Antimicrobial use in food and companion animals

The vast literature on antimicrobial drug use in animals has expanded considerably recently as the antimicrobial resistance (AMR) crisis in human medicine leads to questions about all usage of antimicrobial drugs, including long-term usage in intensively managed food animals for growth promotion and disease prevention. Attention is also increasingly focusing on antimicrobial use and on bacterial resistance in companion animals, which are in intimate contact with the human population. They may share resistant bacteria with their owners, amplify resistant bacteria acquired from their owners, and act as a reservoir for human infection. Considerable effort is being made to describe the basis of AMR in bacterial pathogens of animals. Documentation of many aspects of use of antimicrobials in animals is, however, generally less developed and only a few countries can describe quantities of drugs used in animals to kg levels annually. In recent years, many national veterinary associations have produced 'prudent use guidelines' to try to improve antimicrobial drug use and decrease resistance, but the impact of guidelines is unknown. Within the evolving global movement for 'antimicrobial stewardship', there is considerable scope to improve many aspects of antimicrobial use in animals, including infection control and reduction of use, with a view to reducing resistance and its spread, and to preserving antimicrobial drugs for the future.     

Antimicrobial selection, administration and dosage

Various types of information contribute to the selection of an antimicrobial agent. Initial requirements are diagnosis of the site and nature of the infection, assessment of the severity of the infectious process and medical condition of the diseased animal; these are embodied in clinical experience. Additional considerations include identification of the causative pathogenic microorganism, knowledge of its susceptibility to antimicrobial agents (microbiological considerations) and of the pharmacokinetic properties of the drug of choice and alternative drugs, and their potential toxicity (pharmacological considerations) in the animal species. Select an antimicrobial drug and dosage form appropriate for use in the particular animal species. Usual dosage regimens may be applied, except in the presence of renal or hepatic impairment, when either modified dosage or a drug belonging to another class should be used. The duration of therapy is determined by monitoring the response both by clinical assessment and bacterial culture. A favourable clinical response is the ultimate criterion of successful therapy.     

Alternatives to conventional antimicrobial drugs: a review of future prospects

BACKGROUND: Growing antimicrobial resistance poses the threat that before long no suitable drugs will be available for treatment of common infections. This review examines promising new strategies for treatment and control of microbial diseases, with an emphasis on staphylococcal infection. NEW DRUGS AND TARGETS: Advances in microbial genomics have provided tools identifying many new targets for antimicrobial drugs. Of particular interest amongst these are inhibition of microbial efflux pump activity, interruption or diversion of riboswitches controlling bacterial metabolism, and metagenomics, which allows analysis of genes from unculturable organisms. BIOLOGICAL APPROACHES: Advances are also being made in biological systems for disease control, with the exploitation of antimicrobial peptides to attack micro-organisms and modulate immune responses, and the use of bacteriophages or their lysins to eliminate bacteria. There are new approaches in the development and targeting of vaccines and immunoglobulin preparations based on advanced knowledge of microbial physiology and immunoregulation. WORKING WITH THE BIOME: With increasing recognition of the value of the normal microbiota in modulating immunity and the establishment of pathogens, there is growing interest in understanding the mammalian microbiome. Strategies are being developed to promote or maintain the normal microbiota, including the use of probiotics, and there is re-evaluation of the potential of bacterial interference. LOOKING AHEAD: Whilst these approaches are likely to generate new methods of disease control, few will yield usable products within the near future. There will be a continuing need for careful use of existing drugs based on firm diagnosis, rigorous hygiene and prudent antimicrobial stewardship.     

Overview of the use of antimicrobials for the treatment of bacterial infections in horses

Use of antimicrobial drugs is central to the treatment of primary and secondary bacterial infection in horses. When selecting an antimicrobial to treat confirmed or suspected bacterial infection multiple factors should be considered, including: the likely infectious agent; distribution and dosage of selected drugs; mechanisms of action; and potential side effects. Many of these issues will be covered in subsequent articles in this series. The aim of this paper is to aid the clinician in the rational selection of antimicrobials by reviewing the mode of action, spectrum of activity, pharmacokinetics, pharmacodynamics, indications and potential side effects of the main classes of antimicrobial drugs. Extralabel use of drugs is common in veterinary medicine due to a lack of licensed products. This increases the importance of a thorough understanding of antimicrobials and their possible adverse effects.     

Perioperative antimicrobial considerations for gastrointestinal surgery of cattle

Perioperative use of antimicrobial drugs constitutes extra-label use of those drugs. Principles of therapeutic and prophylactic use of antimicrobial drugs can guide decisions about their perioperative use. Regimens currently suggested are based on those principles, theoretical information, pharmacokinetic and pharmacodynamic data, extrapolation from studies with other species, empirical data, personal bias, and experience. Controlled clinical investigations are necessary to provide objective data from which specific recommendations can be derived.     

Antimicrobial chemotherapy in the dog

The concept is expounded that, in canine practice, antimicrobial therapy normally should be based on the pharmacology of the drug employed and the therapeutic responses that have been observed to it, as well as a knowledge of the in vitro sensitivities of causal agents. In so doing, information is presented on the concentrations of antimicrobials found to be inhibitory to micro-organisms by in vitro tests and following clinical use. Guide-lines to therapy are related to body systems and organs infected and to Gram-stain reactions of isolates; also presented are dose rates, routes of administration and some general considerations employed when using the antimicrobial drugs for systemic therapy in the dog.     

Antimicrobial drug use and resistance in dogs

Fifteen years (1984-1998) of records from a Veterinary Teaching Hospital were analyzed to determine whether antimicrobial drug resistance in coagulase-positive Staphylococcus spp. (S. aureus, S. intermedius) isolated from clinical infections in dogs has increased, and whether there has been a change in the species of bacteria isolated from urinary tract infections in dogs. In coagulase-positive Staphylococcus spp., a complex pattern showing both increases and decreases of resistance to different classes of antimicrobial drugs was observed, reflecting the changing use of different antimicrobial drug classes in the hospital over a similar period (1990-1999). In canine urinary tract infections identified from 1984 to 1998, an increase in the incidence of multiresistant Enterococcus spp. was apparent, with marginal increases also in incidence in Enterobacter spp. and in Pseudomonas aeruginosa, both of which, like Enterococcus spp., are innately antimicrobial-resistant bacteria. A survey of directors of veterinary teaching hospitals in Canada and the United States identified only 3 hospitals that had any policy on use of "last resort" antimicrobial drugs (amikacin, imipenem, vancomycin). Evidence is briefly reviewed that owners may be at risk when dogs are treated with antimicrobial drugs, as well as evidence that some resistant bacteria may be acquired by dogs as a result of antimicrobial drug use in agriculture. Based in part on gaps in our knowledge, recommendations are made on prudent use of antimicrobial drugs in companion animals, as well as on the need to develop science-based infection control programs in veterinary hospitals.     

兽用抗菌药物联合用药的PK-PD研究进展

随着养殖业的迅速发展，兽用抗菌药物的应用越来越广泛，但由于抗菌药物的不合理选择与滥用导致细菌对抗菌药物的耐药率在逐渐提高，几乎所有细菌都获得耐药基因。目前，细菌耐药已成为一个全球性问题，并且临床上，疾病病因复杂，常表现为多种病原菌的继发感染和混合感染，单一用药往往难以有效控制疾病，严重危害养殖业发展。抗菌药物的联合用药可以提升药物的治疗效果，缓解或减少不良反应，降低细菌耐药性发生率，对混合感染或不能进行细菌学诊断的病例，联合用药还可扩大抗菌范围。而药物代谢动力学（PK）与药效学（PD）结合模型可以有效综合药物、机体和致病菌之间的相互关系，为临床提供合理用药方案。因此，作者通过介绍联合用药的优势与问题，抗菌药物PK/PD的分类及PK/PD对联合用药给药方案的优化与指导，总结现阶段兽药抗菌药物联合用药的PK-PD研究进展，以期促进兽医临床抗菌药物的合理使用。     

Pharmacokinetic/pharmacodynamic relationships of antimicrobial drugs used in veterinary medicine

The rise in incidence of antimicrobial resistance, consumer demands and improved understanding of antimicrobial action has encouraged international agencies to review the use of antimicrobial drugs. More detailed understanding of relationships between the pharmacokinetics (PK) of antimicrobial drugs in target animal species and their action on target pathogens [pharmacodynamics (PD)] has led to greater sophistication in design of dosage schedules which improve the activity and reduce the selection pressure for resistance in antimicrobial therapy. This, in turn, may be informative in the pharmaceutical development of antimicrobial drugs and in their selection and clinical utility. PK/PD relationships between area under the concentration time curve from zero to 24 h (AUC(0-24)) and minimum inhibitory concentration (MIC), maximum plasma concentration (C(max)) and MIC and time during which plasma concentrations exceed the MIC have been particularly useful in optimizing efficacy and minimizing resistance. Antimicrobial drugs have been classified as concentration-dependent where increasing concentrations at the locus of infection improve bacterial kill, or time-dependent where exceeding the MIC for a prolonged percentage of the inter-dosing interval correlates with improved efficacy. For the latter group increasing the absolute concentration obtained above a threshold does not improve efficacy. The PK/PD relationship for each group of antimicrobial drugs is 'bug and drug' specific, although ratios of 125 for AUC(0-24):MIC and 10 for C(max):MIC have been recommended to achieve high efficacy for concentration-dependent antimicrobial drugs, and exceeding MIC by 1-5 multiples for between 40 and 100% of the inter-dosing interval is appropriate for most time-dependent agents. Fluoroquinolones, aminoglycosides and metronidazole are concentration-dependent and beta-lactams, macrolides, lincosamides and glycopeptides are time-dependent. For drugs of other classes there is limited and conflicting information on their classification. Resistance selection may be reduced for concentration-dependent antimicrobials by achieving an AUC(0-24):MIC ratio of greater than 100 or a C(max):MIC ratio of greater than 8. The relationships between time greater than MIC and resistance selection for time-dependent antimicrobials have not been well characterized.     

Antimicrobial Resistance of Faecal Escherichia coli Isolates from Pig Farms with Different Durations of In‐feed Antimicrobial Use

Antimicrobial use and resistance in animal and food production are of concern to public health. The primary aims of this study were to determine the frequency of resistance to 12 antimicrobials in Escherichia coli isolates from 39 pig farms and to identify patterns of antimicrobial use on these farms. Further aims were to determine whether a categorization of farms based on the duration of in‐feed antimicrobial use (long‐term versus short‐term) could predict the occurrence of resistance on these farms and to identify the usage of specific antimicrobial drugs associated with the occurrence of resistance. Escherichia coli were isolated from all production stages on these farms; susceptibility testing was carried out against a panel of antimicrobials. Antimicrobial prescribing data were collected, and farms were categorized as long term or short term based on these. Resistance frequencies and antimicrobial use were tabulated. Logistic regression models of resistance to each antimicrobial were constructed with stage of production, duration of antimicrobial use and the use of 5 antimicrobial classes included as explanatory variables in each model. The greatest frequencies of resistance were observed to tetracycline, trimethoprim/sulphamethoxazole and streptomycin with the highest levels of resistance observed in isolates from first‐stage weaned pigs. Differences in the types of antimicrobial drugs used were noted between long‐term and short‐term use farms. Categorization of farms as long‐ or short‐term use was sufficient to predict the likely occurrence of resistance to 3 antimicrobial classes and could provide an aid in the control of resistance in the food chain. Stage of production was a significant predictor variable in all models of resistance constructed and did not solely reflect antimicrobial use at each stage. Cross‐selection and co‐selection for resistance was evident in the models constructed, and the use of trimethoprim/sulphonamide drugs in particular was associated with the occurrence of resistance to other antimicrobials.     

Plasma concentration and disposition of antimicrobial agents in the dog

Although there is sufficient information on the pharmacology and therapeutic application of the antimicrobial drugs to permit their effective use, they are still often misused in canine practice. This paper collates the data on drug dose rate/plasma concentration relationships observed in dogs after the administration of specific members of the major antimicrobial drug groups and on the possible impact of drug disposition (distribution and elimination) on therapeutic effect. Some information gleaned from studies in other animal species is added.     

Prevalence of antimicrobial residues in raw table eggs from farms and retail outlets in Enugu State,Nigeria

The use of antimicrobial agents in poultry production results in their accumulation in the body tissues and products such as milk and egg. The subsequent accumulation of these drugs and their metabolites in body cells is known as drug residue. This study was designed to determine the prevalence of antimicrobial residues in eggs from poultry farms and retail outlets in Enugu State, Nigeria. Eggs from 25 selected commercial farms and ten retail outlets were screened for the prevalence of antimicrobial residue. Also, structured questionnaires were administered to 25 commercial farms in the state to determine the management practices and the most widely used antimicrobial drugs in farms and possible association between the management practices and the occurrence of antimicrobial residues in eggs from these farms. All the 25 farms surveyed use oxytetracycline. Eggs from nine of the surveyed farms tested positive for antimicrobial residue and three of the ten surveyed farms also tested positive for antimicrobial residue. No association was observed (p 0.05; Fisher’s exact test) between the occurrence of antibiotic residues in eggs and farm size, feed source and housing systems. This study was able to demonstrate the presence of antimicrobial residues in eggs destined for human consumption. Drugs like nitrofurans which has been banned for use in food animals are still very much in use in Enugu State, Nigeria. Antibiotics given as feed additives may give rise to drug residues in food animals.     

Responsible antimicrobial use in critically ill adult horses

Due to increasing antimicrobial resistance, pressure on veterinarians is mounting to adhere to responsible use of antimicrobial drugs. Antimicrobials are frequently included in the treatment of systemically ill horses due to the strong likelihood of an infection and the innate difficulties in differentiating systemic inflammation secondary to noninfectious from infectious causes. In light of increasing antimicrobial drug resistance and the potential negative impact of antimicrobials on equine patients, every attempt should be made to identify noninfectious disease, choose first-line antimicrobials and discontinue treatment as soon as possible. In most cases, a short duration of antimicrobial therapy ranging from a single dose (e.g. preoperatively) to 24–72 h might be sufficient with long-term treatment being rarely required. This article aims to provide practical guidelines for antimicrobial drug usage in critically ill adult horses by describing ancillary diagnostic aids that can help establishing whether or not an infection is present, discussing commonly encountered pathogens and their typical antimicrobial drug sensitivity patterns, and providing some guidance how to safely shorten the duration of antimicrobial therapy.     

Public health and policy

Antimicrobial agent usage data are essential for focusing efforts to reduce misuse and overuse of antimicrobial agents in food producing animals because these practices may select for resistance in bacteria of animals. Transfer of resistant bacteria from animals to humans can lead to human infection caused by resistant pathogens. Resistant infections can lead to treatment failures, resulting in prolonged or more severe illness. Multiple World Health Organization (WHO) reports have concluded that both antimicrobial resistance and antimicrobial usage should be monitored on the national level. The system for collecting antimicrobial usage data should be clear and transparent to facilitate trend analysis and comparison within and among countries. Therapeutic, prophylactic and growth promotion use should be recorded, along with route of administration and animal species and/or production class treated. The usage data should be compared to resistance data, and the comparison should be made available in a timely manner. In the United States, surveillance of antimicrobial resistance in foodborne bacteria is performed by the National Antimicrobial Resistance Monitoring System (NARMS) for enteric bacteria, however, the United States still lacks a mechanism for collecting antimicrobial usage data. Combined with antimicrobial resistance information from NARMS, antimicrobial usage data will help to direct education efforts and policy decisions, minimizing the risk that people will develop antimicrobial resistant infections as a result of eating food of animal origin. Ultimately mitigation strategies guided by usage data will be more effective in maintaining antimicrobial drugs for appropriate veterinary use and in protecting human health.     

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.     

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.     

Bacterial septic arthritis in 19 dogs

OBJECTIVE: To provide information on the clinical features, diagnosis and treatment of bacterial septic arthritis in dogs. DESIGN: A retrospective study examining case records of all dogs diagnosed with bacterial septic arthritis at Murdoch University Veterinary Hospital between 1988 and 1997. RESULTS: Nineteen dogs were diagnosed with bacterial septic arthritis, which most commonly occurred after surgery involving the stifle joint. Haematogenous infection occurred in only five dogs. Diagnosis was based on clinical signs, joint fluid analysis, radiography, microbiology and/or response to treatment. Chronic lameness was the most common problem at presentation. Analysis of joint fluid invariably revealed large number of nucleated cells, which consisted primarily of neutrophils. In all but one case the neutrophils were nondegenerate. Culture of joint fluid was frequently successful. Staphylococcus spp were the most common bacteria isolated. Treatment involved antimicrobial drugs only in five dogs. Other dogs received antimicrobial drugs in combination with surgical procedures such as joint lavage and removal of nonabsorbable suture material (eight), arthrodesis (two) or amputation (one). Two dogs were euthanased. Most dogs responded well to treatment and were free of signs of septic arthritis at follow-up. CONCLUSION: Bacterial septic arthritis may often be mild and manifest as chronic lameness. Analysis of joint fluid will detect an inflammatory arthropathy but the presence of toxic neutrophils should not be relied on as an indicator of sepsis. Culture of infected joint fluid is likely to be successful if antimicrobials are not given prior to collection and if the sample is inoculated into enrichment broth. Treatment should involve antimicrobial drugs, open-joint lavage and removal of joint prostheses if the infection is associated with previous surgery.     

Management of anaerobic infections

Successful management of anaerobic infection first requires an accurate diagnosis. Cytologic examination of wound exudates and inspection for characteristic clinical clues greatly facilitates an accurate initial diagnosis of anaerobic infection. Knowledge of antimicrobial activity against specific anaerobic pathogens is essential, since antibiotic susceptibility information is not routinely available. Whenever possible, antimicrobial and surgical therapy should be combined in managing anaerobic infections. Chloramphenicol, clindamycin, and metronidazole provide the most consistently reliable activity against pathogenic anaerobes, including Bacteroides. Penicillins are also generally effective, except for treatment of infections caused by penicillinase-producing strains of Bacteroides. Cephalosporins are not considered drugs of choice for anaerobic infections, although cefoxitin may in some instances be useful as monotherapy of mixed infections containing obligate anaerobes and coliform bacteria. Aminoglycosides and sulfonamides are ineffective and should be avoided for treatment of anaerobic infection.