A comparison of concomitant administration of Azithromycin and Cefixime to Azithromycin alone in the treatment of Typhoid

Typhoidand paratyphoid (enteric) fever affects more than 11 million children andadults globally each year including 7 million in South Asia. Up to 1% ofpatients who get typhoid may die of the disease and,in those that survive,aprolonged period of ill health and catastrophic financial cost to the familymay follow. In the last 20 years, treatment of typhoid fever with a 7-daycourse of a single oral antimicrobial,such as ciprofloxacin, cefixime orazithromycin, given in an out-patient setting has led to patient recovery in 4to 6 days without the need for expensive hospitalization. Increasing antimicrobialresistance in Asia and sub-Saharan Africa threatens the effectiveness of these treatments and increases the risk of prolonged illness and severe disease. The recentemergence of a particularly resistant typhoid strain in Pakistan, andsubsequent international spread, adds urgency to this problem andSalmonellaisnow listed as a high(Priority 2) pathogen by WHO.

Treatment with combinations of antimicrobials may be moreeffective for treating typhoid fever and mitigate the problems of resistance.This suggestion is based on expert opinion but not backed up by good qualityevidence. The ACT-South Asia study aims to compare a combination ofazithromycin and cefixime with azithromycin alone in the outpatient treatmentof clinically suspected and confirmed uncomplicated typhoid fever. We willrecruit 1500 patients across sites in Bangladesh, India, Nepal and Pakistan. Aplacebo (sugar pill) will be used instead of cefixime in the single drug arm sothat neither the patient nor the study team know which patient is receivingwhich treatment. We will assess whether treatment outcomes are better with thecombination after one week of treatment and at one and three month follow-up.Both antimicrobials are widely used and have excellent safety profiles. If thecombination treatment is better than the single antibiotic treatment, this willbe an important result for patients across South Asia and other typhoid endemicareas. We will additionally investigate the financial implications for familiesand health system.