28 March 2019

For more than 40 years, patients with tuberculosis have been prescribed almost the same dose of rifampicin. Some studies suggest that the dose is too low and not optimal. In an article in the scientific journal PlosOne, researchers at Radboudumc have stated that they have prescribed significantly higher doses to a group of patients with severe tuberculosis. The doses proved to be safe and well tolerated. Can the treatment regime be adjusted?

Tuberculosis, the infectious disease that kills the most people must be eliminated as quickly as possible. If it is up to the World Health Organization (WHO), the number of people dying from tuberculosis will have decreased by 90 percent in 2035. By then, the number of people with the disease should even be reduced by 95%.
Nice plans, but how can they be realized? Well, among other things by fighting the infectious disease even better with new and already available medicines. In 2013 and 2014, the medications bedaquiline and delamanide were marketed early, enabling the treatment of multi-resistant tuberculosis. However, the medicines that have already been around for a longer time can also be used better. This is the conclusion of a study by Radboudumc researchers into the drug rifampicin.
 
No optimum dosage
Rifampicin has been used since the early 1970s. Patients receive a daily dose that is currently around 10 milligrams per kilogram body weight. The maximum dose per day is 600 milligrams. Cecile Magis-Escurra, a pulmonologist at Radboudumc specialized in tuberculosis: “In recent years, various studies have found indications that a high dose of rifampicin ensures an optimal treatment. Indeed, the regular low dose may even contribute to the development of multi-resistant forms of tuberculosis. The idea is that the dosage is too low to effectively kill the tuberculosis bacterium so that the bacterium can slowly but surely arm itself against the drug. Higher doses may prevent this and probably also provide a more effective treatment.”
 
Safe and tolerable
Between January 2008 and May 2018, 88 patients in Radboudumc were treated with a considerably higher dose, up to a maximum of 32 milligrams per kilogram body weight. As a result, the maximum daily dosage shifted in the direction of 900 to a maximum of 2400 milligrams. The prevention of multi-resistance or a better outcome of the treatment were not assessed. "Safety is always the absolute priority," says Magis-Escurra. "That's why we first looked at that, in combination with its tolerability. The patients could decide for themselves whether they wanted to participate in the study. To participate, patients either had to have proven low levels of the medication in their blood or they had to have tuberculosis in the central nervous system.”
 
Serious patients, higher doses
Only one patient required a small dose reduction during treatment due to intestinal problems. All other patients had no problems with the high dose of rifampicin during the six-month treatment. Magis-Escurra: “This is the first study in which the safety of and tolerance for such high doses during the entire treatment was properly established under well-controlled conditions. Based on our research, we recommend that patients with severe tuberculosis or with a low concentration of rifampicin in the blood be prescribed higher doses. That approach is safe and provides better results. From our research, it is impossible to say whether higher doses can shorten the treatment and lead to less multi-resistance. These are questions that - certainly in light of the WHO strategy - must now be addressed quickly.”


Publication in PlosOne
High-dose rifampicin in tuberculosis: experiences from a Dutch tuberculosis centre
Charlotte Seijger, Wouter Hoefsloot, Inge Bergsma-de Guchteneire, Lindsey te Brake, Jakko van Ingen, Saskia Kuipers, Reinout van Crevel, Rob Aarnoutse, Martin Boeree, Cecile Magis-Escurra.

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