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

Abstract

AbstractInfections 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, ESBL-E rapidly emerged. Concurrently, resistance to CHL inEscherichia coliandKlebsiellaspp. decreased, raising the possibility of CHL re-introduction. However, many phenotypically susceptible isolates still carry CHL acetyltransferase (CAT) genes.We used a combination of genomics, phenotypic susceptibility assays, experimental evolution and functional assays for CAT activity to understand the molecular mechanisms and stability of this re-emerging CHL susceptibility.Of 840 Malawian isolates, 31% had discordant CHL susceptibility genotype-phenotype, and we selected 42 isolates for in-depth analysis. Stable degradation ofcatgenes by insertion sequences led to re-emergence of CHL susceptibility. Our study suggests CHL could be reintroduced as 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.