Clinical insights: Antimicrobials in an age of resistance

Antimicrobial-resistant bacteria cause at least 700,000 human deaths per year according to the World Health Organization 1. The veterinary field remains a relatively minor contributor to the development of antimicrobial resistance, and significant morbidity and mortality associated with antimicrobial resistance remains relatively limited in companion and food animals. However, the risk of antimicrobial-resistant determinants travelling among bacteria, animals and humans through the food chain, direct contact and environmental contamination has made the issue of judicious antimicrobial use in the veterinary field a trending topic both among lawmakers and human healthcare professionals. Reliable estimates for equine morbidity and mortality relating to infection with antimicrobial-resistant bacteria are not yet available. However, cases doubtless occur and the most significant threat to both human and equine populations is multidrug-resistant (MDR) pathogens, including methicillin resistant Staphylococcus aureus (MRSA), extended spectrum beta-lactamase (ESBL) producing Escherichia coli, MDR Klebsiella pneumoniae, Pseudomonas aeruginosa, Enterococcus faecium, and rising MDR strains of Salmonella spp. and Clostridium difficile. Veterinarians and their staff carry a higher risk of MRSA colonisation compared to the general population, and nosocomial MRSA infections have been reported in equine hospitals resulting in patient morbidity and significant financial losses 2. In an analysis of 12,695 antibiograms in France between 2012 and 2016, the highest proportion (22.5%) of MDR-resistant isolates was S. aureus 3. Carriage and isolation of ESBL E. coli strains that are resistant to all available antimicrobial classes has increased markedly in horses, and are being seen as a rising cause of nosocomial disease in equine hospitals 2. In a sampling of healthy adult horses at 41 premises in France in 2015, 44% of horses sampled shed MDR-resistant E. coli, with 29% of premises shedding ESBL isolates 4. Resistance to even ‘reserved’ classes of antimicrobials has been reported in equine and canine Salmonella isolates, such as the fluoroquinolone-resistant serovar ST198 as well as ESBL and ceftiofur-resistant strains 2. Macrolide and rifampicin-resistant strains of R. equi have been demonstrated in farms in the United States, and an increasing prevalence has been noted in Kentucky over the period of 2007–2017 compared with the period 1995–2006 5. Antimicrobial use is critical to the practice of veterinary medicine and safeguarding animal welfare; however, inappropriate antimicrobial use in equine and companion animal practice may lead the industry to face legislative regulations on par with food animal practices. The World Health Organization has identified five classes of antimicrobials, later generation cephalosporins, glycopeptides, macrolides, polymyxins and quinolones, as being critically important, and therefore reserved, antimicrobials in human medicine 1. In a recent review of prescribing behaviour of three ‘reserved’ antimicrobials at first-opinion equine practices in the USA and Canada between 2006–2012, only 5% of prescriptions for the ‘reserved’ antimicrobials enrofloxacin, ceftiofur and clarithromycin were informed by culture and sensitivity testing 6. There was also an overall trend of increased prescribing of enrofloxacin across the entire study period, and decreasing proportion of enrofloxacin prescriptions based on culture and sensitivity results 6. These results suggest that the financial effects of the global economic crisis, owner demand and convenience, may have mitigated the number of culture and sensitivity tests performed despite dissemination of stewardship advice to practitioners 2, 6. A common use of antimicrobials by equine veterinarians is during the peri-operative period. In both human and veterinary medicine, antimicrobial use for surgical prophylaxis has been a target for reducing or eliminating inappropriate antimicrobial administration. The British Equine Veterinary Association (BEVA) has released antimicrobial use guidelines to improve peri-operative prescribing practices. The BEVA guidelines recommend administration of penicillin pre- and post-operatively for 24 h for clean surgeries, penicillin and gentamicin pre- and post-operatively for 5 days for contaminated surgeries, and penicillin and gentamicin pre- and post-operatively for 10 days for complicated surgeries. Furthermore, for uncomplicated contaminated wounds (e.g. hoof abscesses), antimicrobial therapy is not recommended. A 2018 survey of peri-operative antimicrobial use among equine practitioners in Australia revealed most practitioners selected an appropriate antimicrobial agent; however, subtherapeutic dosing of penicillin was common, and therapy was prolonged beyond recommendations in all scenarios except for castration 7. Timing of pre-operative antimicrobial administration is also critical. Intramuscular procaine penicillin G (PPG) is commonly administered as a peri-operative prophylactic antimicrobial in horses. A study by Hardefeldt et al. revealed 38% of respondents administered PPG within 30 min of surgery, and 33% of respondents administered the first dose after surgery. However, maximal plasma concentrations, and therefore tissue concentrations, are not typically reached until approximately 3.5 h post-administration of intramuscular PPG 8. A new hybrid administration protocol wherein potassium penicillin (22,000 IU/kg) is administered intravenously at 0 and 6 h, followed by intramuscular PPG (22,000 IU/kg) at 12 h achieves plasma concentrations above the MIC for Streptococcus spp. (≤0.06 μg/mL) for 50% of a 24 h dosing interval, representing an option for treatment pre- and post-surgery that balances both cost and efficacy9. Due to increasing isolation of MDR organisms, research into local therapy of ‘reserved’ classes of antimicrobials is of interest. Intravenous regional limb perfusion (IVRLP) of ceftiofur sodium has been proposed as a treatment of septic arthritis and osteomyelitis in horses. While this route may be efficacious for septic arthritis, a newer study questions its efficacy for osteomyelitis. IVRLP of 2 g of ceftiofur sodium in 60 mL of sterile saline only reached bone concentrations above MIC for common pathogens immediately post-tourniquet removal, despite maintaining plasma concentrations and subcutaneous concentrations above MIC for 12 and 24 h, respectively, in healthy adult horses 10. Meropenem and imipenem, WHO classified ‘critically important’ carbapenems, have been investigated for IVRLP use in horses against MDR pathogens with a suggested dosage of 500 mg once daily. However, IVRLP of meropenem resulted in synovial fluid concentrations above MIC breakpoints for common pathogens for only 4.1 h post-administration 11, and imipenem for only 6 h post-administration 12. While a post-antibiotic effect has been noted with systemic administration of imipenem against some pathogens, this phenomenon has not been investigated for equine specific pathogens commonly isolated from septic arthritis. Oral and rectal administration of antimicrobials are common means to provide cost effective and convenient treatment options for owners. However, these routes of administration can lead to variable absorption and therefore the potential for subtherapeutic concentrations. For example, feeding has been shown to decrease the absorption of minocycline, with a mean bioavailability of 38.6% in fasted horses vs. 15.7% in fed horses 13. Additionally, fed horses had a lower Cmax and longer half-life compared with fasted horses. Therefore, oral administration of minocycline should be performed at least 2 h prior to feeding of a hay meal 13. Rectal administration of some antimicrobials has been explored in order to provide antimicrobials to horses with diseases that preclude administration of oral formulations (e.g. proximal enteritis) or to provide an alternative for horses with behavioural or palatal aversions to the formulation. Metronidazole is one of the few drugs that has actually been studied via this route and bioavailability is decreased (mean 30%) compared with oral (mean 74%) administration 14. Furthermore, metronidazole pharmacokinetics following rectal administration are not significantly affected by rectal evacuation prior to administration 15. However, metronidazole did not reach a clinically efficacious Cmax:MIC ratio in either evacuated or nonevacuated horses following rectal administration, suggesting that higher doses or more frequent dosing intervals may be required to achieve efficacious ratios 15. When investigating the prescribing behaviour of reserved antimicrobials, Welsh and colleagues found a strong seasonal association with clarithromycin prescribing behaviours that was compatible with prevalence of Rhodococcus equi infections in foals 6. Macrolides combined with rifampicin remain a mainstay of treatment for R. equi pneumonia in foals, however newer data regarding drug-drug interactions bring the necessity of combination therapy into question. Rifampicin, when given at 10 mg/kg once daily generates concentrations above MIC90 for R. equi in pulmonary compartments, but also induces intestinal p-glycoprotein efflux pump expression 16. This induction affects oral absorption and pulmonary distribution of clarithromycin when both drugs are given concomitantly, lowering the systemic exposure to levels below MIC90 for R. equi 17, 18. Separating the administration of these drugs by 4 h may mitigate this effect to a certain degree, but not to a clinically significant degree 18. A similar drug-drug interaction was not found when a combination of intravenous gamithromycin (6 mg/kg once weekly) and oral rifampicin (10 mg/kg once daily) was studied. Co-administration of these antimicrobials resulted in significantly increased plasma exposure of gamithromycin due to likely inhibition of hepatic elimination mechanisms leading to prolonged mean residence time and reduced clearance 19. Further work needs to be done to determine if rifampicin co-administration is necessary for successful treatment of R. equi pneumonia in foals. Rifampicin is considered to be an essential drug for treatment of tuberculosis in humans and therefore its use in veterinary medicine may soon become regulated in some countries. Finally, the clinician must decide whether or not antimicrobial treatment of R. equi is necessary at all. Many foals with subclinical disease or small lesions will resolve without treatment. This is important, as macrolides are associated with several severe adverse effects. Oral macrolide administration, particularly with erythromycin, has reported adverse side effects such as diarrhoea, and hyperthermia due to induced anhidrosis. Clarithromycin and azithromycin have also been found to suppress sweating, albeit to a lesser degree than erythromycin, in a quantitative terbutaline sweat test challenge in normal foals 20. The sweat suppressing effects of these macrolides was not substantially affected by concurrent administration of rifampicin 20. Future considerations for decreasing antimicrobial use for the treatment of R. equi in foals may involve passive or active immune stimulation. Recently, pre-treatment of foals with an antibody to poly-N-acetyl glucosamine (PNAG), a conserved surface microbial polysaccharide, has been found to be protective in foals when challenged with live R. equi 21. Furthermore, maternal PNAG vaccination and antibody transfer to foals was found to enhance in vitro cell-mediated immune responses against R. equi 21. PNAG, while requiring further study before clinical implementation can occur, is an exciting new avenue that could lead to equine industry-wide reductions in macrolide use in foals. Given the increasing prevalence of resistant bacteria affecting the equine population, judicious use of antimicrobials is necessary. Appropriate antibiotic selection, as well as choosing the correct dose, frequency, duration and route of administration should all be considered. Veterinarians should encourage culture and sensitivity testing to allow for guided and narrow spectrum therapies whenever possible. Practitioners should alter drug treatment schedules and selection as new information regarding the characterisation of drug pharmacokinetics and the pharmacodynamics of drug-pathogen interactions becomes available. Appropriate antimicrobial stewardship in veterinary medicine will ensure the availability and legal use of antimicrobials remains an option for our equine patients.

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