Abstract
BackgroundTreatment of melioidosis comprises intravenous drugs for at least 10 days, followed by oral trimethoprim-sulfamethoxazole (TMP-SMX) for 12 to 20 weeks. Oral TMP-SMX is recommended for 12 weeks in Australia and 20 weeks in Thailand.Methods For this open-label, pragmatic, multicenter, noninferiority, 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 treatment (12-week regimen) or continue treatment for another 8 weeks (20-week regimen). The primary end point was culture-confirmed recurrent melioidosis within 1 year after enrollment. The noninferiority margin was a hazard ratio (HR) of 2.0. The secondary composite end point, combining overall recurrent melioidosis and mortality, was assessed post hoc.Results We enrolled 658 patients: 322 to the 12-week regimen and 336 to the 20-week regimen. There were 5 patients (2%) in the 12-week regimen and 2 patients (1%) in the 20-week regimen who developed culture-confirmed recurrent melioidosis (HR, 2.66; 95% confidence interval [CI], .52–13.69). The criterion for noninferiority of the primary event was not met (1-sided P = .37). However, all-cause mortality was significantly lower in the 12-week regimen group than in the 20-week regimen group (1 [.3%] vs 11 [3%], respectively; HR, 0.10; 95% CI, .01–.74). The criterion for noninferiority of the secondary composite end point, combining overall recurrent melioidosis and mortality, was met (1-sided P = .022).ConclusionsBased on the lower total mortality and noninferiority of the secondary composite end point observed, we recommend the 12-week regimen of TMP-SMX for oral eradication treatment of melioidosis.Clinical Trials RegistrationNCT01420341.
Highlights
Melioidosis is a difficult-to-treat infection caused by the Gramnegative bacillus Burkholderia pseudomallei, found in soil and water [1]
The disease is considered highly endemic in northeast Thailand and northern Australia, where the annual incidence is up to 50 cases per 100 000 people [2, 3]
We proposed that TMP-SMX for 12 weeks is an adequate treatment for melioidosis, and conducted a clinical trial to compare the efficacy of 12 versus 20 weeks of TMP-SMX for the oral eradication treatment of melioidosis
Summary
For this open-label, pragmatic, multicenter, noninferiority, randomized controlled trial, we enrolled patients with cultureconfirmed melioidosis who had received oral eradication treatment for 12 weeks and had no clinical evidence of active melioidosis. The primary end point was culture-confirmed recurrent melioidosis within 1 year after enrollment. We enrolled adult patients (aged >15 years) with culture-confirmed melioidosis who had completed 12 weeks of oral TMP-SMX treatment and had no clinical evidence of active melioidosis. We excluded patients if they were infected with B. pseudomallei that was resistant to TMP-SMX, if their melioidosis infection was recurrent (defined as having a previous episode of culture-confirmed melioidosis within the past 2 years), if they had a contraindication to TMP-SMX (pregnancy, lactation, aminotransferase >5 times the upper limit of normal, known glucose-6-phosphate dehydrogenase deficiency, or history of hypersensitivity to TMP-SMX), or if they had a history of a grade 3 or 4 adverse drug reaction [17] during their first 12 weeks of TMP-SMX treatment. Minimal inhibitory concentration by E-test was done to confirm TMP-SMX resistance if the result from disc diffusion testing reported TMP-SMX resistance [18, 19]
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