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Graf, Fabrice 
ORCID: https://orcid.org/0000-0003-1132-5348, Goodman, Richard, Gallichan, Sarah, Forrest, Sally, Picton-Barlow, Esther, Fraser, Alice, Phan, Minh-Duy, Mphasa, Madalitso, Hubbard, Alasdair ORCID: https://orcid.org/0000-0001-6668-9179, Musicha, Patrick, Schembri, Mark A., Roberts, Adam ORCID: https://orcid.org/0000-0002-0760-3088, Edwards, Thomas, Lewis, Joseph ORCID: https://orcid.org/0000-0002-3837-5188 and Feasey, Nicholas ORCID: https://orcid.org/0000-0003-4041-1405
(2024)
'Molecular mechanisms of re-emerging chloramphenicol susceptibility in extended-spectrum beta-lactamase-producing Enterobacterales'. Nature Communications, Vol 15, Issue 1, e9019.
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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.
| Item Type: | Article |
|---|---|
| Subjects: | QV Pharmacology > Anti-Bacterial Agents. Tissue Extracts > QV 350.5.C5 Chloramphenicol WC Communicable Diseases > Infection. Bacterial Infections > Enteric Infections > WC 290 Escherichia coli infections |
| Faculty: Department: | Biological Sciences > Department of Tropical Disease Biology Biological Sciences > Vector Biology Department Clinical Sciences & International Health > Clinical Sciences Department |
| Digital Object Identifer (DOI): | https://doi.org/10.1038/s41467-024-53391-2 |
| SWORD Depositor: | JISC Pubrouter |
| Depositing User: | JISC Pubrouter |
| Date Deposited: | 06 Nov 2024 12:08 |
| Last Modified: | 06 Nov 2024 12:08 |
| URI: | https://archive.lstmed.ac.uk/id/eprint/25486 |
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