Cresswell, Fiona V; Meya, David B; Kagimu, Enock; Grint, Daniel; Te Brake, Lindsey; Kasibante, John; Martyn, Emily; Rutakingirwa, Morris; Quinn, Carson M; Okirwoth, Micheal; +10 more... Tugume, Lillian; Ssembambulidde, Kenneth; Musubire, Abdu K; Bangdiwala, Ananta S; Buzibye, Allan; Muzoora, Conrad; Svensson, Elin M; Aarnoutse, Rob; Boulware, David R; Elliott, Alison 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 : an official publication of the Infectious Diseases Society of America, 73 (5). pp. 876-884. ISSN 1058-4838 DOI: https://doi.org/10.1093/cid/ciab162
Permanent Identifier
Use this Digital Object Identifier when citing or linking to this resource.
Abstract
BACKGROUND: High-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.
Item Type | Article |
---|---|
Faculty and Department |
Faculty of Infectious and Tropical Diseases > Dept of Clinical Research Faculty of Epidemiology and Population Health > Dept of Infectious Disease Epidemiology & International Health (2023-) |
PubMed ID | 33693537 |
Elements ID | 157795 |
Download
Filename: High-Dose Oral and Intravenous Rifampicin for the Treatment of Tuberculous Meningitis in Predominantly Human Immunodeficienc.pdf
Licence: Creative Commons: Attribution 3.0
Download