The purpose of the study is to determine whether azithromycin or cotrimoxazole is the best empirical treatment for undifferentiated febrile illness in Nepal

Fever is one of the most common presenting symptoms of patients presenting to health centers in Nepal. Many of the times, it is difficult to diagnose the cause of the fever by initial history, clinical examination and basic laboratory tests and the patents are treated as presumed enteric fever or fever without focus needing antimicrobials. In fact there are various causes of similarly presenting febrile illnesses including typhoid, paratyphoid, murine typhus, scrub typhus etc.

Many of the traditionally used drugs including fluoroquinolones are now resistant against enteric fever in south asia. Oral azithromycin is now commonly used to treat undifferentiated febrile illness and remains effective against enteric fever. Many physicians now also use co-trimoxazole as it was very commonly used in the treatment of enteric fever in the past. Resistance to co-trimoxazole emerged two decades ago, but has subsequently largely disappeared and nearly all Salmonella Typhi and Paratyphi A strains from Nepal are now susceptible. Anecdotal reports claim that it seems to work very well against undifferentiated febrile illness in Nepal; it is largely stocked in government health facilities and is a popular and cheap treatment option.

Both azithromycin and co-trimoxazole are available in Nepal and are extensively used in the treatment of undifferentiated febrile illness. Therefore it is important to know the better oral option to treat enteric fever and other febrile illnesses and also to have an alternative oral treatment in case resistance to azithromycin emerges.

The investigators purpose to conduct a head to head, parallel group, 1:1, double blinded randomized controlled trial to compare azithromycin and co-trimoxazole for the treatment of undifferentiated febrile illness and determine the best empirical treatment for undifferentiated febrile illness in Nepal.

Inclusion Criteria:

• Fever of ≥ 38.0°C and for ≥4 days without a focus of infection
• ≥ 2 years and <65 years of age
• Able to take tablets orally
• Patient residing in Kathmandu Valley
• Able to come for follow up
• Can be reached by telephone/mobile phone 24 hours a day.
• Written informed consent to participate in the study including assent for minors in addition to parental consent.

Exclusion Criteria:

• Fever >14 days
• Pregnancy
• Obtundation
• Shock
• Visible jaundice
• Presence of signs of gastrointestinal bleeding
• History of hypersensitivity to either of the trial drugs
• Patient requiring intravenous antibiotic or hospital admission for any reason.
• Contraindication of drug for any reason (e.g. drug interactions).
• Any patient fulfilling inclusion criteria but already on antimicrobials and responding clinically to the treatment

Anonymised individual participant data will be made available to researcher and public as a supporting material via open access journal and/or upon request by qualified research groups