Mapping the resistance landscape: A large-scale study of polymyxin-resistant pathogens circulating in low-and middle-income countries.

The increasing prevalence of antimicrobial resistance is a major public health challenge, particularly in low- and middle-income countries (LMICs). Polymyxins are last-resort antibiotics used for treating highly drug-resistant infections, however, the rise of polymyxin-resistant bacterial strains is further reducing treatment options in LMICs, where the burden is exacerbated by limited diagnostic capacity, poor antimicrobial stewardship, and limited surveillance infrastructure. There is a lack of comprehensive population-based surveillance of the emerging polymyxin resistance and a need to comprehend what genetic determinants are associated with this resistance. In this study, we collected 634 clinical isolates of polymyxin-resistant bacteria from 28 LMICs, then used whole genome sequencing, phylogenetic and bioinformatic analyses to identify species, sequence types and antibiotic resistance gene profiles. We found 12 bacterial species and focussed downstream analyses on 4 high priority pathogens: K. pneumoniae, E. coli, A. baumannii, and P. aeruginosa.. The analysis revealed clonal expansion of high-risk lineages across geographically dispersed LMIC settings. Phenotypic antimicrobial susceptibility testing using both VITEK 2 automated systems and broth microdilution (BMD) assays against an expanded panel of 44 antibiotics allowed us to correlate the bioinformatic analyses to the resistance profiles. These findings show clonal spread and horizontal gene transfer feature in the propagation of antimicrobial resistance and highlight that enhanced genomic surveillance is essential to inform treatment strategies and mitigate the spread of resistance to last-line antimicrobials.