Bitar Maria, Le Moigne Vincent, Herrmann Jean-Louis, Arthur Michel, Mainardi Jean-Luc
INSERM ERL 1336, UMRS 8228, Sorbonne Université-ENS-PSL-CNRS, Paris F-75006, France.
Inserm, Université Paris-Saclay, UVSQ, Infection et inflammation, Montigny-Le-Bretonneux F-78180, France.
J Antimicrob Chemother. 2025 Jun 3;80(6):1560-1567. doi: 10.1093/jac/dkaf101.
Mycobacterium abscessus is the most frequent of the rapidly growing mycobacteria responsible for lung infections in patients suffering from cystic fibrosis and COPD. Imipenem is currently recommended in the treatment of these infections in spite of β-lactamase production. Since the targets of β-lactams include transpeptidases of both the l,d and d,d specificities, we tested, in vitro, intracellularly and in vivo, a combination of two β-lactams active on these enzymes, amoxicillin and imipenem, alone or in combination with the β-lactamase inhibitor relebactam.
Drug combinations were evaluated against M. abscessus CIP 104536T and clinical isolates (n = 35) by determining MICs, FIC indices and time-killing. Drug combinations were also evaluated in macrophages and in mice.
In the presence of relebactam, synergy between amoxicillin and imipenem was observed against both M. abscessus CIP 104536T and the clinical isolates. Against M. abscessus CIP 104536T, the addition of 1 mg/L imipenem and 4 mg/L relebactam led to a decrease in the MIC of amoxicillin from 64 to 1 mg/L. The triple combination was active in vitro and intracellularly (a 4.30 decrease in the log10 cfu/mL and 82% killing, respectively). The triple combination was effective in reducing log10 cfu in mouse organs and mouse spleen weights, and in preventing losses in mouse weights.
The amoxicillin/imipenem/relebactam combination was synergistic in vitro and effective in vivo against M. abscessus. Since these drugs are clinically available, the triple combination should be considered by clinicians and further evaluated based on the reporting of the patient outcomes.
脓肿分枝杆菌是导致囊性纤维化和慢性阻塞性肺疾病（COPD）患者肺部感染的最常见快速生长分枝杆菌。尽管该菌可产生β-内酰胺酶，但目前仍推荐使用亚胺培南治疗这些感染。由于β-内酰胺类药物的作用靶点包括具有l,d和d,d特异性的转肽酶，我们在体外、细胞内和体内测试了两种作用于这些酶的β-内酰胺类药物阿莫西林和亚胺培南单独使用或与β-内酰胺酶抑制剂瑞巴坦联合使用的效果。
通过测定最低抑菌浓度（MIC）、联合抑菌指数（FIC）和杀菌曲线，评估药物组合对脓肿分枝杆菌CIP 104536T和临床分离株（n = 35）的抗菌活性。还在巨噬细胞和小鼠中评估了药物组合的效果。
在瑞巴坦存在的情况下，观察到阿莫西林和亚胺培南对脓肿分枝杆菌CIP 104536T和临床分离株均具有协同作用。对于脓肿分枝杆菌CIP 104536T，添加1 mg/L亚胺培南和4 mg/L瑞巴坦可使阿莫西林的MIC从64 mg/L降至1 mg/L。三联组合在体外和细胞内均具有活性（分别使log10 cfu/mL降低4.30 ，杀菌率达82%）。三联组合可有效降低小鼠器官中的log10 cfu以及小鼠脾脏重量，并防止小鼠体重减轻。
阿莫西林/亚胺培南/瑞巴坦组合在体外具有协同作用，且在体内对脓肿分枝杆菌有效。由于这些药物在临床上均可获得，临床医生应考虑使用该三联组合，并根据患者预后报告进行进一步评估。
