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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

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.
Meya, David B. (author)
Makerere Univ, Infect Dis Inst, Kampala, Uganda.
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.
Te Brake, Lindsey (author)
Radboud Univ Nijmegen Med Ctr, Radboud Inst Hlth Sci, Dept Pharm, Nijmegen, Netherlands.
Kasibante, John (author)
Makerere Univ, Infect Dis Inst, Kampala, Uganda.
Martyn, Emily (author)
London Sch Hyg & Trop Med, Clin Res Dept, Keppel St, London WC1E 7HT, England.
Rutakingirwa, Morris (author)
Makerere Univ, Infect Dis Inst, Kampala, Uganda.
Quinn, Carson M. (author)
Univ Calif San Francisco, San Francisco, CA 94143 USA.
Okirwoth, Micheal (author)
Makerere Univ, Infect Dis Inst, Kampala, Uganda.
Tugume, Lillian (author)
Makerere Univ, Infect Dis Inst, Kampala, Uganda.
Ssembambulidde, Kenneth (author)
Makerere Univ, Infect Dis Inst, Kampala, Uganda.
Musubire, Abdu K. (author)
Makerere Univ, Infect Dis Inst, Kampala, Uganda.
Bangdiwala, Ananta S. (author)
Univ Minnesota, Div Biostat, Minneapolis, MN USA.
Buzibye, Allan (author)
Makerere Univ, Infect Dis Inst, Kampala, Uganda.
Muzoora, Conrad (author)
Mbarara Univ Sci & Technol, Mbarara, Uganda.
Svensson, Elin, 1985- (author)
Uppsala universitet,Institutionen för farmaci,Radboud Univ Nijmegen Med Ctr, Radboud Inst Hlth Sci, Dept Pharm, Nijmegen, Netherlands.
Aarnoutse, Rob (author)
Radboud Univ Nijmegen Med Ctr, Radboud Inst Hlth Sci, Dept Pharm, Nijmegen, Netherlands.
Boulware, David R. (author)
Univ Minnesota, Div Infect Dis & Int Med, Minneapolis, MN USA.
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.
In: Clinical Infectious Diseases. - : Oxford University Press. - 1058-4838 .- 1537-6591. ; 73:5, s. 876-884
Related links:
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  • Journal article (peer-reviewed)
Abstract Subject headings
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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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