Synergistic Activity of Colistin/Fosfomycin Combination against Carbapenemase-Producing Klebsiella pneumoniae in an In Vitro Pharmacokinetic/Pharmacodynamic Model.

Jin Wang,Rui Wang,Yan Bai,Yun Cai,Ji-Tong He

doi:10.1155/2018/5720417

Abstract

Carbapenemase-producing Klebsiella pneumoniae is globally recognized as one of the greatest threats to public health, and combination therapy may be the chemotherapeutic option. In the present study, we aimed to evaluate the antibacterial effects of colistin/fosfomycin combination against carbapenemase-producing K. pneumoniae. The antibacterial effects were determined in a one-compartment in vitro pharmacokinetic model over a period of 24 h. The initial inoculum was 108 CFU/mL. Low, medium, and high Cmax values of colistin at 0.5, 2, and 5 mg/L as well as Cmax of fosfomycin at 100 mg/L were simulated in the model. Doses of both colistin and fosfomycin were given every 8 h until 24 h. For the colistin- and fosfomycin-susceptible isolate KP47, three combination regimens showed greater killing effect compared with colistin monotherapy. The greatest killing effect was observed in combination regimen containing 5 mg/L colistin. For colistin-heteroresistant and fosfomycin-susceptible isolate KP79, combination regimen containing low dose colistin (0.5 mg/L) showed no synergistic or additive effects. However, combination regimens containing 2 and 5 mg/L colistin maintained the bactericidal effect until 24 h compared with colistin monotherapy. For colistin-heteroresistant and fosfomycin-resistant isolates KP42 and KP11, bactericidal activity was barely enhanced by combination regimens. Moreover, combination regimen containing 5 mg/L colistin could only prevent the emergence of colistin-resistant subpopulation in colistin and fosfomycin-susceptible isolate. It is necessary to know the resistant patterns of the K. pneumoniae before using combination of colistin and fosfomycin in clinical practice.

Highlights

The emergence of carbapenem-resistant Enterobacteriaceae (CRE), carbapenemase-producing Klebsiella pneumoniae, has greatly increased over the past decade and become a significant public health concern as carbapenem is one of the few antibiotics to treat severe infections caused by these pathogens [1]
We aimed to evaluate the antibacterial effects of colistin/fosfomycin combination against carbapenemase-producing K. pneumoniae with varying susceptibility to fosfomycin
Minimum inhibitory concentration (MIC) of colistin was tested via broth microdilution method, while MIC of fosfomycin was determined via agar (Mueller-Hinton agar with 25 μg/mL glucose-6phosphate, G6P) dilution method

Summary

Introduction

The emergence of carbapenem-resistant Enterobacteriaceae (CRE), carbapenemase-producing Klebsiella pneumoniae, has greatly increased over the past decade and become a significant public health concern as carbapenem is one of the few antibiotics to treat severe infections caused by these pathogens [1]. Enterobacteriaceae, including more than 400 hospitals, has shown that 850 (37%) of 2,301 K. pneumoniae samples are carbapenemase producers [2]. Prevalence of resistance coupled with scarcity of novel antimicrobials forces us to reevaluate some “old but efficacious” antibiotics. An alarming increase in the rate of resistance to most available antimicrobials and a shortage of new antimicrobial agents have forced researchers to reevaluate the use of colistin, despite its potential risk of nephrotoxicity and neurotoxicity [5]. Colistin has been recently applied against the widespread multidrugresistant (MDR) Gram-negative pathogens, including K

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