Molecular mechanisms of re-emerging chloramphenicol susceptibility in extended-spectrum beta-lactamase-producing Enterobacterales

Fabrice E. Graf*, Richard N. Goodman, Sarah Gallichan, Sally Forrest, Esther Picton-Barlow, Alice J. Fraser, Minh-Duy Phan, Madalitso Mphasa, Alasdair T. M. Hubbard, Patrick Musicha, Mark A. Schembri, Adam P. Roberts, Thomas Edwards, Joseph M. Lewis, Nicholas A. Feasey

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Infections with Enterobacterales (E) are increasingly difficult to treat due to antimicrobial resistance. After ceftriaxone replaced chloramphenicol (CHL) as empiric therapy for suspected sepsis in Malawi in 2004, extended-spectrum beta-lactamase (ESBL)-E rapidly emerged. Concurrently, resistance to CHL in Escherichia coli and Klebsiella spp. decreased, raising the possibility of CHL re-introduction. However, many phenotypically susceptible isolates still carry CHL acetyltransferase (cat) genes. To understand the molecular mechanisms and stability of this re-emerging CHL susceptibility we use a combination of genomics, phenotypic susceptibility assays, experimental evolution, and functional assays for CAT activity. Here, we show that of 840 Malawian E. coli and Klebsiella spp. isolates, 31% have discordant CHL susceptibility genotype–phenotype, and we select a subset of 42 isolates for in-depth analysis. Stable degradation of cat genes by insertion sequences leads to re-emergence of CHL susceptibility. Our study suggests that CHL could be reintroduced as a reserve agent for critically ill patients with ESBL-E infections in Malawi and similar settings and highlights the ongoing challenges in inferring antimicrobial resistance from sequence data.
Original languageEnglish
Article number9019
Number of pages12
JournalNature Communications
Volume15
DOIs
Publication statusPublished - 18 Oct 2024

Fingerprint

Dive into the research topics of 'Molecular mechanisms of re-emerging chloramphenicol susceptibility in extended-spectrum beta-lactamase-producing Enterobacterales'. Together they form a unique fingerprint.

Cite this