5 July 2018

In Clinical Infectious Diseases Elin Svensson and colleagues showed that increasing rifampicin exposure shortened the time needed to reach undetectable levels of bacteria in sputum. The effect did not plateau within the studied range of exposures, indicating that doses higher than 35 mg/kg could be yet more effective.

Abstract
Background. Tuberculosis remains a huge public health problem and the prolonged treatment duration obstructs effective tuberculosis control. Higher rifampicin doses have been associated with better bactericidal activity, but optimal dosing is uncertain. This analysis aimed to characterize the relationship between rifampicin plasma exposure and treatment response over 6 months in a recent study investigating the potential for treatment shortening with high-dose rifampicin.
 
Methods. Data were analyzed from 336 patients with pulmonary tuberculosis (97 with pharmacokinetic data) treated with rifampicin doses of 10, 20, or 35 mg/kg. The response measure was time to stable sputum culture conversion (TSCC). We derived individual exposure metrics with a previously developed population pharmacokinetic model of rifampicin. TSCC was modeled using a parametric time-to-event approach, and a sequential exposure-response analysis was performed.
 
Results. Higher rifampicin exposures increased the probability of early culture conversion. No maximal limit of the effect was detected within the observed range. The expected proportion of patients with stable culture conversion on liquid medium at week 8 was predicted to increase from 39% (95% confidence interval, 37%–41%) to 55% (49%–61%), with the rifampicin area under the curve increasing from 20 to 175 mg/L·h (representative for 10 and 35 mg/kg, respectively). Other predictors of TSCC were baseline bacterial load, proportion of culture results unavailable, and substitution of ethambutol for either moxifloxacin or SQ109.
 
Conclusions. Increasing rifampicin exposure shortened TSCC, and the effect did not plateau, indicating that doses >35 mg/kg could be yet more effective. Optimizing rifampicin dosage while preventing toxicity is a clinical priority.
 
Publication
The Potential for Treatment Shortening With Higher Rifampicin Doses: Relating Drug Exposure to Treatment Response in Patients With Pulmonary Tuberculosis.
Svensson EM, Svensson RJ, Te Brake LHM, Boeree MJ, Heinrich N, Konsten S, Churchyard G, Dawson R, Diacon AH, Kibiki GS, Minja LT, Ntingiya NE, Sanne I, Gillespie SH, Hoelscher M, Phillips PPJ, Simonsson USH, Aarnoutse R.

Elin Svensson , Rob Aarnoutse , Lindsey te Brake and Martin Boeree are members of theme Infectious diseases and global health.

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