14-day bactericidal activity of PA-824, bedaquiline, pyrazinamide, and moxifloxacin combinations: a randomised trial

被引：355

作者：

Diacon, Andreas H. ^{[1
,4
]}

Dawson, Rodney ^{[5
,6
]}

von Groote-Bidlingmaier, Florian ^{[4
]}

Symons, Gregory ^{[5
,6
]}

Venter, Amour ^{[2
]}

Donald, Peter R. ^{[3
]}

van Niekerk, Christo ^{[8
]}

Everitt, Daniel ^{[7
]}

Winter, Helen ^{[9
]}

Becker, Piet ^{[10
]}

Mendel, Carl M. ^{[7
]}

Spigelman, Melvin K. ^{[7
]}

机构：

[1] Univ Stellenbosch, Div Physiol, Dept Med Biochem, Fac Med & Hlth Sci, Cape Town, South Africa

[2] Univ Stellenbosch, MRC Ctr Mol & Cellular Biol, Fac Med & Hlth Sci, Cape Town, South Africa

[3] Univ Stellenbosch, Dept Paediat & Child Hlth, Fac Med & Hlth Sci, Cape Town, South Africa

[4] Karl Bremer Hosp, Cape Town, South Africa

[5] Groote Schuur Hosp, Div Pulmonol, Dept Med, ZA-7925 Cape Town, South Africa

[6] Univ Cape Town, Lung Inst, ZA-7925 Cape Town, South Africa

[7] Global Alliance TB Drug Dev, New York, NY USA

[8] Global Alliance TB Drug Dev, Pretoria, South Africa

[9] Univ Otago, Sch Pharm, Dunedin, New Zealand

[10] MRC, Pretoria, South Africa

来源：

LANCET | 2012年 / 380卷 / 9846期

关键词：

MULTIDRUG-RESISTANT TUBERCULOSIS; PULMONARY TUBERCULOSIS; MURINE MODEL; PHASE-II; MYCOBACTERIUM-TUBERCULOSIS; DIARYLQUINOLINE TMC207; MOUSE MODEL; ETHAMBUTOL; DRUGS; PHARMACOKINETICS;

D O I：

10.1016/S0140-6736(12)61080-0

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Background New drugs, but also shorter, better-tolerated regimens are needed to tackle the high global burden of tuberculosis complicated by drug resistance and retroviral disease. We investigated new multiple-agent combinations over the first 14 days of treatment to assess their suitability for future development. Methods In this prospective, randomised, early bactericidal activity (EBA) study, treatment-naive, drug-susceptible patients with uncomplicated pulmonary tuberculosis were admitted to hospitals in Cape Town, South Africa, between Oct 7, 2010, and Aug 19, 2011. Patients were randomised centrally by computer-generated randomisation sequence to receive bedaquiline, bedaquiline-pyrazinamide, PA-824-pyrazinamide, bedaquiline-PA-824, PA-824-moxifloxacin-pyrazinamide, or unmasked standard antituberculosis treatment as positive control. The primary outcome was the 14-day EBA assessed in a central laboratory from the daily fall in colony forming units (CFU) of M tuberculosis per mL of sputum in daily overnight sputum collections. Bilinear regression curves were fitted for each group separately and groups compared with ANOVA for ranks, followed by pair-wise comparisons adjusted for multiplicity. Clinical staff were partially masked but laboratory personnel were fully masked. This study is registered, NCT01215851. Findings The mean 14-day EBA of PA-824-moxifloxacin-pyrazinamide (n=13; 0.233 [SD 0.128]) was significantly higher than that of bedaquiline (14; 0.061 [0.068]), bedaquiline-pyrazinamide (15; 0.131 [0.102]), bedaquiline-PA-824 (14; 0.114 [0.050]), but not PA-824-pyrazinamide (14; 0.154 [0.040]), and comparable with that of standard treatment (ten; 0.140 [0.094]). Treatments were well tolerated and appeared safe. One patient on PA-824-moxifloxacin-pyrazinamide was withdrawn because of corrected QT interval changes exceeding criteria prespecified in the protocol. Interpretation PA-824-moxifloxacin-pyrazinamide is potentially suitable for treating drug-sensitive and multidrug-resistant tuberculosis. Multiagent EBA studies can contribute to reducing the time needed to develop new antituberculosis regimens.

引用

页码：986 / 993

页数：8