The discovery of ceftazidime/avibactam as an anti-Mycobacterium avium agent
The discovery of ceftazidime/avibactam as an anti-Mycobacterium avium agent
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DOI：
10.1093/jac/dkx306
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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：
--
作者：
Deshpande, Devyani;Srivastava, Shashikant;Gumbo, Tawanda
目的：确定头孢洛林和头孢他啶联合阿维巴坦是否对肺分枝杆菌复合群（MAC）疾病有效。方法：首先，我们在试管中进行了头孢洛林和头孢他啶/阿维巴坦对细胞外 MAC 的浓度效应研究。考虑到在实验时获得阿维巴坦的困难，我们使用单一浓度的商业头孢他啶/阿维巴坦，以及两组未处理的对照，一组含有头孢他啶/阿维巴坦，另一组不含头孢他啶/阿维巴坦。在发现头孢他啶/阿维巴坦“对照”的抗菌活性后，我们在试管中针对细胞外 MAC 和在 24 孔板中针对细胞内 MAC 进行了头孢他啶/阿维巴坦剂量效应研究。然后，我们在细胞内肺 MAC (HFS-MAC) 的中空纤维系统模型中进行了头孢他啶/阿维巴坦暴露效应和剂量分割研究。在每个实验中，我们在指定时间对每个 HFS-MAC 重复取样，以验证头孢他啶/阿维巴坦药代动力学并量化细菌负荷。结果：头孢洛林杀死细胞外 MAC，最大微生物杀灭 (E-max) 为 4.87 +/- 0.26 log(10) cfu/mL。然而，与未处理的对照相比，头孢他啶/阿维巴坦“对照”也杀死了 MAC。头孢他啶/阿维巴坦对细胞外杆菌的 E-max 为 3.8 log10 cfu/mL，对细胞内 MAC 的 E-max 为 3.6 log(10) cfu/mL。在 HFS-MAC 中，头孢他啶/阿维巴坦的半衰期为 2.5-3.3 小时，杀死的 MAC 比起始细菌负荷低 0.61-2.40 log(10) cfu/mL。头孢他啶/阿维巴坦的疗效与浓度持续高于 MIC (fT (> MIC)) 的给药间隔比例相关，无药物 fT(> MIC) 时的最佳疗效为 52% (r(2) = 0.95)。结论：头孢他啶/阿维巴坦在临床剂量轻松达到的肺部暴露量下可有效杀死 MAC。疗效高于阿奇霉素和乙胺丁醇的临床可实现剂量。
Objectives: To determine if ceftaroline and ceftazidime combined with avibactam are efficacious against pulmonary Mycobacterium aviumcomplex (MAC) disease.Methods: First, we performed a concentration-effect study of ceftaroline and ceftaroline/avibactam against extracellular MAC in test tubes. Given the difficulty of obtaining avibactam at the time of experimentation, we used a single concentration of commercial ceftazidime/avibactam, and two sets of non-treated controls, one with ceftazidime/avibactam and the other without. After finding antimicrobial activity with the ceftazidime/avibactam 'control', we performed ceftazidime/avibactam dose-effect studies in test tubes against extracellular MAC and in 24-well plates against intracellular MAC. We then performed a ceftazidime/avibactam exposureeffect and dose-fractionation studies in the hollow-fibre system model of intracellular pulmonary MAC (HFS-MAC). In each experiment, we repetitively sampled each HFS-MAC at specified times to validate ceftazidime/ avibactam pharmacokinetics and to quantify bacterial burden.Results: Ceftaroline killed extracellular MAC with maximal microbial kill (E-max) of 4.87 +/- 0.26 log(10) cfu/mL. However, the ceftazidime/avibactam 'control' also killed MAC compared with the non-treated control. Ceftazidime/avibactam E-max was 3.8 log10 cfu/mL against extracellular bacilli and 3.6 log(10) cfu/mL against intracellular MAC. In the HFS-MAC, ceftazidime/avibactam achieved a half-life of 2.5-3.3 h and killed MAC 0.61-2.40 log(10) cfu/mL below the starting bacterial burden. The ceftazidime/avibactamefficacy was linked to the proportion of the dosing interval for which the concentration persists above the MIC (fT (> MIC)), with optimal efficacy at free-drug fT(> MIC) of 52% (r(2) = 0.95).Conclusions: Ceftazidime/avibactam effectively kills MAC at exposures easily achieved in the lung by clinical doses. Efficacy was higher than with clinically achievable doses of azithromycin and ethambutol.