Outpacing the resistance tsunami: Antimicrobial stewardship in equine medicine,an overview

Antimicrobial stewardship (AMS) is the term increasingly used to describe the multiple approaches needed to sustain the efficacy of antimicrobial drugs in the face of the increasing development and spread of antimicrobial resistance in bacterial pathogens, and the global crisis in medicine that it is engendering. The concept and the practices associated with AMS continue to evolve but the general approach is a dynamic and multifaceted one of continuous improvement based on reducing, improving, monitoring and evaluating the use of antimicrobials so as to preserve their future efficacy and to protect human and animal health. Using many equine examples, this basic overview discusses the multiple and interacting elements of AMS: Practice guidelines, infection control and prevention, clinical microbiology, resistance and use surveillance, dosage, pharmacokinetics and pharmacodynamics, regulation, education and owner compliance, leadership, coordination and measurement. There have been impressive advances in recent years in reporting and analysis of AMR in horses, in the scrutiny and assessment of how antimicrobial drugs are used in horses and in identification of areas for improvement including dosing, surgical prophylaxis, infection control, development of practice standards and the use of clinical microbiology. Antimicrobial stewardship is taking shape as we start to see the emergence of evidence-based recommendations but far more is required. Containing and even rolling back AMR will need the continued engagement of practitioners, equine national and international practitioner organisations, researchers and educators in the academic community, horse owners, regulators and others.     

Antimicrobial labelling in Australia: a threat to antimicrobial stewardship?

Antimicrobial resistance is a public health emergency, placing veterinary antimicrobial use under growing scrutiny. Antimicrobial stewardship, through appropriate use of antimicrobials, is a response to this threat. The need for antimicrobial stewardship in Australian veterinary practices has had limited investigation. A 2016 survey undertaken to investigate antimicrobial usage patterns by Australian veterinarians found that antimicrobial dose rates were varied and often inappropriate. Doses of procaine penicillin in horses and cattle were often low, with 68% and 90% of respondents, respectively, reporting doses that were unlikely to result in plasma concentrations above minimum inhibitory concentrations for common equine and bovine pathogens. Frequency of penicillin administration was also often inappropriate. Gentamicin doses in horses were largely appropriate (89% of dose rates appropriate), but 9% of respondents reported twice daily dosing. Amoxycillin and amoxycillin‐clavulanate were administered at the appropriate doses, or above, to dogs and cats by 54% and 70% of respondents, respectively. Here, we explore the potential reasons for inappropriate antimicrobial dose regimens and report that antimicrobial labels often recommend incorrect dose rates and thus may be contributing to poor prescribing practices. Changes to legislation are needed to ensure that antimicrobial drug labels are regularly updated to reflect the dose needed to effectively and safely treat common veterinary pathogens. This will be especially true if changes in legislation restrict antimicrobial use by veterinarians to the uses and doses specified on the label, thus hampering the current momentum towards improved antimicrobial stewardship.     

Antibacterial drug resistance and equine practice

The equine practitioner is in a position to make day‐to‐day decisions regarding antimicrobial drug (AMD) use for their patients as well as to educate their clients regarding judicious use. General guidelines regarding judicious use of AMDs in equine patients have been developed by the American Association of Equine Practitioners. Detailed guidelines for AMD use in specific equine diseases supported by clinical trials and results of surveillance studies focused on resistance among equine bacterial pathogens are lacking. Studies that could lead to detailed and justifiable use recommendations would allow the equine practitioner to make more informed decisions regarding when to use AMDs, which drugs should be used and how they should be used (e.g. dose, route and duration).     

Systemic antimicrobial therapy in foals

Antimicrobial agents are commonly used in neonatal foals for the treatment or prevention of sepsis. However, due to concerns about the development of antimicrobial resistance and increasing pressure on veterinarians to rationalise antimicrobial use, we should be trying to reduce the unnecessary use of antimicrobials. This article reviews many of the important considerations when selecting an antimicrobial for use in neonatal foals. Firstly, we consider general differences in neonatal pharmacology and physiology. Secondly, we review common antimicrobial drugs and their indications. Finally, we review antimicrobial stewardship.     

Antimicrobial ratings: the importance of importance

Debate about antimicrobial resistance (AMR) in animals and the impact on humans is often inappropriately focussed on the crude amount of antimicrobials used in animals without deference to issues of ‘intensity of use’, ‘quality of use’ and especially the class of agents being administered. In the latter case, tools for helping to manage how the use of specific antimicrobial agents impact on the risk and consequences of antimicrobial resistance in humans have been available for almost two decades. These consist of antimicrobial ratings systems, which formally define the importance of each individual agent in human health by assigning them to a position on a graduated scale of ‘importance’ comprising up to four categories of risk. Until recently, these published ratings have only had a modest impact on antimicrobial stewardship at the frontline of medical and veterinary practice, although they will undoubtedly have a substantial influence into the future. This article considers the evolution of the available ‘antimicrobial ratings systems’ applicable to Australian and international settings and their pivotal future‐role in the educating of animal managers, policy makers and prescribers. Faithful application of these rating systems at all levels of decision making to do with antimicrobial use is now seen as central to the protection of animals, humans and economies from the scourge of AMR.     

Dosing equine antimicrobials: Ensuring clinical success and avoiding antimicrobial resistance

Underdosing of equine antimicrobials is a global issue and may be contributing to antimicrobial resistance in horses. Recent research in Australia has identified that most antimicrobial use in peer-reviewed literature is at a higher dose than that currently on the label for many common equine antimicrobials in the United States, the UK and Australia. These dosing regimens used are now considered the most appropriate doses to be using in horses and veterinarians treating equine patients should be aware of the contemporary dosing regimens.     

Antimicrobial‐associated diarrhoea in three equine referral practices

Reasons for performing study: Although antimicrobial‐associated diarrhoea (AAD) is the most frequently observed adverse effect of antimicrobial therapy in horses, few multicentred studies on the prevalence of AAD have been performed. Objectives: To determine the prevalence of AAD in horses that developed diarrhoea after antimicrobial treatment for nondiarrhoeic conditions and identify the antimicrobials used. Methods: The 2009 database of 3 referral hospitals was searched to identify nonhospitalised horses (weanling age or older) treated with antimicrobials for nongastrointestinal conditions. Horses with these criteria that presented with diarrhoea during 2009 were included in the study. Additional information, including antimicrobial administered and results of faecal pathogen testing, was gathered on each hospitalised case. Results: Of the 5251 horses treated with antimicrobials for nongastrointestinal signs, 32 were diagnosed with probable AAD, a prevalence of 0.6% (95% confidence interval: 0.43–0.86%). The AAD‐diagnosed horses had an 18.8% (6/32) mortality rate. Horses with AAD had been treated for an average of 4.2 days. The most frequently used antimicrobials in horses with AAD were gentamicin in combination with penicillin (n = 7), enrofloxacin (n = 7) and doxycycline (n = 4). Clostridium difficile was identified in faecal samples from 4 horses, 2 of which died and Salmonella from 3 horses. Conclusions: Results indicated that the prevalence of AAD is low. Any antimicrobial class commonly used in equine practice is a potential cause of equine AAD. Other risk factors, such as opportunistic enteropathogens, may play a part in the development of diarrhoea secondary to antimicrobial usage. Potential relevance: Although the risk of equine AAD is low, this sequela of antimicrobial treatment is possible especially when opportunistic enteropathogens or other risk factors are present. Because drugs from any antimicrobial class can be potentially involved in AAD, clinicians have additional incentive to ensure the judicious use of antimicrobial agents.     

Overview of the use of antimicrobial drugs for the treatment of bacterial infections in horses

The use of antimicrobials in veterinary medicine is under great scrutiny with the emergence of antimicrobial resistance in the human population. Equine veterinarians rely on antimicrobials as an essential tool for the treatment of infections in horses, but there is much criticism of some use, particularly prophylaxis. While the appropriate use of antimicrobials can be justified in equine medicine, the misuse cannot. The definition of appropriate use is complex and involves the indication for therapy, antimicrobial selection, dosing regimen and timing and route of administration, duration of therapy and modification of therapy based on microbial susceptibility and clinical response. The aim of this article is to provide guidance on these factors to assist equine veterinarians in determining what constitutes appropriate antimicrobial use in horses.     

Survey of complications and antimicrobial use in equine patients at veterinary teaching hospitals that underwent surgery because of colic

OBJECTIVE: To determine current practices regarding use of antimicrobials in equine patients undergoing surgery because of colic at veterinary teaching hospitals. DESIGN: Survey. SAMPLE POPULATION: Diplomates of the American College of Veterinary Surgeons performing equine surgery at veterinary teaching hospitals in the United States. PROCEDURE: A Web-based questionnaire was developed, and 85 surgeons were asked to participate. The first part of the survey requested demographic information and information about total number of colic surgeries performed at the hospital, number of colic surgeries performed by the respondent, and whether the hospital had written guidelines for antimicrobial drug use. The second part pertained to nosocomial infections. The third part provided several case scenarios and asked respondents whether they would use antimicrobial drugs in these instances. RESULTS: Thirty-four (40%) surgeons responded to the questionnaire. Respondents indicated that most equine patients undergoing surgery because of colic at veterinary teaching hospitals in the United States received antimicrobial drugs. Drugs that were used were similar for the various hospitals that were represented, and for the most part, the drugs that were used were fairly uniform irrespective of the type of colic, whereas the duration of treatment varied with the type of colic and the surgical findings. The combination of potassium penicillin and gentamicin was the most commonly used treatment. CONCLUSIONS AND CLINICAL RELEVANCE: Results of this study document the implementation of recommendations by several authors in veterinary texts that antimicrobial drugs be administered perioperatively in equine patients with colic that are undergoing surgery. However, the need for long-term antimicrobial drug treatment in equine patients with colic is unknown.     

Advances in diagnostic ultrasonography

A wide variety of ultrasonographic equipment currently is available for use in equine practice, but no one machine is optimal for every type of imaging. Image quality is the most important factor in equipment selection once the needs of the practitioner are ascertained. The transducer frequencies available, transducer footprints, depth of field displayed, frame rate, gray scale, simultaneous electrocardiography, Doppler, and functions to modify the image are all important considerations. The ability to make measurements off of videocassette recorder playback and future upgradability should be evaluated. Linear array and sector technology are the backbone of equine ultrasonography today. Linear array technology is most useful for a high-volume broodmare practice, whereas sector technology is ideal for a more general equine practice. The curved or convex linear scanner has more applications than the standard linear array and is equipped with the linear array rectal probe, which provides the equine practitioner with a more versatile unit for equine ultrasonographic evaluations. The annular array and phased array systems have improved image quality, but each has its own limitations. The new sector scanners still provide the most versatile affordable equipment for equine general practice.     

Antibiotic prophylaxis in veterinary cancer chemotherapy: A review and recommendations

Bacterial infection following cancer chemotherapy‐induced neutropenia is a serious cause of morbidity and mortality in human and veterinary patients. Antimicrobial prophylaxis is controversial in the human oncology field, as any decreased incidence in bacterial infections is countered by patient adverse effects and increased antimicrobial resistance. Comprehensive guidelines exist to aid human oncologists in prescribing antimicrobial prophylaxis but similar recommendations are not available in veterinary literature. As the veterinarian's role in antimicrobial stewardship is increasingly emphasized, it is vital that veterinary oncologists implement appropriate antimicrobial use. By considering the available human and veterinary literature we present an overview of current clinical practices and are able to suggest recommendations for prophylactic antimicrobial use in veterinary cancer chemotherapy patients.     

Multidrug-resistant Salmonella and nosocomial infections.

Nosocomial infections are a serious threat to optimum patient care. In addition, nosocomial infections can have far-reaching consequences for the hospital personnel and the financial aspects of the hospital. Nosocomial infections with Salmonella spp have been described among hospitalized equine populations more frequently than any other agent. Salmonella spp associated with hospitalized equids often possess more antimicrobial resistance determinants than do Salmonella spp isolated from healthy horses in the general population. There is little evidence to suggest that resistant salmonellae are more virulent than nonresistant forms. MDR forms of Salmonella complicate the selection of appropriate antimicrobials when they are indicated, however. Furthermore, the use of some antimicrobials may apply selection pressure toward enhanced ability of MDR Salmonella to colonize equine patients. Further research should help to elucidate the risky uses of antimicrobials in the hospital setting and define the role of disinfectants and treatments such as NSAIDs in the ecology of MDR forms of nosocomial infections, including Salmonella. In the meantime, thoughtful selection of when and how to use antimicrobials in equine patients, together with deliberate selection of which antimicrobials to use based on monitoring data and other factors, such as safety and spectrum, is advised.     

International trends impacting antimicrobial stewardship in animal health

The Tripartite collaboration (World Health Organization, the Food and Agriculture Organisation of the United Nations, and the World Organisation for Animal Health) produced two documents for consultation with Member Countries in 2017 ‐ Monitoring and Evaluation of the Global Action Plan on Antimicrobial Resistance: Proposed approach and the Global Framework for Development & Stewardship to Combat Antimicrobial Resistance: Draft Roadmap. These documents intend to support a strategic whole‐of‐system approach towards the World Health Organization's Global Action Plan on Antimicrobial Resistance. This paper outlines the recent thinking in antimicrobial stewardship being developed by the major international organisations involved with mitigating global antimicrobial resistance. The directions being set in key frameworks will need to be considered by Australian stakeholders as their own antimicrobial stewardship approaches and activities are formulated.     

Evolution of equine infection control programs.

The science of control of infectious diseases in hospitals was born in 1847 when Semmelweis, a physician, ordered his medical students to scrub their hands in chlorinated lime water between patients and demonstrated that this simple procedure resulted ina dramatic decline in patient morbidity and mortality. In the late nineteenth century came huge breakthroughs in the understanding that microorganisms cause many disorders, and methods to eliminate and control these microorganisms were attempted. By 1910, sterile instruments, gowns, masks, and gloves had become standard for surgical procedures in large university human hospitals, and isolation of human and veterinary patients with contagious diseases became standard. With the advent of vaccines, many epidemic viral diseases could be controlled, and antimicrobial drugs allowed many previously devastating bacterial diseases to be treated effectively. Before long, however, bacterial resistance became an important issue and remains so today, particularly for Salmonella and Staphylococcus aureus in horses. Vaccination has decreased the number of animals susceptible to equine influenza and equine herpesvirus 1, yet these contagious diseases still pose a serious issue in large equine veterinary hospitals. The development of equine isolation facilities and improved methods of barn cleaning; mandatory application of procedures, such as handwashing or use of disinfectant hand wipes, to prevent the spread of infectious diseases; and monitoring of antimicrobial resistance and use of restricted antimicrobial drugs were driven by recognition and necessity and have given rise to current equine infection control programs.     

Rational selection of antimicrobial drugs for treatment of infections of horses

The goal of antimicrobial drug use is quite specific. Consideration of many microbe-related, host-related, and drug-related factors is necessary for appropriate selection and use of antimicrobial drugs in equine patients. The concepts and data presented in this article demonstrate that fact. At the risk of oversimplification, "The bug denotes the drug, and the horse directs the course."     

The antimicrobial activity of honey against common equine wound bacterial isolates

Delayed healing associated with distal limb wounds is a particular problem in equine clinical practice. Recent studies in human beings and other species have demonstrated the beneficial wound healing properties of honey, and medical grade honey dressings are available commercially in equine practice. Equine clinicians are reported to source other non-medical grade honeys for the same purpose. This study aimed to assess the antimicrobial activity of a number of honey types against common equine wound bacterial pathogens. Twenty-nine honey products were sourced, including gamma-irradiated and non-irradiated commercial medical grade honeys, supermarket honeys, and honeys from local beekeepers. To exclude contaminated honeys from the project, all honeys were cultured aerobically for evidence of bacterial contamination. Aerobic bacteria or fungi were recovered from 18 products. The antimicrobial activity of the remaining 11 products was assessed against 10 wound bacteria, recovered from the wounds of horses, including methicillin resistant Staphylococcus aureus and Pseudomonas aeruginosa. Eight products were effective against all 10 bacterial isolates at concentrations varying from <2% to 16% (v/v). Overall, the Scottish Heather Honey was the best performing product, and inhibited the growth of all 10 bacterial isolates at concentrations ranging from <2% to 6% (v/v).Although Manuka has been the most studied honey to date, other sources may have valuable antimicrobial properties. Since some honeys were found to be contaminated with aerobic bacteria or fungi, non-sterile honeys may not be suitable for wound treatment. Further assessment of gamma-irradiated honeys from the best performing honeys would be useful.     

Extended-spectrum beta-lactamases-producing gram-negative bacteria in companion animals: action is clearly warranted!

Extended-spectrum beta-lactamases (ESBL)-producing Gram-negative bacteria pose a serious threat to Public Health in human medicine as well as increasingly in the veterinary context worldwide. Several studies reported the transmission of zoonotic multidrug resistant bacteria between food-producing animals and humans, whilst the contribution of companion animals to this scenario is rather unknown. Within the last decades a change in the social role of companion animals has taken place, resulting in a very close contact between owners and their pets. As a consequence, humans may obtain antimicrobial resistant bacteria or the corresponding resistance genes not only from food-producing animals but also via close contact to their pets.This may give rise to bacterial infections with limited therapeutic options and an increased risk of treatment failure. As beta-lactams constitute one of the most important groups of antimicrobial agents in veterinary medicine, retaliatory actions in small animal and equine practices are urgently needed. This review addresses the increasing burden of extended-spectrum beta-lactam resistance among Enterobacteriaceae isolated from companion animals. It should emphasize the urgent need for the implementation of antibiotic stewardship as well as surveillance and monitoring programs of multi resistant bacteria in particular in view of new putative infection cycles between humans and their pets.