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

Abhishek Giri, Abhilasha Karkey, Sabina Dangol, Amit Arjyal, Sunil Pokharel, Samita Rijal, Damodar Gajurel, Rabi Sharma, Kamal Lamsal, Pradip Shrestha, Gayatri Prajapati, Saruna Pathak, Sita Ram Shrestha, Raj Kumar K C, Sujata Pandey, Abishkar Thapa, Nistha Shrestha, Raj Kumar Thapa, Buddhi Poudyal, Dung Nguyen Thi Phuong, Stephen Baker, Evelyne Kestelyn, Ronald Geskus, Guy Thwaites, Buddha Basnyat, Abhishek Giri, Abhilasha Karkey, Sabina Dangol, Amit Arjyal, Sunil Pokharel, Samita Rijal, Damodar Gajurel, Rabi Sharma, Kamal Lamsal, Pradip Shrestha, Gayatri Prajapati, Saruna Pathak, Sita Ram Shrestha, Raj Kumar K C, Sujata Pandey, Abishkar Thapa, Nistha Shrestha, Raj Kumar Thapa, Buddhi Poudyal, Dung Nguyen Thi Phuong, Stephen Baker, Evelyne Kestelyn, Ronald Geskus, Guy Thwaites, Buddha Basnyat

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 noninferior 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 plus sulfamethoxazole 50 mg/kg/day) orally for 7 days for UFI treatment in Nepal. We enrolled patients >2 years and <65 years of age presenting to 2 Kathmandu hospitals with temperature ≥38.0°C for ≥4 days without localizing signs. The primary endpoint was fever clearance time (FCT); secondary endpoints were treatment failure and adverse events.

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% confidence interval [CI], 2.6-3.3 days) in the SXT arm and 2.1 days (95% CI, 1.6-3.2 days) in the azithromycin arm (hazard ratio [HR], 1.25 [95% CI, .99-1.58]; P = .059). The HR of treatment failures by 28 days between azithromycin and SXT was 0.62 (95% CI, .37-1.05; P = .073). Planned subgroup analysis showed that azithromycin resulted in faster FCT in those with sterile blood cultures and fewer 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 2 arms, significantly fewer complications and relapses make azithromycin a better choice for empirical treatment of UFI in Nepal.

Clinical trials registration: NCT02773407.

Keywords: typhoid fever; South Asia; health economics.

© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America.

Figures

Figure 1.
Figure 1.
Trial participant flowchart. Abbreviations: SXT, trimethoprim-sulfamethoxazole; UFI, undifferentiated febrile illness.
Figure 2.
Figure 2.
Estimated time to fever clearance by treatment arm in the intention-to-treat population (A) and the subgroup of culture-confirmed and culture-negative patients (B). Abbreviation: SXT, trimethoprim-sulfamethoxazole.
Figure 3.
Figure 3.
Kaplan-Meier curves for time to treatment failure in 2 treatment groups in the intention-to-treat population (A) and the subgroups of culture-positive and culture-negative patients (B). Abbreviation: SXT, trimethoprim-sulfamethoxazole.

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