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

In Malawi, chloramphenicol was routinely used in combination with benzylpenicillin from 1998 to 2015 to treat sepsis. Ceftriaxone, a third-generation cephalosporin antibiotic introduced in 2004 and widely used since 2005, has since provided a better alternative to the treatment of sepsis. Between 2003 and 2016, the proportion of E. coli and K. pneumoniae strains producing extended-spectrum beta-lactamases (ESBLs) rose meanwhile susceptibility to chloramphenicol increased. The molecular determinants of this re-emergence of chloramphenicol susceptibility are as of yet unknown, but they could shed light on how best to treat sepsis in the future within this setting, especially in the face of rising resistances to beta-lactams. In our study we used genomics, antimicrobial susceptibility assays and functional assays to determine the molecular mechanisms underpinning the re-emergence of chloramphenicol susceptibility.