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High-Dose Oral and ...
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
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- Cresswell, Fiona, V (author)
- London Sch Hyg & Trop Med, Clin Res Dept, Keppel St, London WC1E 7HT, England.;Makerere Univ, Infect Dis Inst, Kampala, Uganda.;Uganda Virus Res Inst, Med Res Council, LSHIM Uganda Res Unit, Entebbe, Uganda.
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- Meya, David B. (author)
- Makerere Univ, Infect Dis Inst, Kampala, Uganda.
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- Kagimu, Enock (author)
- Makerere Univ, Infect Dis Inst, Kampala, Uganda.
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- Grint, Daniel (author)
- London Sch Hyg & Trop Med, Trop Epidemiol Grp, Keppel St, London, England.
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- Te Brake, Lindsey (author)
- Radboud Univ Nijmegen Med Ctr, Radboud Inst Hlth Sci, Dept Pharm, Nijmegen, Netherlands.
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- Kasibante, John (author)
- Makerere Univ, Infect Dis Inst, Kampala, Uganda.
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- Martyn, Emily (author)
- London Sch Hyg & Trop Med, Clin Res Dept, Keppel St, London WC1E 7HT, England.
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- Rutakingirwa, Morris (author)
- Makerere Univ, Infect Dis Inst, Kampala, Uganda.
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- Quinn, Carson M. (author)
- Univ Calif San Francisco, San Francisco, CA 94143 USA.
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- Okirwoth, Micheal (author)
- Makerere Univ, Infect Dis Inst, Kampala, Uganda.
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- Tugume, Lillian (author)
- Makerere Univ, Infect Dis Inst, Kampala, Uganda.
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- Ssembambulidde, Kenneth (author)
- Makerere Univ, Infect Dis Inst, Kampala, Uganda.
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- Musubire, Abdu K. (author)
- Makerere Univ, Infect Dis Inst, Kampala, Uganda.
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- Bangdiwala, Ananta S. (author)
- Univ Minnesota, Div Biostat, Minneapolis, MN USA.
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- Buzibye, Allan (author)
- Makerere Univ, Infect Dis Inst, Kampala, Uganda.
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- Muzoora, Conrad (author)
- Mbarara Univ Sci & Technol, Mbarara, Uganda.
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- Svensson, Elin, 1985- (author)
- Uppsala universitet,Institutionen för farmaci,Radboud Univ Nijmegen Med Ctr, Radboud Inst Hlth Sci, Dept Pharm, Nijmegen, Netherlands.
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- Aarnoutse, Rob (author)
- Radboud Univ Nijmegen Med Ctr, Radboud Inst Hlth Sci, Dept Pharm, Nijmegen, Netherlands.
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- Boulware, David R. (author)
- Univ Minnesota, Div Infect Dis & Int Med, Minneapolis, MN USA.
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- Elliott, Alison M. (author)
- London Sch Hyg & Trop Med, Clin Res Dept, Keppel St, London WC1E 7HT, England.;Uganda Virus Res Inst, Med Res Council, LSHIM Uganda Res Unit, Entebbe, Uganda.
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London Sch Hyg & Trop Med, Clin Res Dept, Keppel St, London WC1E 7HT, England;Makerere Univ, Infect Dis Inst, Kampala, Uganda.;Uganda Virus Res Inst, Med Res Council, LSHIM Uganda Res Unit, Entebbe, Uganda. Makerere Univ, Infect Dis Inst, Kampala, Uganda. (creator_code:org_t)
- 2021-03-08
- 2021
- English.
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In: Clinical Infectious Diseases. - : Oxford University Press. - 1058-4838 .- 1537-6591. ; 73:5, s. 876-884
- Related links:
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https://doi.org/10.1...
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Abstract
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- 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 (AUC(0-24)), maximum concentration (C-max), CSF concentration, and grade 3-5 adverse events. Results: We enrolled 61 adults, 92% were living with HIV, median CD4 count was 50 cells/mu L (interquartile range [IQR] 46-56). On day 2, geometric mean plasma AUC(0-24hr) 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 AUC(0-24hr) 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 similar to 6- and similar to 8-fold higher than standard of care, and CSF levels above the MIC.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Infektionsmedicin (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Infectious Medicine (hsv//eng)
Keyword
- tuberculous meningitis
- rifampicin
- intensified therapy
- HIV
- TBM
Publication and Content Type
- ref (subject category)
- art (subject category)
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Cresswell, Fiona ...
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Meya, David B.
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Kagimu, Enock
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Grint, Daniel
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Te Brake, Lindse ...
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Kasibante, John
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Martyn, Emily
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Rutakingirwa, Mo ...
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Quinn, Carson M.
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Okirwoth, Michea ...
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Tugume, Lillian
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Ssembambulidde, ...
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Musubire, Abdu K ...
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Bangdiwala, Anan ...
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Buzibye, Allan
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Muzoora, Conrad
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Svensson, Elin, ...
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Aarnoutse, Rob
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Boulware, David ...
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Elliott, Alison ...
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Clinical Infecti ...
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Uppsala University