The emergence and impact of azithromycin-resistant Salmonella enterica serovar Typhi

Typhoid fever remains a significant public health and economic burden in LMICs.

The global spread of extensively drug-resistant (XDR) Salmonella Typhi has limited the effectiveness of antimicrobial therapy and threatened lives. Resistance of S.

Typhi to azithromycin, the only remaining effective oral drug to treat XDR typhoid, recently emerged in South Asia, posing an immediate threat of untreatable typhoid fever. I aim to investigate the emergence and epidemiology of azithromycin-resistant (AzithR) S. Typhi and determine its impact on typhoid treatment.

I will perform genome sequencing of ~500 S.

Typhi isolates from the ACT-South Asia Trial conducted in Nepal, India, Bangladesh and Pakistan to investigate the evolutionary and epidemiological dynamics of AzithR S. Typhi. I will conduct laboratory experiments to understand the evolutionary drivers of AzithR S. Typhi and measure the impact of AzithR mutations on bacterial growth dynamics, antimicrobial tolerance, and fitness.

Further, I will assess the correlation between clinical responses to azithromycin and in vitro intracellular azithromycin susceptibility of S. Typhi isolates from the above trial. These research investigations are essential to understand the evolutionary and epidemiological landscape of AzithR S.

Typhi, as well as clinical responses to azithromycin and appropriate dosages for guiding control measures and clinical practice.