MOLECULAR EVOLUTION OF ANTIMICROBIAL RESISTANCE AND DRUG RESPONSE IN MULTIDRUG-RESISTANT BACTERIAL PATHOGENS

Abstract

Pakistan carries one of the heaviest antimicrobial resistance burdens in the world, and it is also the setting in which one of the clearest documented events in resistance evolution took place. This review assembles the Pakistani evidence base — national surveillance, published prevalence studies, genomic analyses of Pakistani isolates, and the national policy documents — and asks what it shows about how resistance evolves and spreads in this country specifically.

The picture that emerges differs from the one described in reviews written from North American and European data, and the differences are mechanistic rather than merely epidemiological. Extended-spectrum β-lactamase production, overwhelmingly CTX-M-15, is close to universal among Pakistani Enterobacterales, so any further resistance determinant lands on a genome already primed for β-lactam resistance. Carbapenem resistance here is driven by NDM and OXA-48-like enzymes rather than KPC, which means the β-lactamase inhibitor combinations that transformed treatment elsewhere address a smaller share of the local problem. Colistin and tigecycline resistance are already measurable. Methicillin resistance is reported in roughly half of Staphylococcus aureus isolates, and Pakistan carries one of the world's largest burdens of multidrug-resistant tuberculosis.

The extensively drug-resistant Salmonella Typhi outbreak that began in Hyderabad in 2016 is examined in detail, because its genomics demonstrate the central argument: a multidrug-resistant clone that had circulated locally for years acquired a single conjugative plasmid and became extensively drug-resistant in one step.

We close with the drivers that make these pressures unusually strong in Pakistan — non-prescription dispensing, veterinary and poultry use, untreated effluent — with the limits of the available data, and with what containment measures have so far been evaluated.