Deshpande Devyani, Srivastava Shashikant, Pasipanodya Jotam G, Lee Pooi S, Gumbo Tawanda
Center for Infectious Diseases Research and Experimental Therapeutics, Baylor Research Institute, Baylor University Medical Center, Dallas, TX, USA.
J Antimicrob Chemother. 2017 Sep 1;72(suppl_2):i48-i53. doi: 10.1093/jac/dkx307.
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 avium complex (MAC) disease.
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.
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.
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.
比较头孢他啶/阿维巴坦联合替加环素的联合治疗方案与阿奇霉素、乙胺丁醇和利福布汀的标准疗法治疗肺部鸟分枝杆菌复合群（MAC）病的疗效。
我们模拟了头孢他啶/阿维巴坦与替加环素联合、头孢他啶/阿维巴坦、利福布汀、替加环素和莫西沙星（CARTM）的人体肺部浓度-时间曲线，以及标准治疗方案，并在细胞内肺部MAC（HFS-MAC）单元的三重中空纤维系统模型中检测微生物杀灭情况。所用的替加环素和莫西沙星剂量未优化；替加环素剂量与抑菌作用相关。药物每日给药，持续28天。对每个HFS-MAC的中央和外周隔室进行采样，以确定是否达到预期的药物暴露水平。在28天内定期对外周隔室进行采样，以量化MAC的负荷。
HFS-MAC中被MAC感染的巨噬细胞内利福布汀、莫西沙星、头孢他啶/阿维巴坦的浓度比细胞外浓度高几倍。未优化的头孢他啶/阿维巴坦联合替加环素双重疗法在整个28天内使细菌负荷维持在与第0天相同的水平（停滞）。标准疗法在第14天将细菌载量降低至停滞水平以下2 log1０ cfu/mL，但之后开始失效。CARTM方案在第21天使细菌载量降低至停滞水平以下3.2 log1０ cfu/mL，但到第28天已开始失效。
CARTM方案有望具有比标准疗法更高的杀灭率。为了设计一个短程化疗方案，需要进行实验以确定CARTM联合方案中四种药物各自达到最佳效果的暴露水平。
