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.
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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DOI：
10.1093/cid/ciab162
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发表时间：
2021-09-07
期刊：
影响因子：
--
通讯作者：
Elliott AM
中科院分区：
文献类型：
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作者：
Cresswell FV;Meya DB;Kagimu E;Grint D;Te Brake L;Kasibante J;Martyn E;Rutakingirwa M;Quinn CM;Okirwoth M;Tugume L;Ssembambulidde K;Musubire AK;Bangdiwala AS;Buzibye A;Muzoora C;Svensson EM;Aarnoutse R;Boulware DR;Elliott AM
大剂量利福平可改善结核性脑膜炎(TBM)的预后。大剂量利福平在人类免疫缺陷病毒(HIV)混合感染中的安全性或药代动力学(PK)数据很少，非洲也没有脑脊液(CSF)PK数据。我们假设大剂量利福平会增加血清和脑脊液的浓度，而不会产生额外的毒性。在这项II期开放试验中，乌干达成年疑似TBM患者被随机分为标准护理对照组(PO-10，利福平10 mg/kg/d)、静脉注射利福平(IV-20，20 mg/kg/d)或大剂量口服利福平(PO-35，35 mg/kg/d)。我们在第2天和第14天进行PK采样。主要结果是总暴露(AUC0-24)、最大浓度(Cmax)、脑脊液浓度和3-5级不良事件。我们招募了61名成年人，其中92%是艾滋病毒携带者，CD_4细胞计数的中位数为50个/微米L(四分位数范围46-56)。第2天，标准剂量10 mg/kg、IV-20和PO-35的几何平均血药浓度分别为42.9h/L、249.h/L和327.h/ (P .001)。在脑脊液中，56%的受试者达到了未检测到的利福平浓度和几何平均值AUC0-24小时0.27毫克/L，而IV-20和PO-35方案分别为1.74毫克/L(95%可信区间[CI]1.2-2.5)和2.17毫克/L(1.6-2.9)(P <； .001)。达到脑脊液浓度高于利福平最低抑菌浓度(MIC)的比例分别为11%(2/18)、93%(14/15)和95%(18/19)。第14天维持较高的血清和脑脊液水平。不良事件没有剂量差异(P = .34)。目前的国际指南导致89%的乌干达TBM患者的脑脊液利福平浓度处于亚治疗性水平。大剂量静脉注射和口服利福平是安全的，其暴露剂量分别是标准护理的~6倍和~8倍，脑脊液水平高于MIC。在标准剂量下，大多数结核脑膜炎患者的脑脊液(CSF)中检测不到利福平。在主要由人类免疫缺陷病毒(HIV)携带者组成的人群中，静脉注射大剂量利福平20 mg/kg和口服35 mg/kg导致治疗性脑脊液利福平浓度没有过量毒性。
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. 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. 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). 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. Rifampicin is undetectable in the cerebrospinal fluid (CSF) of the majority of tuberculosis meningitis patients at standard dosing. Highdose rifampicin administered intravenously 20 mg/kg and orally 35 mg/kg resulted in therapeutic CSF rifampicin concentrations with no excess toxicity in a population consisting predominantly of people living with human immunodeficiency virus (HIV).
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影响因子：
3.7
作者：
Abbara A;Chitty S;Roe JK;Ghani R;Collin SM;Ritchie A;Kon OM;Dzvova J;Davidson H;Edwards TE;Hateley C;Routledge M;Buckley J;Davidson RN;John L
通讯作者：
John L
DOI：
10.1093/jac/dky152
发表时间：
2018-09-01
期刊：
The Journal of antimicrobial chemotherapy
影响因子：
--
作者：
Stott KE;Pertinez H;Sturkenboom MGG;Boeree MJ;Aarnoutse R;Ramachandran G;Requena-Méndez A;Peloquin C;Koegelenberg CFN;Alffenaar JWC;Ruslami R;Tostmann A;Swaminathan S;McIlleron H;Davies G
通讯作者：
Davies G
影响因子：
5.2
作者：
Hu Y;Liu A;Ortega-Muro F;Alameda-Martin L;Mitchison D;Coates A
通讯作者：
Coates A
影响因子：
6.4
作者：
Srivastava, Shashikant;Pasipanodya, Jotam G.;Gumbo, Tawanda
通讯作者：
Gumbo, Tawanda
DOI：
10.1093/cid/ciz1071
发表时间：
2020-11-05
期刊：
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America
影响因子：
--
作者：
Svensson EM;Dian S;Te Brake L;Ganiem AR;Yunivita V;van Laarhoven A;Van Crevel R;Ruslami R;Aarnoutse RE
通讯作者：
Aarnoutse RE