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.



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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