High-Dose Oral and Intravenous Rifampicin for the Treatment of Tuberculous Meningitis in Predominantly Human Immunodeficiency Virus (HIV)-Positive Ugandan Adults: A Phase II Open-Label Randomized Controlled Trial

Abstract

Background High-dose rifampicin may improve outcomes of tuberculous meningitis (TBM). Little safety or pharmacokinetic (PK) data exist on high-dose rifampicin in HIV co-infection, and no cerebrospinal fluid (CSF) PK data exist from Africa. We hypothesized that high-dose rifampicin would increase serum and CSF concentrations without excess toxicity. Methods In this phase II open-label trial, Ugandan adults with suspected TBM were randomised to standard-of-care control (PO-10, rifampicin 10mg/kg/day), intravenous rifampicin (IV-20, 20mg/kg/day), or high-dose oral rifampicin (PO-35, 35mg/kg/day). We performed PK sampling on day 2 and 14. The primary outcomes were total exposure (AUC0-24), maximum concentration (Cmax), CSF concentration and grade 3-5 adverse events. Results We enrolled 61 adults, 92% were HIV-positive, median CD4 count was 50cells/µL (IQR 46–56). On day 2, geometric mean plasma AUC0-24hr was 42.9h.mg/L with standard-of-care 10mg/kg dosing, 249h.mg/L for IV-20 and 327h.mg/L for PO-35 (P<0.001). In CSF, standard-of-care achieved undetectable rifampicin concentration in 56% of participants and geometric mean AUC0-24hr 0.27mg/L, compared with 1.74mg/L (95%CI 1.2–2.5) for IV-20 and 2.17mg/L (1.6–2.9) for PO-35 regimens (p<0.001). Achieving CSF concentrations above rifampicin minimal inhibitory concentration (MIC) occurred in 11% (2/18) of standard-of-care, 93% (14/15) of IV-20, and 95% (18/19) of PO-35 participants. Higher serum and CSF levels were sustained at day 14. Adverse events did not differ by dose (p=0.34) Conclusion Current international guidelines result in sub-therapeutic CSF rifampicin concentration for 89% of Ugandan TBM patients. High-dose intravenous and oral rifampicin were safe, and respectively resulted in exposures ~6- and ~8-fold higher than standard-of-care, and CSF levels above the MIC

High-dose rifampin improves bactericidal activity without increased intracerebral inflammation in animal models of tuberculous meningitis

“…Therefore, higher rifampin levels were noted in rabbits versus mice. Importantly, these rifampin levels are consistent with studies evaluating CSF rifampin levels in adults (29) and children (30) with TB meningitis.…”

Intensified Antituberculosis Therapy Regimen Containing Higher Dose Rifampin for Tuberculous Meningitis: A Systematic Review and Meta-Analysis

“…The liquid chromatography-tandem mass spectrometry assay was performed to measure the rifampin concentration in two studies by Wasserman and Ding (13,14). In addition, Cresswell et al (15) used high-performance liquid chromatography with ultraviolet detection (HPLC-UV) to measure the concentration of rifampin in plasma and CSF. And in the study conducted by Dian S ( 16), concentration was assessed through the ultraperformance liquid chromatography method (UPLC).…”

“…The Cochrane Risk of Bias Tool was applied to assess the risk of bias of the included studies. Two studies could not be blinded because intravenous and oral administration of rifampin was compared (10,15), so these studies were found to have a high risk of performance bias and detection bias. The study conducted by Wasserman and colleagues also had two intervention groups, which received either high-dose oral rifampin at 35 mg/kg/day or intravenously at 20 mg/kg/day.…”

“…Four eligible studies reported the plasma C max of rifampin (10,13,15,16). The random effects model meta-analysis showed that there were significant differences in plasma rifampin C max 3].…”

Tuberculous Meningitis in Children: Reducing the Burden of Death and Disability

“…Several first-line anti-tuberculosis drugs (e.g., rifampicin and ethambutol) have poor penetration across the blood-brain and the blood-CSF barriers [63]. Rifampicin remains an essential medication for TBM [64] but standard dosing yields CSF concentrations that are below the minimal inhibitory concentration (MIC) for M. tuberculosis in a large proportion of patients, including children [65][66][67]. A recent model-based meta-analysis using emerging data from adult trials showed a strong positive correlation between rifampicin concentrations and survival, with doses of at least 30 mg/kg predicted to improve survival substantially compared to 10 mg/kg [68].…”