Selectivity of ertapenem for Pseudomonas aeruginosa mutants cross-resistant to other carbapenems
Selectivity of ertapenem for Pseudomonas aeruginosa mutants cross-resistant to other carbapenems
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DOI：
10.1093/jac/dki009
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发表时间：
2005-03-01
影响因子：
5.2
通讯作者：
Warner, M
中科院分区：
文献类型：
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作者：
Livermore, DM;Mushtaq, S;Warner, M
目的：厄他培南和其他碳青霉烯类将越来越多地使用，因为超广谱β-内酰胺酶甚至在社区获得性病原体中也变得更加普遍。然而，人们担心，这种使用将选择耐亚胺培南和美罗培南在医院的病原体，特别是铜绿假单胞菌，我们调查了这种concerns.Methods的有效性：单步选择实验进行平板铜绿假单胞菌培养物上的琼脂含有加倍稀释的厄他培南。MIC模式，外膜蛋白的配置文件和外排抑制剂的影响进行了检查为选定的mutuals.Results：在2-8 × MIC，厄他培南选择（i）的OprD（-）铜绿假单胞菌的突变体，仅与交叉耐药碳青霉烯类，（ii）为推定的外排类型与更广泛的交叉耐药，以及（iii）为各种不太熟悉的表型。外排突变体主要（但不完全）选自羧苄青霉素高敏感性菌株，OprD（-）突变体主要来自羧苄青霉素敏感性正常的菌株。虽然这些数据表明了潜在的交叉选择性，但它们必须与20%血清使厄他培南MIC和突变体选择所需的药物浓度提高4倍以上的观察结果相对照，这反映了该化合物的强蛋白结合。由于，1克静脉注射剂量后，血清中的游离厄他培南浓度福尔斯4 mg/L以下，对应于较低的两个MIC 50估计值，在4小时内（17%的剂量间隔）的选择性在体内should be minimized.Conclusions：虽然厄他培南可以选择铜绿假单胞菌突变体与交叉耐药性亚胺培南和厄他培南在体外，这种选择性应在临床条件下最小。
Objectives: Ertapenem and other carbapenems will be used increasingly, as extended-spectrum beta-lactamases become more prevalent even among community-acquired pathogens. There is, however, concern that this use will select for resistances to imipenem and meropenem in nosocomial pathogens, notably Pseudomonas aeruginosa, and we investigated the validity of this concern.Methods: Single-step selection experiments were performed by plating P. aeruginosa cultures on to agar containing doubling dilutions of ertapenem. MIC patterns, outer membrane protein profiles and the effects of efflux inhibitors were examined for selected mutants.Results: At 2-8 x MIC, ertapenem selected (i) for OprD(-) mutants of P. aeruginosa, with cross-resistance only to carbapenems, (ii) for putative efflux types with broader cross-resistance, and also (iii) for various less familiar phenotypes. Efflux mutants were predominantly, but not exclusively, selected from carbenicillin-hypersusceptible strains and OprD(-) mutants largely from strains with normal levels of carbenicillin susceptibility. Whilst these data indicate potential cross-selectivity, they must be set against the observation that 20% serum raised the ertapenem MICs, and the drug concentrations needed for mutant selection, by over four-fold, reflecting the compound's strong protein binding. Since, following a 1 g intravenous dose the free ertapenem concentration in the serum falls below 4 mg/L-corresponding to the lower of two MIC50 estimates-within 4 h (17% of the dosage interval) selectivity in vivo should be minimized.Conclusions: Whilst ertapenem can select for P. aeruginosa mutants with cross-resistance to imipenem and ertapenem in vitro, this selectivity should be minimal under clinical conditions.