Genomic Epidemiology of Typhoid Highlights the Need for Lineage Resolution Diagnosis in Treatment Decisions

Background: Large amounts of genomic information are available on typhoid epidemiology, however, no attempts have been made to evaluate the clinical impact of antibiotic treatment options with respect to Salmonella Typhi lineages.Methods: Clinical isolates of S. Typhi were collected prospectively as part of a national multi-centric surveillance study comprising 19 sites across India. A subset of 991 isolates was sequenced on an Illumina platform and detailed phylogenomics and antimicrobial resistance profiling were performed. Genomically identified lineages of H58 and non-H58 were compared with the clinical spectrum and outcomes based on the antibiotics used.Findings: We observed a substantial genetic diversity of 20 distinct genotypes of S. Typhi, with regional dominance of both H58 and non-H58 lineages. Antimicrobial resistance varied geographically but it has continued to shape the emergence and persistence of these lineages in India (MDR-2.5%; FQNS-98%). The clinical presentations of S . Typhi lineages were heterogeneous. However, patients with non-H58 infections receiving beta-lactams had fewer mean fever days as compared to H58 cases (10.17 Vs. 12.67 days, p-value: 0.013 ). In contrast, patients with H58 infections who received azithromycin had fewer mean fever days, than the non-H58 cases (13.29 Vs. 19.67 days, p-value: > 0.5 ).Interpretation: Integrated clinical and genomic data showed a significant correlation between antibiotic therapy, infecting lineages and the mean duration of fever. Our data suggest that H58 lineages that cause prolonged fever may be better managed with azithromycin, while beta-lactams could be the preferred antibiotic choice non-H58 infections. A lineage-level molecular diagnostic approach could be adapted to better guide the clinical management of typhoid.Funding: This work was supported by grants from Bill & Melinda Gates Foundation, USA (Investment ID INV-009497 OPP1159351) for the Project “National Surveillance System for Enteric Fever in India”, Genome sequencing was partially supported by The Wellcome Trust (STRATAA), The Gates Foundation (TyVac), The Department of Biotechnology, India and the National Institute of Health Research Cambridge Biomedical Research Council funding.Declaration of Interest: Authors declare that they have no competing interests.Ethical Approval: This study was approved by the Institutional Review Board (IRB) of Christian Medical College, Vellore (IRB Min No: 10393 dated 30.11.2016).