Abstract
Amikacin and piperacillin/tazobactam are frequent antibiotic choices to treat bloodstream infection, which is commonly fatal and most often caused by bacteria from the family Enterobacterales. Here we show that two gene cassettes located side-by-side in and ancestral integron similar to In37 have been "harvested" by insertion sequence IS26 as a transposon that is widely disseminated among the Enterobacterales. This transposon encodes the enzymes AAC(6')-Ib-cr and OXA-1, reported, respectively, as amikacin and piperacillin/tazobactam resistance mechanisms. However, by studying bloodstream infection isolates from 769 patients from three hospitals serving a population of 1.2 million people in South West England, we show that increased enzyme production due to mutation in an IS26/In37-derived hybrid promoter or, more commonly, increased transposon copy number is required to simultaneously remove these two key therapeutic options; in many cases leaving only the last-resort antibiotic, meropenem. These findings may help improve the accuracy of predicting piperacillin/tazobactam treatment failure, allowing stratification of patients to receive meropenem or piperacillin/tazobactam, which may improve outcome and slow the emergence of meropenem resistance.
Copyright: © 2024 Dulyayangkul et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
MeSH terms
-
Amikacin / pharmacology
-
Anti-Bacterial Agents* / pharmacology
-
Bacteremia / drug therapy
-
Bacteremia / genetics
-
Bacteremia / microbiology
-
DNA Transposable Elements* / genetics
-
Drug Resistance, Multiple, Bacterial / genetics
-
Enterobacteriaceae / drug effects
-
Enterobacteriaceae / genetics
-
Enterobacteriaceae Infections / drug therapy
-
Enterobacteriaceae Infections / genetics
-
Enterobacteriaceae Infections / microbiology
-
Humans
-
Integrons / genetics
-
Microbial Sensitivity Tests
-
Piperacillin / pharmacology
Substances
-
Anti-Bacterial Agents
-
DNA Transposable Elements
-
Piperacillin
-
Amikacin
Grants and funding
This work was funded by Medical Research Council grants MR/T005408/1 (to P.B.W. and M.B.A), MR/N013646/1 (to M.B.A. and K.J.H.) and MR/S004769/1 (to M.B.A) and by Natural Environment Research Council grant NE/N01961X/1 (to M.B.A.), by grant 82459 (to M.B.A.) from the Welsh Government Rural Communities - Rural Development Programme 2014-2020 supported by the European Union and the Welsh Government (Llywodraeth Cymru). W.W.Y.L. received a scholarship from the Medical Research Foundation National PhD Training Program in Antimicrobial Resistance Research (MRF-145-0004-TPG-AVISO). Clinical training fellowships were funded by the Wellcome Trust (to F.E. and F.H) and National Institute for Health Research (to I.H.). P.P. was supported by a Royal Thai Government scholarship. N.S. was supported by a postgraduate scholarship from the University of Bristol. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. No author received a salary directly from any funder.