Randomised trial of azithromycin versus ofloxacin for the treatment of Typhoid fever in adult

In recent years multi-resistant (MDR) strains of Salmonella typhi have emerged in many countries including Vietnam. In Vietnam and the Indian sub-continent isolates of S. typhi resistant to nalidixic acid with a reduced sensitivity to fluoroquinolones have also appeared. Third generation cephalosporins and fluoroquinolones are currently used widely for treating typhoid fever (TF). Azithromycin (AZM) has moderate in-vitro activity against S. typhi but achieves high intracellular concentrations and has been shown to be effective for treating TF when given for 7 or more days. There have been no randomised comparisons using shorter courses of AZM. Five blood culture positive Vietnamese adults were enrolled in a pilot study and received AZM 1 gm orally once a day for 5 days. Blood cultures were repeated on day 6 and stool cultures on days 6, 7, 8 and 30 days after the start of therapy. All five patients were cured with a median (range) fever clearance time of 138 (78-228) hours. No relapses were detected. An open randomised comparison was therefore commenced comparing AZM 1 gm orally once a day for 5 days versus Ofloxacin 200 mg orally twice a day for 5 days. An interim analysis of the first 26 blood culture positive adults included 12 treated with AZM and 14 with OFL. 17/24 (71%) of the isolates were MDR, 1/24 (4%) were nalidixic acid resistant but none were resistant to either of the study drugs. All patients in both groups were cured. The median (range) fever clearence time was 126 (60-252) hours for Azithromycin and 99 (42-228) hours for Ofloxacin (p=0.08). Cultures of blood and faeces after the end of therapy were negative in all cases. There were mild self limiting gastrointestinal side effects in the AZM treated patients but no other significant side effects attributable to either antibiotic. These interim results suggest that a five day course of AZM or OFL are both effective for the treatment of the TF in adults due to multi-resistant S. typhi.