Chronic carriers and multidrug resistance in typhoid fever: pathogenesis, challenges, and integrated control strategies.

Typhoid fever, a systemic disease caused by Salmonella enterica serovar Typhi (S. Typhi), remains a major global health problem, particularly in regions with poor sanitation. Despite advancements in diagnostics and treatment, S. Typhi continues to impose a heavy disease burden, worsened by the emergence of multidrug-resistant (MDR) strains. Chronic carriers, accounting for 2-5% of infections, play a crucial role in disease transmission. These carriers are often asymptomatic but intermittently shed bacteria, sustaining S. Typhi within the human population. Gallstones are strongly associated with the chronic carrier state, providing a niche for bacterial biofilm formation that enhances persistence and antibiotic resistance. Furthermore, long-term colonisation of the gallbladder is linked to an increased risk of gallbladder cancer, a condition common in typhoid-endemic areas. The pathogenesis of typhoid fever involves bacterial invasion of the gastrointestinal mucosa, evasion of innate immunity, and systemic spread. Biofilm formation on gallstones promotes long-term persistence within the gallbladder, while immune responses and intestinal microbiota dynamics influence disease progression and bacterial shedding. Current diagnostic methods, including culture and serology, often fall short in identifying carriers, necessitating the development of innovative approaches for effective surveillance and control. Treating chronic carriers remains difficult due to the biofilm-associated resistance of S. Typhi. Although cholecystectomy combined with targeted antimicrobial therapy shows promise, it does not guarantee the elimination of the carrier state. This review emphasises the importance of integrating strategies that combine improved diagnostic tools, targeted therapies, and public health interventions to reduce the burden of typhoid fever and its chronic carriers.