{"doi":"10.1093/cid/ciab162","title":"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 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.","journal":"Clinical Infectious Diseases","year":2021,"id":151630,"datarank":0.6610078870896381,"base_score":4.406719247264253,"endowment":4.406719247264253,"self_citation_contribution":0.6610078870896381,"citation_network_contribution":0.0,"self_endowment_contribution":0.6610078870896381,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":81,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9538,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":397657,"name":"David B. Meya","orcid":"0000-0002-8854-0321","position":1,"is_corresponding":false},{"id":498936,"name":"Enock Kagimu","orcid":"0000-0002-0291-651X","position":2,"is_corresponding":false},{"id":492284,"name":"Daniel Grint","orcid":"0000-0001-8001-6544","position":3,"is_corresponding":false},{"id":645432,"name":"Lindsey te Brake","orcid":null,"position":4,"is_corresponding":false},{"id":644484,"name":"John Kasibante","orcid":"0000-0002-7252-4052","position":5,"is_corresponding":false},{"id":447828,"name":"Emily Martyn","orcid":"0000-0003-4981-9298","position":6,"is_corresponding":false},{"id":644485,"name":"Morris K Rutakingirwa","orcid":"0000-0003-2276-360X","position":7,"is_corresponding":false},{"id":498935,"name":"Carson Quinn","orcid":"0000-0001-8858-8563","position":8,"is_corresponding":false},{"id":644486,"name":"Michael Okirwoth","orcid":"0000-0002-8651-7478","position":9,"is_corresponding":false},{"id":452981,"name":"Lillian Tugume","orcid":"0000-0002-1293-1545","position":10,"is_corresponding":false},{"id":645433,"name":"Kenneth Ssembambulidde","orcid":null,"position":11,"is_corresponding":false},{"id":578702,"name":"Abdu K Musubire","orcid":"0000-0003-2410-5344","position":12,"is_corresponding":false},{"id":267645,"name":"Ananta Bangdiwala","orcid":"0000-0003-0062-9434","position":13,"is_corresponding":false},{"id":644487,"name":"Allan Buzibye","orcid":"0000-0001-5874-3219","position":14,"is_corresponding":false},{"id":399943,"name":"Conrad Muzoora","orcid":"0000-0002-7866-5198","position":15,"is_corresponding":false},{"id":308899,"name":"Elin M. Svensson","orcid":"0000-0002-0093-6445","position":16,"is_corresponding":false},{"id":644488,"name":"Rob E. Aarnoutse","orcid":"0000-0001-8925-969X","position":17,"is_corresponding":false},{"id":267658,"name":"David R. Boulware","orcid":"0000-0002-4715-0060","position":18,"is_corresponding":false},{"id":454873,"name":"Alison M. Elliott","orcid":"0000-0003-2818-9549","position":19,"is_corresponding":false},{"id":418473,"name":"Fiona V Cresswell","orcid":"0000-0002-5070-532X","position":0,"is_corresponding":true}],"reference_count":40,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-18T23:43:16.823357Z","pmid":"33693537","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}