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[Lancet Infect Dis在线发表]:吸入阿米卡星辅助静脉抗生素治疗接受机械通气的革兰阴性杆菌肺炎
2020年01月07日 时讯速递, 进展交流 暂无评论

Inhaled amikacin adjunctive to intravenous standard-of-care antibiotics in mechanically ventilated patients with Gram-negative pneumonia (INHALE): a double-blind, randomised, placebo-controlled, phase 3, superiority trial

Michael S Niederman, Jeff Alder, Matteo Bassetti, et al

Lancet Infect Dis December 19, 2019 DOI:https://doi.org/10.1016/S1473-3099(19)30574-2

Background 背景

Treatment of ventilated pneumonia is often unsuccessful, even when patients are treated according to established guidelines. Therefore, we aimed to investigate the efficacy of the combination drug device Amikacin Inhale as an adjunctive therapy to intravenous standard-of-care antibiotics for pneumonia caused by Gram-negative pathogens in intubated and mechanically ventilated patients.

即使根据现有指南进行治疗,接受机械通气的肺炎患者的治疗常常并不成功。因此,我们旨在研究联合阿米卡星吸入作为静脉标准抗生素治疗的辅助治疗措施,用于治疗接受机械通气的革兰阴性杆菌肺炎患者的疗效。

Methods 方法

INHALE was a prospective, double-blind, randomised, placebo-controlled, phase 3 study comprising two trials (INHALE 1 and INHALE 2) done in 153 hospital intensive-care units in 25 countries. Eligible patients were aged 18 years or older; had pneumonia that had been diagnosed by chest radiography and that was documented as being caused by or showing two risk factors for a Gram-negative, multidrug-resistant pathogen; were intubated and mechanically ventilated; had impaired oxygenation within 48 h before screening; and had a modified Clinical Pulmonary Infection Score of at least 6. Patients were stratified by region and disease severity (according to their Acute Physiology and Chronic Health Evaluation [APACHE] II score) and randomly assigned (1:1) via an interactive voice-recognition system to receive 400 mg amikacin (Amikacin Inhale) or saline placebo, both of which were aerosolised, administered every 12 h for 10 days via the same synchronised inhalation system, and given alongside standard-of-care intravenous antibiotics. All patients and all staff involved in administering devices and monitoring outcomes were masked to treatment assignment. The primary endpoint, survival at days 28–32, was analysed in all patients who received at least one dose of study drug, were infected with a Gram-negative pathogen, and had an APACHE II score of at least 10 at diagnosis. Safety analyses were done in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, numbers NCT01799993 and NCT00805168.

INHALE是一项前瞻、双盲、随机、安慰剂对照、3期临床试验,包括2个部分 (INHALE 1 和 INHALE 2),在25个国家153家医院的ICU进行。入选患者为18岁以上;根据胸片诊断肺炎且由多重耐药革兰阴性杆菌引起,或具有多重耐药革兰阴性杆菌感染的2个危险因素;气管插管接受机械通气;筛查前48小时内出现氧合障碍;校正后临床肺部感染评分至少6分。根据地域及疾病严重程度 (根据APACHE II 评分) 对患者进行分层,并通过互动语音识别系统按照1:1的比例随机接受400 mg 阿米卡星 (吸入阿米卡星) 或生理盐水安慰剂,两者均采用相同的同步雾化吸入系统,每12小时雾化一次,疗程10天,同时给予标准的静脉抗生素治疗。治疗分组对所有患者以及参与用药及监测预后的人员隐藏。主要预后终点为28-32天生存率,针对接受至少一剂研究药物、确诊为革兰阴性杆菌感染且确诊时APACHE II评分至少10分的所有患者进行分析。针对接受至少一剂研究药物的所有患者进行安全性分析。研究在 ClinicalTrials.gov 注册,注册号 NCT01799993 和 NCT00805168

Findings 结果

Between April 13, 2013, and April 7, 2017, 807 patients were assessed for eligibility and 725 were randomly assigned to Amikacin Inhale (362 patients) or aerosolised placebo (363 patients). 712 patients received at least one dose of study drug (354 in the Amikacin Inhale group and 358 in the placebo group), although one patient assigned to Amikacin Inhale received placebo in error and was included in the placebo group for safety analyses. 508 patients (255 in the Amikacin Inhale group and 253 in the placebo group) were assessed for the primary endpoint. We found no between-group difference in survival: 191 (75%) patients in the Amikacin Inhale group versus 196 (77%) patients in the placebo group survived until days 28–32 (odds ratio 0·841, 95% CI 0·554–1·277; p=0·43). Similar proportions of patients in the two treatment groups had a treatment-emergent adverse event (295 [84%] of 353 patients in the Amikacin Inhale group vs 303 [84%] of 359 patients in the placebo group) or a serious treatment-emergent adverse event (101 [29%] patients vs 97 [27%] patients).

在2013年4月13日至2017年4月7日间,共对807名患者进行评估,725名接受随机分组至吸入阿米卡星组 (362 名患者) 或雾化安慰剂组 (363 名患者)。712名患者接受至少一剂研究药物 (吸入阿米卡星组 354 名,安慰剂组 358 名),但有1名吸入阿米卡星组患者错误地接受了安慰剂,因而在安全性分析中纳入安慰剂组。508 名患者 (吸入阿米卡星组 255 名,安慰剂组 253 名) 可以进行主要预后终点的评估。我们未能发现两组间生存率存在差异:吸入阿米卡星组 191 名 (75%) 患者与安慰剂组 196 名 (77%) 患者在28-32天仍存活 (比数比 0·841, 95% CI 0·554–1·277; p=0·43)。两组中有相似比例的患者发生治疗相关不良事件 (吸入阿米卡星组 353 名患者中 295 名 [84%] vs 安慰剂组 359 名患者中 303 名 [84%] ) 或严重不良事件 (101 名 [29%] 患者 vs 97 名 [27%] 患者)。

Interpretation 结论

Our findings do not support use of inhaled amikacin adjunctive to standard-of-care intravenous therapy in mechanically ventilated patients with Gram-negative pneumonia.

我们的研究结果不支持在标准静脉抗生素治疗的基础上,加用吸入阿米卡星作为辅助治疗措施,用于治疗接受机械通气的革兰阴性杆菌肺炎患者。

Funding 资助

Bayer AG.

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