Data Sheet 1_Activity of combinations of bactericidal and bacteriostatic compounds in Mycobacterium abscessus-infected mice: an overview.pdf

Treatment of Mycobacterium abscessus (MAB) infections is complicated by the lack of bactericidal antibiotics, the ability of MAB to persist in the hypoxic environment of granulomas and the intrinsic antibiotic resistance, which results in patient treatment with drug combinations for several months. Therefore, the search for new drugs/drug combinations is an urgent need. This review provides a comprehensive update on the activity in the lungs of MAB-infected mice of new and old bactericidal and bacteriostatic compounds, alone and in combination, which showed killing greater than or equal to clinically used antibiotics and combination components. The acute model (4–14 days of treatment) was preferred in most single-drug efficacy testing procedures while the chronic model (28–42 days) was primarily used for combinations. Overall, 15 of 17 new compounds and 13 of 14 combinations decreased MAB colony forming units (CFUs) more than comparator drugs or combination components. The most potent combinations were those formed by bactericidal agents (≥1−log10 CFU reduction compared to the initial bacterial burden), consisting of two β-lactams and a β-lactam plus a β-lactamase inhibitor. Among the other combinations, activity of the bactericidal compounds was usually slightly increased by the bacteriostatic agents that, however, preserved the bactericidal core of combinations and suppressed emergence of drug resistance. Overall, these data suggest that there is an urgent need for systematic in vivo investigations on anti-MAB activity of combinations containing bactericidal drugs that are part of current treatment guidelines or of new, preferably oral compounds, to ultimately eradicate non-replicating persisters at the sites of disease.

脓肿分枝杆菌（Mycobacterium abscessus, MAB）感染的治疗面临诸多复杂困境，这源于缺乏针对该菌的杀菌抗生素、MAB可在肉芽肿的缺氧微环境中持续存活，以及其固有抗生素耐药性，这使得患者需接受数月的联合药物治疗。因此，研发新型药物及联合用药方案已成为迫切的临床需求。
本综述全面更新了针对MAB感染小鼠肺部的杀菌与抑菌化合物（包括单用及联合使用的新旧化合物）的相关研究进展，这些化合物的杀菌效果优于或等同于临床使用的抗生素及联合用药组分。
多数单药疗效评估实验优先选用急性感染模型（给药时长4~14天），而联合用药实验则主要采用慢性感染模型（给药时长28~42天）。总体而言，17种新型化合物中有15种、14种联合用药方案中有13种，其降低MAB菌落形成单位（colony forming units, CFU）的效果优于对照药物或联合用药组分。
疗效最佳的联合用药方案由杀菌类药物构成（与初始细菌载量相比，可使CFU降低≥1 log10），包括两种β-内酰胺类药物联用，以及β-内酰胺类与β-内酰胺酶抑制剂联用的方案。在其余联合用药方案中，抑菌类药物通常可轻度增强杀菌类化合物的活性，同时保留联合用药的杀菌核心属性，并抑制耐药性的产生。
综上，现有数据表明，亟需开展系统性体内研究，评估包含现行治疗指南推荐的杀菌类药物，或是新型（优选口服）化合物的联合用药方案的抗MAB活性，以最终清除病灶部位的非复制持留菌。