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 and Nicholas A. Feasey
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Fabrice E. Graf: Liverpool School of Tropical Medicine
Richard N. Goodman: Liverpool School of Tropical Medicine
Sarah Gallichan: Liverpool School of Tropical Medicine
Sally Forrest: Liverpool School of Tropical Medicine
Esther Picton-Barlow: Liverpool School of Tropical Medicine
Alice J. Fraser: Liverpool School of Tropical Medicine
Minh-Duy Phan: The University of Queensland
Madalitso Mphasa: Kamuzu University of Health Sciences
Alasdair T. M. Hubbard: Liverpool School of Tropical Medicine
Patrick Musicha: Kamuzu University of Health Sciences
Mark A. Schembri: The University of Queensland
Adam P. Roberts: Liverpool School of Tropical Medicine
Thomas Edwards: Liverpool School of Tropical Medicine
Joseph M. Lewis: Liverpool School of Tropical Medicine
Nicholas A. Feasey: Liverpool School of Tropical Medicine

Nature Communications, 2024, vol. 15, issue 1, 1-12

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-53391-2

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