TY - JOUR
T1 - Molecular mechanisms of re-emerging chloramphenicol susceptibility in extended-spectrum beta-lactamase-producing Enterobacterales
AU - Graf, Fabrice E.
AU - Goodman, Richard N.
AU - Gallichan, Sarah
AU - Forrest, Sally
AU - Picton-Barlow, Esther
AU - Fraser, Alice J.
AU - Phan, Minh-Duy
AU - Mphasa, Madalitso
AU - Hubbard, Alasdair T. M.
AU - Musicha, Patrick
AU - Schembri, Mark A.
AU - Roberts, Adam P.
AU - Edwards, Thomas
AU - Lewis, Joseph M.
AU - Feasey, Nicholas A.
N1 - Funding: This work was supported by iiCON (infection innovation consortium) via UK Research and Innovation (107136) and Unilever (MA-2021-00523N). R.N.G. has been supported by the Medical Research Council via the LSTM-Lancaster doctoral training partnership (grant no. MR/N013514/1). R.N.G and A.P.R. are supported by the Medical Research Council (MRC), Biotechnology and Biological Sciences Research Council (BBSRC) and Natural Environmental Research Council (NERC) which are all Councils of UK Research and Innovation (grant no. MR/W030578/1) under the umbrella of the JPIAMR—Joint Programming Initiative on Antimicrobial Resistance.
PY - 2024/10/18
Y1 - 2024/10/18
N2 - 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.
AB - 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.
U2 - 10.1038/s41467-024-53391-2
DO - 10.1038/s41467-024-53391-2
M3 - Article
SN - 2041-1723
VL - 15
JO - Nature Communications
JF - Nature Communications
M1 - 9019
ER -