Human health aspects of antibiotic use in food animals: a review

Antibiotic use not only selects for resistance in pathogenic bacteria, but also in the commensal flora of exposed individuals. Veterinary surgeons regularly prescribe antibiotics for food animals to treat bacterial infections just as doctors do for human patients. In addition, however, animal feeds contain added antibiotics not for therapy but for economic reasons: to enhance the growth rate of these animals. Several of the antibiotics used as growth promoters are analogues of and fully cross resistant with important antibiotics used in human medicine. As a result of this high exposure to antibiotics, the prevalence of resistant bacteria in the faecal flora of these animals is high. These resistant bacteria can be directly and indirectly, via foods of animal origin, transferred to humans and either colonize the human intestinal tract or exchange their resistance genes with commensal bacteria of humans. As the intestinal flora functions as a reservoir of resistance genes for pathogenic bacteria and because many bacterial species of the intestinal flora are potential pathogens, the efficacy of antibiotic therapy in human medicine may be jeopardized.     

Nosocomial infections.

Nosocomial infections and antimicrobial resistance are topics that have been intensely studied in human medicine because of their significant impact on human health. In recent years, concerns have been raised that the use of antibiotics in veterinary medicine, animal husbandry, and agriculture may be contributing to the development of resistance in common bacterial species affecting human beings. Although there is inadequate proof at this time that the resistance is transmitted from animals to people, if antibiotics continue to be used indiscriminately in veterinary medicine, veterinarians may find themselves facing regulations restricting the use of some antibiotics. Nosocomial infections have been reported in veterinary medicine and are likely to increase in prevalence with the increase in intensive care practices in many hospitals. Prolonged hospitalization and the use of invasive devices and procedures increase the risk of nosocomial disease. As in human medicine, organisms isolated in the nosocomial infections reported in veterinary patients have an increasingly broad spectrum of antimicrobial resistance. Despite these findings, the use of empiric and prophylactic antibiotic therapy is still widespread in veterinary medicine. Nosocomial infections and antimicrobial resistance may have a serious impact on the future of [table: see text] veterinary medicine, because the cost and ability to treat our patients may be affected by the loss of access to or effectiveness of antimicrobial drugs. Despite the millions of dollars spent on research to reduce the incidence of nosocomial infections in human patients, the strategies that have consistently proven successful are simple and inexpensive to implement. The most important factor in preventing nosocomial infections is improving the hygiene practices of health care providers. Hand-washing or the use of disposable gloves can dramatically reduce the transmission of bacteria between patients. Aseptic technique should be used in the placement and management of all invasive devices. All staff members should be educated on the risks and symptoms associated with nosocomial infections so that cases can be detected early and treated appropriately. We in the veterinary profession have the opportunity to learn from the experiences of the human medical profession and can take steps to prevent the escalation of nosocomial infections and their impact on our profession.     

The situation concerning antibiotic resistance from the viewpoint of the bacteriologist

Already fifty years ago, when antibiotics were introduced, their effectiveness was challenged by certain bacteria which had the ability to resist the bacteriocidal effect of the antibiotics. Development of such resistance is due to selection pressure that results from the use of antibiotics in therapy, particularly in human medicine. In Switzerland, the veterinary public health aspect of this problem has become of current interest. The ban on the use of growth promoters has triggered the need for an update of the statistical information on the phenomena of resistance and the setting up of a surveillance system of antibioresistance in animals and in products of animal origin.     

Resistance to various antibiotics of Salmonella and Escherichia coli isolated from registrable farm feeds

Resistance to 20 antibiotics of 128 Salmonella and 97 Escherichia coli isolates from various registrable farm feeds was determined. A high frequency of comparatively low levels of resistance was found in both the Salmonella and E. coli isolates. This, together with an elevated frequency of multiple resistance, indicates that problems related to an effective transfer in bacterial populations of resistance to certain antibiotics are a distinct possibility. The addition of antibiotics, such as penicillin and tetracyclines, to animal feeds can create conditions for rapid selection amongst bacteria resistant to antibiotics. The numbers of resistant bacteria in the animal environment may be increased and may lead to the development of veterinary and human health problems from the possible transfer of antimicrobial resistance from animal pathogens to human pathogens or spreading in the human population of animal pathogens resistant to antibiotics. There is a need for caution in the use of antibiotics, particularly in animal feeds. Extended survey of, and epidemiological research on, farm feeds, manufacturing mills and animal production units are emphasized.     

Antimicrobial resistance in Campylobacter spp., Escherichia coli and enterococci associated with pigs in Australia

The major influences on the amplification and spread of antibiotic-resistant bacteria are the therapeutic use of antibiotics in human medicine and their use in livestock for therapy, prophylaxis and growth promotion. The use of veterinary antibiotics has many benefits to the livestock industries ensuring animal health and welfare, but use at subtherapeutic levels also exerts great selective pressure on emergence of resistant bacteria. The possible effect on human health is a problem of current debate. This study involved sampling pig carcasses, pig meat and assessing the level of resistance in zoonotic enteric bacteria of concern to human health. In South Australian pigs, thermophilic Campylobacter species showed widespread resistance (60-100%) to tylosin, erythromycin, lincomycin, ampicillin and tetracycline. No resistance was seen to ciprofloxacin. The enterococci demonstrated little resistance (0-30%) to vancomycin or virginiamycin, but the overall results from the antibiotic sensitivity testing of the enterococci have demonstrated how widespread their resistance has become. Escherichia coli strains showed widespread resistance to tetracycline and moderately common resistance (30-60%) to ampicillin and sulphadiazine. Resistance to more than one antibiotic was common. Pigs from New South Wales were also sampled and differences in resistance patterns were noted, perhaps reflecting different antibiotic use regimens in that state.     

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。     

The consequences of generic marketing on antibiotic consumption and the spread of microbial resistance: the need for new antibiotics

In both human and veterinary medicine, it has been shown that flooding the market with different generics and/or ‘me‐too’ branded drugs has increased overall antibiotic consumption correlating with the emergence and spread of bacterial resistance to antibiotics. Another possible undesirable consequence of the promotion of generics is the promotion of an economic incentive that encourages the use of old drug products with very poor oral bioavailability, marketed with historical dosage regimens and extensively excreted in the environment. What veterinary medicine rather needs is new innovative and ‘ecofriendly’ antibiotics to actually enforce a more prudent use of antibiotics. For a pharmaceutical company, generics are inexpensive to manufacture and on a short‐term basis, the generic market is very appealing. However, on a long‐term basis, this marketing orientation provides a disincentive to the development of new and innovative products that will be required to meet the therapeutic needs of the veterinary community while being consistent with public health concerns. Indeed, for veterinary medicine, the key issue surrounding antibiotics is public health. It is the opinion of the authors that veterinary antibiotics and/or veterinary drug formulations should be innovative in terms of selectivity (no or minimal impact on the commensal gut flora), biodegradable (with minimal environmental disruption), and more expensive, with a strictly regulated market rather than unselective, cheap, and freely available drugs.     

Current and future prospects for nanotechnology in animal production

Nanoparticles have been used as diagnostic and therapeutic agents in the human medical field for quite some time, though their application in veterinary medicine and animal production is still relatively new. Recently,production demands on the livestock industry have been centered around the use of antibiotics as growth promoters due to growing concern over microbial antibiotic resistance. With many countries reporting increased incidences of antibiotic-resistant bacteria, laws and regulations are being updated to end in-feed antibiotic use in the animal production industry. This sets the need for suitable alternatives to be established for inclusion in feed.Many reports have shown evidence that nanoparticles may be good candidates for animal growth promotion and antimicrobials. The current status and advancements of nanotechnological applications in animal production will be the focus of this review and the emerging roles of nanoparticles for nutrient delivery, biocidal agents, and tools in veterinary medicine and reproduction will be discussed. Additionally, influences on meat, egg, and milk quality will be reviewed.     

Maggot-therapy in veterinary medicine

Maggot-therapy is the application of disinfected fly larvae to chronic wounds to debride the wound bed of necrotic tissue, reduce bacterial contamination and enhance the formation of healthy granulation tissue. Interest in the use of maggot-therapy in human medicine is growing as a result of the prevalence of antibiotic resistant bacteria. Maggot therapy, however, is used relatively little in veterinary medicine. Nevertheless, concern over antibiotic resistance and the increase in demand for organic husbandry and residue-free meat and milk, suggest that it is an option which merits further consideration.     

Why is Anti‐Microbial Resistance a Veterinary Problem As Well?

Resistance to anti‐microbial agents has become one of the main issues in public health strategies world‐wide. Much attention has been paid to the emergence of pathogenic micro‐organisms such as enterococci or Salmonella that have developed resistance mechanisms that render them almost untreatable with current antibiotics. One of the alleged reasons for such an emergence is the non‐medical use of antibiotics, especially in animals. However, only recently have veterinary forums and journals begun to discuss this topic. On the other hand, anti‐microbial resistance has also become a problem in veterinary medicine and the number of reports indicating high rates of resistance among animal‐originated micro‐organisms is considerable. The present review deals with the mechanisms of resistance known for antibiotics in common veterinary use, the problem of anti‐microbial resistance in veterinary medicine and the links between the use of antibiotics in animals and the emergence of anti‐microbial resistance in humans.     

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.     

Antimicrobial‐resistant Enterobacteriaceae recovered from companion animal and livestock environments

Antimicrobial‐resistant bacteria represent an important concern impacting both veterinary medicine and public health. The rising prevalence of extended‐spectrum beta‐lactamase (ESBL), AmpC beta‐lactamase, carbapenemase (CRE) and fluoroquinolone‐resistant Enterobacteriaceae continually decreases the efficiency of clinically important antibiotics. Moreover, the potential for zoonotic transmission of antibiotic‐resistant enteric bacteria increases the risk to public health. Our objective was to estimate the prevalence of specific antibiotic‐resistant bacteria on human contact surfaces in various animal environments. Environmental surface samples were collected from companion animal shelters, private equine facilities, dairy farms, livestock auction markets and livestock areas of county fairs using electrostatic cloths. Samples were screened for Enterobacteriaceae expressing AmpC, ESBL, CRE or fluoroquinolone resistance using selective media. Livestock auction markets and county fairs had higher levels of bacteria expressing both cephalosporin and fluoroquinolone resistance than did equine, dairy, and companion animal environments. Equine facilities harboured more bacteria expressing cephalosporin resistance than companion animal shelters, but less fluoroquinolone resistance. The regular use of extended‐spectrum cephalosporins in livestock populations could account for the increased levels of cephalosporin resistance in livestock environments compared to companion animal and equine facilities. Human surfaces, as well as shared human and animal surfaces, were contaminated with resistant bacteria regardless of species environment. Detecting these bacteria on common human contact surfaces suggests that the environment can serve as a reservoir for the zoonotic transmission of antibiotic‐resistant bacteria and resistance genes. Identifying interventions to lower the prevalence of antibiotic‐resistant bacteria in animal environments will protect both animal and public health.     

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.     

Comparing the minimum inhibitory and mutant prevention concentrations of selected antibiotics against animal isolates of Pasteurella multocida and Salmonella typhimurium

Historically, the use of antibiotics was not well regulated in veterinary medicine. The emergence of antibiotic resistance (ABR) in pathogenic bacteria in human and veterinary medicine has driven the need for greater antibiotic stewardship. The preservation of certain antibiotic classes for use exclusively in humans, especially in cases of multidrug resistance, has highlighted the need for veterinarians to reduce its use and redefine dosage regimens of antibiotics to ensure efficacy and guard against the development of ABR pathogens. The minimum inhibitory concentration (MIC), the lowest concentration of an antibiotic drug that will prevent the growth of a bacterium, is recognised as a method to assist in antibiotic dosage determination. Minimum inhibitory concentrations sometimes fail to deal with first-step mutants in bacterial populations; therefore dosing regimens based solely on MIC can lead to the development of ABR. The mutant prevention concentration (MPC) is the minimum inhibitory antibiotic concentration of the most resistant first-step mutant. Mutant prevention concentration determination as a complementary and sometimes preferable alternative to MIC determination for veterinarians when managing bacterial pathogens. The results of this study focused on livestock pathogens and antibiotics used to treat them, which had a MIC value of 0.25 µg/mL for enrofloxacin against all 27 isolates of Salmonella typhimurium. The MPC values were 0.50 µg/mL, with the exception of five isolates that had MPC values of 4.00 µg/mL. The MPC test yielded 65.52% (18 isolates) Salmonella isolates with florfenicol MICs in the sensitive range, while 11 isolates were in the resistant range. Seventeen isolates (58.62%) of Pasteurella multocida had MIC values in the susceptible range and 41.38% (12 isolates) had an intermediate MIC value. Mutant prevention concentration determinations as done in this study is effective for the antibiotic treatment of bacterial infections and minimising the development of resistance. The MPC method can be used to better control to prevent the development of antibiotic drug resistance used in animals.     

New trends in regulatory rules and surveillance of antimicrobial resistance in bacteria of animal origin.

Since the introduction in the 1940s of antibiotics as drugs against bacterial infections in human and then veterinary medicine, two major events have caused a shift in the antibiotherapy era: (1) the emergence of resistant bacteria and (2) the awareness of the limits of new drug development. It rapidly became urgent to set up measures in order to evaluate the importance of resistant bacteria and their origin as well as to limit the dissemination of resistant vectors (bacteria and bacterial genes). This led to the establishment of guidelines and regulatory rules necessary for risk assessment and clearly dependent upon monitoring and research organisations. At a veterinary level, the possible dissemination of multiresistant bacteria from animals to humans, through feeding, urged various national European and international institutions to give general recommendations to monitor and contain the emergence and diffusion of resistant strains. This paper gives an overview of the evolution of regulatory rules and monitoring systems dealing with multiresistant bacteria.     

Use of antimicrobials in veterinary medicine and mechanisms of resistance.

This review deals with the application of antimicrobial agents in veterinary medicine and food animal production and the possible consequences arising from the widespread and multipurpose use of antimicrobials. The various mechanisms that bacteria have developed to escape the inhibitory effects of the antimicrobials most frequently used in the veterinary field are reported in detail. Resistance of bacteria to tetracyclines, macrolide-lincosamide-streptogramin antibiotics, beta-lactam antibiotics, aminoglycosides, sulfonamides, trimethoprim, fluoroquinolones and chloramphenicol/florfenicol is described with regard to enzymatic inactivation, decreased intracellular drug accumulation and modification/protection/replacement of the target sites. In addition, basic information is given about mobile genetic elements which carry the respective resistance genes, such as plasmids, transposons, and gene cassettes/integrons, and their ways of spreading via conjugation, mobilisation, transduction, and transformation.     

beta-Lactam resistance and beta-lactamases in bacteria of animal origin

beta-Lactams are among the most clinically important antimicrobials in both human and veterinary medicine. Bacterial resistance to beta-lactams has been increasingly observed in bacteria, including those of animal origin. The mechanisms of beta-lactam resistance include inaccessibility of the drugs to their target, target alterations and/or inactivation of the drugs by beta-lactamases. The latter contributes predominantly to beta-lactam resistance in Gram-negative bacteria. A variety of beta-lactamases have been identified in bacteria derived from food-producing and companion animals and may further serve as a reservoir for beta-lactamase-producing bacteria in humans. While this review mainly describes beta-lactamases from animal-derived Escherichia coli and Salmonella spp., beta-lactamases from animal-derived Campylobacter spp., Enterococcus spp., Staphylococcus spp. and other pathogens are also discussed. Of particular concern are the increasingly-isolated plasmid-encoded AmpC-type CMY and extended-spectrum CTX-M beta-lactamases, which mediate acquired resistance to extended-spectrum beta-lactams. The genes encoding these enzymes often coexist with other antimicrobial resistance determinants and can also be associated with transposons/integrons, increasing the potential enrichment of multidrug resistant bacteria by multiple antimicrobial agents as well as dissemination of the resistance determinants among bacterial species. Characterization of beta-lactam-resistant animal-derived bacteria warrants further investigation of the type and distribution of beta-lactamases in bacteria of animal origin and their potential impact on human medicine.     

替代抗生素饲料添加剂研究进展

抗生素作为主要的饲料添加剂在几十年的广泛应用过程中造成了致病菌耐药性增强、动物免疫力降低、影响动物疫苗的效价、通过食物链影响人体健康等亟待解决的问题。我国农业农村部已发布公告,自2020年起我国饲料全面禁止添加使用抗生素类添加剂,饲料行业正式进入“无抗时代”。长期以来,研究人员积极寻求研发各种抗生素替代品及绿色无害的饲料添加剂,以消除或减轻禁用抗生素带来的一系列影响。就目前主要抗生素替代品的抗菌特点及抗菌机理进行综述,旨在为“禁抗”后抗菌性添加剂在饲料中的应用提供参考。     

兽用抗菌增效剂制剂的研究进展

抗菌增效剂属于人工合成的二氨基嘧啶类药物，此类药物与抗菌药物联合使用时会以特定的机制来增强抗菌药的药物活性。近年来，由于抗生素的广泛使用甚至滥用导致细菌耐药的问题日益显现，通过加入抗菌增效剂而研制出的新制剂可以提高抗菌药在动物体内的利用率、降低药物用量、增强药物疗效、降低兽药残留及减少细菌耐药性。文章分析了近年来甲氧苄啶、二甲氧苄啶和艾地普林与各类抗生素的联合使用制备的制剂产品，发现其对疾病的治疗效果普遍优于单独使用抗生素。同时，配合中药的使用对细菌耐药的问题有显著改善，为后期抗菌增效剂的研究打开新的局面。随着对兽药制剂的研究，其不再局限于简单的剂型，通过运用新技术、新材料研制出的制剂，针对不同的给药部位和给药途径可以对病患进行更精准的治疗，减少药物达到靶部位的时间，增加患病部位的药量，此思路可为后续的研发方向提供支持和参考。文章将对抗菌药-抗菌增效剂联用制剂的研发情况进行综述。     

Antibiotic resistance patterns in fecal bacteria isolated from Christmas shearwater (Puffinus nativitatis) and masked booby (Sula dactylatra) at remote Easter Island

Antibiotic use and its implications have been discussed extensively in the past decades. This situation has global consequences when antibiotic resistance becomes widespread in the intestinal bacterial flora of stationary and migratory birds. This study investigated the incidence of fecal bacteria and general antibiotic resistance, with special focus on extended spectrum beta-lactamase (ESBL) isolates, in two species of seabirds at remote Easter Island. We identified 11 species of bacteria from masked booby (Sula dactylatra) and Christmas shearwater (Puffinus nativitatis); five species of gram-negative bacilli, four species of Streptococcus (Enterococcus), and 2 species of Staphylococcus. In addition, 6 types of bacteria were determined barely to the genus level. General antibiotic susceptibility was measured in the 30 isolated Enterobacteriaceae to 11 antibiotics used in human and veterinary medicine. The 10 isolates that showed a phenotypic ESBL profile were verified by clavulanic acid inhibition in double mixture discs with cefpodoxime, and two ESBL strains were found, one strain in masked booby and one strain in Christmas shearwater. The two bacteria harboring the ESBL type were identified as Serratia odorifera biotype 1, which has zoonotic importance. Despite minimal human presence in the masked booby and Christmas shearwater habitats, and the extreme geographic isolation of Easter Island, we found several multiresistant bacteria and even two isolates with ESBL phenotypes. The finding of ESBLs has animal and public health significance and is of potential concern, especially because the investigation was limited in size and indicated that antibiotic-resistant bacteria now are distributed globally.