Dalbavancin exposure in vitro selects for dalbavancin-non-susceptible and vancomycin-intermediate strains of methicillin-resistant Staphylococcus aureus.
Dalbavancin exposure in vitro selects for dalbavancin-non-susceptible and vancomycin-intermediate strains of methicillin-resistant Staphylococcus aureus.
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体外达巴霉素暴露选择耐甲氧西林金黄色葡萄球菌的达巴霉素非敏感和万古霉素中间菌株。
DOI：
10.1016/j.cmi.2020.08.025
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发表时间：
2021-06
期刊：
影响因子：
--
通讯作者：
Xu L
中科院分区：
文献类型：
--
作者：
Werth BJ;Ashford NK;Penewit K;Waalkes A;Holmes EA;Ross DH;Shen T;Hines KM;Salipante SJ;Xu L
达巴万星是一种抗耐甲氧西林金黄色葡萄球菌（MRSA）的脂糖肽。它的半衰期长（8.5 - 16天）允许每周一次或单次给药治疗，但可能延长突变体选择窗口，促进对万古霉素等相关抗菌药物的耐药性和交叉耐药性。本研究的目的是评估达巴霉素的分布后药代动力学暴露在MRSA中选择耐药性和交叉耐药性的能力。我们在体外PK/PD模型中模拟了单次给药（1500 mg）达巴霉素（fCmax 9.9 μ g/mL，β消除t1/2 204 h）28天（672 h）对5种MRSA和1种甲氧西林敏感菌株的平均分布后暴露。至少每天收集样品，分别对存活的菌落进行计数并在无药物和添加达巴霉素的培养基上筛选抗性。对来自耐药筛选平板的分离株进行全基因组测序（WGS），并对达巴霉素、万古霉素、达托霉素和6种具有不同青霉素结合蛋白亲和力的β-内酰胺类药物进行敏感性检测。达巴万星对大多数菌株杀菌1 - 4天，然后发生较不敏感的亚群的再生长。早在第4天就检测到达巴霉素MIC增加8倍的分离株，但到第28天在所有模型中增加64 - 128倍。万古霉素和达托霉素的MIC增加了4 - 16倍，超过了两种抗生素的临界值。β-内酰胺MIC通常降低2 - 8倍，表明达巴霉素-β-内酰胺的跷跷板效应，但在某些分离株中增加≥ 8倍。耐药菌株携带多种基因突变，最常见的是walKR、apt、stp1和atl。在我们的体外系统中，分布后达巴霉素暴露选择了对达巴霉素、万古霉素和达托霉素敏感性降低的稳定突变体，并且在所有测试的MRSA菌株中通常增加了对β-内酰胺类药物的敏感性。这些发现的临床意义尚不清楚，但创造了第一次对一组独特的达巴霉素耐药菌株进行基因分型的机会。突变涉及先前与万古霉素中间体和达托霉素不敏感性相关的基因，最常见的是WalKR相关基因。
Dalbavancin is a lipoglycopeptide active against methicillin-resistant Staphylococcus aureus (MRSA). Its long half-life (8.5–16 days) allows for once-weekly or single-dose treatments but could prolong the mutant selection window, promoting resistance and cross-resistance to related antimicrobials like vancomycin. The objective of this study was to evaluate the capacity of post-distributional pharmacokinetic exposures of dalbavancin to select for resistance and cross-resistance in MRSA. We simulated average, post-distributional exposures of single-dose (1500mg) dalbavancin (fCmax 9.9μg/mL, β-elimination t1/2 204h) in an in vitro PK/PD model for 28 days (672h) against 5 MRSA and 1 methicillin-susceptible strain. Samples were collected at least daily, and surviving colonies were enumerated and screened for resistance on drug-free and dalbavancin-supplemented medium respectively. Isolates from resistance screening plates were subjected to whole genome sequencing (WGS) and susceptibly testing against dalbavancin, vancomycin, daptomycin, and 6 beta-lactams with varying penicillin-binding protein affinities. Dalbavancin was bactericidal against most strains for days 1–4, before regrowth of less-susceptible subpopulations occurred. Isolates with 8-fold increases in dalbavancin MIC were detected as early as day-4 but increased 64–128-fold in all models by day-28. Vancomycin and daptomycin MICs increased by 4–16-fold, exceeding susceptibly breakpoints for both antibiotics. Beta-lactam MICs generally decreased by 2–8-fold, suggesting a dalbavancin-beta-lactam seesaw effect, but increased by ≥8-fold in certain isolates. Resistant isolates carried mutations in a variety of genes, most commonly walKR, apt, stp1, and atl. In our in vitro system, post-distributional dalbavancin exposures selected for stable mutants with reduced susceptibility to dalbavancin, vancomycin, and daptomycin, and generally increased susceptibility to beta-lactams in all strains of MRSA tested. The clinical significance of these findings remains unclear but created an opportunity to genotype a unique collection of dalbavancin-resistant strains for the first time. Mutations involved genes previously associated with vancomycin-intermediate and daptomycin non-susceptibility, most commonly walKR-associated genes.
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