Aye Su Mon, Galani Irene, Yu Heidi, Wang Jiping, Chen Ke, Wickremasinghe Hasini, Karaiskos Ilias, Bergen Phillip J, Zhao Jinxin, Velkov Tony, Giamarellou Helen, Lin Yu-Wei, Tsuji Brian T, Li Jian
Monash Biomedicine Discovery Institute, Department of Microbiology, Monash University, Clayton, Victoria, Australia.
Fourth Department of Internal Medicine, National and Kapodistrian University of Athens, Athens, Greece.
Antimicrob Agents Chemother. 2020 Jul 22;64(8). doi: 10.1128/AAC.00246-20.
Resistance to polymyxin antibiotics is increasing. Without new antibiotic classes, combination therapy is often required. We systematically investigated bacterial killing with polymyxin-based combinations against multidrug-resistant (including polymyxin-resistant), carbapenemase-producing Monotherapies and double- and triple-combination therapies were compared to identify the most efficacious treatment using static time-kill studies (24 h, six isolates), an pharmacokinetic/pharmacodynamic model (IVM; 48 h, two isolates), and the mouse thigh infection model (24 h, six isolates). In static time-kill studies, all monotherapies (polymyxin B, rifampin, amikacin, meropenem, or minocycline) were ineffective. Initial bacterial killing was enhanced with various polymyxin B-containing double combinations; however, substantial regrowth occurred in most cases by 24 h. Most polymyxin B-containing triple combinations provided greater and more sustained killing than double combinations. Standard dosage regimens of polymyxin B (2.5 mg/kg of body weight/day), rifampin (600 mg every 12 h), and amikacin (7.5 mg/kg every 12 h) were simulated in the IVM. Against isolate ATH 16, no viable bacteria were detected across 5 to 25 h with triple therapy, with regrowth to ∼2-log CFU/ml occurring at 48 h. Against isolate BD 32, rapid initial killing of ∼3.5-log CFU/ml at 5 h was followed by a slow decline to ∼2-log CFU/ml at 48 h. In infected mice, polymyxin B monotherapy (60 mg/kg/day) generally was ineffective. With triple therapy (polymyxin B at 60 mg/kg/day, rifampin at 120 mg/kg/day, and amikacin at 300 mg/kg/day), at 24 h there was an ∼1.7-log CFU/thigh reduction compared to the starting inoculum for all six isolates. Our results demonstrate that the polymyxin B-rifampin-amikacin combination significantly enhanced and bacterial killing, providing important information for the optimization of polymyxin-based combinations in patients.
对多粘菌素类抗生素的耐药性正在增加。由于缺乏新的抗生素类别，常常需要联合治疗。我们系统地研究了基于多粘菌素的联合用药对多重耐药（包括对多粘菌素耐药）、产碳青霉烯酶细菌的杀菌作用。通过静态时间杀菌研究（24小时，6株菌株）、体外药代动力学/药效学模型（IVM；48小时，2株菌株）和小鼠大腿感染模型（24小时，6株菌株），比较了单一疗法以及双联和三联联合疗法，以确定最有效的治疗方法。在静态时间杀菌研究中，所有单一疗法（多粘菌素B、利福平、阿米卡星、美罗培南或米诺环素）均无效。各种含多粘菌素B的双联组合增强了初始细菌杀灭作用；然而，在大多数情况下，到24小时时出现了大量细菌再生长。大多数含多粘菌素B的三联组合比双联组合提供了更强且更持久的杀菌效果。在IVM中模拟了多粘菌素B（2.5mg/kg体重/天）、利福平（每12小时600mg）和阿米卡星（每12小时7.5mg/kg）的标准给药方案。对于菌株ATH 16，三联疗法在5至25小时内未检测到活菌，在48小时时细菌再生长至约2-log CFU/ml。对于菌株BD 32，在5小时时迅速初始杀灭约3.5-log CFU/ml，随后在48小时时缓慢下降至约2-log CFU/ml。在感染小鼠中，多粘菌素B单一疗法（60mg/kg/天）通常无效。采用三联疗法（多粘菌素B 60mg/kg/天、利福平120mg/kg/天和阿米卡星300mg/kg/天），与所有6株菌株的起始接种量相比，在24小时时大腿处的CFU减少了约1.7-log。我们的结果表明，多粘菌素B-利福平-阿米卡星组合显著增强了细菌杀灭作用，为优化患者基于多粘菌素的联合用药提供了重要信息。
