Spontaneous Emergence of Azithromycin Resistance in Independent Lineages of Salmonella Typhi in Northern India

Abstract

Background The emergence and spread of antimicrobial resistance (AMR) pose a major threat to the effective treatment and control of typhoid fever. The ongoing outbreak of extensively drug-resistant Salmonella Typhi (S. Typhi) in Pakistan has left azithromycin as the only remaining broadly efficacious oral antimicrobial for typhoid in South Asia. Ominously, azithromycin-resistant S. Typhi organisms have been subsequently reported in Bangladesh, Pakistan, and Nepal. Methods Here, we aimed to understand the molecular basis of AMR in 66 S. Typhi organisms isolated in a cross-sectional study performed in a suburb of Chandigarh in Northern India using whole-genome sequencing and phylogenetic analysis. Results We identified 7 S. Typhi organisms with the R717Q mutation in the acrB gene that was recently found to confer resistance to azithromycin in Bangladesh. Six out of the seven azithromycin-resistant S. Typhi isolates also exhibited triple mutations in gyrA (S83F and D87N) and parC (S80I) genes and were resistant to ciprofloxacin. These contemporary ciprofloxacin/azithromycin-resistant isolates were phylogenetically distinct from each other and from those reported from Bangladesh, Pakistan, and Nepal. Conclusions The independent emergence of azithromycin-resistant typhoid in Northern India reflects an emerging broader problem across South Asia and illustrates the urgent need for the introduction of typhoid conjugate vaccines in the region.

Safety and Efficacy of a Typhoid Conjugate Vaccine in Malawian Children

“…In the context of the rise in fluoroquinolone-resistance among S. typhi across Asia, 8 the emergence in Malawi of four S. typhi strains with reduced susceptibility to fluroquinolones, from participants enrolled in this trial, is particularly concerning. Finally, the threat of independent emergence of azithromycin-resistant typhoid, as seen in several Asian countries, 35 adds urgency and relevance to efforts to introduce this safe and efficacious Vi-TCV vaccine across the African continent and globally. Disclosure forms provided by the authors are available with the full text of this article at NEJM.org .…”

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“…particular concern for India, where enteric fever is highly endemic, with an estimated annual incidence of 377 cases per 100,000 population, and azithromycin has been increasingly chosen for empirical treatment [52]. The recent emergence of azithromycin-resistant Salmonella enterica serotype Typhi (S. Typhi) strains in India sounds a further alarm bell [53]. Another threat coming from this unexpected increase in azithromycin use is the possible selection of…”

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