Synergistic Activity of Niclosamide in Combination With Colistin Against Colistin-Susceptible and Colistin-Resistant Acinetobacter baumannii and Klebsiella pneumoniae.

Rafael Ayerbe-Algaba,Viviana Sánchez-Encinales,Jerónimo Pachón,Younes Smani,María Eugenia Pachón-Ibáñez,Manuel Enrique Jiménez-Mejías,María Luisa Gil-Marqués,Raquel Parra-Millán

doi:10.3389/fcimb.2018.00348

Abstract

Colistin is among the few antibiotics effective against multidrug-resistant Acinetobacter baumannii and Klebsiella pneumoniae clinical isolates. However, in the last few years, colistin-resistant A. baumannii and K. pneumoniae strains have emerged. Therefore, combination therapies, between colistin and other old drugs, restoring the activity of colistin are required. The main objective of this study was to analyse the activity of niclosamide, an anthelmintic drug, in combination with colistin against colistin-susceptible (Col-S) and colistin-resistant (Col-R) A. baumannii and K. pneumoniae. The MIC were determined by microdilution assay and the time-kill curves were performed. The zeta potential of Col-S and Col-R of A. baumannii and K. pneumoniae in presence of niclosamide was assessed. Niclosamide in combination with colistin showed improved activity against Col-S and Col-R A. baumannii and K. pneumoniae. Time-killing curves showed synergic activity between niclosamide and colistin against Col-S and Col-R A. baumannii and K. pneumoniae, especially when niclosamide or colistin was added for second time at 4 h of the 24 h killing curve. Col-R A. baumannii and K. pneumoniae in presence of niclosamide exhibited a greater negative charge (−34.95 ± 0.35 mV and −38.85 ± 0.92 mV; P < 0.05) than Col-R A. baumannii and K. pneumoniae in absence of niclosamide (−26.85 ± 3.65 mV and −35.27 ± 0.72 mV). These data suggest that niclosamide might be combined with colistin, being a potential alternative for treatment of Col-R Gram-negative bacilli infections.

Highlights

A number of infections caused by multidrugresistant Acinetobacter baumannii and Klebsiella pneumoniae required the use of colistin, but both pathogens may rapidly acquire specific resistance mechanisms against colistin (Bonnin et al, 2013; Ah et al, 2014)
Niclosamide alone or in combination with colistin was tested against reference and clinical Col-S and Col-R A. baumannii and K. pneumoniae strains
Niclosamide alone showed a range of MIC from 6.25 to 400 μM for Col-S and Col-R A. baumannii strains, and from 400 to >800 μM for Col-S and Col-R K. pneumoniae strains

Summary

Introduction

A number of infections caused by multidrugresistant Acinetobacter baumannii and Klebsiella pneumoniae required the use of colistin, but both pathogens may rapidly acquire specific resistance mechanisms against colistin (Bonnin et al, 2013; Ah et al, 2014). The rates of colistin resistance worldwide vary between 3 and 28% for A. baumannii, and 2.8 and 10.5% for K. pneumoniae (Fernández-Cuenca et al, 2013; Ah et al, 2014) In this context, combination therapies between colistin and other drugs are among the new promising strategies to treat bacterial infections (Vila and Pachón, 2012; Cassir et al, 2014). Few randomized controlled trials examining specific combinations have been completed or are ongoing, and are not sufficient to guide clinical practice (Paul et al, 2014; Poulikakos et al, 2014) This joins with the relatively short window of therapeutic application for severely ill patients for some combinations, and for the rapid emergence of drug resistance (Poulikakos et al, 2014)

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