由于噬菌体与临床可达到浓度的抗生素之间的体外协同相互作用，多重耐药产碳青霉烯酶肺炎克雷伯菌临床分离株的表型耐药性得以逆转。
Reversal of phenotypic resistance in multi-drug resistant carbapenemase-producing K. pneumoniae clinical isolates due to in vitro synergistic interactions between bacteriophages and antibiotics at clinically achievable concentrations.
作者信息
Paranos Paschalis, Siopi Maria, Papanikolaou Eleni, Vourli Sophia, Kolia Panagoula, Pournaras Spyros, Meletiadis Joseph
机构信息
Clinical Microbiology Laboratory, Attikon University Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
Department of Human Genetics, Faculty of Biology, National and Kapodistrian University of Athens, Athens, Greece.
出版信息
J Antimicrob Chemother. 2025 Jul 1;80(7):1997-2006. doi: 10.1093/jac/dkaf163.
BACKGROUND
Therapeutic options for MDR carbapenemase-producing Klebsiella pneumoniae (CRKP) are limited. We therefore assessed the in vitro activity of five antibiotics from different classes in combination with lytic bacteriophages (phages) against MDR CRKP isolates.
MATERIAL AND METHODS
A total of 15 non-repetitive, well-characterized MDR CRKP isolates and four phages belonging to the Podoviridae family were used in chequerboard assays with amikacin, meropenem, ciprofloxacin, colistin and ceftazidime/avibactam. The spectrophotometrically determined MIC of drugs and phages alone and in combination were used to calculate the fractional inhibitory concentration index (FICi). The clinical relevance was assessed based on the MIC reductions at clinically achievable concentrations and below the corresponding susceptibility breakpoints. Emergence of resistance was studied in growth curves and time-kill experiments.
RESULTS
Synergy was found for ciprofloxacin in 6/15 (40%) isolates, meropenem in 10/15 (67%), ceftazidime/avibactam in 11/15 (73%), colistin in 8/15 (53%) and amikacin in 9/15 (60%) with all four phages against host bacteria. The synergistic interactions were strong as the FICi were 0.01-0.35 reducing the MICs (>90% growth inhibition) to clinically achievable concentrations for 87%-100% of strains, except ciprofloxacin. Reversal of phenotypic resistance was observed for amikacin, meropenem, colistin and ceftazidime/avibactam in 100%, 53%, 89% and 80% of isolates, respectively. No emergence of resistance was found for isolates with low level resistance to amikacin (MΙC 64 mg/L).
CONCLUSIONS
The phage-antibiotic combinations were synergistic against more than half of the isolates for all antibiotics except ciprofloxacin reversing resistance in most strains particularly with amikacin.
背景
治疗产多重耐药碳青霉烯酶的肺炎克雷伯菌（CRKP）的选择有限。因此，我们评估了来自不同类别的五种抗生素与裂解性噬菌体（噬菌体）联合使用对多重耐药CRKP分离株的体外活性。
材料与方法
使用15株非重复、特征明确的多重耐药CRKP分离株和4株属于短尾噬菌体科的噬菌体，与阿米卡星、美罗培南、环丙沙星、黏菌素和头孢他啶/阿维巴坦进行棋盘法试验。通过分光光度法测定单独及联合使用药物和噬菌体时的最低抑菌浓度（MIC），以计算分数抑菌浓度指数（FICi）。根据临床可达到浓度及低于相应药敏折点时的MIC降低情况评估临床相关性。通过生长曲线和时间杀菌实验研究耐药性的产生。
结果
在与所有四种噬菌体针对宿主细菌的联合使用中，环丙沙星在6/15（40%）的分离株中表现出协同作用，美罗培南在10/15（67%），头孢他啶/阿维巴坦在11/15（73%），黏菌素在8/15（53%），阿米卡星在9/15（60%）。协同相互作用很强，因为FICi为0.01 - 0.35，除环丙沙星外，87% - 100%的菌株的MIC降低至临床可达到浓度（>90%生长抑制）。分别在100%、53%、89%和80%的分离株中观察到阿米卡星、美罗培南、黏菌素和头孢他啶/阿维巴坦的表型耐药逆转。对阿米卡星低水平耐药（MIC 64 mg/L）的分离株未发现耐药性产生。
结论
除环丙沙星外，噬菌体 - 抗生素组合对超过一半的分离株具有协同作用，在大多数菌株中可逆转耐药性，尤其是与阿米卡星联合时。
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