Background The high mortality of systemic anthrax is likely a consequence of the severe central nervous system (CNS) inflammation that occurs in anthrax meningitis. Effective treatment of such infections requires, at a minimum, adequate cerebrospinal fluid (CSF) antimicrobial concentrations. Methods We reviewed English medical literature and regulatory documents to extract information on serum and CSF exposures for antimicrobials with in vitro activity against Bacillus anthracis. Using CSF pharmacokinetic exposures and in vitro B. anthracis susceptibility data, we employed population pharmacokinetic modeling and Monte Carlo simulations to predict whether a specific antimicrobial dosage would likely achieve effective CSF antimicrobial activity in patients with normal to inflamed meninges (i.e., an intact to markedly disrupted blood brain barrier). Results Probability of microbiologic success at achievable antimicrobial dosages was high (≥95%) for ciprofloxacin, levofloxacin (500 mg q12 h), meropenem, imipenem/cilastatin, penicillin G, ampicillin, ampicillin/sulbactam, doxycycline, and minocycline; acceptable (90-95%) for piperacillin/tazobactam and levofloxacin (750 mg q24 h); and low (<90%) for vancomycin, amikacin, clindamycin, and linezolid. Conclusion Prompt empiric antimicrobial therapy of patients with suspected or confirmed anthrax meningitis may reduce the high morbidity and mortality. Our data support using several β-lactam-, fluoroquinolone-, and tetracycline-class antimicrobials as first-line and alternative agents for treatment of patients with anthrax meningitis; all should achieve effective microbiologic exposures. Our data also suggest antimicrobials that should not be relied upon to treat suspected or documented anthrax meningitis. Furthermore, the protein synthesis inhibitors clindamycin and linezolid can decrease toxin production and may be useful components of combination therapy.

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炭疽脑膜炎的中枢神经系统抗生素暴露和建议剂量

背景 系统性炭疽的高死亡率可能是炭疽脑膜炎中发生的严重中枢神经系统（CNS）炎症的结果。有效治疗此类感染至少需要足够的脑脊液 (CSF) 抗菌浓度。方法 我们查阅了英文医学文献和监管文件，以提取具有体外抗炭疽杆菌活性的抗菌药物的血清和脑脊液暴露信息。利用脑脊液药代动力学暴露和体外炭疽芽孢杆菌敏感性数据，我们采用群体药代动力学模型和蒙特卡罗模拟来预测特定抗菌剂量是否可能在正常至发炎脑膜（即完整至显着脑膜）的患者中实现有效的脑脊液抗菌活性。破坏了血脑屏障）。结果 对于环丙沙星、左氧氟沙星（500 mg q12 h）、美罗培南、亚胺培南/西司他丁、青霉素 G、氨苄青霉素、氨苄西林/舒巴坦、多西环素和米诺环素，在可达到的抗菌剂量下微生物学成功的可能性较高（≥95%）；哌拉西林/他唑巴坦和左氧氟沙星（750 mg q24 h）可接受（90-95%）；对于万古霉素、阿米卡星、克林霉素和利奈唑胺则较低(＜90％)。结论 对疑似或确诊炭疽脑膜炎患者及时进行经验性抗菌治疗可降低其高发病率和死亡率。我们的数据支持使用几种β-内酰胺类、氟喹诺酮类和四环素类抗菌药物作为治疗炭疽脑膜炎患者的一线和替代药物；所有人都应实现有效的微生物暴露。我们的数据还表明不应依赖抗菌药物来治疗疑似或记录的炭疽脑膜炎。此外，蛋白质合成抑制剂克林霉素和利奈唑胺可以减少毒素的产生，可能是联合治疗的有用成分。