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耐万古霉素的金黄色葡萄球菌从达托霉素初治菌血症患者中分离出对宿主防御性阳离子肽和达托霉素敏感性降低的现象。

Reduced susceptibility to host-defense cationic peptides and daptomycin coemerge in methicillin-resistant Staphylococcus aureus from daptomycin-naive bacteremic patients.

机构信息

Los Angeles Biomedical Research Institute.

出版信息

J Infect Dis. 2012 Oct;206(8):1160-7. doi: 10.1093/infdis/jis482. Epub 2012 Aug 16.

Abstract

BACKGROUND

We hypothesized that, for methicillin-resistant Staphylococcus aureus (MRSA), in vitro daptomycin susceptibility could be influenced by exposures to endogenous host defense peptides (HDPs) prior to clinical exposure to daptomycin.

METHODS

Two endovascular HDPs were used: thrombin-induced platelet microbicidal protein (tPMP) and human neutrophil defensin-1 (hNP-1) from neutrophils. Forty-seven unique MRSA isolates obtained from bacteremic patients in multicenter prospective clinical trials were studied. Clinical characteristics, microbiologic parameters, prior vancomycin therapy, and susceptibilities to tPMP, hNP-1, and daptomycin were compared using univariate and multivariate analyses.

RESULTS

All strains were daptomycin susceptible. Daptomycin minimum inhibitory concentrations (MICs) were inversely related to in vitro tPMP (but not hNP-1) killing. Strains with a daptomycin MIC of 1 mg/L exhibited significantly less killing by tPMP, compared with strains with an MIC of ≤ 0.5 mg/L. Prior vancomycin therapy did not influence this relationship. Regression tree modeling confirmed that reduced tPMP-induced killing in vitro was the strongest predictor of higher daptomycin MICs within the daptomycin-susceptible range.

CONCLUSIONS

Among daptomycin-susceptible MRSA isolates from patients who had never received daptomycin, higher daptomycin MICs tracked with increased resistance to killing by platelet-derived but not neutrophil-derived HDPs. These findings support the notion that endogenous exposure of MRSA to specific HDPs may play a role in selecting strains with an intrinsically higher daptomycin MIC phenotype.

摘要

背景

我们假设,对于耐甲氧西林金黄色葡萄球菌(MRSA),在临床接触达托霉素之前,内源性宿主防御肽(HDPs)的暴露会影响达托霉素的体外药敏性。

方法

使用两种血管内 HDPs:凝血酶诱导的血小板杀菌蛋白(tPMP)和中性粒细胞来源的人中性粒细胞防御素-1(hNP-1)。研究了来自多中心前瞻性临床试验中菌血症患者的 47 个独特的 MRSA 分离株。使用单变量和多变量分析比较了临床特征、微生物学参数、万古霉素治疗前以及对 tPMP、hNP-1 和达托霉素的敏感性。

结果

所有菌株均对达托霉素敏感。达托霉素最低抑菌浓度(MIC)与体外 tPMP(但不是 hNP-1)杀伤呈负相关。达托霉素 MIC 为 1 mg/L 的菌株与 MIC 为≤0.5 mg/L 的菌株相比,tPMP 杀伤明显减少。万古霉素治疗前并未影响这种关系。回归树模型证实,体外 tPMP 诱导杀伤减少是达托霉素敏感范围内更高达托霉素 MIC 的最强预测因子。

结论

在从未接受过达托霉素治疗的患者中,达托霉素敏感的 MRSA 分离株中,较高的达托霉素 MIC 与对血小板衍生而不是中性粒细胞衍生 HDP 杀伤的抵抗力增加相关。这些发现支持这样一种观点,即内源性 MRSA 暴露于特定 HDPs 可能在选择具有固有较高达托霉素 MIC 表型的菌株方面发挥作用。

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