A Comparison Between 12 Versus 20 Weeks of Trimethoprim-Sulfamethoxazole as Oral Eradication Treatment for Melioidosis (12vs20): An Open-label, Pragmatic, Multicenter, Non-inferiority, Randomized Controlled Trial.
Anunnatsiri S., Chaowagul W., Teparrukkul P., Chetchotisakd P., Tanwisaid K., Khemla S., Narenpitak S., Pattarapongsin M., Kongsawasd W., Pisuttimarn P., Thipmontree W., Mootsikapun P., Chaisuksant S., Chierakul W., Day NPJ., Limmathurotsakul D.
BACKGROUND:Treatment of melioidosis comprises intravenous drugs for at least 10 days, followed by oral trimethoprim-sulfamethoxazole (TMP-SMX) for 12 to 20 weeks. Twelve weeks of oral TMP-SMX is recommended in Australia, and 20 weeks in Thailand. METHODS:For this open-label, pragmatic, multicenter, non-inferiority, randomized controlled trial, we enrolled patients with culture-confirmed melioidosis who had received oral eradication treatment for 12 weeks and had no clinical evidence of active melioidosis. We randomly assigned patients to stop (12-week regimen) or continue treatment for another eight weeks (20-week regimen). The primary endpoint was culture-confirmed recurrent melioidosis within one year after enrollment. The non-inferiority margin was a hazard ratio (HR) of 2.0. The secondary composite endpoint combining overall recurrent melioidosis and mortality was assessed post-hoc. RESULTS:658 patients were enrolled: 322 to the 12-week regimen and 336 to the 20-week regimen. Five patients (2%) in the 12-week regimen and 2 patients (1%) in the 20-week regimen developed culture-confirmed recurrent melioidosis (HR 2.66; 95% confidence interval [CI] 0.52-13.69). The criterion for non-inferiority of primary event was not met (one-sided P=.37). However, all-cause mortality was significantly lower in the 12-week regimen group than in the 20-week regimen group (1 [0.3%] vs. 11 [3%]; HR 0.10; 95% CI 0.01-0.74). The criterion for non-inferiority of the secondary composite endpoint combining overall recurrent melioidosis and mortality was met (one-sided P=.022). CONCLUSIONS:Based on the lower total mortality and non-inferiority of the secondary composite endpoint observed, we recommend the 12-week regimen of TMP-SMX for oral eradication treatment of melioidosis.