A treatment regimen including high-dose rifampicin administered intravenously in addition to standard or high-dose moxifloxacin has an acceptable safety profile and could improve survival for patients with tuberculous meningitis, indicate phase II trial results.
Specifically, patients randomly assigned to receive the treatment regimen had a three-times higher drug concentration in their bloodstream, and an almost three-times higher concentration in their cerebrospinal fluid than individuals treated with standard-dose regimens, note the researchers.
Furthermore, mortality rates after 6 months of treatment were lower among those who received the high-dose rifampicin.
"We feel that our results challenge the current treatment model for tuberculous meningitis," say Reinout van Crevel (Radboud University Nijmegen Medical Centre, the Netherlands) and colleagues in TheLancet Infectious Diseases.
Definition of the optimum regimen for individuals with this condition would help implement intensified treatment in settings where it is most needed, they add.
Despite more than half of the cohort experiencing adverse events related to the study drug, hepatotoxicity was evenly distributed between high- and low-dose patients, and Grade 3 transaminase increases were transient. Just four patients experienced a Grade 4 hepatotoxic event, resulting in them ceasing to take the study drugs.
A total of 60 patients with tuberculous meningitis were randomly assigned to receive rifampicin at a standard dose (450 mg once daily, orally) or high dose (600 mg once daily, intravenously), with either oral ethambutol, standard-dose moxifloxacin (400 mg), or high-dose moxifloxacin (800 mg). This regimen continued for 2 weeks after which standard treatment was resumed.
Patients were followed up with twice-weekly electrocardiographies, full blood counts, and liver transaminases.
The researchers found that in addition to plasma and cerebrospinal fluid concentrations of rifampicin being higher in the high-dose group compared with the standard-dose group, 64% of patients in the standard-dose group had concentrations of the latter below the limit of measurement. By contrast, just 4% of high-dose rifampicin recipients' concentrations fell below this level.
Similarly, high-dose moxifloxacin resulted in 1.6 times higher concentrations in cerebrospinal fluid compared with low-dose.
Cumulative mortality rates at 6 months were 65% in the low-dose rifampicin group and 34% in the high-dose group, and adjusted analysis confirmed that high-dose rifampicin significantly predicted survival.
Van Crevel and team warn that these mortality data should be interpreted with caution due to the small study size.
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