Mechanisms of tigecycline resistance in the Enterobacteriaceae and Acinetobacter baumannii

Hornsey, Michael Andrew (2011). Mechanisms of tigecycline resistance in the Enterobacteriaceae and Acinetobacter baumannii. PhD thesis The Open University.

DOI: https://doi.org/10.21954/ou.ro.0000ee3b

Abstract

Tigecycline is the first glycylcycline to enter clinical use and displays good in vitro activity against a broad range of Gram-positive and Gram-negative pathogens. It is often used as an agent of last resort for the treatment of infections caused by multidrug-resistant Gram-negative bacteria including some Enterobacteriaceae species and Acinetobacter baumannii. Therefore, the recent emergence of tigecycline resistance in some strains of these species is a serious public health concern. Efflux was investigated as a possible mechanism of tigecycline resistance using pre- and post-therapy pairs of clinical isolates and laboratory-selected, tigecycline-resistant mutants of A. baumannii and Enterobacter cloacae and a type strain, laboratory mutants, and a clinical isolate of Serratia marcescens. Minimum inhibitory concentrations (MICs) of tigecycline and other agents were determined by agar dilution. Pulsed-field gel electrophoresis was used to assign clones / determine isolate relatedness. Expression of efflux pump genes and genes thought to be implicated in their regulation was monitored by real-time reverse-transcriptase polymerase chain reaction and their role in tigecycline resistance was further investigated by knockout mutagenesis. There was an association between increased expression of specific resistance-nodulation-division (RND) efflux pump genes and elevated tigecycline MICs in all species studied. Insertional inactivation of RND efflux pump genes implicated the AdeABC, AcrAB and SdeXY-HasF systems of A. baumannii, E. cloacae and S. marcescens, respectively. The results of this study support the hypothesis that tigecycline resistance in clinical isolates of Gram-negative bacteria arises as a result of the up-regulated activity of intrinsic efflux systems of the RND family.

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