Deshpande Devyani, Srivastava Shashikant, Chapagain Moti L, Lee Pooi S, Cirrincione Kayle N, Pasipanodya Jotam G, 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):i36-i42. doi: 10.1093/jac/dkx306.
To determine if ceftaroline and ceftazidime combined with avibactam are efficacious against pulmonary Mycobacterium avium complex (MAC) disease.
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 exposure-effect 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.
Ceftaroline killed extracellular MAC with maximal microbial kill (Emax) of 4.87 ± 0.26 log10 cfu/mL. However, the ceftazidime/avibactam 'control' also killed MAC compared with the non-treated control. Ceftazidime/avibactam Emax was 3.8 log10 cfu/mL against extracellular bacilli and 3.6 log10 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 log10 cfu/mL below the starting bacterial burden. The ceftazidime/avibactam efficacy 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% (r2 = 0.95).
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.
确定头孢洛林以及头孢他啶联合阿维巴坦对肺部鸟分枝杆菌复合群（MAC）疾病是否有效。
首先，我们在试管中进行了头孢洛林以及头孢洛林/阿维巴坦针对细胞外MAC的浓度效应研究。鉴于实验时获取阿维巴坦存在困难，我们使用了单一浓度的市售头孢他啶/阿维巴坦，并设置了两组未处理的对照组，一组含头孢他啶/阿维巴坦，另一组不含。在用头孢他啶/阿维巴坦“对照组”发现抗菌活性后，我们在试管中针对细胞外MAC以及在24孔板中针对细胞内MAC进行了头孢他啶/阿维巴坦的剂量效应研究。然后我们在细胞内肺部MAC的中空纤维系统模型（HFS - MAC）中进行了头孢他啶/阿维巴坦的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进行重复采样，以验证头孢他啶/阿维巴坦的药代动力学并量化细菌负荷。
头孢洛林可杀死细胞外MAC，最大微生物杀灭率（Emax）为4.87±0.26 log10 cfu/mL。然而，与未处理的对照组相比，头孢他啶/阿维巴坦“对照组”也能杀死MAC。头孢他啶/阿维巴坦对细胞外杆菌的Emax为3.8 log10 cfu/mL，对细胞内MAC的Emax为3.6 log10 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，可使MAC的杀灭量比起始细菌负荷低0.61 - 2.40 log10 cfu/mL。头孢他啶/阿维巴坦的疗效与药物浓度持续高于最低抑菌浓度（MIC）的给药间隔比例（fT>MIC）相关，游离药物fT>MIC为52%时疗效最佳（r2 = 0.95）。
头孢他啶/阿维巴坦在临床剂量下于肺部易于达到的暴露水平时能有效杀死MAC。其疗效高于阿奇霉素和乙胺丁醇的临床可达到剂量。
