Addition of Trimethoprim-Sulfamethoxazole to Ceftazidime during Parenteral Treatment of Melioidosis Is Not Associated with a Long-Term Outcome Benefit

TO THE EDITOR—In October 2005, we published an article in Clinical Infectious Diseases about the comparative efficacy of ceftazidime alone versus ceftazidime plus trimethoprim-sulfamethoxazole (TMP-SMX) for the treatment of severe melioidosis [1]. The primary end point of this meta-analysis of 2 independent prospective randomized trials in Ubon Ratchathani and Khon Kaen, in northeast Thailand, was in-hospital mortality. There was no difference in death rate for all deaths (stratified P = .70; OR, 0.88; 95% CI, 0.48–1.6) or death occurring after 48 h (stratified P = .73; OR, 0.88; 95% CI, 0.41–1.9). However, this study did not address whether the 2 treatment groups differed in terms of recurrent infection, which occurs in 6% of patients within the first 12 months following primary melioidosis. It is plausible that the addition of TMP-SMX to the initial phase of parenteral therapy is associated with a higher rate of bacterial eradication. To investigate this possibility, we extended the patient follow-up period for an additional 12 months after trial completion and compared the overall mortality rate and rate of recurrent melioidosis between the 2 groups.

One hundred ninety patients with culture-confirmed melioidosis survived until discharge from the hospital, 92 patients (48%) in the ceftazidime group and 98 patients (52%) in the ceftazidime plus TMP-SMX group. Patients were followed up every 1–3 months for at least 6 months and every 4–6 months thereafter. Patients who were lost to follow-up were contacted by mail or visited at home. The outcome measure was time to culture-confirmed recurrent melioidosis and/or death, as measured from hospital discharge. If patients were lost to follow-up, the record was censored at the last known contact.

The total duration of follow-up was 17,804 patient-weeks, with a median duration of follow-up of 71 weeks (interquartile range, 25–154 weeks). The proportion of patients who were lost to follow-up was similar in both groups (10 [11%] of 92 patients in the ceftazidime group and 8 [8%] of 98 in the ceftazidime plus TMP-SMX group; stratified P = .75). table 1 indicates that choice of oral antimicrobial eradication therapy (a strong predictor of recurrence) was the same in both treatment arms. There was no difference between the 2 parenteral treatment groups with regard to mortality and the number of patients experiencing culture-confirmed melioidosis recurrences after discharge (15 [18.3%] of 82 patients in the ceftazidime group and 16 [17.8%] of 90 in the ceftazidime plus TMP-SMX group; stratified P = .35).

Table 1

Oral antibiotic eradication treatment and outcome in 190 patients with culture-confirmed melioidosis who survived until hospital discharge, by study location and treatment group.

A Kaplan-Meier graph of disease-free and/or survival duration after hospital discharge showed no statistically significant difference between the groups (stratified P = .12, by Wilcoxon test) (figure 1). A second analysis, in which the starting point was the first day of parenteral therapy (and thereby included in-hospital deaths), also failed to show a difference between the 2 groups (stratified P = .34, by Wilcoxon test). The total case-fatality rates for the ceftazidime and ceftazidime plus TMP-SMX groups were 33.3% (36 of 108 patients) and 30.4% (35 of 115 patients), respectively (stratified P = .62).

Figure 1

Kaplan-Meier survival plot illustrating time to death or culture-confirmed melioidosis during follow-up of 190 patients treated for acute melioidosis with ceftazidime alone or ceftazidime plus trimethoprim-sulfamethoxazole (TMP-SMX).

These findings, combined with the in-hospital mortality results described previously, suggest that the addition of TMP-SMX to the acute treatment regimen for severe melioidosis has neither a short-term nor long-term benefit.

Acknowledgments

We thank the directors, medical staff, and nursing staff of the Department of Medicine at Sappasithiprasong (Uban Ratchathani, Thailand) and Srinagarind Hospitals (Khon Kaen University, Khon Kaen, Thailand); Drs. P. Mootsikapun, J. M. Short, A. J. H. Simpson, D. Limmathurotsakul, A. C. Cheng, and P. N. Newton, who participated in patient enrollment; and V. Wuthiekanun, N. Getchalarat, and J. Suwannapruk, for laboratory and administrative support.

Financial support.Khon Kaen University and the Mahidol-Oxford Research Unit were supported by the Wellcome Trust of Great Britain. S.P. was supported by a Wellcome Trust Career Development Award in Clinical Tropical Medicine.

Potential conflicts of interest.All authors: no conflicts.