Center for Infectious Diseases Research and Experimental Therapeutics, Baylor Research Institute, Baylor University Medical Center, Dallas, TX, USA.
Texas Tech University Health Science Center, School of Pharmacy, Division of Clinical and Translational Research, Dallas, TX, USA.
J Antimicrob Chemother. 2020 May 1;75(5):1212-1217. doi: 10.1093/jac/dkz523.
The current treatment regimens recommended for Mycobacterium abscessus subspecies abscessus (Mab) pulmonary disease are not effective. We identified 16 drugs with potential to build new regimens, translating to 560 possible three-drug combination regimens.
To determine MICs and efficacy of drugs from different antibiotic classes for treatment against Mab, in order to winnow down the potential drugs for combination therapy to tractable numbers, for future use in hollow-fibre studies.
The MICs of levofloxacin, minocycline, meropenem, imipenem, tedizolid, bedaquiline, azithromycin, clarithromycin, amikacin, vancomycin, delafloxacin, tebipenem/avibactam and omadacycline were determined for 20 Mab isolates. In addition, concentration-response studies with tedizolid, bedaquiline, clarithromycin, amikacin, tebipenem/avibactam, cefdinir, faropenem, omadacycline and daunorubicin were performed and data were fitted to the inhibitory sigmoid Emax model. Efficacy was defined as maximal kill, expressed as cfu/mL kill below day 0 burden.
The lowest MICs among the 13 antibiotics were of bedaquiline, tebipenem/avibactam and omadacycline. The antibiotics that killed Mab below the day 0 burden were the anticancer agent daunorubicin (3.36 log10 cfu/mL), cefdinir (1.85 log10 cfu/mL), faropenem (2.48 log10 cfu/mL) and tebipenem/avibactam (1.71 log10 cfu/mL kill). The EC50 values of these drugs were 11.67, 9.52, 48.2 and 0.33 mg/L, respectively, below peak concentrations of these drugs.
The low MICs and efficacy at clinically achievable concentrations mean that tebipenem/avibactam, daunorubicin, omadacycline and bedaquiline give a view of components of a three-drug regimen likely to effectively kill Mab. We propose pharmacokinetic/pharmacodynamic studies to identify such a regimen and the doses to be combined.
目前推荐的治疗脓肿分枝杆菌亚种（Mab）肺病的治疗方案并不有效。我们发现了 16 种具有潜在构建新方案的药物，这转化为 560 种可能的三联药物组合方案。
确定不同抗生素类别的药物对 Mab 的 MIC 和疗效，以便将潜在的联合治疗药物缩小到可处理的数量，以便将来用于中空纤维研究。
我们测定了 20 株 Mab 分离株对左氧氟沙星、米诺环素、美罗培南、亚胺培南、替加环素、贝达喹啉、阿奇霉素、克拉霉素、阿米卡星、万古霉素、德拉沙星、替比培南/阿维巴坦和奥马环素的 MIC。此外，还进行了替加环素、贝达喹啉、克拉霉素、阿米卡星、替比培南/阿维巴坦、头孢地尼、法罗培南、奥马环素和柔红霉素的浓度反应研究，并将数据拟合到抑制性 sigmoid Emax 模型中。疗效定义为最大杀伤，以低于第 0 天负荷的 cfu/mL 杀伤表示。
在 13 种抗生素中，最低 MIC 是贝达喹啉、替比培南/阿维巴坦和奥马环素。低于第 0 天负荷的 Mab 杀伤药物是抗癌药物柔红霉素（3.36 log10 cfu/mL）、头孢地尼（1.85 log10 cfu/mL）、法罗培南（2.48 log10 cfu/mL）和替比培南/阿维巴坦（1.71 log10 cfu/mL 杀伤）。这些药物的 EC50 值分别为 11.67、9.52、48.2 和 0.33 mg/L，低于这些药物的峰值浓度。
低 MIC 和临床可达到浓度下的疗效意味着替比培南/阿维巴坦、柔红霉素、奥马环素和贝达喹啉为 Mab 的三联药物方案提供了有效的治疗方案。我们建议进行药代动力学/药效学研究，以确定这样的方案和联合用药剂量。
