Deziel Mark R, Heine Henry, Louie Arnold, Kao Mark, Byrne William R, Basset Jennifer, Miller Lynda, Bush Karen, Kelly Michael, Drusano G L
Ordway Research Institute, 150 New Scotland Avenue, Albany, New York 12208, USA.
Antimicrob Agents Chemother. 2005 Dec;49(12):5099-106. doi: 10.1128/AAC.49.12.5099-5106.2005.
Expanded options for treatments directed against pathogens that can be used for bioterrorism are urgently needed. Treatment regimens directed against such pathogens can be identified only by using data derived from in vitro and animal studies. It is crucial that these studies reliably predict the efficacy of proposed treatments in humans. The objective of this study was to identify a levofloxacin treatment regimen that will serve as an effective therapy for Bacillus anthracis infections and postexposure prophylaxis. An in vitro hollow-fiber infection model that replicates the pharmacokinetic profile of levofloxacin observed in humans (half-life [t(1/2)], 7.5 h) or in animals, such as the mouse or the rhesus monkey (t(1/2), approximately 2 h), was used to evaluate a proposed indication for levofloxacin (500 mg once daily) for the treatment of Bacillus anthracis infections. The results obtained with the in vitro model served as the basis for the doses and the dose schedules that were evaluated in the mouse inhalational anthrax model. The effects of levofloxacin and ciprofloxacin treatment were compared to those of no treatment (untreated controls). The main outcome measure in the in vitro hollow-fiber infection model was a persistent reduction of culture density (> or = 4 log10 reduction) and prevention of the emergence of levofloxacin-resistant organisms. In the mouse inhalational anthrax model the main outcome measure was survival. The results indicated that levofloxacin given once daily with simulated human pharmacokinetics effectively sterilized Bacillus anthracis cultures. By using a simulated animal pharmacokinetic profile, a once-daily dosing regimen that provided a human-equivalent exposure failed to sterilize the cultures. Dosing regimens that "partially humanized" levofloxacin exposures within the constraints of animal pharmacokinetics reproduced the antimicrobial efficacy seen with human pharmacokinetics. In a mouse inhalational anthrax model, once-daily dosing was significantly inferior (survival end point) to regimens of dosing every 12 h or every 6 h with identical total daily levofloxacin doses. These results demonstrate the predictive value of the in vitro hollow-fiber infection model with respect to the success or the failure of treatment regimens in animals. Furthermore, the model permits the evaluation of treatment regimens that "humanize" antibiotic exposures in animal models, enhancing the confidence with which animal models may be used to reliably predict the efficacies of proposed antibiotic treatments in humans in situations (e.g., the release of pathogens as agents of bioterrorism or emerging infectious diseases) where human trials cannot be performed. A treatment regimen effective in rhesus monkeys was identified.
迫切需要针对可用于生物恐怖主义的病原体的更多治疗选择。只有通过使用体外和动物研究的数据，才能确定针对此类病原体的治疗方案。至关重要的是，这些研究要可靠地预测所提议治疗方法对人类的疗效。本研究的目的是确定一种左氧氟沙星治疗方案，该方案可作为炭疽芽孢杆菌感染和暴露后预防的有效疗法。使用一种体外中空纤维感染模型来评估左氧氟沙星（每日一次，500毫克）治疗炭疽芽孢杆菌感染的拟用适应症，该模型可复制在人类（半衰期[t(1/2)]，7.5小时）或动物（如小鼠或恒河猴[t(1/2)，约2小时]）中观察到的左氧氟沙星药代动力学特征。体外模型获得的结果作为在小鼠吸入性炭疽模型中评估的剂量和给药方案的基础。将左氧氟沙星和环丙沙星治疗的效果与未治疗（未处理对照）的效果进行比较。体外中空纤维感染模型的主要结局指标是培养密度持续降低（≥4个对数10降低）以及防止出现左氧氟沙星耐药菌。在小鼠吸入性炭疽模型中，主要结局指标是生存。结果表明，以模拟人类药代动力学每日给药一次的左氧氟沙星有效地清除了炭疽芽孢杆菌培养物。通过使用模拟动物药代动力学特征，每日一次的给药方案虽提供了与人类相当的暴露量，但未能清除培养物。在动物药代动力学限制范围内“部分人源化”左氧氟沙星暴露的给药方案重现了人类药代动力学所见的抗菌效果。在小鼠吸入性炭疽模型中，每日一次给药在生存终点方面明显不如每日总左氧氟沙星剂量相同但每12小时或每6小时给药一次的方案。这些结果证明了体外中空纤维感染模型对于动物治疗方案成败的预测价值。此外，该模型允许评估在动物模型中“人源化”抗生素暴露的治疗方案，增强了在无法进行人体试验的情况下（例如，作为生物恐怖主义或新发传染病病原体释放）使用动物模型可靠预测所提议抗生素治疗对人类疗效的信心。确定了一种对恒河猴有效的治疗方案。
