美罗培南对产KPC-31、KPC-33、KPC-90、KPC-106和KPC-114的头孢他啶-阿维巴坦耐药肺炎克雷伯菌的疗效。

Efficacy of meropenem against ceftazidime-avibactam-resistant Klebsiella pneumoniae producing KPC-31, KPC-33, KPC-90, KPC-106 and KPC-114.

作者信息

Pariona Jesus G M, Vásquez-Ponce Felipe, Pariona Eva M M, Sousa-Carmo Rubens R, Martins-Gonçalves Thais, Becerra Johana, de Lima Aline V, Queiroga Gustavo, Sampaio Jorge L M, Lincopan Nilton

机构信息

Department of Clinical Analysis, Faculty of Pharmaceutical Sciences, Universidade de São Paulo, São Paulo, Brazil.

Department of Microbiology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.

出版信息

J Antimicrob Chemother. 2025 Jan 3;80(1):162-168. doi: 10.1093/jac/dkae389.

DOI:10.1093/jac/dkae389

PMID:39468752

Abstract

BACKGROUND

Klebsiella pneumoniae producing KPC variants conferring resistance to ceftazidime-avibactam often remain susceptible to meropenem, suggesting a potential therapeutic use of this antibiotic.

OBJECTIVES

In this study, the efficacy of clinically relevant concentrations of meropenem was evaluated against high-risk clones of ceftazidime-avibactam-resistant K. pneumoniae strains producing KPC variants, in a tandem in vitro time-kill/in vivo Galleria mellonella survival model.

METHODS

In vitro/in vivo efficacy of meropenem against ceftazidime-avibactam-resistant K. pneumoniae of CG16, CG25 and CG258, producing KPC-31, KPC-33, KPC-90, KPC-106 and KPC-114 variants, was evaluated using EUCAST dosing recommendation adjusted to the G. mellonella model. For in vivo assays, untreated, meropenem (40 mg/kg × 1)-treated and ceftazidime-avibactam (40 mg/kg ceftazidime-10 mg/kg avibactam × 1)-treated groups were established, with 60 larvae per group. Kaplan-Meier curves, log-rank tests, univariate Cox regression and hazard ratios (HR) were used to assess treatment effects (P < 0.05).

RESULTS

For all KPC-variant producers, time-kill assays showed >3 log-kills reduction (-6.91 ± 1.28 SD) after 6 h interaction when exposed to 8-32 mg/L meropenem MIC values (i.e. ≥ × 4 MIC). In the assessment of in vivo efficacy of meropenem, at the 4-day follow-up, mortality rates were 96.7% (untreated), 83.3% (ceftazidime-avibactam-treated) and 13.3% (meropenem-treated) (P < 0.05). Univariate Cox regression analysis showed significantly lower risk in the meropenem group compared to untreated group [HR 0.02 (95% CI: 0.01-0.05)].

CONCLUSIONS

These pre-clinical results might support use of meropenem as a potential alternative for treatment of infections due to KPC-variant producers displaying in vitro susceptibility to meropenem.

摘要

背景

产KPC变体且对头孢他啶-阿维巴坦耐药的肺炎克雷伯菌通常对美罗培南仍敏感，提示该抗生素具有潜在治疗用途。

目的

在体外时间杀菌/体内大蜡螟存活串联模型中，评估临床相关浓度美罗培南对产KPC变体的头孢他啶-阿维巴坦耐药肺炎克雷伯菌高危克隆株的疗效。

方法

根据调整至大蜡螟模型的欧洲抗菌药物敏感性试验委员会（EUCAST）给药建议，评估美罗培南对产KPC-31、KPC-33、KPC-90、KPC-106和KPC-114变体的CG16、CG25和CG258型头孢他啶-阿维巴坦耐药肺炎克雷伯菌的体外/体内疗效。对于体内试验，设立未治疗组、美罗培南（40mg/kg×1）治疗组和头孢他啶-阿维巴坦（头孢他啶40mg/kg-阿维巴坦10mg/kg×1）治疗组，每组60只幼虫。采用Kaplan-Meier曲线、对数秩检验、单变量Cox回归和风险比（HR）评估治疗效果（P<0.05）。

结果

对于所有产KPC变体菌株，时间杀菌试验显示，当暴露于8-32mg/L美罗培南MIC值（即≥×4 MIC）时，6小时相互作用后杀菌对数减少>3 log（-6.91±1.28 SD）。在美罗培南体内疗效评估中，随访4天时，死亡率分别为96.7%（未治疗组）、83.3%（头孢他啶-阿维巴坦治疗组）和13.3%（美罗培南治疗组）（P<0.05）。单变量Cox回归分析显示，美罗培南组风险显著低于未治疗组[HR 0.02（95%CI：0.01-0.05）]。