title: Gatifloxacin versus ceftriaxone for uncomplicated enteric fever in Nepal: an open-label, two-centre, randomised controlled trial.
abstract: BACKGROUND
  Because treatment with third-generation cephalosporins is associated with slow clinical improvement and high relapse burden for enteric fever, whereas the fluoroquinolone gatifloxacin is associated with rapid fever clearance and low relapse burden, we postulated that gatifloxacin would be superior to the cephalosporin ceftriaxone in treating enteric fever.
  
  
  METHODS
  We did an open-label, randomised, controlled, superiority trial at two hospitals in the Kathmandu valley, Nepal. Eligible participants were children (aged 2-13 years) and adult (aged 14-45 years) with criteria for suspected enteric fever (body temperature ≥38·0°C for ≥4 days without a focus of infection). We randomly assigned eligible patients (1:1) without stratification to 7 days of either oral gatifloxacin (10 mg/kg per day) or intravenous ceftriaxone (60 mg/kg up to 2 g per day for patients aged 2-13 years, or 2 g per day for patients aged ≥14 years). The randomisation list was computer-generated using blocks of four and six. The primary outcome was a composite of treatment failure, defined as the occurrence of at least one of the following: fever clearance time of more than 7 days after treatment initiation; the need for rescue treatment on day 8; microbiological failure (ie, blood cultures positive for Salmonella enterica serotype Typhi, or Paratyphi A, B, or C) on day 8; or relapse or disease-related complications within 28 days of treatment initiation. We did the analyses in the modified intention-to-treat population, and subpopulations with either confirmed blood-culture positivity, or blood-culture negativity. The trial was powered to detect an increase of 20% in the risk of failure. This trial was registered at ClinicalTrials.gov, number NCT01421693, and is now closed.
  
  
  RESULTS
  Between Sept 18, 2011, and July 14, 2014, we screened 725 patients for eligibility. On July 14, 2014, the trial was stopped early by the data safety and monitoring board because S Typhi strains with high-level resistance to ciprofloxacin and gatifloxacin had emerged. At this point, 239 were in the modified intention-to-treat population (120 assigned to gatifloxacin, 119 to ceftriaxone). 18 (15%) patients who received gatifloxacin had treatment failure, compared with 19 (16%) who received ceftriaxone (hazard ratio [HR] 1·04 [95% CI 0·55-1·98]; p=0·91). In the culture-confirmed population, 16 (26%) of 62 patients who received gatifloxacin failed treatment, compared with four (7%) of 54 who received ceftriaxone (HR 0·24 [95% CI 0·08-0·73]; p=0·01). Treatment failure was associated with the emergence of S Typhi exhibiting resistance against fluoroquinolones, requiring the trial to be stopped. By contrast, in patients with a negative blood culture, only two (3%) of 58 who received gatifloxacin failed treatment versus 15 (23%) of 65 who received ceftriaxone (HR 7·50 [95% CI 1·71-32·80]; p=0·01). A similar number of non-serious adverse events occurred in each treatment group, and no serious events were reported.
  
  
  CONCLUSIONS
  Our results suggest that fluoroquinolones should no longer be used for treatment of enteric fever in Nepal. Additionally, under our study conditions, ceftriaxone was suboptimum in a high proportion of patients with culture-negative enteric fever. Since antimicrobials, specifically fluoroquinolones, are one of the only routinely used control measures for enteric fever, the assessment of novel diagnostics, new treatment options, and use of existing vaccines and development of next-generation vaccines are now a high priority.
  
  
  BACKGROUND
  Wellcome Trust and Li Ka Shing Foundation.
authors.affiliation: Oxford University Clinical Research Unit, Patan Academy of Health Sciences, Kathmandu, Nepal.
authors.forename: Amit
authors.initials: A
authors.lastname: Arjyal
authors.affiliation: Oxford University Clinical Research Unit, Patan Academy of Health Sciences, Kathmandu, Nepal; Global Antibiotic Resistance Partnership, Kathmandu, Nepal; Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, Oxford University, Oxford, UK. Electronic address: buddha.basnyat@ndm.ox.ac.uk.
authors.forename: Buddha
authors.initials: B
authors.lastname: Basnyat
authors.affiliation: The Hospital for Tropical Diseases, Wellcome Trust Major Overseas Programme, Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam.
authors.forename: Ho Thi
authors.initials: HT
authors.lastname: Nhan
authors.affiliation: Oxford University Clinical Research Unit, Patan Academy of Health Sciences, Kathmandu, Nepal.
authors.forename: Samir
authors.initials: S
authors.lastname: Koirala
authors.affiliation: Oxford University Clinical Research Unit, Patan Academy of Health Sciences, Kathmandu, Nepal.
authors.forename: Abhishek
authors.initials: A
authors.lastname: Giri
authors.affiliation: Oxford University Clinical Research Unit, Patan Academy of Health Sciences, Kathmandu, Nepal.
authors.forename: Niva
authors.initials: N
authors.lastname: Joshi
authors.affiliation: Oxford University Clinical Research Unit, Patan Academy of Health Sciences, Kathmandu, Nepal.
authors.forename: Mila
authors.initials: M
authors.lastname: Shakya
authors.affiliation: Oxford University Clinical Research Unit, Patan Academy of Health Sciences, Kathmandu, Nepal.
authors.forename: Kamal Raj
authors.initials: KR
authors.lastname: Pathak
authors.affiliation: Oxford University Clinical Research Unit, Patan Academy of Health Sciences, Kathmandu, Nepal.
authors.forename: Saruna Pathak
authors.initials: SP
authors.lastname: Mahat
authors.affiliation: Oxford University Clinical Research Unit, Patan Academy of Health Sciences, Kathmandu, Nepal.
authors.forename: Shanti Pradhan
authors.initials: SP
authors.lastname: Prajapati
authors.affiliation: Oxford University Clinical Research Unit, Patan Academy of Health Sciences, Kathmandu, Nepal.
authors.forename: Nabin
authors.initials: N
authors.lastname: Adhikari
authors.affiliation: Patan Hospital, Patan Academy of Health Sciences, Kathmandu, Nepal.
authors.forename: Rajkumar
authors.initials: R
authors.lastname: Thapa
authors.affiliation: The Hospital for Tropical Diseases, Wellcome Trust Major Overseas Programme, Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam; Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, Oxford University, Oxford, UK.
authors.forename: Laura
authors.initials: L
authors.lastname: Merson
authors.affiliation: Civil Services Hospital, Kathmandu, Nepal.
authors.forename: Damodar
authors.initials: D
authors.lastname: Gajurel
authors.affiliation: Civil Services Hospital, Kathmandu, Nepal.
authors.forename: Kamal
authors.initials: K
authors.lastname: Lamsal
authors.affiliation: Civil Services Hospital, Kathmandu, Nepal.
authors.forename: Dinesh
authors.initials: D
authors.lastname: Lamsal
authors.affiliation: Patan Hospital, Patan Academy of Health Sciences, Kathmandu, Nepal.
authors.forename: Bharat Kumar
authors.initials: BK
authors.lastname: Yadav
authors.affiliation: Patan Hospital, Patan Academy of Health Sciences, Kathmandu, Nepal.
authors.forename: Ganesh
authors.initials: G
authors.lastname: Shah
authors.affiliation: Oxford University Clinical Research Unit, Patan Academy of Health Sciences, Kathmandu, Nepal.
authors.forename: Poojan
authors.initials: P
authors.lastname: Shrestha
authors.affiliation: Oxford University Clinical Research Unit, Patan Academy of Health Sciences, Kathmandu, Nepal.
authors.forename: Sabina
authors.initials: S
authors.lastname: Dongol
authors.affiliation: Oxford University Clinical Research Unit, Patan Academy of Health Sciences, Kathmandu, Nepal.
authors.forename: Abhilasha
authors.initials: A
authors.lastname: Karkey
authors.affiliation: The Hospital for Tropical Diseases, Wellcome Trust Major Overseas Programme, Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam; Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, Oxford University, Oxford, UK.
authors.forename: Corinne N
authors.initials: CN
authors.lastname: Thompson
authors.affiliation: Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, Oxford University, Oxford, UK.
authors.forename: Nga Tran Vu
authors.initials: NTV
authors.lastname: Thieu
authors.affiliation: Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, Oxford University, Oxford, UK.
authors.forename: Duy Pham
authors.initials: DP
authors.lastname: Thanh
authors.affiliation: The Hospital for Tropical Diseases, Wellcome Trust Major Overseas Programme, Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam; Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, Oxford University, Oxford, UK; the London School of Hygiene & Tropical Medicine, London, UK.
authors.forename: Stephen
authors.initials: S
authors.lastname: Baker
authors.affiliation: The Hospital for Tropical Diseases, Wellcome Trust Major Overseas Programme, Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam; Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, Oxford University, Oxford, UK.
authors.forename: Guy E
authors.initials: GE
authors.lastname: Thwaites
authors.affiliation: The Hospital for Tropical Diseases, Wellcome Trust Major Overseas Programme, Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam; Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, Oxford University, Oxford, UK.
authors.forename: Marcel
authors.initials: M
authors.lastname: Wolbers
authors.affiliation: The Hospital for Tropical Diseases, Wellcome Trust Major Overseas Programme, Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam; Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, Oxford University, Oxford, UK; Department of Zoology, Oxford University, Oxford, UK.
authors.forename: Christiane
authors.initials: C
authors.lastname: Dolecek
mesh_terms: D000293:Adolescent; D000900:Anti-Bacterial Agents / Q000627:therapeutic use*; D002443:Ceftriaxone / Q000627:therapeutic use*; D005260:Female; D024841:Fluoroquinolones / Q000627:therapeutic use*; D000077734:Gatifloxacin; D006801:Humans; D008297:Male; D009390:Nepal; D019779:Salmonella enterica / Q000187:drug effects / Q000302:isolation & purification; D012485:Salmonella typhi / Q000187:drug effects / Q000302:isolation & purification; D017211:Treatment Failure; D014435:Typhoid Fever / Q000097:blood / Q000188:drug therapy*; D055815:Young Adult
chemical_list: D000900:Anti-Bacterial Agents; D024841:Fluoroquinolones; D002443:Ceftriaxone; D000077734:Gatifloxacin
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