title: Clinical outcomes in typhoid fever: adverse impact of infection with nalidixic acid-resistant Salmonella typhi.
abstract: BACKGROUND
  Widespread use of fluoroquinolones has resulted in emergence of Salmonella typhi strains with decreased susceptibility to fluoroquinolones. These strains are identifiable by their nalidixic acid-resistance. We studied the impact of infection with nalidixic acid-resistant S. typhi (NARST) on clinical outcomes in patients with bacteriologically-confirmed typhoid fever.
  
  
  METHODS
  Clinical and laboratory features, fever clearance time and complications were prospectively studied in patients with blood culture-proven typhoid fever, treated at a tertiary care hospital in north India, during the period from November 2001 to October 2003. Susceptibility to amoxycillin, co-trimoxazole, chloramphenicol, ciprofloxacin and ceftriaxone were tested by disc diffusion method. Minimum inhibitory concentrations (MIC) of ciprofloxacin and ceftriaxone were determined by E-test method.
  
  
  RESULTS
  During a two-year period, 60 patients (age [mean +/- SD]: 15 +/- 9 years; males: 40 [67%]) were studied. All isolates were sensitive to ciprofloxacin and ceftriaxone by disc diffusion and MIC breakpoints. However, 11 patients had clinical failure of fluoroquinolone therapy. Infections with NARST isolates (47 [78%]) were significantly associated with longer duration of fever at presentation (median [IQR] 10 [7-15] vs. 4 [3-6] days; P = 0.000), higher frequency of hepatomegaly (57% vs. 15%; P = 0.021), higher levels of aspartate aminotransferase (121 [66-235] vs. 73 [44-119] IU/L; P = 0.033), and increased MIC of ciprofloxacin (0.37 +/- 0.21 vs. 0.17 +/- 0.14 microg/mL; P = 0.005), as compared to infections with nalidixic acid-susceptible isolates. All 11 patients with complications were infected with NARST isolates. Total duration of illness was significantly longer in patients who developed complications than in patients who did not (22 [14.8-32] vs. 12 [9.3-20.3] days; P = 0.011). Duration of prior antibiotic intake had a strong positive correlation with the duration of fever at presentation (r = 0.61; P = 0.000) as well as the total duration of illness (r = 0.53; P = 0.000).
  
  
  CONCLUSIONS
  Typhoid fever caused by NARST infection is associated with poor clinical outcomes, probably due to delay in initiating appropriate antibiotic therapy. Fluoroquinolone breakpoints for S. typhi need to be redefined and fluoroquinolones should no longer be used as first-line therapy, if the prevalence of NARST is high.
authors.affiliation: Department of Medicine, All India Institute of Medical Sciences, New Delhi, India. kadhiravant@yahoo.co.in
authors.forename: Tamilarasu
authors.initials: T
authors.lastname: Kadhiravan
authors.forename: Naveet
authors.initials: N
authors.lastname: Wig
authors.forename: Arti
authors.initials: A
authors.lastname: Kapil
authors.forename: S K
authors.initials: SK
authors.lastname: Kabra
authors.forename: K
authors.initials: K
authors.lastname: Renuka
authors.forename: Anoop
authors.initials: A
authors.lastname: Misra
mesh_terms: D000293:Adolescent; D000328:Adult; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D020682:Cefixime / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D002939:Ciprofloxacin / Q000627:therapeutic use; D024881:Drug Resistance, Bacterial; D005260:Female; D006801:Humans; D007194:India / Q000453:epidemiology; D007223:Infant; D008297:Male; D008826:Microbial Sensitivity Tests; D009268:Nalidixic Acid / Q000494:pharmacology*; D015242:Ofloxacin / Q000627:therapeutic use; D012485:Salmonella typhi / Q000187:drug effects* / Q000472:pathogenicity; D016896:Treatment Outcome; D014435:Typhoid Fever / Q000188:drug therapy* / Q000453:epidemiology / Q000382:microbiology*
chemical_list: D000900:Anti-Bacterial Agents; D009268:Nalidixic Acid; D002939:Ciprofloxacin; D020682:Cefixime; D015242:Ofloxacin