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

Abstract

BackgroundUndifferentiated 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/designThis 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.DiscussionBoth 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 registrationClinicalTrials.gov, ID: NCT02773407. Registered on 5 May 2016.Electronic supplementary materialThe online version of this article (doi:10.1186/s13063-017-2199-6) contains supplementary material, which is available to authorized users.

Seroprevalence and Clinical Features of Scrub Typhus among Febrile Patients Attending a Referral Hospital in Kathmandu, Nepal

“…Most of the participants in our study responded that they had used at least one antibiotic prior to the hospital visit, and most ST patients were given antibiotics against typhoid fever. UFIs in Nepal are empirically treated as presumed enteric fever [47]. Since enteric fever is endemic to the country and similar nonspecific clinical presentations are observed in enteric fever and ST patients, it is apparent for a clinician or pharmacist to have recommended antibiotics against enteric fever.…”

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 ].…”

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

“…We conducted a parallel-group, double-blind, randomized controlled trial of SXT vs azithromycin for the treatment of UFI in Nepal at Patan Hospital and Civil Services Hospital in the Kathmandu Valley, Nepal. [ 29 ] The study protocol was reviewed and approved by the Ethics Committee of the Nepal Health Research Council and the Oxford Tropical Research Ethics Committee, United Kingdom.…”

“…Therefore, we conducted a randomized, double-blind comparison of azithromycin vs SXT for the treatment of UFI in Nepal. We hypothesized [ 29 ] that azithromycin would be superior to SXT for the treatment of patients with UFI and sterile blood cultures but that the 2 drugs would be noninferior to one another for the treatment of blood culture–confirmed enteric fever.…”