Axel B Janssen1, Denise van Hout2, Marc J M Bonten1,2, Rob J L Willems1, Willem van Schaik1,3. 1. Department of Medical Microbiology, University Medical Center Utrecht, Utrecht University, Heidelberglaan 100, 3584CX Utrecht, The Netherlands. 2. Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Heidelberglaan 100, 3584CX Utrecht, The Netherlands. 3. Institute of Microbiology and Infection, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
Abstract
BACKGROUND: Colistin is an antibiotic that targets the LPS molecules present in the membranes of Gram-negative bacteria. It is used as a last-resort drug to treat infections with MDR strains. Colistin is also used in selective decontamination of the digestive tract (SDD), a prophylactic therapy used in patients hospitalized in ICUs to selectively eradicate opportunistic pathogens in the oropharyngeal and gut microbiota. OBJECTIVES: To unravel the mechanisms of acquired colistin resistance in Gram-negative opportunistic pathogens obtained from SDD-treated patients. RESULTS: Routine surveillance of 428 SDD-treated patients resulted in 13 strains with acquired colistin resistance (Escherichia coli, n = 9; Klebsiella aerogenes, n = 3; Enterobacter asburiae, n = 1) from 5 patients. Genome sequence analysis showed that these isolates represented multiple distinct colistin-resistant clones but that colistin-resistant strains within the same patient were clonally related. We identified previously described mechanisms that lead to colistin resistance, i.e. a G53 substitution in the response regulator PmrA/BasR and the acquisition of the mobile colistin resistance gene mcr-1.1, but we also observed novel variants of basR with an 18 bp deletion and a G19E substitution in the sensor histidine kinase BasS. We experimentally confirmed that these variants contribute to reduced colistin susceptibility. In a single patient, we observed that colistin resistance in a single E. coli clone evolved through two unique variants in basRS. CONCLUSIONS: We show that prophylactic use of colistin during SDD can select for colistin resistance in species that are not intrinsically colistin resistant. This highlights the importance of continued surveillance for strains with acquired colistin resistance in patients treated with SDD.
BACKGROUND: Colistin is an antibiotic that targets the LPS molecules present in the membranes of Gram-negative bacteria. It is used as a last-resort drug to treat infections with MDR strains. Colistin is also used in selective decontamination of the digestive tract (SDD), a prophylactic therapy used in patients hospitalized in ICUs to selectively eradicate opportunistic pathogens in the oropharyngeal and gut microbiota. OBJECTIVES: To unravel the mechanisms of acquired colistin resistance in Gram-negative opportunistic pathogens obtained from SDD-treated patients. RESULTS: Routine surveillance of 428 SDD-treated patients resulted in 13 strains with acquired colistin resistance (Escherichia coli, n = 9; Klebsiella aerogenes, n = 3; Enterobacter asburiae, n = 1) from 5 patients. Genome sequence analysis showed that these isolates represented multiple distinct colistin-resistant clones but that colistin-resistant strains within the same patient were clonally related. We identified previously described mechanisms that lead to colistin resistance, i.e. a G53 substitution in the response regulator PmrA/BasR and the acquisition of the mobile colistin resistance gene mcr-1.1, but we also observed novel variants of basR with an 18 bp deletion and a G19E substitution in the sensor histidine kinase BasS. We experimentally confirmed that these variants contribute to reduced colistin susceptibility. In a single patient, we observed that colistin resistance in a single E. coli clone evolved through two unique variants in basRS. CONCLUSIONS: We show that prophylactic use of colistin during SDD can select for colistin resistance in species that are not intrinsically colistin resistant. This highlights the importance of continued surveillance for strains with acquired colistin resistance in patients treated with SDD.
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