Animal drug human food safety toxicology and antimicrobial resistance--the square peg

This paper presents the traditional approach for the evaluation of human food safety used for animal drugs intended for food animals, and describes some of the difficulties posed by antimicrobial drug resistance. Like human drugs, animal drugs must be safe and effective for the patient. However, unlike human drugs, food derived from animals treated with the animal drug must also be shown to be safe for human consumption. The Food and Drug Administration has come to realize that antimicrobial drugs used in the treatment of the food animal have the potential to create a unique residue--increased numbers of microorganism that are resistant to antimicrobial drug treatment. The traditional toxicological paradigm for chemical residues does not apply to this unique microbiological residue. Information useful to a food safety evaluation may include the potential for the animal antimicrobial drug to diminish the susceptibility of microorganisms to human antimicrobial drugs, any human medical use of the drug, relationship to other human antimicrobial drugs, and the ability of the animal drug to alter the susceptibility of relevant microorganism to important human antimicrobial drugs. Yet to be developed are standardized approaches to quantify an acceptable level of resistant microorganism in food and to mitigate the hazard to assure that there is a reasonable certainty of no harm following the consumption of the edible food derived from the treated animal.     

Association between the consumption of antimicrobial agents in animal husbandry and the occurrence of resistant bacteria among food animals

Antimicrobial agents are used in food animals for therapy and prophylaxis of bacterial infections and in feed to promote growth. The use of antimicrobial agents for food animals may cause problems in the therapy of infections by selecting for resistance among bacteria pathogenic for animals or humans. The emergence of resistant bacteria and resistance genes following the use of antimicrobial agents is relatively well documented and it seems evident that all antimicrobial agents will select for resistance. However, current knowledge regarding the occurrence of antimicrobial resistance in food animals, the quantitative impact of the use of different antimicrobial agents on selection for resistance and the most appropriate treatment regimens to limit the development of resistance is incomplete. Surveillance programmes monitoring the occurrence and development of resistance and consumption of antimicrobial agents are urgently needed, as is research into the most appropriate ways to use antimicrobial agents in veterinary medicine to limit the emergence and spread of antimicrobial resistance.     

Impact of antimicrobial resistance on regulatory policies in veterinary medicine: Status report

Increasing resistance to antimicrobial agents is of growing concern to public health officials worldwide. The concern includes infections acquired in hospitals, community infections acquired in outpatient care settings, and resistant foodborne disease associated with drug use in food-producing animals. In the United States, a significant source of antimicrobial-resistant foodborne infections in humans is the acquisition of resistant bacteria originating from animals. The US Food and Drug Administration's (FDA's) goal in resolving the public health impact arising from the use of antimicrobial drugs in food-producing animals is to ensure that significant human antimicrobial therapies are not compromised or lost while providing for the safe use of antimicrobials in food animals. The FDA's approach to the problem is multipronged and innovative. The strategy includes revision of the pre-approval safety assessment for new animal drug applications, use of risk assessment to determine the human health effect resulting from the use of antimicrobials in food animals, robust monitoring for changes in susceptibilities among foodborne pathogens to drugs that are important both in human and veterinary medicine, research, and risk management.     

Use of antimicrobial agents in veterinary medicine and food animal production

Antimicrobial resistance is a growing area of concern in both human and veterinary medicine. This review presents an overview of the use of antimicrobial agents in animals for therapeutic, metaphylactic, prophylactic and growth promotion purposes. In addition, factors favouring resistance development and transfer of resistance genes between different bacteria, as well as transfer of resistant bacteria between different hosts, are described with particular reference to the role of animals as a reservoir of resistance genes or resistant bacterial pathogens which may cause diseases in humans.     

Veterinary drug usage and antimicrobial resistance in bacteria of animal origin

In the production of food animals, large amounts of antimicrobial agents are used for therapy and prophylaxis of bacterial infections and in feed to promote growth. There are large variations in the amounts of antimicrobial agents used to produce the same amount of meat among the different European countries, which leaves room for considerable reductions in some countries. The emergence of resistant bacteria and resistance genes due to the use of antimicrobial agents are well documented. In Denmark it has been possible to reduce the usage of antimicrobial agents for food animals significantly and in general decreases in resistance have followed. Guidelines for prudent use of antimicrobial agents may help to slow down the selection for resistance and should be based on knowledge regarding the normal susceptibility patterns of the causative agents and take into account the potential problems for human health. Current knowledge regarding the occurrence of antimicrobial resistance in food animals, the quantitative impact of the use of different antimicrobial agents on selection of resistance and the most appropriate treatment regimes to limit the development of resistance is incomplete. Programmes monitoring the occurrence and development of resistance and consumption of antimicrobial agents are strongly desirable, as is research into the most appropriate ways to use antimicrobial agents in veterinary medicine.     

The future challenges facing the development of new antimicrobial drugs

The emergence of resistance to antibacterial agents is a pressing concern for human health. New drugs to combat this problem are therefore in great demand, but as past experience indicates, the time for resistance to new drugs to develop is often short. Conventionally, antibacterial drugs have been developed on the basis of their ability to inhibit bacterial multiplication, and this remains at the core of most approaches to discover new antibacterial drugs. Here, we focus primarily on an alternative novel strategy for antibacterial drug development that could potentially alleviate the current situation of drug resistance--targeting non-multiplying latent bacteria, which prolong the duration of antimicrobial chemotherapy and so might increase the rate of development of resistance.     

Effects of food on the clinical pharmacokinetics of anticancer agents: underlying mechanisms and implications for oral chemotherapy

Pharmacokinetic interactions between food and orally administered drugs involve changes mainly in the absorption and metabolism of a drug, and may have clinical implications. Such interactions, in particular, may be of major clinical significance for cancer chemotherapy since the majority of anticancer agents are toxic, have a low therapeutic index and are administered long term, most often in combination with other cytotoxic agents. The purpose of this review is to compare the pharmacokinetic profiles of various anticancer drugs, including chemopreventive agents that have been examined previously in fasted and fed conditions, and to discuss the underlying basis/mechanisms of food effect in light of a drug's physicochemical and pharmacokinetic properties. Clinical pharmacokinetic parameters such as maximum concentration, area under the concentration-time curve, time to maximum concentration and half-life for each drug are compared in fasted and fed states, and specific dietary recommendations are summarised accordingly. In addition, the effects of food on the metabolite kinetics and pharmacodynamic responses, and the potential role of food effect in the modulation of oral biovariability and multidrug resistance have been extensively discussed. Overall, this comprehensive pharmacokinetic analysis indicates that a broad spectrum of food effects is seen among anticancer agents because of diverse factors regulating each drug's oral bioavailability and its interactions with food. The consideration of such effects is important, as it could lead to more rational pharmacological monitoring and possibly improve the oral chemotherapy of cancer in children, adults and the elderly.     

Characterizing chronic and acute health risks of residues of veterinary drugs in food: latest methodological developments by the joint FAO/WHO expert committee on food additives

The risk assessment of residues of veterinary drugs in food is a field that continues to evolve. The toxicological end-points to be considered are becoming more nuanced and in light of growing concern about the development of antimicrobial resistance, detailed analysis of the antimicrobial activity of the residues of veterinary drugs in food is increasingly incorporated in the assessment. In recent years, the Joint FAO/WHO Expert Committee on Food Additives (JECFA) has refined its approaches to provide a more comprehensive and fit-for-purpose risk assessment. This publication describes in detail the consideration of acute and chronic effects, the estimation of acute and chronic dietary exposure, current approaches for including microbiological endpoints in the risk assessment, and JECFA’s considerations for the potential effects of food processing on residues from veterinary drugs. JECFA now applies these approaches in the development of health-based guidance values (i.e. safe exposure levels) for residues of veterinary drugs. JECFA, thus, comprehensively addresses acute and chronic risks by using corresponding estimates for acute and chronic exposure and suitable correction for the limited bioavailability of bound residues by the Gallo-Torres model. On a case-by-case basis, JECFA also considers degradation products that occur from normal food processing of food containing veterinary drug residues. These approaches will continue to be refined to ensure the most scientifically sound basis for the establishment of health-based guidance values for veterinary drug residues.     

我国临床抗菌药物合理应用现状与思考

我国临床目前仍存在较为严重的不合理抗菌药物应用现象,包括无指针用药、过长时间用药、过大剂量用药和不恰当联合用药,其主要原因包括医疗卫生体制和技术性原因,如"以药养医"、临床医务人员抗菌药物知识缺乏等;我国卫生行政管理部门已经就抗菌药物应用建立了系统的管理体系和部分技术支撑,如"抗菌药物临床应用指导原则"、"细菌耐药监测...     

养殖业抗生素的使用及其潜在危害

细菌耐药性和食品安全问题业已引起全球的普遍关注。越来越多的证据表明,畜牧养殖业滥用抗生素对于细菌耐药性的出现和耐药基因的传播起着重要作用。了解养殖业抗生素的使用现状和滥用抗生素对人类健康的潜在危害,对我国限制及禁止畜牧养殖业抗生素的使用具有重要作用。     

Effects of food on clinical pharmacokinetics.

Food-drug interactions can be associated with alterations in the pharmacokinetic and pharmacodynamic profile of various drugs that may have clinical implications. The various phases in which food may interact with a coadministered drug are: (i) before and during gastrointestinal absorption; (ii) during distribution; (iii) during metabolism; and (iv) during elimination. Absorption and metabolism are the phases where food has most effect, and this review will focus on those areas. It will also review the variable and complex effects of antacids and metal ions on drug absorption. Mechanisms related to food effects on drug absorption have been described under 5 categories: those causing decreased, delayed, increased or accelerated absorption, and those in which food has no significant effect. Among the major variables that interface between differential effects of food and postprandial bioavailability are: (i) the physicochemical characteristics and enantiomorphic composition of the drug; (ii) timing of meals in relation to time of drug administration; (iii) size and composition of meals (especially fat, protein and fibre); and (iv) dose size. However, the influence of food is largely a matter of the design of the pharmaceutical formulation. In addition, the mechanism of 'food effect' may involve physiological and sensory responses to food, such as changes in gastrointestinal milieu and gastric emptying rate, reflex action, and may also involve the site and route (either portal or lymphatic) of drug absorption. Mixing drugs with fruit juice, such as grapefruit and orange juice, and acidic beverages, such as commercial soft drinks, may affect absorption because of decreases in gastric pH, which could offer a therapeutic advantage in certain clinical conditions, such as patients with HIV disease and cancer. The increased bioavailability caused by the concomitant intake of grapefruit juice results from the inhibition of intestinal cytochrome P450(CYP)3A4, but not hepatic CYP3A4 or colon CYP3A5, which probably involves the bioflavonoid naringenin and furanocoumarins. Although there is a vast amount of literature, there is still no rational scientific basis to predict the effect of food for a particular chemical entity or a chemical class of therapeutic agents. A mechanistic understanding of the effects of food may serve as a key to the pharmacokinetic optimisation of patient therapy, both in outpatients and hospitalised patients of various age groups.     

The effect of food on the oral bioavailability of drugs: a review of current developments and pharmaceutical technologies for pharmacokinetic control

Here we review the mediation of the food effects on drugs by pharmaceutical technologies. The pharmacokinetics of drugs are affected by the interaction of drugs with food, which changes drug physicochemical and physiological properties (food effects). Several pharmaceutical technologies may be used to control food effects. Drugs exhibit different patterns of solubilization depending on release formulations. Formulations such as nanoparticle, solid dispersion and cyclodextrin systems, may control the solubility and release of insoluble drugs. Other controlled-release technologies, such as osmotic-controlled release or colon-specific delivery systems may also control food effects. As the structure of drug candidates becomes more complex, different methods of investigation, such as in vitro and in vivo correlation and in silico simulation will be required to predict drug characteristics and food effects.     

Identification and validation of novel drug targets in tuberculosis

There is an urgent need for new antimycobacterial drugs, and in particular for novel agents that will shorten the duration of tuberculosis chemotherapy, or overcome drug-resistant strains of the causative organism, Mycobacterium tuberculosis. Our knowledge of the tubercle bacillus and its complex interaction with the human host has improved dramatically in recent years, particularly with the determination of its complete genome sequence. New genome-scale tools are being applied to aid in drug target identification, alongside traditional approaches aimed at understanding the basic biology of M. tuberculosis. Many potential drug targets have been identified, but very few have been validated by showing that they are essential for growth or survival of the bacterium. In this review, the landscape of potential drug targets is surveyed.Structural Bioinformatic Approaches to the Discovery of New Antimycobacterial Drugs.     

Ethical aspects for veterinarians regarding antimicrobial drug use in Italy

Antimicrobial drugs are used in the treatment and control of many types of infections in a wide variety of animal species. As more antibiotics were discovered and introduced to veterinary clinical practice, it became clear that choice among rational agents needed to be guided by the agreement of antibiotic policies or 'ethical' measures. Prudent use of antimicrobial drugs is an integral part of good veterinary practice; it is an attitude to maximise therapeutic efficacy and to minimise selection of resistant microorganisms. This paper presents an overview of the judicious use of antimicrobial agents in animals, with particular emphasis on ethical aspects.     

Pharmacokinetic considerations for antimicrobial therapy in patients receiving renal replacement therapy

Continuous renal replacement therapy (CRRT), particularly continuous venovenous haemofiltration (CVVH) and continuous venovenous haemodiafiltration (CVVHDF), are gaining increasing relevance in routine clinical management of intensive care unit patients. The application of CRRT, by leading to extracorporeal clearance (CL(CRRT)), may significantly alter the pharmacokinetic behaviour of some drugs. This may be of particular interest in critically ill patients presenting with life-threatening infections, since the risk of underdosing with antimicrobial agents during this procedure may lead to both therapeutic failure and the spread of breakthrough resistance. The intent of this review is to discuss the pharmacokinetic principles of CL(CRRT) of antimicrobial agents during the application of CVVH and CVVHDF and to summarise the most recent findings on this topic (from 1996 to December 2006) in order to understand the basis for optimal dosage adjustments of different antimicrobial agents. Removal of solutes from the blood through semi-permeable membranes during RRT may occur by means of two different physicochemical processes, namely, diffusion or convection. Whereas intermittent haemodialysis (IHD) is essentially a diffusive technique and CVVH is a convective technique, CVVHDF is a combination of both. As a general rule, the efficiency of drug removal by the different techniques is expected to be CVVHDF > CVVH > IHD, but indeed CL(CRRT) may vary greatly depending mainly on the peculiar physicochemical properties of each single compound and the CRRT device's characteristics and operating conditions. Considering that RRT substitutes for renal function in clearing plasma, CL(CRRT) is expected to be clinically relevant for drugs with dominant renal clearance, especially when presenting a limited volume of distribution and poor plasma protein binding. Consistently, CL(CRRT) should be clinically relevant particularly for most hydrophilic antimicrobial agents (e.g. beta-lactams, aminoglycosides, glycopeptides), whereas it should assume much lower relevance for lipophilic compounds (e.g. fluoroquinolones, oxazolidinones), which generally are nonrenally cleared. However, there are some notable exceptions: ceftriaxone and oxacillin, although hydrophilics, are characterised by primary biliary elimination; levofloxacin and ciprofloxacin, although lipophilics, are renally cleared. As far as CRRT characteristics are concerned, the extent of drug removal is expected to be directly proportional to the device's surface area and to be dependent on the mode of replacement fluid administration (predilution or postdilution) and on the ultrafiltration and/or dialysate flow rates applied.Conversely, drug removal by means of CVVH or CVVHDF is unaffected by the drug size, considering that almost all antimicrobial agents have molecular weights significantly lower (<2000Da) than the haemofilter cut-off (30,000-50,000Da). Drugs that normally have high renal clearance and that exhibit high CL(CRRT) during CVVH or CVVHDF may need a significant dosage increase in comparison with renal failure or even IHD. Conversely, drugs that are normally nonrenally cleared and that exhibit very low CL(CRRT) during CVVH or CVVHDF may need no dosage modification in comparison with normal renal function. Bearing these principles in mind will almost certainly aid the management of antimicrobial therapy in critically ill patients undergoing CRRT, thus containing the risk of inappropriate exposure. However, some peculiar pathophysiological conditions occurring in critical illness may significantly contribute to further alteration of the pharmacokinetics of antimicrobial agents during CRRT (i.e. hypoalbuminaemia, expansion of extracellular fluids or presence of residual renal function). Accordingly, therapeutic drug monitoring should be considered a very helpful tool for optimising drug exposure during CRRT.     

Comparative pharmacokinetics and the evaluation of human food safety for veterinary drugs

The evaluation of human food safety for veterinary drugs used in food animals is required as part of the veterinary drug approval process in most countries.Two elements necessary to demonstrate human food safety are toxicology data concerning the acute and chronic toxicity of the parent drug and its metabolites,and data describing the pharmacokinetics of residues of the drug and metabolites in the species of animals in which the drug will be used.Interspecies differences in metabolism can be qualitative and quantitative.In most food animals,qualitative differences in metabolism of veterinary drugs is not seen.Differences are almost always in the amounts of individual metabolites and their distribution.Because residues are composed of the parent drug and metabolites,interspecies comparisons must involve consideration of comparative xenobiotic metabolism.Aspects of comparative food animal drug metabolism which can afect the composition of residues will be reviewed.Additionally,the residue studies which are required to establish human food safety,and interspecies differences and similarities in the pharmacokinetics of drugs which impact residues of drugs in animal derived foods will be studied.To illustrate the factors which can complicate and assist these comparisons,two drugs will be examined in detail;ivemectin and fenbendazole.The results of recent residue studies exploring comparative pharmacokinetics and metabolism in avian species will be presented.Lastly,the activities of two US programs,FARAD and The NRSP-7 Minor Use Animal Drug Program,which routinely address interspecies comparisons will be presented along with potential strategies which may be employed in the study of species diffecences.     

2007—2008年某院抗菌药物的使用情况及鲍曼不动杆菌的耐药性分析

目的对山西医科大学第二医院2007、2008年抗菌药物使用情况和鲍曼不动杆菌耐药性进行分析,为临床用药提供依据。方法采用世界卫生组织(WHO)推荐的限定日剂量(DDD)法分析各种抗菌药的用药频度(DDDs)。采用K-B纸片扩散法对所分离的鲍曼不动杆菌属细菌进行药敏试验,用HONET5.3软件对数据进行统计学分析。结果2007、2008年全年药物销售总金额(不含中药部分)及抗菌药物每年的销售总金额呈上升趋势,但抗菌药物比全年药物销售总金额上升的趋势明显。鲍曼不动杆菌2008年的总菌株比2007年增长了10%,亚胺培南2008年比2007年的耐药率上升幅度大,但仍对亚胺培南保持了比较高的敏感性,对其他11种常用抗菌药物敏感率均>50%,大部分抗菌药物耐药率比2007年有不同程度的增高。结论抗菌药物销售金额和用药频度总体呈上升趋势。鲍曼不动杆菌对亚胺培南仍保持了比较好的敏感性。加酶抑制剂类的药物头孢哌酮+舒巴坦的耐药率相对较低。鲍曼不动杆菌的检出集中在重症监护病房、神经外科、骨科、血液科、呼吸科。     

Bacterial genomics as a potential tool for discovering new antimicrobial agents

The past 30 years have witnessed the emergence of new infectious diseases as well as the re-emergence of those thought to be defeated or under control. It is likely that this threat will continue and that infectious micro-organisms will be found to be responsible for numerous diseases whose etiology had been previously unknown. Compounding this threat is the rapid evolution of drug resistance by micro-organisms that is rendering many existing antimicrobial agents obsolete. Thus, there is an urgent need for the development of new classes of antimicrobial agents and the identification of new drug targets. Over the past decade, advances in high-throughput automated DNA sequencing have delivered a wealth of genetic information in the form of whole genome sequences of microbial pathogens. Coupled with this advancement has been the development of new genetic tools and computational advances capable of selecting genes of particular interest as well as testing for the effects of candidate drugs. While no new drugs have yet been developed, further study into the application and limitations of these new approaches to the identification of novel targets will aid in overcoming the current problem of antimicrobial drug resistance.     

Differential effects of morphine on food and water intake in food deprived and freely-feeding rats

In two experiments the effects of a range of doses of morphine (1, 3, 10 and 30 mg/kg) on the food and water consumption of rats were studied. The results of the first experiment showed that in 24 h food-deprived rats, morphine reduced levels of food and water intake. The duration of these actions was dependent upon dose, with only the highest dose (30 mg/kg) producing any effect persisting for longer than 4 h. In contrast a second experiment showed that morphine increased levels of food and water intake in non-deprived animals. The effect on food intake was most apparent when measurements were taken at 2 h and 4 h after drug administration, while water intake remained above control levels for over 6 h. This study shows that the actions of morphine on ingestion of food and water are affected by food deprivation, and the results are consistent with the hypothesised role of endogenous opiates in the mediation of such behaviour.