Ren Huan, He Xin, Zou Xiaoli, Wang Guoqing, Li Shuhua, Wu Yanxia
Department of Public Health Laboratory Sciences, West China School of Public Health, Sichuan University, Chengdu, Sichuan, China.
No.4 West China Teaching Hospital, West China School of Public Health, Sichuan University, Chengdu, Sichuan, China.
J Antimicrob Chemother. 2015 Dec;70(12):3267-72. doi: 10.1093/jac/dkv251. Epub 2015 Aug 25.
Sublethal bactericidal antibiotics promote the formation of multidrug-tolerant persisters. Clinically, serum drug concentration increases gradually and reaches the peak level with high killing efficiency some time after administration. This study aimed to investigate if the initial low antibiotic concentration would promote persister formation in Klebsiella pneumoniae, an increasingly important nosocomial pathogen.
Time-dependent killings of K. pneumoniae by different types of bactericidal antibiotics were conducted to determine the existence of multidrug-tolerant K. pneumoniae persisters. Killing experiments with antibiotic gradient feeding were then conducted for a K. pneumoniae laboratory strain (ATCC 10031) and a clinical isolate (YWSCU-03) by adding antibiotics step by step until the drug peak serum concentration was attained.
Multidrug-tolerant persisters indeed existed in K. pneumoniae and the persistence decreased with increasing drug concentrations or prolonged treatments. Antibiotic gradient feeding, to simulate a gradual increase in serum drug concentration, not only significantly elevated the persistence of ATCC 10031 and YWSCU-03, but also increased the frequency of drug-resistant mutant formation in YWSCU-03.
After administration, the initial low serum drug concentration could promote the formation of multidrug-tolerant bacterial persisters, which could survive the lethal drug concentrations attained later and potentially render the antibiotic treatment fruitless. Therefore, antibiotic treatments should be based on the comprehensive analysis of, not only drug pharmacokinetics, but also the synergistic effect between pharmacokinetics and persister formation.
亚致死剂量的杀菌性抗生素会促进多药耐受性持留菌的形成。临床上，血清药物浓度会逐渐升高，并在给药后的一段时间达到具有高杀菌效率的峰值水平。本研究旨在调查初始低抗生素浓度是否会促进肺炎克雷伯菌（一种日益重要的医院病原体）中持留菌的形成。
通过不同类型的杀菌性抗生素对肺炎克雷伯菌进行时间依赖性杀灭实验，以确定多药耐受性肺炎克雷伯菌持留菌的存在情况。然后，通过逐步添加抗生素直至达到药物血清峰值浓度，对肺炎克雷伯菌实验室菌株（ATCC 10031）和临床分离株（YWSCU - 03）进行抗生素梯度投喂杀灭实验。
肺炎克雷伯菌中确实存在多药耐受性持留菌，且随着药物浓度的增加或处理时间的延长，持留性降低。模拟血清药物浓度逐渐升高的抗生素梯度投喂，不仅显著提高了ATCC 10031和YWSCU - 03的持留性，还增加了YWSCU - 03中耐药突变体形成的频率。
给药后，初始低血清药物浓度可促进多药耐受性细菌持留菌的形成，这些持留菌能够在随后达到的致死药物浓度下存活，并可能导致抗生素治疗无效。因此，抗生素治疗不仅应基于药物药代动力学的综合分析，还应考虑药代动力学与持留菌形成之间的协同效应。
