BAYESIAN ANALYSIS OF S. TYPHI STRAINS FROM NEPALI CHILDREN REVEAL CHANGES IN THE PATHOGEN POPULATION STRUCTURE WITH IMPLICATIONS FOR ANTIMICROBIAL TREATMENT REGIMENS AND VACCINE POLICY
ESPID Education. Britto C. May 29, 2018; 218724
Dr. Carl Britto
Dr. Carl Britto

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Learning Objectives
Abstract
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- Understanding the response of S. Typhi to antimicrobial pressure
- Understanding the difference in lineages conferring AMR
Background
Enteric fever accounts for the majority of invasive bacterial disease among children in Nepal. Multi-drug resistant S. Typhi is now rare and appears to be replaced by highly fluoroquinolone resistant strains. This study aims to characterize the temporal trends in the evolution of S. Typhi in Nepal.

Methods
Whole genome sequences of 154 S. Typhi strains from Nepali children isolated between 2008-2016 along with 107 other Nepali strains for contextualization were subjected to phylogenomic analysis using BEAST2 to assess population structure and estimate divergence dates. The signal of these Bayesian estimates were then assessed using a date-randomization test. Finally, 5 independent runs were conducted with a chain length of 600,000,000 states, sampling every 300,000 iterations, using LogCombiner. Maximum-clade credibility (MCC) trees were then generated with ‘keep target heights’.

Results
The most recent common ancestor (mrca) for all H58 strains in Nepal existed circa 1993, and both sublineages of H58 (I and II) were present.
Lineage II was significantly more common (40% pre-2010 vs 74%, p=1x10-7) from 2011 onwards and associated with different antimicrobial resistance (AMR) patterns from lineage I (MDR - 59% lineage I vs 0% lineage II, p<1x10-15) and quinolone resistance determining region (QRDR) mutations (50% lineage I vs. 99% lineage II, p<1x10-15).
A distinct monophyletic clade of lineage II isolates harbouring distinct QRDR mutations formed a local monophyletic clade indicative of local clonal expansion in Nepal.

Conclusion
The clonal replacement of the MDR-associated lineage I with the expansion of the quinolone resistance-associated lineage II over time reflect the changing antimicrobial pressure conferred on the S. Typhi population in Nepal. These results underscore the importance of employing vaccination strategies to prevent further development of AMR in S. Typhi.
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