Higher-dose rifampin for the treatment of pulmonary tuberculosis: a systematic review

To provide a descriptive synthesis of the evidence assessing the efficacy and safety of higher doses of rifampin (RMP) for the treatment of pulmonary tuberculosis (TB).

Systematic review of randomized controlled trials that evaluate a range of RMP doses, including doses higher than standard (>10 mg/kg or >600 mg), used as part of combination drug therapies for pulmonary TB. Two reviewers applied inclusion criteria, assessed trial quality and extracted data. Inclusion criteria were smear- or culture-confirmed pulmonary TB, and English and French language articles. Exclusion criteria were RMP monotherapy and smear-negative TB. Outcomes included were sputum culture conversion, treatment failure, recurrence and adverse events, including hepatotoxicity and flu-like syndrome.

Of 14 trials (4256 participants) identified, 12 were conducted before 1980. Four trials were considered high quality according to published guidelines. Study characteristics, including history of prior TB treatment, dose of RMP, duration of treatment, timing of introduction of intervention treatment, concomitant drugs, and duration of follow-up, varied, making synthesis of efficacy data challenging. Several trials suggested an advantage in terms of likelihood of culture conversion among patients receiving at least 900 mg RMP. However, an increased incidence of flu-like syndrome was seen when RMP doses of 900 mg and higher were given intermittently.

Historical trials suggest that higher than standard RMP dosing results in improved culture conversion rates. Phase 2 and 3 clinical trials evaluating higher doses of RMP and other rifamycins are needed to confirm efficacy and assure tolerability. Pharmacokinetic studies will be needed to inform the development of such trials.