Trimethoprim-sulfamethoxazole versus trimethoprim-sulfamethoxazole plus doxycycline as oral eradicative treatment for melioidosis (MERTH): a multicentre, double-blind, non-inferiority, randomised controlled trial

Abstract

SummaryBackgroundMelioidosis, an infectious disease caused by the Gram-negative bacillus Burkholderia pseudomallei, is difficult to cure. Antimicrobial treatment comprises intravenous drugs for at least 10 days, followed by oral drugs for at least 12 weeks. The standard oral regimen based on trial evidence is trimethoprim-sulfamethoxaxole (TMP-SMX) plus doxycycline. This regimen is used in Thailand but is associated with side-effects and poor adherence by patients, and TMP-SMX alone is recommended in Australia. We compared the efficacy and side-effects of TMP-SMX with TMP-SMX plus doxycycline for the oral phase of melioidosis treatment.MethodsFor this multi-centre, double-blind, non-inferiority, randomised placebo-controlled trial, we enrolled patients (aged ≥15 years) from five centres in northeast Thailand with culture-confirmed melioidosis who had received a course of parenteral antimicrobial drugs. Using a computer-generated sequence, we randomly assigned patients to receive TMP-SMX plus placebo or TMP-SMX plus doxycycline for 20 weeks (1:1; block size of ten, stratified by study site). We followed patients up every 4 months for 1 year and annually thereafter to the end of the study. The primary endpoint was culture-confirmed recurrent melioidosis, and the non-inferiority margin was a hazard ratio (HR) of 1·7. This study is registered with www.controlled-trials.com, number ISRCTN86140460.FindingsWe enrolled and randomly assigned 626 patients: 311 to TMP-SMX plus placebo and 315 to TMP-SMX plus doxycycline. 16 patients (5%) in the TMP-SMX plus placebo group and 21 patients (7%) in the TMP-SMX plus doxycycline group developed culture-confirmed recurrent melioidosis (HR 0·81; 95% CI 0·42–1·55). The criterion for non-inferiority was met (p=0.01). Adverse drug reactions were less common in the TMP-SMX plus placebo group than in the TMP-SMX plus doxycycline group (122 [39%] vs 167 [53%]).InterpretationOur findings suggest that TMP-SMX is not inferior to TMP-SMX plus doxycycline for the oral phase of melioidosis treatment, and is preferable on the basis of safety and tolerance by patients.FundingThailand Research Fund, the Melioidosis Research Center, the Center of Excellence in Specific Health Problems in Greater Mekong Sub-region cluster, and the Wellcome Trust.

Antibiotic resistance in Burkholderia species

“…Current recommended therapy for melioidosis consists of two weeks of intravenous ceftazidime or a carbapenem, followed by up to six months of oral trimethoprim+sulfamethoxazole (co-trimoxazole)(Chetchotisakd et al, 2014; Dance, 2014; Lipsitz et al, 2012; Pitman et al, 2015). In either phase of therapy, the administration of amoxicillin+clavulanate (co-amoxiclav) is used in instances where other drugs are contraindicated (Dance, 2014; Lipsitz et al, 2012; McLeod et al, 2015).…”

Cutaneous melioidosis in a healthy Danish man after travelling to South-East Asia

“…In that study, nine patients were cured exclusively with an oral antibiotic regimen and one patient even recovered without therapy. In another recent randomised controlled non-inferiority trial from Thailand comparing TMP-SMX and doxycycline combination therapy versus TMP-SMX alone for the maintenance phase of melioidosis treatment, 40 patients were treated solely with oral antibiotics with only one relapse 8. Twenty-nine of these patients had cutaneous melioidosis and none had sepsis at presentation (Direk Limmathurotsakul, personal communication).…”

“Melioidosis in Antioquia, Colombia: an emerging or endemic disease? A cases series”

“…29,30 The treatment of melioidosis consists of an initial phase of 14 days of ceftazidime or carbapenems, followed by oral eradication therapy, usually with trimethoprim-sulfamethoxazole with or without tetracyclines for 3 to 6 months. [24][25][26][27][28][29][30][31] A series of cases occurring in Antioquia, Colombia, which has geographic regions and weather similar to those of endemic areas, is presented below.…”