A novel ciprofloxacin-resistant subclade of H58 Salmonella Typhi is associated with fluoroquinolone treatment failure

Elife. 2016 Mar 11;5:e14003. doi: 10.7554/eLife.14003.

Abstract

The interplay between bacterial antimicrobial susceptibility, phylogenetics and patient outcome is poorly understood. During a typhoid clinical treatment trial in Nepal, we observed several treatment failures and isolated highly fluoroquinolone-resistant Salmonella Typhi (S. Typhi). Seventy-eight S. Typhi isolates were genome sequenced and clinical observations, treatment failures and fever clearance times (FCTs) were stratified by lineage. Most fluoroquinolone-resistant S. Typhi belonged to a specific H58 subclade. Treatment failure with S. Typhi-H58 was significantly less frequent with ceftriaxone (3/31; 9.7%) than gatifloxacin (15/34; 44.1%)(Hazard Ratio 0.19, p=0.002). Further, for gatifloxacin-treated patients, those infected with fluoroquinolone-resistant organisms had significantly higher median FCTs (8.2 days) than those infected with susceptible (2.96) or intermediately resistant organisms (4.01)(pS. Typhi clade internationally, but there are no data regarding disease outcome with this organism. We report an emergent new subclade of S. Typhi-H58 that is associated with fluoroquinolone treatment failure.

Keywords: s. enterica serovar typhi; H58; epidemiology; fluoroquinolones; global health; human; infectious disease; microbiology; nepal; randomised controlled trial; treatment failure; typhoid fever.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Bacterial Agents / pharmacology*
  • Anti-Bacterial Agents / therapeutic use*
  • Bacterial Typing Techniques
  • Ceftriaxone / therapeutic use
  • Ciprofloxacin / pharmacology*
  • Fluoroquinolones / therapeutic use*
  • Gatifloxacin
  • Genotype*
  • Humans
  • Nepal
  • Salmonella typhi / classification
  • Salmonella typhi / drug effects*
  • Salmonella typhi / isolation & purification
  • Sequence Analysis, DNA
  • Treatment Failure
  • Typhoid Fever / drug therapy*
  • Typhoid Fever / microbiology

Substances

  • Anti-Bacterial Agents
  • Fluoroquinolones
  • Ciprofloxacin
  • Ceftriaxone
  • Gatifloxacin

Associated data

  • ISRCTN/ISRCTN63006567