Department of Respiratory and Critical Care Medicine, Peking University People's Hospital, Beijing, 100044, China.
Department of Respiratory Diseases, Chinese PLA General Hospital, Beijing, 100853, China.
J Antibiot (Tokyo). 2018 May;71(5):506-513. doi: 10.1038/s41429-017-0024-9. Epub 2018 Feb 7.
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.
本研究评估了米诺环素-氨基糖苷类药物组合对产碳青霉烯酶肺炎克雷伯菌（KPC）的肺炎克雷伯菌的体外抗菌活性。从血流感染患者中收集了 70 株非重复的产 KPC 肺炎克雷伯菌临床分离株。通过棋盘法和时间杀伤试验研究了不同敏感性菌株中米诺环素-氨基糖苷类药物组合的协同活性，并测定了药物单独和联合的突变预防浓度（MPC）和突变选择窗（MSW）。棋盘法发现该组合对氨基糖苷类敏感分离株表现出协同和部分协同活性，但对氨基糖苷类耐药分离株无协同活性。时间杀伤试验进一步证明了该组合对两种药物均敏感的分离株存在强大的协同和杀菌作用。但对于耐药分离株，时间杀伤试验显示无协同作用。米诺环素或氨基糖苷类的 MPC 比 MIC 高 8-32 倍，表明这些药物的 MSWs 相当宽。对于抗生素组合，添加 1×MIC 浓度的阿米卡星或庆大霉素可使米诺环素的 MPC 降低 4-16 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未回收耐药突变体。总之，这些结果表明，米诺环素-氨基糖苷类药物组合可作为产 KPC 肺炎克雷伯菌感染的替代药物，因为该组合在敏感分离株中显示出强大的协同和杀菌活性，并能有效防止耐药突变体的出现。应进一步进行体外药代动力学/药效学研究和临床试验，以充分评估该药物组合的疗效。
