TYPHOID FEVER AND MULTIDRUG RESISTANCE: A COMPREHENSIVE REVIEW OF MECHANISMS, EPIDEMIOLOGY, AND THERAPEUTIC CHALLENGE

Abstract

Background: Typhoid fever, caused by Salmonella enterica serovar Typhi (S. Typhi), remains a major infectious disease burden in low- and middle-income countries, with an estimated 13 million cases and over 130,000 deaths annually. The emergence and global dissemination of multidrug-resistant (MDR), fluoroquinolone-non-susceptible (FQNS), and extensively drug-resistant (XDR) strains has substantially reduced treatment options. Objectives: This review synthesises current evidence on the molecular epidemiology, resistance mechanisms, clinical management, and preventive strategies for MDR typhoid. Methods: A systematic literature search was conducted across PubMed, Embase, and Web of Science covering publications from 2000 to 2024, using the MeSH terms “Salmonella Typhi,” “multidrug resistance,” “XDR typhoid,” “plasmid-mediated resistance,” and “typhoid conjugate vaccine.” Results: MDR S. Typhi emerged in the 1980s and is predominantly encoded by IncHI1 plasmids. The globally dominant H58 haplotype (genotype 4.3.1) carries chromosomally integrated resistance cassettes conferring resistance to first-line drugs. The XDR clone, first identified in Sindh, Pakistan in November 2016, additionally carries the IncY plasmid harbouring blaCTX-M-15 and qnrS, rendering it resistant to third-generation cephalosporins and fluoroquinolones, leaving only azithromycin and carbapenems as treatment options. Emerging azithromycin resistance, driven by acrB mutations, represents a critical threat. Typhoid conjugate vaccines (TCVs) demonstrate 81–97% efficacy and represent the most promising near-term control strategy. Conclusion: MDR and XDR typhoid fever represent an evolving global health emergency. An integrated approach combining rapid genomic surveillance, rational antimicrobial stewardship, expanded TCV rollout, and sustained WASH investment is essential to prevent an era of untreatable typhoid.