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.     

The plasma kinetics of sulbactam-ampicillin administered to calves by the intramuscular and subcutaneous routes

Sulbactam-ampicillin combines ampicillin, a broad spectrum beta-lactam antibiotic, with sulbactam, an irreversible beta-lactamase inhibitor. The sulbactam component prevents the degradation of ampicillin by several major classes of bacterial beta-lactamases and restores the activity of ampicillin against most strains of bacteria in which resistance is mediated by beta-lactamase production.A crossover study was conducted in Friesian calves of 98–119 kg bodyweight in which the plasma kinetics of sulbactam-ampicillin adminstered by the intramuscular and subcutaneous routes were defined, and the plasma kinetics of ampicillin derived from sulbactam-ampicillin and a commercially available formulation of ampicillin trihydrate were compared. Subsequent to both intramuscular and subcutaneous administration of sulbactam-ampicillin, peak plasma concentrations of sulbactam and ampicillin were recorded two hours post-injection. Higher peak plasma concentrations of both sulbactam and ampicillin were achieved by the subcutaneous route of administration and, for ampicillin, the difference between the two routes was statistically significant (p < 0·01). However, there was no significant difference in bioavailability (as measured by area under the curve) between the two routes of administration for either component. In addition, there were no significant differences between the peak plasma concentrations or areas under the curves for ampicillin derived from intramuscular administration of sulbactam-ampicillin, and ampicillin alone, indicating that combination with sulbactam does not alter the plasma kinetics of ampicillin.     

Efficacy of sulbactam-ampicillin in the treatment of neonatal calf diarrhoea

Sulbactam-ampicillin is a combination of sulbactam, a beta-lactamase inhibitor, and ampicillin, a broad spectrum beta-lactam antibiotic. The efficacy of sulbactam-ampicillin was evaluated in the treatment of neonatal calf diarrhoea under conditions where a major proportion of the calves were excreting enterobacteria which were resistant to beta-lactam antibiotics. In a series of six studies with a common experimental design, three treatments (sulbactam-ampicillin, ampicillin alone and untreated control) were compared in over 300 Friesian and Ayrshire calves aged between three and 10 days and of known immunological status as determined by their zinc sulphate turbidity values. A mortality rate of 26.4 per cent in the negative control calves was reduced to 14.0 per cent with ampicillin alone and 9.5 per cent with sulbactam-ampicillin. The probability of diarrhoea subsequent to initiation of treatment was reduced from 0.50 in the negative control calves to 0.44 with ampicillin alone and 0.35 with sulbactam-ampicillin. The differences in mortality and diarrhoea observed between the calves treated with sulbactam-ampicillin and the calves in each of the other treatment groups were statistically significant. The superior efficacy of sulbactam-ampicillin is explained by the inhibitory effect of sulbactam on the beta-lactamases produced by resistant bacteria, thus rendering them susceptible to the ampicillin in the combination.     

Rational antibiotic therapy for respiratory disorders in dogs and cats.

Therapy of respiratory tract infections presents some unique challenges to the veterinary practitioner. These infections often involve underlying disease processes that have predisposed the patient to secondary bacterial infection and may complicate the response to therapy. Because of the diversity of microbial organisms that may colonize and invade the respiratory tract, treatment targeted at the infecting pathogens is best accomplished with bacterial culture and susceptibility testing. When these data are unavailable, rational antibiotic treatment should be based on familiarity with historical data and clinical experience. Optimal drug selection is based on predicted microbial susceptibility, drug distribution in the respiratory tract, and safety of the patient. Instituting the appropriate dosage regimen and duration of therapy maximizes the opportunity for a successful resolution of bacterial infections.     

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.     

头孢喹诺的研究进展

头孢喹诺是动物专用的第 1个第 4代头孢菌素类抗生素 ,其抗菌谱广 ,抗菌活性强 ,对临床分离的各种 G 菌、G-菌的 MIC50 、MIC90 值均较小 ,而且对绿脓杆菌有很强的抗菌活性 ;其动力学特点优良 ,吸收快 ,达峰时间短 ,生物利用度较高 ,可以在肺、乳腺等组织达到较高的组织浓度 ;头孢喹诺毒性低 ,在动物的可食性组织中残留较少 ;国外已广泛应用于猪、牛的呼吸系统感染及奶牛乳房炎的临床治疗。因此 ,在我国兽医临床上具有广阔的应用前景。为了促进其在我国兽医临床上的合理应用、研制与开发 ,现对其抗菌活性、药动学、毒性及残留、临床应用等有关资料进行综述     

Antibiotic resistance in Escherichia coli O157 isolated between 1998 and 2003 in The Netherlands

Little is known about the antibiotic resistance of E. coli O157 in The Netherlands. In this study, 218 human and 247 nonhuman samples, isolated between 1998 and 2003, were tested for antimicrobial resistance. About 5.5% of E. coli O157 isolates from human samples were resistant, as were about 4.00% of E. coli O157 isolates from non-human samples. These figures are lower than those reported in the literature. Class I integrons were found in six multiresistant isolates. This type of integron is also found in commensal E. coli in food animals and Salmonella spp. One of the integron-positive isolates contained the beta-lactamase bla(TEM-1b) and an extended spectrum beta-lactamase (ESBL), which belongs to the group 2 CTX-M enzymes. This is the first report of these beta-lactamases in E. coli O157 isolated from chicken.     

The efficacy of sulbactam-ampicillin in the therapy of respiratory disease associated with ampicillin resistant Pasteurella species in housed calves

Sulbactam-ampicillin is a combination of sulbactam, a beta-lactamase inhibitor, and ampicillin, a broad spectrum beta-lactam antibiotic. The efficacy of sulbactam-ampicillin was evaluated in the treatment of calf respiratory disease associated with ampicillin-sensitive and ampicillin-resistant strains of Pasteurella haemolytica and Pasteurella multocida. Treatment with sulbactam-ampicillin was compared with treatment with ampicillin alone in 123 Friesian calves, between three and five weeks old, exhibiting clinical signs of respiratory disease. Seven of the 59 calves treated with ampicillin died whereas only one death occurred in the 64 calves treated with sulbactam-ampicillin. In the calves which survived, treatment with sulbactam-ampicillin resulted in a significantly better clinical response, as measured by the reduction in severity of clinical signs. The results of bacteriological examinations indicated that there was a marked increase in the proportion of ampicillin-resistant isolates of P haemolytica subsequent to treatment with ampicillin, whereas the proportion of ampicillin-resistant isolates of P. haemolytica recovered from calves treated with sulbactam-ampicillin had declined. The superior efficacy of sulbactam-ampicillin observed in this study is explained by the inhibitory effect of sulbactam on beta-lactamases produced by resistant bacteria, thus rendering them susceptible to the ampicillin.     

ANTIMICROBIAL SUSCEPTIBILITY TESTING IN SURGICAL MICROBIOLOGY

Bacterial infections are not infrequent problems in the surgical patient. Until recently, it was not economically feasible for most practicing veterinarians to determine the antimicrobial susceptibility of the organisms causing infections. The treatment regimen of such infections was based on experience and the use of antibiotic combinations or broad-spectrum antibiotics. A number of recent reports have shown the multiple resistance of bacterial isolates from animals, especially to Streptomycin, Tetracycline and Penicillin.^{5, 14, 15, 20, 21} Since these antimicrobials are some of the most liberally used in veterinary medicine, it appears that the incorporation of susceptibility testing into the evaluation and treatment of the infected patient would be helpful.     

Bovine mastitis therapy and why it fails

Treatment of bovine mastitis depends on the cause, the clinical manifestation and the antibiotic susceptibility of the agent. Mastitis therapy is commonly unsuccessful owing to pathological changes that occur in the udder parenchyma as a result of the inflammatory reaction to mastitogenic bacteria, pharmacokinetic properties of antimicrobial mastitis drugs, mastitogenic bacterial and related factors, and poor animal husbandry and veterinary interventions.     

泰地罗新研究进展

概述了泰地罗新的理化性质、作用机理、抗菌活性、药动学、药效学、不良反应及残留,以期为该药在兽医临床的应用提供参考资料。泰地罗新是动物专用的新型大环内酯类抗生素,其吸收快,达峰时间短,生物利用度高,肺组织浓度高,消除半衰期长,药效持久。单次肌注或皮下注射给药,即能提供全程治疗,在兽医临床具有广阔的应用前景。     

In vitro complex formation and inhibition of hepatic cytochrome P450 activity by different macrolides and tiamulin in goats and cattle

In humans, clinically relevant drug-drug interactions occur with some macrolide antibiotics via the formation of stable metabolic intermediate (MI) complexes with enzymes of the cytochrome P4503A (CYP3A) subfamily. The formation of such complexes can result in a decreased biotransformation rate of simultaneously administered drugs. In previous studies it was shown that the veterinary antibiotic tiamulin was also able to form a stable MI complex in pigs and rats. In the present study the relative CYP3A inhibiting potency and MI complex formation of a series of macrolide antibiotics and tiamulin were studied in microsomal fractions of goat and cattle and in a cell-line expressing bovine CYP3A. Tiamulin and triacetyloleandomycin (TAO) were found to be effective inhibitors of CYP450 activity in all systems tested. Erythromycin and tilmicosin were found to be relatively less effective inhibitors of CYP450 activity in microsomes, and their activity in the bovine CYP3A4 expressing cell line was relatively weak. Tylosin was shown to be a weak inhibitor in microsomes and not in the cell line, whereas spiramycin had no effect at all. MI-complex formation measured by spectral analysis was seen with TAO, tiamulin, erythromycin and tylosin, but not with tilmicosin and spiramycin. Although additional factors play a role in vivo, these results may explain potential drug-drug interactions and differences between related compounds in this respect.     

Approaches in the safety evaluations of veterinary antimicrobial agents in food to determine the effects on the human intestinal microflora

The administration of antimicrobial agents to livestock creates potential for antibiotic residues to enter the food supply and be consumed by humans. Therefore, as a process of food animal drug registration, national regulatory agencies and international committees evaluate data regarding the chemical, microbiologic, pharmacokinetic, pharmacodynamic, pharmacologic, toxicologic, and antimicrobial properties of veterinary drugs to assess the safety of ingested antimicrobial residues to consumers. Currently, European, Australian and United States guidelines for veterinary drug registration require a safety assessment of microbiologic hazards from consumption of antimicrobial residues taking into account the potentially adverse effects on human intestinal microflora. The main concerns addressed are selection of resistant bacteria in the gastrointestinal tract and disruption of the colonization barrier of the resident intestinal microflora. Current requirements differ among national agencies. Efforts are ongoing internationally to review and harmonize approaches and test methods and protocols for application to these microbiologic safety evaluations of antimicrobial drug residues in food. This review describes the background to current regulatory approaches used in applying in vitro and in vivo methods to set a microbiologic acceptable daily intake for residues in food derived from animals treated with an antimicrobial agent. This paper also examines the current research needs to support these evaluations.     

动物专用大环内酯类新药——泰拉霉素

泰拉霉素是动物专用的新型大环内酯类抗生素,国内已批准用于猪呼吸系统疾病的防治。泰拉霉素的药动学特性优良,吸收快,达峰时间短,生物利用度高,在肺中可达到很高的组织浓度,消除半衰期长,药效持久。单次肌注或皮下给药即能提供全程的治疗,在兽医临床具有广阔的应用前景。本文综述了泰拉霉素的理化性质、作用机理、抗菌活性、药动学、药效学、不良反应及残留,为该药在兽医临床的应用提供参考资料。     

Treatment of clinical mastitis. Using antimicrobial susceptibility profiles for treatment decisions.

Antibiotic susceptibility of clinical mastitis pathogens has traditionally been determined using the agar diffusion method that was designed to reflect the antibiotic concentration in serum and interstitial fluid of human patients after receiving oral or intravenous administration. The validity of applying agar diffusion susceptibility breakpoints derived from humans to the treatment of bovine mastitis has not been established and is extremely questionable because (1) bovine milk pH and electrolyte, fat, protein, and leukocyte concentrations, growth factor composition, and pharmacokinetic profiles are different than those for human plasma and (2) human bacterial pathogens are often different from bovine mastitis pathogens. Also, antibiotics are distributed unevenly in an inflamed gland, and high antibiotic concentrations can alter neutrophil morphology or function in vitro and thereby inhibit bacterial clearance in vivo. The current cost of antibiotic susceptibility testing is $12 to $20 per test. Because the dairy industry is economically driven, any diagnostic test should be validated, have appropriate sensitivity and specificity, and have an acceptable economic return on the cost of testing before it can be routinely recommended. In the authors' opinion, antimicrobial susceptibility testing of mastitis pathogens has not been adequately validated for most mastitis pathogens and antibiotics; therefore, the authors do not currently recommend the use of susceptibility testing to guide treatment decisions for individual cows. Additional research is needed to further define the role, if any, that antimicrobial susceptibility testing should play in the treatment of clinical mastitis.     

Evaluation of the in vitro cytotoxicity of mitoxantrone following repeated freeze-thaw cycles

Mitoxantrone, an antineoplastic anthracycline antibiotic with a wide range of veterinary applications, was developed as a less cardiotoxic alternative to doxorubicin, a related compound in this family of chemotherapy agents. Mitoxantrone has not gained widespread acceptance in the veterinary community, primarily due to its cost and single-dose packaging in a volume that exceeds the needs of the majority of veterinary cancer patients. The in vitro cytotoxicity of mitoxantrone following repeated freeze-thaw cycles was evaluated to determine whether long-term storage at -20 degrees C resulted in decreased efficacy. The drug was frozen between treatment cycles to minimize the risk of bacterial contamination because it is supplied as a preservative-free solution. Results indicated mitoxantrone maintained its cytotoxicity against cancer cells in culture following multiple freeze-thaw cycles spanning at least 12 months.     

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.     

Integration and modelling of pharmacokinetic and pharmacodynamic data to optimize dosage regimens in veterinary medicine

In veterinary drug development procedures, pharmacokinetic (PK) and pharmacodynamic (PD) data have generally been established in separate, parallel studies to assist in the design of dosage schedules for subsequent evaluation in clinical trials. This review introduces the concept of PK/PD modelling, an approach in which PK and PD data are generated in the same study, and used to derive numerical values for PD parameters based on drug plasma concentrations. The PD parameters define the efficacy, potency and slope (sensitivity) of the concentration-effect relationship. It is proposed that the parameters derived from PK/PD modelling may be used as an alternative and preferred approach to dose titration studies for selecting rational dosage regimens (both dose and dosing interval) for further evaluation in clinical trials. In PK/PD modelling, the explicative variable for effect is the plasma concentration profile. The PK/PD approach provides several advantages over dose-titration studies, including determination of a projected dosage regimen by investigation of a single dose, in contrast to dose-ranging studies which by definition require testing of multiple dosage. Implementation of PK/PD modelling in the veterinary drug development process is currently constrained by the limited number of veterinary studies performed to date, and the consequently limited understanding of PK/PD concepts and their absence from regulatory authority guidelines. Nevertheless, PK/PD modelling has major potential for rational dosage regimen determination, as it considers and quantifies the two main sources of interspecies variability (PK and PD). It is therefore applicable to interspecies extrapolation and to multiple species drug development. As well as the currently limited appreciation of PK/PD principles in the veterinary scientific community, a further constraint in implementing PK/PD modelling is the need to validate PK/PD approaches and thereby gain confidence in its value by pharmaceutical companies and regulatory authorities.     

细菌耐药拮抗剂的研究

本文介绍了具有拮抗细菌耐药性作用的物质的研究进展情况，包括灭活酶抑制剂、药物渗透促进剂、外输泵抑制剂、细菌生物被膜抑制剂、抗菌药物增强剂、耐药质粒消除剂等。     

基于非线性混合效应模型分析兽药药代动力学研究进展

利用数学建模分析兽药药代动力学历来已久。兽药药代动力学中应用数学建模和模拟分析可简化和加快兽药研发进程。非线性混合效应模型分析方法是兽药药代动力学建模和模拟的主要方法之一,该方法对临床合理用药、新药研发及评审更高效具有很大意义,同时阐明一些传统药动学无法回答的问题。本文综述了非线性混合效应模型在分析兽药药代动力学主要原理及应用进展,以期望非线性混合效应模型分析方法在我国新兽药研发与评审中应用提供积极有益的参考。