Azithromycin and cefixime combination versus azithromycin alone for the out-patient treatment of typhoid in South Asia; a randomised controlled trial Typhoid fever is characterized by fever and abdominal symptoms. It affects more than 14 million children and adults globally each year. Between one and two million of these patients may progress to severe and life-threatening complications including intestinal bleeding, intestinal puncture (perforation) with surrounding inflammation (peritonitis) and a syndrome of somnolence and coma (encephalopathy). Up to 1% of patients who get typhoid may die of the disease. A typhoid illness can be followed by a relapse 2-3 weeks later and lead to a prolonged period of ill health and catastrophic financial cost to the family with a resulting burden on the health system and society. In South Asia, which is the largest typhoid hub in the world, the annual burden of disease is estimated at seven million.   Effective antimicrobial treatment leads to a resolution of the patient illness in 4 to 6 days and reduces risk of progression to life-threatening complications. If started early in the disease a 7 to 10-day course of treatment with a single oral antimicrobial treatment can be given in an out-patient setting without the need for expensive hospitalization. In the last 20 years fluoroquinolones, such as ciprofloxacin, have been successfully used. However antimicrobial resistance in the bacteria that cause typhoid fever has now become common in Asia and sub-Saharan Africa. In South Asia resistance to ciprofloxacin in typhoid is widespread. Resistance limits the choice of effective antimicrobials and increases the risk of patients developing severe disease. Because of these concerns Salmonella has been recently listed in the 'Priority 2: HIGH on the WHO Priority Pathogens List.   A number of experts have called for the use of antimicrobial combinations in typhoid fever to improve the efficacy of treatment and mitigate the problems of resistance. This suggestion is not backed up by good quality evidence. A current standard regimen, recommended by the World Health Organization, is a 7-day course of the oral antimicrobial azithromycin. Emerging evidence from small studies suggests that a combination of azithromycin and cefixime may achieve a better cure than azithromycin alone. The ACT-South Asia study aims to answer the question whether a combination of azithromycin and cefixime is more effective than azithromycin alone in the outpatient treatment of uncomplicated typhoid fever. In this trial we will recruit 1500 patients across four sites in typhoid-endemic areas of Bangladesh, India, Nepal and Pakistan. We will use a placebo (sugar pill) instead of cefixime in the single drug arm so that neither the patient nor the study team know which patient is receiving which treatment. Our aim is to assess whether treatment outcomes are better with the combination regime at completion of the one week of treatment and again at follow-up one and three months after treatment was started. Both of these antimicrobials are widely used and have an excellent safety profiles, but we will carefully monitor for side effects. We will additionally investigate the financial implications for families and the health system.   The recent emergence and spread of a particularly resistant typhoid strain in Pakistan adds urgency to this question. If the combination treatment is better than the single antibiotic treatment, the involvement of four countries in the study will allow generalization of the results across South Asia and other typhoid endemic areas. Considering the high burden of typhoid fever in this region even small improvements in the treatment success will translate into a benefit for many individuals and families and the health system as a whole. For example, a reduction in treatment failures in the 7 million patients with typhoid fever in South Asia from 15 % (with azithromycin alone) to 10 % using the antimicrobial combination, will mean at least 350,000 patients will experience a faster cure, fewer hospital admissions with less financial impact. The Global Challenges Research Fund (GCRF) supports cutting-edge research to address challenges faced by developing countries. The fund addresses the UN sustainable development goals. It aims to maximise the impact of research and innovation to improve lives and opportunity in the developing world.