Cresswell, Fiona V.Meya, David B.Kagimu, EnockGrint, DanielBrake, Lindsey teKasibante, JohnMartyn, EmilyRutakingirwa, MorrisQuinn, Carson M.Okirwoth, MichealTugume, LillianSsembambulidde, KennethMusubire, Abdu K.Bangdiwala, Ananta S.Buzibye, AllanMuzoora, ConradSvensson, Elin M.Aarnoutse, RobBoulware, David R.Elliott, Alison M.2023-03-032023-03-032021Cresswell, F. V., Meya, D. B., Kagimu, E., Grint, D., Te Brake, L., Kasibante, J., ... & Elliott, A. M. (2021). 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. Clinical Infectious Diseases, 73(5), 876-884. DOI: 10.1093/cid/ciab16210.1093/cid/ciab162https://nru.uncst.go.ug/handle/123456789/8067High-dose rifampicin may improve outcomes of tuberculous meningitis (TBM). Little safety or pharmacokinetic (PK) data exist on high-dose rifampicin in human immunodeficiency virus (HIV) coinfection, 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 randomized to standard-of-care control (PO-10, rifampicin 10 mg/kg/day), intravenous rifampicin (IV-20, 20 mg/kg/day), or high-dose oral rifampicin (PO-35, 35 mg/kg/ day). We performed PK sampling on days 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 living with HIV, median CD4 count was 50 cells/μL (interquartile range [IQR] 46–56). On day 2, geometric mean plasma AUC0–24hr was 42.9·h mg/L with standard-of-care 10 mg/kg dosing, 249·h mg/L for IV-20 and 327·h mg/L for PO-35 (P < .001). In CSF, standard of care achieved undetectable rifampicin concentration in 56% of participants and geometric mean AUC0–24hr 0.27 mg/L, compared with 1.74 mg/L (95% confidence interval [CI] 1.2–2.5) for IV-20 and 2.17 mg/L (1.6–2.9) for PO-35 regimens (P < .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 = .34). Conclusions. 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.enTuberculous meningitisRifampicinIntensified therapyHIVTBMArticle