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.     

Erythema multiforme associated with zonisamide in a dog

This report describes a dog that developed erythema multiforme in temporal association with administration of the sulphonamide‐based anticonvulsant drug zonisamide. Similar adverse drug reactions have been associated with sulphonamide antimicrobial drugs. Caution should be exercised when prescribing this medication for dogs with known hypersensitivity to sulphonamides.     

Antimicrobial chemotherapy in the dog

This paper presents the rationale for the use of antimicrobial therapy in the dog according to the body system or organ in which an infection is located. In so doing, it correlates information on the abilities possessed by the different groups of antimicrobial drugs to penetrate sites of infection in particular body tissues. It also presents information on the clinical results reported after the use of particular antimicrobial drugs in the treatment of infections involving specific body systems and organs. The information provided on dose rates is qualitative rather than quantitative.     

Adverse reactions to veterinary drugs reported in Sweden during 1991–1995

The present article gives a summary of suspected adverse reactions reported by Swedish veterinarians during the period 1991–1995. The summary shows that severe adverse drug-reactions sometimes occur in Swedish veterinary practice. In horses, several cases of acute reactions in animals treated with procaine benzylpenicillin were reported and seven horses died within a few minutes after intramuscular injections of the drug. In cattle and swine most reports referred to the use of antimicrobial agents. In dogs reactions to vaccines were the most frequently reported adverse effects. The reactions were, however, usually rather mild. In dogs there were also several reports of severe reactions related to treatments with non-steroid anti-inflammatory drugs (NSAID) and α₂-receptor agonists. Amongst the reports six deaths were observed for each of these groups of drugs. In cats, as in dogs, adverse effects to vaccines were the most frequently reported reactions.     

Establishment of a cell line for assessing drugs as canine P‐glycoprotein substrates: proof of principle

P‐glycoprotein (P‐gp), encoded by the ABCB1 (MDR1) gene, dramatically impacts drug disposition. P‐gp is expressed in the intestines, biliary canaliculi, renal tubules, and brain capillaries where it functions to efflux substrate drugs. In this capacity, P‐gp restricts oral absorption, enhances biliary and renal excretion, and inhibits central nervous system entry of substrate drugs. Many drugs commonly used in veterinary medicine are known substrates for canine P‐gp (vincristine, loperamide, ivermectin, others). Because these drugs have a narrow therapeutic index, defective P‐gp function can cause serious adverse drug reactions due to enhanced brain penetration and/or decreased clearance. P‐gp dysfunction in dogs can be intrinsic (dogs harboring ABCB1‐1Δ) or acquired (drug interactions between a P‐gp inhibitor and P‐gp substrate). New human drug candidates are required to undergo assessment for P‐gp interactions according to FDA and EMA regulations to avoid adverse drug reactions and drug–drug interactions. Similar information regarding canine P‐gp could prevent adverse drug reactions in dogs. Because differences in P‐gp substrates have been documented between species, one should not presume that human or murine P‐gp substrates are necessarily canine P‐gp substrates. Thus, our goal was to develop a cell line for assessing drugs as canine P‐gp substrates.     

Detection of levamisole and ivermectin in organ samples from a dead collie.]

A collie, known for its breed-dependent adverse reaction to ivermectin, was without any clinical signs. The dog was prophylactically treated with 3 mg/kg KG (s.c.) of levamisole. Within 15 minutes, the dog showed convulsions, vomitus, and dyspnea, and perished 2.5 hours after injection of the drugs. The pathological findings were not informative as to the cause of death, and with regard to the adverse reactions, additional application of ivermectin was not excluded. Therefore, organ samples were submitted for toxicological analysis of both levamisole and ivermectin. For detection of levamisole and ivermectin, modified GC/MS and HPLC procedures were developed. Concentrations up to 535 micrograms levamisole and up to 26 ng ivermectin were found per g tissue. Both analytical methods are sensitive enough to detect these drugs after application of low doses. This study elucidates that combination of low-dosed ivermectin and levamisole is no recommendable means against adverse effects of ivermectin, with respect to collies. Moreover, the synergistic effects of ivermectin and levamisole suggests the same drug incompatibility in other dog breeds and animal species.     

Current concepts on the use of antimicrobials in cats

This article reviews the general pharmacological properties of antimicrobial drugs used in feline medicine. It focuses on recent advances in pharmacokinetics, providing an update on indications, drug interactions and adverse reactions or toxicity in the cat. Attention is given to the most used groups, such as cephalosporins and fluoroquinolones, reviewing their basic features and clinical uses, and discusses the pharmacokinetic advantages of the newer members of each group. The older groups (penicillins, aminoglycosides, macrolides and tetracyclines) are also considered with regard to their general features and current uses, and any recent reports on adverse reactions in cats are provided.     

Generalised peripheral oedema associated with amlodipine therapy in two dogs

This report details two cases of adverse drug reactions to amlodipine. The first case presented with diffuse peripheral oedema and a history of amlodipine therapy. Haematology, clinical chemistry, endocrine testing, thoracic, abdominal and cardiac imaging revealed no cause for oedema. Amlodipine therapy was discontinued and oedema diminished markedly within 72 hours. The second case presented for bilateral retinal detachments secondary to systemic hypertension. Haematology, clinical chemistry, thoracic and abdominal imaging were unremarkable and amlodipine therapy was begun. Within 72 hours, diffuse peripheral oedema developed that was unresponsive to therapy and the dog was euthanised. Veterinarians should be aware of the potential serious adverse events associated with commonly used drugs; severe, diffuse oedema is a possible adverse drug event in dogs treated with amlodipine .     

Mechanisms of hypersensitivity to intravenous agents

Adverse reactions to intravenous anaesthetic drugs and plasma substitutes in man and other mammals exhibit features commonly attributed to immediate Type I immunological hypersensitivity (anaphylaxis). However, the majority of reported reactions have occurred upon first exposure and consequently have little possibility of antibody mediation. In such responders, reactions may re-occur unpredictably with other unrelated substances at a later date. Investigation of the mechanism of reactions becomes essential not only for the individual but also for the evaluation of new intravenous agents. Several major reaction mechanisms can be demonstrated: IgE and other antibody mediated reactions (the latter involving complement), and non-immune reactions such as direct activation of the C3 alternative pathway and pharmacological reactions in which the drugs cause vasodilation either by direct physiological action or indirectly through the chemical release of vasoactive substances from cells. In mammals other than man, dose related responses play an important role. Barbiturate hypnotic drugs produce fewer adverse reactions in all mammals than those which contain Cremophor as a surfactant (e.g., Saffan). Although Althesin (Saffan) reactions are rarely fatal in man, they are predominantly fatal in cats and dogs. This increased risk is associated with the use of this particular surfactant which gives rise to remarkable species difference in adverse response to the same drug. Thus immune reactions to Cremophor or to Althesin may be accurately predicted in the pig following a repeat exposure to the drug, whereas in man repeat exposure may only increase the risk of reaction from 1∶10,000 (on first exposure) to 1∶1,000 inductions. Cremophor alone causes severe anaphylactoid shock in the dog, limited response in the cat and none in man. These reactions may occur on first exposure and are mediated by direct histamine release. Unlike anaesthetic drugs, dextran and gelatine plasma substitutes do not release histamine in all species. Even when histamine is released there is a poor correlation with the severity of clinical response.     

Review of prevalence, genetic aspects and adverse effects of the mdr1-1Delta mutation in dogs

A mutation in the canine MDR1 gene causes multiple drug sensitivity in dog breeds of the Collie lineage. Dogs with this genetic defect show severe neurotoxic adverse effects if they are treated with particular drugs. Clinical signs depending on the administered drug and its concentration vary from mild toxicosis with salivation and disorientation to severe effects with coma and finally death of the dog. Drugs which provoke adverse effects are structurally different. Although they are used for many different indications, all of these drugs are substrates of a transporting protein encoded by the MDR1 gene.This P-glycoprotein loses its normal protecting function at the tissue barriers in dogs with the mdrl-1Delta mutation.This article gives a short overview about the present state of analyses regarding the canine MDR1 gene.The genetic background, effects and prevalence in affected dog breeds of the mdrl-1Delta mutation are summarized. On the one hand, the overview might help practical veterinarians to understand the aetiology of drug sensitivity in dogs with the mdrl-1Delta mutation, and on the other hand, it might point out appendages for future research works about the canine MDR1 gene as well as for breeding strategies in affected dog breeds.     

Antimicrobial resistance in livestock

Antimicrobial resistance may become a major problem in veterinary medicine as a consequence of the intensive use and misuse of antimicrobial drugs. Related problems are now arising in human medicine, such as the appearance of multi-resistant food-borne pathogens. Product characteristics, dose, treatment interval and duration of treatment influence the selection pressure for antimicrobial drug resistance. There are theoretical, experimental and clinical indications that the emergence of de novo resistance in a pathogenic population can be prevented by minimizing the time that suboptimal drug levels are present in the infected tissue compartment. Until recently, attention has been focused on target pathogens. However, it should be kept in mind that when antimicrobial drugs are used in an individual, resistance selection mainly affects the normal body flora. In the long term, this is at least equally important as resistance selection in the target pathogens, as the horizontal transfer of resistance genes converts almost all pathogenic bacteria into potential recipients for antimicrobial resistance. Other factors contributing to the epidemiology of antimicrobial resistance are the localization and size of the microbial population, and the age, immunity and contact intensity of the host. In livestock, dynamic herd-related resistance patterns have been observed in different animal species.     

Emergency treatments for police dogs used for illicit drug detection

The key to saving police dogs that have been exposed to large quantities of illicit substances is rapid action. Removal from the gastrointestinal tract, adsorption, and catharsis are the first steps. Some of these measures can be instituted on site by the attending officer. In case of accidental drug exposures of a dog during a search, police officers should have on hand apomorphine, syringes for administration of the drug and rinsing of the conjunctival sac, activated charcoal, a saline cathartic such as sodium sulfate (not needed if the activated charcoal product contains sorbitol), a resuscitator bag, and a well-fitting canine face mask. If bags of drugs are ingested intact, immediate surgery by a veterinarian may be required to remove the bag and prevent an obstruction or rapid absorption of a lethal dose. Injectible medications to antagonize the effects of the drugs should be reserved for administration by a readily available veterinarian upon arrival of the dog at the veterinary hospital. Pharmacologic antagonistic agents may have adverse side effects, especially if used in the treatment of a drug exposure against which they are not specifically indicated. Proper dosage and route of administration are additional important factors with such treatment. The veterinarian must instruct the police officers on the proper use, dosages, and methods of administration of the detoxifying agents as well as the proper procedures for using the face mask and resuscitator bag before an emergency arises. The officer should also be aware of the clinical signs likely to be produced following exposure to the agents for which these dogs search.(ABSTRACT TRUNCATED AT 250 WORDS)     

The human health implication of the use of antimicrobial agents in animal feeds

Antimicrobials given in subtherapeutic levels in feed are credited with having contributed to lower cost of meat, milk and eggs. The practice often is associated with the acquisition of resistant enteric flora by the involved animals, and this may in turn contribute to the human reservoir of antimicrobial resistant coliforms and salmonellae. Associated farm workers may transiently acquire resistant flora and on rare occasions develop salmonellosis. Although irrefutable evidence of growth promotant properties of antibiotics in animal feed was provided 30 to 40 years ago, additional studies on mechanisms of the effect are presently needed. It may be possible to identify factors effective in promoting growth without deleterious effects on flora. A national surveillance programme of antimicrobial utilisation (both subtherapeutic and therapeutic) among food producing animals should be established. Molecular epidemiologic research efforts will need to be undertaken to establish whether genetic information of animal origin importantly contributes to the human environmental pool of antimicrobial resistance. In the meantime, it does not appear that the use of drugs as feed additives, while allowing their unrestricted use for therapy in both animals and persons, would favorably influence the problems of antimicrobial resistance of salmonellosis in human populations.     

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。     

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.     

Veterinary Products Committee working group report on feline and canine vaccination

* The working group was set up by the Veterinary Products Committee in response to current concern in both the public domain and in the scientific community about possible health risks related to the routine vaccination of cats and dogs. The working group concluded that vaccination plays a very valuable role in the prevention and control of the major infectious diseases in cats and dogs. Although adverse reactions to vaccination, including lack of efficacy, occasionally occur, the working group concluded that the overall risk/benefit analysis strongly supports their continued use. * Although for some diseases there is evidence of a longer duration of immunity following vaccination than the one year which is typically recommended on the product literature, there is currently insufficient information to propose revaccination intervals other than those proposed by the manufacturer and approved by the regulatory process. * Notwithstanding this, in view of the occasional occurrence of adverse reactions, the working group recommends that the product literature indicates that the regime for booster vaccinations is based on a minimum duration of immunity rather than a maximum. The working group further recommends that the product literature should state that a risk/benefit assessment should be made for each individual animal by the veterinary surgeon in consultation with the owner with respect to the necessity for each vaccine and the frequency of its use. * The evidence suggests that cats appear to be susceptible to the occasional development of sarcomas at sites of injection and there is some further evidence to suggest that, although other products may be involved, this may be more associated with the use of vaccines containing aluminium-based adjuvants. The working group therefore recommends that a generic warning to this effect should appear on the product literature for all feline vaccines administered by injection. The working group also highlighted the need for professional and educational bodies in the UK to bring to the attention of veterinary practitioners appropriate methods for prevention, diagnosis and treatment of this serious condition. * The working group considered in depth the monitoring of adverse reactions, including the advantages and disadvantages of surveillance schemes. A range of options for carrying out further epidemiological (analytical) studies was also considered. However, the working group emphasised that surveillance schemes, and the UK Veterinary Medicines Directorate (VMD) Suspected Adverse Reaction (SAR) Surveillance Scheme in particular, provided a very valuable resource. The large database within the VMD scheme (collected since 1985) was analysed as part of this report. Figures were derived in terms of incidence (reporting rate) of certain clinical signs per 10,000 doses, and risk factors as identified by statistical analysis. However, due to a number of constraints, the analysis was not fully comprehensive and the interaction of possible risk factors was not determined. * Product-related control charts were developed in order to detect changes in incidence rates of adverse reactions (per 10,000 doses sold) both within and between different vaccines. Such charts provide a powerful way to detect changing trends in incidence and, when used in conjunction with product characteristics, they may identify possible causes. In general, the data showed that the incidence of adverse reactions to cat and dog vaccines per 10,000 doses of product sold was relatively low. Although under-reporting is a feature of such surveillance schemes, it does appear that, overall, vaccination of cats and dogs should be considered safe and effective. * Finally, the working group was conscious, while preparing this report, of the extensive media coverage that has been given to the issue of the safety of human vaccines, in particular the mumps, measles and rubella (MMR) vaccine. The working group emphasises that the conclusions and recommendations included in this report relate only to the vaccines used in cats and dogs. The issues identified are specific to the diseases and species examined and no attempt should be made to draw analogous conclusions in relation to vaccines administered to humans.     

Salmonella enteritis in dogs,not relevant?

In order to shed some light on the different opinions regarding the importance of Salmonella infections in dogs, we gathered some data from our laboratory database. Of the 6589 faecal samples from diarrhoeic dogs examined, 69 (1%) yielded Salmonella spp. Another eleven isolates were cultured from materials other than faeces. If Salmonella spp. can be cultured directly from faeces, this should be interpreted as clinically significant; however, even if the organism is found only after enrichment it may still be a clinical case. Antibiotic therapy is indicated in all dogs that are severely ill or have systemic infection, fluoroquinolones or trimethoprim/sulphonamides being drugs of choice. Double-blind placebo-controlled studies of humans with gastroenteritis have shown that the length of postconvalescent excretion of Salmonella is not affected by antimicrobials. For the elimination of the carrier state, however, fluoroquinolones are successful in human medicine. Salmonellae are zoonotic agents and transmission from dog to man has been reported. This should be taken into account when deciding on antimicrobial therapy. Of our isolates (n = 80), 96% were susceptible to enrofloxacin, 94% to trimethoprim/sulphonamides, 94% to gentamicin, 86% to ampicillin and amoxicillin-clavulanic acid, 47% to cephalexin and 63% to tetracycline.     

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.     

Aspects of pharmacology in the neonatal foal

Other therapeutic agents used in foals for specific diseases are discussed elsewhere. The marked effect of species, age, and degree of maturity on drug metabolism in the neonate reinforces the danger of interspecies extrapolation of pharmacology, the need for information specific for the foal, and the necessity for monitoring drug levels in the individual. Suggested antimicrobial doses are listed in Tables 3, 4, and 6. Recommended doses of anticonvulsants and sedatives are listed in Table 8 and in the article "Intensive Care of the Neonatal Foal." The following are recommendations for drug therapy in the neonate: Avoid unnecessary administration of drug to the dam at parturition because of possible placental transfer of the drug with subsequent effects on the neonate. If possible, avoid unnecessary drug therapy in foals under 30 days of age. Select a drug that undergoes minimal biotransformation (hepatic metabolism) and is not highly protein bound. Owing to probable immunodeficiency in the neonate, broad-spectrum, bactericidal drugs are preferred for treatment of life-threatening infections. Every attempt should be made to identify the etiologic agent so that drug therapy can be based on cultures and sensitivity test results to maximize the benefit-risk ratio. Parenteral (intramuscular or intravenous) drug administration is preferable to oral. Avoid drugs that are known oxidants, which may produce hemolysis or methemoglobinemia. In general, the same or a slightly higher initial dose should be employed in the neonate, but it should be given less frequently than in the adult if it has a high potential to cause toxicity. When possible, individual monitoring of serum levels of potentially toxic drugs should be employed in premature and newborn foals unless specific drug pharmacokinetics are known for that age group.     

The human health implication of the use of antimicrobial agents in animal feeds

Summary

Antimicrobials given in subtherapeutic levels in feed are credited with having contributed to lower cost of meat, milk and eggs. The practice often is associated with the acquisition of resistant enteric flora by the involved animals, and this may in turn contribute to the human reservoir of antimicrobial resistant coliforms and salmonellae. Associated farm workers may transiently acquire resistant flora and on rare occasions develop salmonellosis. Although irrefutable evidence of growth promotant properties of antibiotics in animal feed was provided 30 to 40 years ago, additional studies on mechanisms of the effect are presently needed. It may be possible to identify factors effective in promoting growth without deleterious effects on flora. A national surveillance programme of antimicrobial utilisation (both subtherapeutic and therapeutic) among food producing animals should be established. Molecular epidemiologic research efforts will need to be undertaken to establish whether genetic information of animal origin importantly contributes to the human environmental pool of antimicrobial resistance. In the meantime, it does not appear that the use of drugs as feed additives, while allowing their unrestricted use for therapy in both animals and persons, wouldfavorably influence the problems of antimicrobial resistance of salmonellosis in human populations.