Colistin heteroresistance in Acinetobacter spp.: systematic review and meta-analysis of the prevalence and discussion of the mechanisms and potential therapeutic implications

Abstract

Background: Colistin is one of the few remaining options for carbapenem-resistant Acinetobacter baumannii (A. baumannii); however, emergence of resistance from heteroresistant populations is possible. This review aimed to systematically search and consolidate the literature on the prevalence, mechanisms and therapeutic implications of colistin heteroresistance in Acinetobacter spp.

Methods: A systematic search was conducted in PubMed and Scopus. The pooled prevalence of colistin heteroresistance was calculated using meta-analysis of proportions with the Freeman-Tukey transformation and the random-effects (DerSimonian and Laird) method.

Results: Based on 15 studies the prevalence of colistin heteroresistance was 33% (95% CI 16-53%) but considerable heterogeneity was observed (I² = 96%, P < 0.001). Prior exposure to colistin was associated with a higher proportion of resistant subpopulations. Colistin heteroresistance may result from chromosomal mutations in resistant subpopulations (predominantly in PmrAB and lpx genes) resulting in lipopolysaccharide modification or loss, or overexpression of efflux pumps. No dosage scheme of colistin monotherapy can prevent the emergence of resistant subpopulations in vitro, but few studies have reported in vivo emergence of resistance from heteroresistant A. baumannii during treatment, and studies examining the correlation between heteroresistance and clinical/microbiological outcomes are lacking. Several colistin-based combinations have been shown in vitro to prevent the emergence of the resistant subpopulations but none have been translated so far into clinical benefit. Reasons for this discrepancy are discussed.

Conclusions: Colistin heteroresistance was common but highly variable between studies. The impact of colistin heteroresistance (frequency of emergent resistance during treatment and correlation with treatment outcomes) requires further study.

Keywords: Acinetobacter; Colistin; Epidemiology; Heteroresistance; Treatment.