Treatment response in enteric fever in an era of increasing antimicrobial resistance: an individual patient data analysis of 2,092 participants enrolled into four randomised controlled trials in Nepal.

Background: Enteric fever, caused by Salmonella Typhi and Salmonella Paratyphi A, is the leading cause of bacterial febrile disease in South Asia. Methods: Individual patient data from 2,092 subjects with enteric fever randomised into four trials in Kathmandu, Nepal was pooled. All trials compared gatifloxacin with a comparator drug: cefixime, chloramphenicol, ofloxacin, or ceftriaxone. Treatment outcomes were evaluated according to antimicrobial if S. Typhi/Paratyphi were isolated from blood. We additionally investigated the impact of changing bacterial antimicrobial susceptibility on outcome. Results: Overall, 855 (41%) patients had either S. Typhi (n=581,28%) or S. Paratyphi A (n=274,13%) cultured from blood; 1,237 (59%) were culture negative. There were 139 (6.6%) treatment failures with one death. Except for the last trial with ceftriaxone, the fluoroquinolone gatifloxacin was associated with equivalent or better fever clearance times and lower treatment failure rates in comparison to all other antimicrobials. However, we additionally found the minimum inhibitory concentrations (MIC) against fluoroquinolones have risen significantly since 2005 and were associated with increasing fever clearance times. Notably, all organisms were susceptible to ceftriaxone throughout the study period (2005-2014) and the MICs against azithromycin declined, confirming the utility of these alternative drugs for enteric fever treatment. Conclusion: The World Health Organization and local government health ministries in South Asia still recommend fluoroquinolones as the drug of choice in the treatment of enteric fever. This policy should change based on the evidence provided here. Rapid diagnostics are urgently required given the large numbers of suspected enteric fever patients with a negative culture.