Genomic analysis of extended-spectrum beta-lactamase (ESBL) producing colonising adults in Blantyre, Malawi reveals previously undescribed diversity.

is one of the most prevalent Gram-negative species associated with drug resistant infections. Strains that produce extended-spectrum beta-lactamases (ESBLs) or carbapenemases are both particularly problematic and disproportionately impact resource limited healthcare settings where last-line antimicrobials may not be available. A large number of genomes are now available and have allowed insights into pathogenesis and epidemiology of ESBL but genomes from sub-Saharan Africa (sSA) are significantly underrepresented. To reduce this gap, we investigated ESBL-producing colonising adults in Blantyre, Malawi to assess bacterial diversity and AMR determinants and to place these isolates in the context of the wider population structure. We performed short-read whole-genome sequencing of 473 colonising ESBL isolated from human stool and contextualised the genomes with a previously curated multi-country collection of 10 146 genomes and sequence type (ST)-specific collections for our three most commonly identified STs. These were the globally successful ST131, ST410 and ST167, and the dominant ESBL genes were , mirroring global trends. However, 37 % of Malawian isolates did not cluster with any isolates in the curated multicountry collection and phylogenies were consistent with locally spreading monophyletic clades, including within the globally distributed, carbapenemase-associated B4/H24RxC ST410 lineage. A single ST2083 isolate in this collection harboured a carbapenemase gene. Long read sequencing demonstrated the presence of a globally distributed ST410-associated carbapenemase carrying plasmid in this isolate, which was absent from the ST410 strains in our collection. We conclude there is a risk that carbapenem resistance in could proliferate rapidly in Malawi under increasing selection pressure, and that both ongoing antimicrobial stewardship and genomic surveillance are critical as local carbapenem use increases.