Antimicrobials in an age of resistance

By Jennifer Davis and Celia Marr

Growing numbers of bacterial and viral infections are resistant to antimicrobial drugs, but no new classes of antibiotics have come on the market for more than 25 years. Antimicrobial-resistant bacteria cause at least 700,000 human deaths per year according to the World Health Organization (WHO). Equivalent figures for horses are not available, but where once equine vets would have very rarely encountered antimicrobial-resistant bacteria, in recent years this serious problem is a weekly, if not daily, challenge. 

The WHO has for several years now, designated a World Antibiotic Awareness Week each November and joining this effort, British Equine Veterinary Association and its Equine Veterinary Journal put together a group of articles exploring this problem in horses.

For more information:  https://beva.onlinelibrary.wiley.com/hub/journal/20423306/homepage/sc_antimicrobials_in_an_age_of_resistance

How do bacterial populations develop resistance?

Certain types of bacteria are naturally resistant to specific antimicrobials and susceptible to others. Bacteria can develop resistance to antimicrobials in three ways: bacteria, viruses and other microbes, which can develop resistance through genetic mutations or by one species acquiring resistance from another. Widespread antibiotic use has made more bacteria resistant through evolutionary pressure—the “survival of the fittest” principle means that every time antimicrobials are used, susceptible microbes may be killed; but there is a chance that a resistant strain survives the exposure and continues to live and expand. The more antimicrobials are used, the more pressure there is for resistance to develop.

The veterinary field remains a relatively minor contributor to the development of antimicrobial resistance. However, the risk of antimicrobial-resistant determinants traveling between 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 important for safeguarding human health. Putting that aside, it is also critical for equine vets, owners and trainers to recognize we need to take action now to limit the increase of antimicrobials directly relevant to horse health.

How does antimicrobial resistance impact horse health?

Fig 1. This mare’s problems began with colic; she underwent surgery to correct a colon torsion (twisted gut). When the gut wall was damaged, bacteria easily spread throughout the body. The mare developed an infection in her surgical incision and in her jugular veins, progressing eventually to uncontrollable infection—resistant to all available antimicrobials with infection of the heart and lungs.

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. In an analysis of 12,695 antibiograms collected from horses in France between 2012-2016, the highest proportion (22.5%) of MDR isolates were S. aureus. Identification of ESBL E.coli strains that are resistant to all available antimicrobial classes has increased markedly in horses. In a sampling of healthy adult horses at 41 premises in France in 2015, 44% of the horses shed MDR E.coli, and 29% of premises shedding ESBL isolates were found in one third of the equestrian premises. Resistant E. coli strains are also being found in post-surgical patients with increasing frequency.

Fig 2. Rhodococcus equi is a major cause of illness in young foals. It leads to pneumonia and lung abscesses, which in this example has spread through the entire lung. Research from Kentucky shows that antimicrobial resistance is increasingly common in this bacterial species.

Of major concern to stud owners, antimicrobial-resistant strains of Rhodococcus equi have been identified in Kentucky in the last decade, and this bacteria can cause devastating pneumonia in foals. Foals that are affected by the resistant strains are unlikely to survive the illness. One of the leading authorities on R.equi pneumonia, Dr. Monica Venner has published several studies showing that foals can recover from small pulmonary abscesses just as quickly without antibiotics, and has pioneered an “identify and monitor” approach rather than “identify and treat.”  Venner encourages vets to use ultrasonography to quantify the infected areas within the lung and to use repeat scans, careful clinical monitoring and laboratory tests to monitor recovery. Antimicrobials are still used in foals, which are more severely affected, but this targeted approach helps minimize drug use.

What can we do to reduce the risk of antimicrobial resistance?

The simple answer is stop using antimicrobials in most circumstances except where this is absolutely avoidable. In training yards, antimicrobials are being over-used for coughing horses. Many cases are due to viral infection, for which antibiotics will have little effect. There is also a tendency for trainers to reach for antibiotics rather than focusing on improving air quality and reducing exposure to dust. Many coughing horses will recover without antibiotics, given time. Although it has not yet been evaluated scientifically, adopting the identify and monitor approach, which is very successful in younger foals, might well translate to horses in training in order to reduce overuse of antimicrobials.

Fig 3. Faced with a coughing horse, trainers will often pressure their vet to administer antibiotics, hoping this will clear up the problem quickly. Many respiratory cases will recover without antibiotics, given rest and good ventilation

Vets are also encouraged to choose antibiotics more carefully, using laboratory results to select the drug that will target specific bacteria most effectively. The World Health Organization has identified five classes of antimicrobials as being critically important, and therefore reserved, antimicrobials in human medicine. The critically important antimicrobials which are used in horses are the cephalosporins (e.g., ceftiofur) and quinolones (e.g., enrofloxacin), and the macrolides, which are mainly used in foals for Rhodococcal pneumonia. WHO and other policymakers and opinion leaders have been urging vets and animal owners to reduce their use of critically important antimicrobials for well over a decade now. Critically important antimicrobials should only be used where there is no alternative, where the disease being treated has serious consequences and where there is laboratory evidence to back up the selection. The British Equine Veterinary Association has produced helpful guidelines and a toolkit, PROTECT-ME, to help equine vets achieve this.

How well are we addressing this problem?

Disappointingly, in a recent review of prescribing behavior of three “reserved” antimicrobials at first-opinion equine practices in the USA and Canada between 2006-2012 published in Equine Veterinary Journal, only 5% of prescriptions for the reserved antimicrobials enrofloxacin, ceftiofur and clarithromycin were informed by culture and sensitivity testing. There was also an overall trend of increased prescribing of enrofloxacin across the study period, and despite increasing awareness of the challenge of antimicrobial resistance, a decreasing proportion of enrofloxacin prescriptions were based on culture and sensitivity results.

Judicious use of antimicrobials for surgical patients

Antimicrobials are commonly used in the perioperative 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 recommends administration of penicillin pre- and post-operatively for 24 hours for clean surgeries; penicillin and gentamicin pre- and post-operatively for five 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 perioperative antimicrobial use among equine practitioners in Australia revealed that most equine vets selected an appropriate antimicrobial agent. However, the dose of penicillin chosen was often suboptimal, and therapy was frequently prolonged beyond recommendations in all scenarios except for castration. 

Judicious use of antimicrobials through appropriate routes of administration

Fig 4. Using antimicrobials as effectively as possible helps to reduce their use overall. For septic arthritis, intravenous regional perfusion of antimicrobials can achieve very high concentrations within a specific limb. This involves placing a temporary tourniquet to reduce blood flow away from the area while the antimicrobial is injected into a nearby blood vessel. The technique is suitable for some but not all antimicrobial drugs.

Due to increasing isolation of MDR organisms, research into local therapy of “reserved” classes of antimicrobials is of interest. Intravenous regional limb perfusion of ceftiofur sodium may be appropriate for septic arthritis but is less clear cut for osteomyelitis. 

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 have the potential for subtherapeutic concentrations. Rectal administration of some antimicrobials has been explored in order to provide antimicrobials to horses with diseases that prevent oral administration, such as small intestinal problems or to provide an alternative for horses that find drugs unpalatable and go off their feed. Metronidazole is one of the few drugs for which pharmacokinetic data following rectal administration have been published, but the optimal dosing regimens via this route have yet to be determined.

Clinical conclusions

Given the increasing prevalence of resistant bacteria affecting the equine population, judicious use of antimicrobials is necessary. Trainers and vets must work together to implement this, otherwise before long, we will find we have no effective drugs left. Firstly, in any given situation, we should question whether antibiotics are really 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. It is also important to keep up-to-date with the latest information on drug treatment schedules and be prepared to modify and adapt as new information becomes available. Appropriate antimicrobial stewardship in veterinary medicine will ensure the availability and legal use of antimicrobials remains an option for our equine patients.