1 Department of Infection Control and Prevention, Graduate School of Medicine, Osaka University, Osaka, Japan.
2 Department of Microbiology and Infectious Diseases, Toho University School of Medicine, Tokyo, Japan.
Microb Drug Resist. 2019 Jul/Aug;25(6):839-845. doi: 10.1089/mdr.2018.0397. Epub 2019 Mar 5.
Optimal treatment regimens are yet to be established for carbapenemase-producing (CPE). We assessed the efficacy of meropenem (MEM) and cefmetazole (CMZ) combination treatment against -positive , in comparison with that of double-carbapenem therapy using ertapenem (ERT). We performed checkerboard assay for 10 -positive clinical isolates and BAA-1705 (possessing ), with synergistic effect being defined by a fractional inhibitory concentration index of ≤0.5. Subsequently, we conducted time-kill assays using BAA-1705 with an initial inoculum of 10-10 colony forming unit (CFU)/mL. Bactericidal effect was defined as the reduction of initial bacterial count by ≥10 CFU/mL in 24 hr. Finally, we applied scanning electron microscopy to observe morphological changes induced by the combination of MEM and CMZ. Checkerboard assays revealed a synergistic effect in 7 out of 11 -positive when the MEM and CMZ combination was used, and no effect when the MEM and ERT combination was used. The minimum inhibitory concentration of MEM decreased 4-8-fold when combined with CMZ. Time-kill assays with an initial inoculum of 5 × 10 CFU/mL revealed regrowth under the combination of MEM and ERT (0.25 × minimum inhibitory concentration [MIC] each), whereas the combination of 0.25 × MIC each of MEM and CMZ exhibited bactericidal effect. Scanning electron microscopy results demonstrated that the combination of 0.5 × MIC MEM and 0.5 × MIC CMZ facilitated bacterial cell lysis compared with each antibiotic alone. The combination therapy using MEM and CMZ potentially has bactericidal effect against KPC-producing .
针对产碳青霉烯酶（CPE）的治疗方案仍有待确立。我们评估了美罗培南（MEM）和头孢美唑（CMZ）联合治疗与厄他培南（ERT）双重碳青霉烯治疗相比对 -阳性的疗效。我们对 10 株 -阳性临床分离株和 BAA-1705（携带）进行棋盘微量稀释法检测，协同作用定义为分数抑菌浓度指数≤0.5。随后，我们使用初始接种物为 10-10 菌落形成单位（CFU）/mL 的 BAA-1705 进行时间杀伤试验。杀菌效果定义为在 24 小时内初始细菌计数减少≥10 CFU/mL。最后，我们应用扫描电子显微镜观察 MEM 和 CMZ 联合使用诱导的形态变化。棋盘微量稀释法检测结果显示，在 11 株 -阳性菌株中，MEM 和 CMZ 联合使用时有 7 株表现出协同作用，而 MEM 和 ERT 联合使用时则无协同作用。MEM 与 CMZ 联合使用时，MEM 的最低抑菌浓度降低了 4-8 倍。当初始接种物为 5×10 CFU/mL 时，MEM 和 ERT 联合使用（MEM 和 ERT 各为 0.25×最低抑菌浓度 [MIC]）会出现再生长，而 MEM 和 CMZ 各为 0.25×MIC 的联合使用则表现出杀菌作用。扫描电子显微镜结果表明，与单独使用每种抗生素相比，0.5×MIC MEM 和 0.5×MIC CMZ 的联合使用促进了细菌细胞裂解。MEM 和 CMZ 联合治疗可能对产 KPC 的具有杀菌作用。
