ObjectiveTo assess the efficacy of gatifloxacin versus cefixime in the treatment of uncomplicated culture positive enteric fever.DesignA randomized, open-label, active control trial with two parallel arms.SettingEmergency Room and Outpatient Clinics in Patan Hospital, Lagankhel, Lalitpur, Nepal.ParticipantsPatients with clinically diagnosed uncomplicated enteric fever meeting the inclusion criteria.InterventionsPatients were allocated to receive one of two drugs, Gatifloxacin or Cefixime. The dosages used were Gatifloxacin 10 mg/kg, given once daily for 7 days, or Cefixime 20 mg/kg/day given in two divided doses for 7 days.Outcome MeasuresThe primary outcome measure was fever clearance time. The secondary outcome measure was overall treatment failure (acute treatment failure and relapse).ResultsRandomization was carried out in 390 patients before enrollment was suspended on the advice of the independent data safety monitoring board due to significant differences in both primary and secondary outcome measures in the two arms and the attainment of a priori defined endpoints. Median (95% confidence interval) fever clearance times were 92 hours (84–114 hours) for gatifloxacin recipients and 138 hours (105–164 hours) for cefixime-treated patients (Hazard Ratio[95%CI] = 2.171 [1.545–3.051], p<0.0001). 19 out of 70 (27%) patients who completed the 7 day trial had acute clinical failure in the cefixime group as compared to 1 out of 88 patients (1%) in gatifloxacin group(Odds Ratio [95%CI] = 0.031 [0.004 – 0.237], p<0.001). Overall treatment failure patients (relapsed patients plus acute treatment failure patients plus death) numbered 29. They were determined to be (95% confidence interval) 37.6 % (27.14%–50.2%) in the cefixime group and 3.5% (2.2%–11.5%) in the gatifloxacin group (HR[95%CI] = 0.084 [0.025–0.280], p<0.0001). There was one death in the cefixime group.ConclusionsBased on this study, gatifloxacin is a better treatment for uncomplicated enteric fever as compared to cefixime.Trial RegistrationCurrent Controlled Trials ISRCTN75784880

Background Azithromycin and trimethoprim-sulfamethoxazole (SXT) are widely used to treat undifferentiated febrile illness (UFI). We hypothesized that azithromycin is superior to SXT for UFI treatment, but the drugs are non-inferior to each other for culture-confirmed enteric fever treatment. Methods We conducted a double blind, randomized, placebo-controlled trial of azithromycin (20 mg/kg/day) or SXT (trimethoprim 10 mg/kg/day + sulfamethoxazole 50 mg/kg/day) orally for 7 days for UFI treatment in Nepal. We enrolled patients (aged 3-64 years) presenting to two Kathmandu hospitals with temperature ≥ 38.0°C for ≥4 days without localising signs. The primary endpoint was fever clearance time (FCT); secondary endpoints were treatment failure and adverse events. ClinicalTrials.gov number: NCT02773407. Results From June 2016 to May 2019, we randomized 326 participants (163 in each arm); 87 (26.7%) had blood culture-confirmed enteric fever. In all participants, the median FCT was 2.7 days (95% CI 2.6-3.3) in the SXT arm and 2.1 days (95% CI 1.6-3.2) in the azithromycin arm 1.25 (95% CI 0.99-1.58, P=0.059). The hazard ratio of treatment failures by 28 days between azithromycin and SXT was 0.62 (95% CI 0.37-1.05, p=0.073). Planned sub-group analysis showed azithromycin resulted in faster FCT in those with sterile blood cultures and less relapses in culture-confirmed enteric fever. Nausea, vomiting, constipation, and headache were more common in the SXT arm. Conclusions Despite similar FCT and treatment failure in the two arms, significantly fewer complications and relapses make azithromycin a better choice for empirical treatment of UFI in Nepal.