Open-Label Randomized Trial of Oral Trimethoprim-Sulfamethoxazole, Doxycycline, and Chloramphenicol Compared with Trimethoprim-Sulfamethoxazole and Doxycycline for Maintenance Therapy of Melioidosis

Abstract

Melioidosis (infection caused by Burkholderia pseudomallei) requires a prolonged course of oral antibiotics following initial intravenous therapy to reduce the risk of relapse after cessation of treatment. The current recommendation is a four-drug regimen (trimethoprim [TMP], sulfamethoxazole [SMX], doxycycline, and chloramphenicol) and a total treatment time of 12 to 20 weeks. Drug side effects are common; the aim of this study was to compare the efficacy and tolerance of the four-drug regimen with a three-drug regimen (TMP-SMX and doxycycline). An open-label, randomized trial was conducted in northeast Thailand. A total of 180 adult Thai patients were enrolled, of which 91 were allocated to the four-drug regimen and 89 to the three-drug regimen. The trial was terminated early due to poor drug tolerance, particularly of the four-drug regimen. The culture-confirmed relapse rates at 1 year were 6.6% and 5.6% for the four-and three-drug regimens, respectively (P ‫؍‬ 0.79). The three-drug regimen was better tolerated than the four-drug regimen; 36% of patients receiving four drugs and 19% of patients receiving three drugs required a switch in therapy due to side effects (P ‫؍‬ 0.01). The duration of oral therapy was significantly associated with relapse; after adjustment for confounders, patients receiving less than 12 weeks of oral therapy had a 5.7-fold increase of relapse or death. A combination of TMP-SMX and doxycycline is as effective as and better tolerated than the conventional four-drug regimen for the oral treatment phase of melioidosis.Melioidosis, the infection caused by Burkholderia pseudomallei, is endemic to southeast Asia and northern Australia. Large numbers of cases are seen in northeast Thailand, where it constitutes almost 20% of community-acquired bacteremia (2). An important feature of disease is that recurrence is common after completion of antibiotic treatment and apparent cure, occurring in 3 to 25% of patients. Molecular typing indicates that most cases of recurrence are due to recrudescence of the original infecting strain (relapse) (3,8). Prolonged therapy has been demonstrated to reduce relapse. Current treatment recommendations include administration of intravenous antibiotics (ceftazidime or a carbapenem) for at least 10 days, followed by oral antibiotics for at least 12 weeks.Our current oral regimen is a four-drug combination of trimethoprim-sulfamethoxazole (TMP-SMX), doxycycline, and chloramphenicol. This regimen is associated with high rates of adverse events, including gastrointestinal intolerance, anemia, and allergic reactions. In other centers, the use of a three-drug regimen or even TMP-SMX alone has been associated with low relapse rates (6, 7). Higher relapse rates have been found during clinical trials of amoxicillin-clavulanate with supplemental amoxicillin, doxycycline monotherapy, and a combination of azithromycin and ciprofloxacin (5, 6, 11). The aim of this study was to examine the efficacy and side effects associated with the four-drug (TMP-SMX, doxycycline, and chl...

Outcomes of Patients with Melioidosis Treated with Cotrimoxazole Alone for Eradication Therapy

“…4,5 However, the choice and duration of antibiotic treatment to prevent these recurrences remains unsettled, as evidenced by several different regimen reported in the literatures during the last two decades. 5,8,[10][11][12]14 The currently recommended eradication therapy with the combination of cotrimoxazole and doxycycline, given for 12-20 weeks, has decreased the 1-year recurrence rate of culture-proven melioidosis to~6%. 8 In our study, the 5% recurrence rates in patients who had received this combination regimen drugs is comparable to that of the original clinical trial and the 3.2% culture-proven recurrence rate in recipients of cotrimoxazole alone is quite low.…”

“…5,8,[10][11][12]14 The currently recommended eradication therapy with the combination of cotrimoxazole and doxycycline, given for 12-20 weeks, has decreased the 1-year recurrence rate of culture-proven melioidosis to~6%. 8 In our study, the 5% recurrence rates in patients who had received this combination regimen drugs is comparable to that of the original clinical trial and the 3.2% culture-proven recurrence rate in recipients of cotrimoxazole alone is quite low. Our observational study is the first comparative report to show that a treatment regimen of cotrimoxazole monotherapy is not less efficacious than the traditional combination antibiotics.…”

“…3 The current recommendation for eradication treatment of melioidosis is a three-drug regimen that includes oral cotrimoxazole (trimethoprim/sulfamethoxazole, TMP/SMX) and doxycycline for at least 12-20 weeks. 3,8 Despite this treatment, culture-confirmed recurrences still occurred in~6% of patients at 1-year follow-up. 8 The efficacy of cotrimoxazole plus doxycycline was questioned after an in vitro study indicated that doxycycline antagonized the antibacterial activity of trimethoprim and sulfamethoxazole against B. pseudomallei.…”

“…3,8 Despite this treatment, culture-confirmed recurrences still occurred in~6% of patients at 1-year follow-up. 8 The efficacy of cotrimoxazole plus doxycycline was questioned after an in vitro study indicated that doxycycline antagonized the antibacterial activity of trimethoprim and sulfamethoxazole against B. pseudomallei. 9 Furthermore, 19% of the patients had to switch treatment because of adverse drug events from the three drugs.…”

“…9 Furthermore, 19% of the patients had to switch treatment because of adverse drug events from the three drugs. 8 Because poor adherence to treatment are associated with recurrence of the disease, 5 other less toxic, alternative eradication regimens including amoxicillin-clavulanate with supplemental amoxicillin, quinolone monotherapy, and a combination of azithromycin and ciprofloxacin, have been tried. [10][11][12] However, all these regimens were associated with recurrence rates exceeding 15% and another simple but more effective regimen is needed.…”