Wallis Robert S, Dawson Rodney, Friedrich Sven O, Venter Amour, Paige Darcy, Zhu Tong, Silvia Annette, Gobey Jason, Ellery Craig, Zhang Yao, Eisenach Kathleen, Miller Paul, Diacon Andreas H
Formerly Pfizer Inc, Groton, Connecticut, United States of America.
University of Cape Town, Cape Town, South Africa.
PLoS One. 2014 Apr 14;9(4):e94462. doi: 10.1371/journal.pone.0094462. eCollection 2014.
Sutezolid (PNU-100480) is a linezolid analog with superior bactericidal activity against Mycobacterium tuberculosis in the hollow fiber, whole blood and mouse models. Like linezolid, it is unaffected by mutations conferring resistance to standard TB drugs. This study of sutezolid is its first in tuberculosis patients.
Sputum smear positive tuberculosis patients were randomly assigned to sutezolid 600 mg BID (N = 25) or 1200 mg QD (N = 25), or standard 4-drug therapy (N = 9) for the first 14 days of treatment. Effects on mycobacterial burden in sputum (early bactericidal activity or EBA) were monitored as colony counts on agar and time to positivity in automated liquid culture. Bactericidal activity was also measured in ex vivo whole blood cultures (whole blood bactericidal activity or WBA) inoculated with M. tuberculosis H37Rv.
All patients completed assigned treatments and began subsequent standard TB treatment according to protocol. The 90% confidence intervals (CI) for bactericidal activity in sputum over the 14 day interval excluded zero for all treatments and both monitoring methods, as did those for cumulative WBA. There were no treatment-related serious adverse events, premature discontinuations, or dose reductions due to laboratory abnormalities. There was no effect on the QT interval. Seven sutezolid-treated patients (14%) had transient, asymptomatic ALT elevations to 173±34 U/L on day 14 that subsequently normalized promptly; none met Hy's criteria for serious liver injury.
The mycobactericidal activity of sutezolid 600 mg BID or 1200 mg QD was readily detected in sputum and blood. Both schedules were generally safe and well tolerated. Further studies of sutezolid in tuberculosis treatment are warranted.
ClinicalTrials.gov NCT01225640.
舒替唑胺（PNU - 100480）是一种利奈唑胺类似物，在中空纤维、全血和小鼠模型中对结核分枝杆菌具有更强的杀菌活性。与利奈唑胺一样，它不受赋予对标准抗结核药物耐药性的突变影响。这项关于舒替唑胺的研究是其首次在结核病患者中开展。
痰涂片阳性的结核病患者在治疗的前14天被随机分配接受每日两次600毫克舒替唑胺治疗（N = 25）或每日一次1200毫克治疗（N = 25），或标准四联药物治疗（N = 9）。通过琼脂上的菌落计数和自动液体培养中的阳性时间来监测对痰液中分枝杆菌负荷的影响（早期杀菌活性或EBA）。还在接种结核分枝杆菌H37Rv的离体全血培养物中测量杀菌活性（全血杀菌活性或WBA）。
所有患者均完成了分配的治疗，并根据方案开始了后续的标准抗结核治疗。在14天期间，所有治疗组以及两种监测方法的痰液杀菌活性的90%置信区间（CI）均不包括零，累积WBA的置信区间也是如此。没有与治疗相关的严重不良事件、提前停药或因实验室异常而减少剂量的情况。对QT间期没有影响。7名接受舒替唑胺治疗的患者（14%）在第14天出现短暂的、无症状的谷丙转氨酶升高至173±34 U/L，随后迅速恢复正常；无人符合Hy氏严重肝损伤标准。
每日两次600毫克或每日一次1200毫克舒替唑胺的杀分枝杆菌活性在痰液和血液中均易于检测到。两种给药方案总体上都是安全的且耐受性良好。有必要对舒替唑胺在结核病治疗中的应用进行进一步研究。
ClinicalTrials.gov NCT01225640。
