Cefixime & Azithromycin Vs Azithromycin Alone For The Out-Patient Treatment Of Typhoid Fever In South Asia – A Randomised Comparative Controlled Trial (ACT Asia)

The primary objective of the ACT-South Asia is to determine if the combination of azithromycin and cefixime for seven days results in significantly fewer treatment failures when compared with the current standard regimen of azithromycin alone for seven days in the out-patient treatment of children and adults with uncomplicated typhoid fever (infection due to Salmonella Typhi and Salmonella Paratyphi A) in South Asia. 

Antimicrobial resistance has become a massive problem in tacking typhoid in South Asia. When antimicrobial treatment works, the patient gets better within 4-6 days and is significantly less likely to develop life-threatening complications.  And, if the antimicrobial treatment works, then the treatment is inexpensive and can be given in an outpatient setting.  In the last 20 years fluoroquinolones, such as ciprofloxacin, have been successfully used. However, in South Asia resistance to ciprofloxacin in typhoid is now widespread. Resistance limits the choice of effective antimicrobials and increases the risk of patients developing severe disease. Because of these concerns, Salmonella was listed as Priority 2: HIGH on the WHO Priority Pathogens List in 2017.   

A current standard regimen, recommended by the WHO, 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. In this trial, we have recruited 1500 patients across multiple sites in typhoid-endemic areas of Bangladesh, Nepal and Pakistan. We are using a placebo instead of cefixime in the single drug arm so that neither the patient nor the study team know which patient is receiving which treatment. We aim 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 startedBoth of these antimicrobials are widely used and have an excellent safety profile, but we will carefully monitor for side effects. This project also includes a health economics component to assess the financial implications for families and the health system. 

If the combination treatment is better than the single antibiotic treatment, the involvement of three 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. 



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