. (Durando et al. 1994;Parviainen et al. 2001; Barton et al. 2004). In light of thecurrent evidence, and lack of reported cases ofnephrotoxicity secondary to administration of polymyxin B,the authors consider its use appropriate for the treatmentof endotoxaemia, even in those animals with prerenalazotaemia, alongside other supportive treatments.

Antimicrobial use in neonates

In general, critically ill neonatal foals are consideredimmunocompromised patients with presumed sepsis untilproven otherwise, and broad-spectrum antimicrobialtherapy should therefore be provided (Paradis 1994). Thereis compelling evidence from human medicine that earlyprovision of appropriate antimicrobial therapy increasessurvival (Ibrahim et al. 2000; Raghavan 2006), and the sameis likely to be true of the septic equine neonate. In spite ofthis, clinicians need to avoid the knee-jerk reaction toprovide the best possible antimicrobial coverage, whichmay lead to the selection of extended spectrum drugs thatshould be reserved for more serious infections that do notrespond to first-line drugs. Antimicrobials selected for theseanimals should be primary use drugs, preferably selectedwith an evidence-based approach with directedantimicrobial therapy, following years of information onblood culture isolates and sensitivity patterns in the localgeographic area. If this is not possible, data should beextrapolated and guidelines taken from the many

TABLE 2: Commonly implicated antimicrobials in antimicrobial-associated enterocolitis

EnrofloxacinTrimethoprim-sulphonamide combinationsOxytetracyclinePenicillinCeftiofurDoxycyclineErythromycinNeomycinLincomycinClindamycinMoxifloxacinFlorfenicolTylosin



published studies available treatment of the equineneonate is one of the few areas of equine medicine wheremuch information is available regarding common isolatesand potentially appropriate therapies (Platt 1973; Koterbaet al. 1984; Wilson and Madigan 1989; Brewer and Koterba1990; Paradis 1994; Raisis et al. 1996; Henson and Barton2001; McKenzie and Furr 2001; Marsh and Palmer 2001;Stewart et al. 2002; Furr 2003; Sanchez 2005; Pusterla et al.2006; Corley et al. 2007).

Antimicrobial use in enterocolitis

Many clinicians have very strong opinions on the use ofantimicrobial agents in horses with enterocolitis. There aresome conditions for which specific antimicrobial therapy isdefinitely indicated in enterocolitis; i.v. oxytetracycline forPotomac horse fever (Neorickettsia risticii) infection, andorally administered erythromycin (or clarithromycin/azithromycin) and rifampin for diarrhoea secondary toinfection with Rhodococcus equi.

Oral metronidazole has a specific indication in horseswith enterocolitis for the treatment of clostridial diarrhoea.Clostridium difficile and Clostridium perfringens infectionsare commonly implicated in enterocolitis, especially withantimicrobial associated enterocolitis (Bverud et al. 1997;Donaldson and Palmer 1999; Weese and Stmpfli 2001). Inthe neonatal foal, clostridial toxins are commonlydetected. Of 93 foals aged


contribute to antimicrobial resistance, and further disturbcolonic flora (Oliver and Stmpfli 2006). It has been shownthat antimicrobial treatment does not reduce faecalshedding of Salmonella spp, even if the strain is sensitive tothe antimicrobial agent used (van Duijkeren et al. 1995),and there is no evidence that antimicrobial therapy isbeneficial in altering the course of salmonellosis in adulthorses (Divers and Ball 1996). The decision to beginantimicrobial treatment on the basis of neutropenia,pyrexia and other signs of the systemic inflammatoryresponse syndrome (SIRS) is further complicated by the factthat these signs also occur in response to endotoxaemia,extremely common in horses with diarrhoea. Horses areexquisitely sensitive to the effects of endotoxaemia andoften appear to be endotoxaemic without evidence ofbacteraemia, perhaps due to decreased blood culturesampling in the cases when compared to neonates. Basedon the current evidence, the authors do not advocate theuse of broad-spectrum antimicrobial agents for horses withsalmonellosis or other causes of enterocolitis unlesspersistent bacteraemia is documented, or the animal ispersistently and severely neutropenic (


Antimicrobial prophylaxis in travellinganimals

There is recognised controversy as to the utility ofadministration of prophylactic antimicrobial agents toanimals prior to long distance shipping as an attempt toprevent pleuropneumonia. There is a paucity ofinformation on efficacy of prophylaxis with which to makeevidence-based decisions. It is documented that the mostimportant predisposing factor to lower respiratory diseaseis the lack of physical clearance of material when horsesare restrained and unable to lower their heads, with theaccumulation of bacteria and/or inflammatory exudate inthe trachea being documented within 24 h of suchrestraint (Racklyeft and Love 1990). It has been shown thatsuch situations reduce tracheal mucocilliary clearance(Raidal et al. 1997), and that horses that are transportedfor 12 h without restraint showed no changes in thecytology or bacteriology of broncho-alveolar lavage fluid(Traub-Dargatz et al. 1988). The authors therefore feel thatthe emphasis should be placed on environmentalmodifications rather than antimicrobial prophylaxis.

Antimicrobials in Streptococcus equi ssp.equi infection (strangles)

Veterinary opinion remains divided as to the utility ofantimicrobial therapy in strangles infections. Potentialindications for the use of antimicrobial agents in stranglesinclude treatment of peracutely affected animals duringan outbreak (those with


Methicillin resistant Staphylococcus aureus

Methicillin resistant Staphylococcus aureus (MRSA) is asignificant, international problem in human medicine, andappears to be an emerging problem in equine medicine.MRSA infections have been reported in horses in manycountries, and transmission between horses and man hasbeen identified (OMahoney et al. 2005; Weese et al.2005a,b, 2006a; Cuny et al. 2006). At present, theepidemiology of infection and colonisation of horses ispoorly understood (Weese and Lefebvre 2007). In a recentstudy, MRSA was isolated from 5.3% of 2283 horsesadmitted to a tertiary referral hospital; 50.8% were isolatedat admission. Clinical infections attributable to MRSAoccurred in 11.7% of these horses, with horses colonised atadmission were more likely to develop clinical MRSAinfection than those not colonised at admission. Clinicalinfections included septic arthritis, jugular catheter siteinfection, wound infection, pneumonia, mastitis, rhinitisand body wall abscess (Weese et al. 2006b). In addition,risk factors for community-associated MRSA colonisation ofhorses presenting to an equine hospital have beenidentified, including: previous colonisation of the horse,previous identification of colonised horses on the samefarm, antimicrobial administration within 30 days,admission to the neonatal intensive care unit, andadmission to services other than the surgery service. Asmore epidemiological information becomes availableand high risk patients are identified, appropriate controlmeasures will be possible to reduce animal to man andanimal to animal transmission.

It is the impression of the authors that MRSA infectionsin horses cause significant morbidity, but rarely causemortality. Whilst the majority of identified cases of clinicaldisease caused by MRSA in the authors hospital appearto be catheter site infections that do not require systemictreatment, wound and post operative infections seem tobe the most commonly reported manifestations of MRSAinfections in horses (Leonard and Markey 2008). Prior totreatment of clinical infections, it should be determinedwhether local treatment may be adequate, as localtreatment with chlorhexidine and 1% acetic acid havebeen successfully used to treat incisional and woundinfections (Weese 2004). If specific treatment is required,directed antimicrobial therapy selected according to thesensitivity pattern of the isolated organism is preferred.

It is the opinion of the authors that particular attentionshould be paid to controlling MRSA in horses, guidelines forwhich are presented in Table 4. Surveillance methodsshould be considered in any equine hospital, in order toidentify community acquired strains and documentnosocomial infections. In horses, the nasal passage appearsto be the most common site of colonisation (Weese 2004),therefore any screening programme should involve culturesof nasal swabs. The question then arises as to whether toattempt eradication of colonisation to reduce the risk offurther transmission and the development of clinical

disease. The manner by which this should be undertaken isunclear, and colonisation is transient in most adult horses(Weese 2004) so treatment of colonised but clinicallyunaffected animals is often regarded as unnecessary. Inaddition, antimicrobial therapy of colonised horses may beinadvisable, as MRSA isolates rapidly develop resistance,and there are only limited antimicrobial options availablefor use (Weese 2004). Intranasal antimicrobials are mostcommonly used for eradication in man; however, thedifficulty of applying topical antimicrobials to the entirenasal passage of the horse makes this a questionabletreatment in this species (Weese 2004). Nebulisation ofantimicrobials may be a viable alternative whereeradication is desirable (Weese 2004). Eradication of MRSAcolonisation has been successfully performed on a horsefarm with a policy of segregation, infection controlprecautions and repeated testing (Weese and Rosseau2005), suggesting that these measures would be sufficient ina hospital situation. At present the authors consider itappropriate to use barrier nursing techniques on identifiedcarrier animals in order to limit spread of MRSA, but do notadvise specific treatment unless clinically importantinfections have been identified.

Regardless of the approach to screening for andtreatment of MRSA infections, there is little doubt that earlyinstitution of appropriate surveillance and other infectioncontrol measures should be used to attempt to limit theimpact of MRSA in veterinary medicine (Weese 2004), andit is the responsibility of each individual institution to ensurethat these measures are taken.

Conclusions

There are many controversial topics in the field ofantimicrobial use in equine patients, and as evidence-based medicine becomes more commonplace inveterinary medicine, the answers to many of theaforementioned problems may become available. In themeantime, veterinarians should use antimicrobialsprudently and select appropriate drugs for maximumefficacy, in order to slow the development of potentiallydevastating multidrug resistant bacteria.

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Current controversies in equine antimicrobial therapy