This study assessed the in vitro antibacterial activity of minocycline-aminoglycoside combination against Klebsiella pneumoniae carbapenemase (KPC)-producing K. pneumoniae. Seventy non-duplicate clinical isolates of KPC-producing K. pneumoniae were collected from patients with bloodstream infections. The synergistic activity of minocycline-aminoglycoside combination was studied by the checkerboard method and time-kill assays in strains with different susceptibilities, and the mutant prevention concentration (MPC) and mutant selection window (MSW) of drugs alone and in combination were determined. The checkerboard method found this combination displayed synergistic and partial synergistic activity against aminoglycoside-susceptible isolates, but indifferent activity against aminoglycoside-resistant isolates. Time-kill assays further demonstrated strong synergistic and bactericidal effect of this combination existed against isolates which were susceptible to both drugs. But for resistant isolates, the time-kill assays showed no synergy. The MPCs of minocycline or aminoglycosides were 8- to 32-fold higher than the MICs, suggesting the MSWs of these drugs were quite wide. For the antibiotic combinations, the addition of 1×MIC concentration of amikacin or gentamicin could reduce the MPCs of minocycline by 4- to 16-fold. Generally, no mutants recovered in the plates containing 1×MIC concentration of minocycline and 2×MIC concentration of amikacin or gentamicin. In summary, these results suggest that minocycline-aminoglycoside combination can be an alternative for infections caused by KPC-producing K. pneumoniae because this combination displays strong synergistic and bactericidal activity in susceptible isolates, and can effectively prevent the emergence of resistant mutants. Further in vitro pharmacokinetic/pharmacodynamic studies and clinical trials should be performed to fully evaluate the efficacy of this drug combination.

中文翻译：

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米诺环素与氨基糖苷类药物联合对产肺炎克雷伯菌碳青霉烯酶的肺炎克雷伯菌的体外活性。

这项研究评估了米诺环素-氨基糖苷组合对产肺炎克雷伯菌碳青霉烯酶（KPC）的肺炎克雷伯菌的体外抗菌活性。从患有血流感染的患者中收集了70株产生KPC的肺炎克雷伯菌的非重复临床分离株。通过棋盘法和时间杀灭试验研究了不同敏感性的菌株中米诺环素-氨基糖苷组合的协同活性，并确定了单独和组合使用的药物的突变预防浓度（MPC）和突变选择窗（MSW）。棋盘法发现该组合对氨基糖苷敏感性分离物显示出协同和部分协同活性，而对氨基糖苷耐药性分离物表现出无关的活性。时间杀伤试验进一步证明了这种组合对易受两种药物影响的分离株具有很强的协同作用和杀菌作用。但是对于抗性分离株，时间杀灭试验没有协同作用。米诺环素或氨基糖苷的MPC比MIC高8到32倍，表明这些药物的MSW相当宽。对于抗生素组合，添加1×MIC浓度的丁胺卡那霉素或庆大霉素可使米诺环素的MPC降低4至16倍。通常，在含有1×MIC浓度的米诺环素和2×MIC浓度的阿米卡星或庆大霉素的平板中没有回收到突变体。总之，这些结果表明，米诺环素-氨基糖苷组合可以替代由KPC产生的K引起的感染。由于这种组合在易感菌株中显示出强大的协同作用和杀菌活性，因此可以有效防止耐药突变体的出现。应该进行进一步的体外药代动力学/药效学研究和临床试验，以全面评估该药物组合的疗效。