Trimethoprim-sulfamethoxazole Versus Azithromycin for the Treatment of Undifferentiated Febrile Illness in Nepal: A Double-blind, Randomized, Placebo-controlled Trial

Abstract

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.

Evaluating Antibiotic Treatment Guideline Adherence to Ongoing Antibiotic Stewardship in a Tertiary Care Setting: A Retrospective Observational Study

“…Azithromycin was taken into consideration as the most frequently used prescribed antibiotic, followed by piperacillin/tazobactam. In a similar fashion, several studies undertaken in different healthcare settings in Nepal demonstrated that azithromycin is the most frequently prescribed antibiotic in outpatient departments [ 44 – 46 ], probably due to its high availability, safety, and affordability. Regarding ceftriaxone and levofloxacin, the significant association of adherence to treatment guidelines was in alignment with previous findings observed in Cape Town Metro District, South Africa [ 34 ].…”

Estimating the subnational prevalence of antimicrobial resistant Salmonella enterica serovars Typhi and Paratyphi A infections in 75 endemic countries, 1990–2019: a modelling study

“…Although S Typhi has regained susceptibility to the former first-line drugs (eg, chloramphenicol, ampicillin, and co-trimoxazole) in several countries in south Asia, these options are not as efficacious. 46 , 47 Due to the high prevalence of MDR S Typhi in conjunction with increasing levels of FQNS, patients in sub-Saharan Africa might be unable to obtain or afford effective alternative treatments, such as ceftriaxone or azithromycin. We also highlight the rise of third-generation cephalosporin-resistant S Typhi in south Asia.…”

The Search for Effective Empiric Therapy for Acute Undifferentiated Febrile Illness

“…In this issue of Clinical Infectious Diseases, Giri and colleagues report the results of a pragmatic double-blinded, randomized, placebo-controlled trial of azithromycin or trimethoprimsulfamethoxazole (SXT) for empiric treatment of AUFI in Nepal [3]. The trial included 326 patients between 3 and 64 years of age, 163 in each arm, with a fever of 4-14 days' duration from 2 hospitals in Kathmandu randomly assigned to receive either azithromycin (20 mg/kg/ day) or SXT (trimethoprim 10 mg/kg/day plus sulfamethoxazole 50 mg/kg/day) orally for 7 days.…”