High-dose rifampicin may be of benefit in tuberculosis meningitis

High-dose intravenous and oral rifampicin appear safe and effective in the treatment of HIV-positive patients with tuberculosis meningitis (TBM), with a phase II study showing that the dose increases cerebrospinal fluid (CSF) levels with no additional toxicity.

The phase II open-label trial included 61 adults with suspected TBM, of which 92 percent were HIV-positive, with a median CD4 count of 50 cells/µL (IQR, 46–56). They were randomized to receive intravenous rifampicin (IV-20; 20 mg/kg/day), high-dose oral rifampicin (PO-35; 35 mg/kg/day), or standard of care (control; rifampicin 10 mg/kg/day). Pharmacokinetic (PK) sampling was conducted at days 2 and 14.

Efficacy outcomes included total exposure (area under the curve [AUC] 0-24 hr), maximum concentration (Cmax), CSF concentration, and grade 3–5 adverse events.

At day 2, geometric mean plasma AUC 0-24 hr was highest for PO-35 at 327 h.mg/L, followed by IV-20 at 249 h.mg/L and control at 42.9 h.mg/L (p<0.001). In CSF, control achieved undetectable rifampicin concentration in 56 percent of patients and geometric mean AUC 0-24 hr of 0.27 mg/L, compared with 1.74 mg/L for IV-20 and 2.17 mg/L for PO-35 regimens (p<0.001).

CSF concentrations were above rifampicin minimal inhibitory concentration (MIC) in 95 percent (18/19) of patients on PO-35, 93 percent (14/15) on IV-20, and 11 percent (2/18) on control. Higher serum and CSF levels were sustained at day 14.

In terms of safety, adverse event rates did not differ by treatment dose (p=0.34).

The findings justify further investigation of the safety of high-dose rifampicin in a wider population and determine its impact on death and disability.