A novel ceftazidime/avibactam, rifabutin, tedizolid and moxifloxacin (CARTM) regimen for pulmonary Mycobacterium avium disease
A novel ceftazidime/avibactam, rifabutin, tedizolid and moxifloxacin (CARTM) regimen for pulmonary Mycobacterium avium disease
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DOI：
10.1093/jac/dkx307
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发表时间：
2017-09-01
影响因子：
5.2
通讯作者：
Gumbo, Tawanda
中科院分区：
文献类型：
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作者：
Deshpande, Devyani;Srivastava, Shashikant;Gumbo, Tawanda
目的：比较头孢他啶/阿维巴坦加替地唑酮联合方案与阿奇霉素、乙胺丁醇、利福布汀标准治疗肺禽分枝杆菌（MAC）病的疗效。方法：模拟头孢他啶/阿维巴坦和替他唑胺联用、头孢他啶/阿维巴坦、利法布汀、替他唑胺和莫西沙星（CARTM）、标准方案的人体肺浓度-时间曲线，并在细胞内肺MAC （HFS-MAC）单元的三联体中空纤维系统模型中检测微生物的杀灭效果。使用的替地唑胺和莫西沙星剂量没有优化；泰地唑胺的剂量与抑菌作用有关。每天给药，连续28天。每个HFS-MAC在中央和外周室取样，以确定已达到预期的药物暴露。结果：HFS-MAC中感染mac的巨噬细胞的利法布汀、莫西沙星、头孢他啶/阿维巴坦的细胞内浓度比细胞外浓度高数倍。未经优化的头孢他啶/阿维巴坦加泰德唑胺双药治疗28天内细菌负荷保持在与第0天相同的水平（停滞）。标准治疗使细菌载量在第14天降至2 log10 cfu/mL以下，但此后开始衰竭。CARTM方案在第21天达到3.2 log10 cfu/mL，但在第28天开始失败。结论：CARTM方案有望比标准治疗具有更好的死亡率。为了设计短期化疗方案，需要通过实验确定与CARTM联合治疗中最佳效果相关的四种药物中的每一种的暴露情况。
Objectives: To compare the efficacy of ceftazidime/avibactam plus tedizolid-based combination regimens with the standard therapy of azithromycin, ethambutol and rifabutin for the treatment of pulmonary Mycobacterium aviumcomplex (MAC) disease.Methods: We mimicked the human pulmonary concentration-time profiles of ceftazidime/avibactam and tedizolid in combination, ceftazidime/avibactam, rifabutin, tedizolid and moxifloxacin (CARTM), and the standard regimen and examined microbial kill in triplicate hollow-fibre system model of intracellular pulmonary MAC (HFS-MAC) units. The tedizolid and moxifloxacin doses used were non-optimized; the tedizolid dose was that associated with bacteriostasis. Drugs were administered daily for 28 days. Each HFS-MAC was sampled in the central and peripheral compartment to ascertain that the intended drug exposures had been achieved. The peripheral compartments were sampled at regular intervals over the 28 days to quantify the burden of MAC.Results: MAC-infected macrophages in the HFS-MAC achieved multi-fold higher intracellular versus extracellular concentrations of rifabutin, moxifloxacin, ceftazidime/avibactam. The non-optimized ceftazidime/avibactam plus tedizolid dual therapy held the bacterial burden at the same level as day 0 (stasis) throughout the 28 days. The standard therapy reduced the bacterial load 2 log10 cfu/mL below stasis on day 14 but started failing after that. The CARTM regimen achieved 3.2 log10 cfu/mL kill below stasis on day 21, but had started to fail by day 28.Conclusions: The CARTM regimen promises to have kill rates better than standard therapy. Experiments to identify exposures of each of the four drugs associated with optimal effect in the CARTM combination are needed in order to design a short-course chemotherapy regimen.