School of Pharmaceutical Sciences of Ribeirão Preto (FCFRP), University of São Paulo (USP), Av. Prof. Dr. Zeferino Vaz - Vila Monte Alegre, Ribeirão Preto, SP, 14040-903, Brazil.
Ribeirão Preto Medical School (FMRP), University of São Paulo (USP), Av. Bandeirantes, 3900, Campus da USP - Cidade Universitária, Ribeirão Preto, SP, 14040-900, Brazil.
Curr Microbiol. 2024 Sep 22;81(11):371. doi: 10.1007/s00284-024-03897-1.
We investigated the in vitro antibacterial activity of the combination rifampicin (RIF) + polymyxin B (PB) against extensively drug-resistant (XDR) Klebsiella pneumoniae isolates. We evaluated clinical isolates co-resistant to PB (non-mcr carriers; eptB, mgrB, pmr operon, and ramA mutations) and to carbapenems (KPC, CTX-M, and SHV producers; including KPC + NDM co-producer), belonging to sequence types (ST) ST16, ST11, ST258, ST340, and ST437. We used the standard broth microdilution method to determine RIF and PB minimum inhibitory concentration (MIC) and the checkerboard assay to evaluate the fractional inhibitory concentration index (FICI) of RIF + PB as well as to investigate the lowest concentrations of RIF and PB that combined (RIF + PB) had antibacterial activity. Time-kill assays were performed to evaluate the synergistic effect of the combination against selected isolates. PB MIC (32-256 µg/mL) and RIF MIC (32-1024 µg/mL) were determined. FICI (<0.5) indicated a synergistic effect for all isolates evaluated for the combination RIF + PB. Our results showed that low concentrations of PB (PB minimal effective antibiotic concentration [MEAC], ≤0.25-1 µg/mL) favor RIF (≤0.03-0.125 µg/mL) to reach the bacterial target and exert antibacterial activity against PB-resistant isolates, and the synergistic effect was also observed in time-kill results. The combination of RIF + PB showed in vitro antibacterial activity against XDR, carbapenem-, and PB-resistant K. pneumoniae and could be further studied as a potential combination therapy, with cost-effectiveness and promising efficacy.
我们研究了利福平（RIF）+多黏菌素 B（PB）联合用药对广泛耐药（XDR）肺炎克雷伯菌的体外抗菌活性。我们评估了对 PB（非 mcr 载体；eptB、mgrB、pmr 操纵子和 ramA 突变）和碳青霉烯类药物（KPC、CTX-M 和 SHV 产生者；包括 KPC+NDM 共产生者）均耐药的临床分离株，这些分离株属于 ST16、ST11、ST258、ST340 和 ST437 序列型。我们使用标准肉汤微量稀释法测定 RIF 和 PB 的最小抑菌浓度（MIC），棋盘微量稀释法评估 RIF+PB 的部分抑菌浓度指数（FICI），并研究联合用药（RIF+PB）具有抗菌活性的最低浓度。进行时间杀伤试验以评估联合用药对选定分离株的协同作用。确定了 PB 的 MIC（32-256µg/mL）和 RIF 的 MIC（32-1024µg/mL）。所有评估的 RIF+PB 组合的 FICI（<0.5）均表明具有协同作用。我们的结果表明，低浓度的 PB（PB 最小有效抗生素浓度[MEAC]，≤0.25-1µg/mL）有利于 RIF（≤0.03-0.125µg/mL）达到细菌靶标并发挥对 PB 耐药分离株的抗菌活性，并且协同作用也在时间杀伤结果中观察到。RIF+PB 的联合用药对 XDR、碳青霉烯类和 PB 耐药的肺炎克雷伯菌具有体外抗菌活性，可作为一种潜在的联合治疗方法进一步研究，具有成本效益和良好的疗效。
