Co-trimoxazole versus azithromycin for the treatment of undifferentiated febrile illness in Nepal: study protocol for a randomized controlled trial

Abstract

Background: Undifferentiated febrile illness (UFI) includes typhoid and typhus fevers and generally designates fever without any localizing signs. UFI is a great therapeutic challenge in countries like Nepal because of the lack of available point-of-care, rapid diagnostic tests. Often patients are empirically treated as presumed enteric fever. Due to the development of high-level resistance to traditionally used fluoroquinolones against enteric fever, azithromycin is now commonly used to treat enteric fever/UFI. The re-emergence of susceptibility of Salmonella typhi to co-trimoxazole makes it a promising oral treatment for UFIs in general. We present a protocol of a randomized controlled trial of azithromycin versus co-trimoxazole for the treatment of UFI.

Methods/design: This is a parallel-group, double-blind, 1:1, randomized controlled trial of co-trimoxazole versus azithromycin for the treatment of UFI in Nepal. Participants will be patients aged 2 to 65 years, presenting with fever without clear focus for at least 4 days, complying with other study criteria and willing to provide written informed consent. Patients will be randomized either to azithromycin 20 mg/kg/day (maximum 1000 mg/day) in a single daily dose and an identical placebo or co-trimoxazole 60 mg/kg/day (maximum 3000 mg/day) in two divided doses for 7 days. Patients will be followed up with twice-daily telephone calls for 7 days or for at least 48 h after they become afebrile, whichever is later; by home visits on days 2 and 4 of treatment; and by hospital visits on days 7, 14, 28 and 63. The endpoints will be fever clearance time, treatment failure, time to treatment failure, and adverse events. The estimated sample size is 330. The primary analysis population will be all the randomized population and subanalysis will be repeated on patients with blood culture-confirmed enteric fever and culture-negative patients.

Discussion: Both azithromycin and co-trimoxazole are available in Nepal and are extensively used in the treatment of UFI. Therefore, it is important to know the better orally administered antimicrobial to treat enteric fever and other UFIs especially against the background of fluoroquinolone-resistant enteric fever.

Trial registration: ClinicalTrials.gov, ID: NCT02773407 . Registered on 5 May 2016.

Keywords: Azithromycin; Co-trimoxazole; Enteric fever; Fever clearance time; Undifferentiated febrile illness.

Conflict of interest statement

Ethics approval and consent to participate

This study will be conducted in accordance with the current revision of the Declaration of Helsinki [28] and, as applicable to an interventional study, the ICH Guidelines for Good Clinical Practice 1996. The study has been approved by the Nepal Health Research Council (NHRC) Ethical Review Board (Reference: 1618) and the Oxford Tropical Research Ethics Committee (OxTREC reference: 15-16). Any modifications in the protocol will be reported as protocol amendment to the Ethics Committees at NHRC and OxTREC.

Patients will be enrolled into the study only after signing a written informed consent. Clinicians enrolling the patients will ensure that a patient receives detailed information and complies with the study protocol.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1

Descriptive flow chart of study plan

Fig. 2

Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) Figure: summary of enrollment, intervention and assessment. X Activities at hospital or home visits, Ω Activities that will be recorded over a telephone call, (X) Will be done only for culture-positive patients at day 0 or those with persistent fever/symptoms, X* Will be done retrospectively if blood culture shows no growth after 7 days