Affiliation:
1. Facility for Anti-Infective Drug Development and Innovation, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne
2. School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, SUNY, Buffalo
3. Ordway Research Institute, Albany, New York
4. University of Queensland Centre for Clinical Research, Royal Brisbane and Women's Hospital, Brisbane, Australia
Abstract
ABSTRACT
The use of combination antibiotic therapy may be beneficial against rapidly emerging resistance in
Pseudomonas aeruginosa
. The aim of this study was to systematically investigate
in vitro
bacterial killing and resistance emergence with colistin alone and in combination with imipenem against multidrug-resistant (MDR)
P. aeruginosa
. Time-kill studies were conducted over 48 h using 5 clinical isolates and ATCC 27853 at two inocula (∼10
6
and ∼10
8
CFU/ml); MDR, non-MDR, and colistin-heteroresistant and -resistant strains were included. Nine colistin-imipenem combinations were investigated. Microbiological response was examined by log changes at 6, 24, and 48 h. Colistin combined with imipenem at clinically relevant concentrations increased the levels of killing of MDR and colistin-heteroresistant isolates at both inocula. Substantial improvements in activity with combinations were observed across 48 h with all colistin concentrations at the low inoculum and with colistin at 4× and 16× MIC (or 4 and 32 mg/liter) at the high inoculum. Combinations were additive or synergistic against imipenem-resistant isolates (MICs, 16 and 32 mg/liter) at the 10
6
-CFU inoculum in 9, 11, and 12 of 18 cases (i.e., 9 combinations across 2 isolates) at 6, 24, and 48 h, respectively, and against the same isolates at the 10
8
-CFU inoculum in 11, 7, and 8 cases, respectively. Against a colistin-resistant strain (MIC, 128 mg/liter), combinations were additive or synergistic in 9 and 8 of 9 cases at 24 h at the 10
6
- and 10
8
-CFU inocula, respectively, and in 5 and 7 cases at 48 h. This systematic study provides important information for optimization of colistin-imipenem combinations targeting both colistin-susceptible and colistin-resistant subpopulations.
Publisher
American Society for Microbiology
Subject
Infectious Diseases,Pharmacology (medical),Pharmacology
Cited by
108 articles.
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