Efficacy and tolerability of a cocktail of bacteriophages to treat burn wounds infected by Pseudomonas aeruginosa (PhagoBurn): a randomised, controlled, double-blind phase 1/2 trial
Efficacy and tolerability of a cocktail of bacteriophages to treat burn wounds infected by Pseudomonas aeruginosa (PhagoBurn): a randomised, controlled, double-blind phase 1/2 trial
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DOI：
10.1016/s1473-3099(18)30482-1
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发表时间：
2019-01-01
影响因子：
56.3
通讯作者：
Gabard, Jerome
中科院分区：
文献类型：
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作者：
Jault, Patrick;Leclerc, Thomas;Gabard, Jerome
创面感染是烧伤患者脓毒症的主要原因，并增加了烧伤相关的发病率和死亡率。噬菌体是一种天然的细菌病毒，被认为是治疗多重耐药细菌引起的感染的替代疗法。我们的目的是比较的效力和耐受性的鸡尾酒的裂解抗铜绿假单胞菌噬菌体与标准的护理patients with burns.Methods在这个随机的1/2期试验中，确诊烧伤伤口感染的患者被招募从9个烧伤中心在法国和比利时的医院。如果患者年龄在18岁或以上，并且有临床感染铜绿假单胞菌的烧伤伤口，则患者合格。通过使用交互式网络应答系统将合格的参与者随机分配（1：1）至12种天然溶解性抗铜绿假单胞菌噬菌体（PP 1131; 1 x 106空斑形成单位[PFU]/mL）或标准护理（1%磺胺嘧啶银乳剂乳膏）的混合物，均作为每日局部治疗给予7天，随访14天。由于两种治疗的外观（标准治疗是一种厚乳膏，PP 1131是一种通过敷料涂抹的澄清液体），因此无法对临床医生进行治疗掩蔽，但对分析样本和患者的微生物学家进行分配（在患者全身麻醉时进行治疗）。主要终点是通过四象限方法，在第0天有微生物记录的感染并接受至少一种磺胺嘧啶银或噬菌体敷料的所有参与者中，通过每日拭子评估细菌负荷持续减少至少两个象限的中位时间（改良意向治疗人群）。在根据方案接受至少一种敷料的所有参与者中评估安全性。在符合方案人群（完成7天治疗的所有PP 1131受试者）中进行了辅助研究，以评估噬菌体治疗成功或失败的原因。本试验已在欧洲临床试验数据库（编号2014-000714-65）和ClinicalTrials中注册。在2015年7月22日至2017年1月2日期间，在跨越13个月的两个招募期内，招募了27名患者并随机分配接受噬菌体治疗（n=13）或标准护理（n=14）。标准治疗组1例患者未暴露于治疗，安全性人群为26例患者（PP 1131 n=13，标准治疗n=13），PP 1131组1例患者在第0天未发生感染，有效性人群为25例患者（PP 1131 n=12，标准治疗n=13）。由于PP 1131的疗效不足，试验于2017年1月2日停止。PP 1131组达到主要终点的中位时间为144小时（95% CI 48-未达到），而标准治疗组的中位时间为47小时（23-122）（风险比0.29，95% CI 0.10-0.79; p= 0.018）。在PP 1131组中，12名可分析参与者中有6名（50%）具有最大细菌负荷，而标准治疗组中有2名（15%）具有最大细菌负荷。PP 1131滴度在生产后降低，并且参与者接受的PP 1131浓度低于预期（1 × 10（2）PFU/mL/日剂量）。在PP 1131组中，13名可分析参与者中有3名（23%）发生不良事件，而标准治疗组中有7名（54%）发生不良事件。每组中有1名参与者在随访后死亡，死亡被确定为与治疗无关。辅助研究表明，从PP 1131治疗失败的患者中分离的细菌对低噬菌体剂量具有抗性。解释在非常低的浓度下，PP 1131以比标准护理更慢的速度降低烧伤伤口中的细菌负荷。进一步的研究使用增加噬菌体浓度和吞噬图在更大的样本参与者是必要的。版权所有（c）2018 Elsevier Ltd.保留所有权利。
Background Wound infections are the main cause of sepsis in patients with burns and increase burn-related morbidity and mortality. Bacteriophages, natural bacterial viruses, are being considered as an alternative therapy to treat infections caused by multidrug-resistant bacteria. We aimed to compare the efficacy and tolerability of a cocktail of lytic anti-Pseudomonas aeruginosa bacteriophages with standard of care for patients with burns.Methods In this randomised phase 1/2 trial, patients with a confirmed burn wound infection were recruited from nine burn centres in hospitals in France and Belgium. Patients were eligible if they were aged 18 years or older and had a burn wound clinically infected with P aeruginosa. Eligible participants were randomly assigned (1: 1) by use of an interactive web response system to a cocktail of 12 natural lytic anti-P aeruginosa bacteriophages (PP1131; 1 x 106 plaque-forming units [PFU] per mL) or standard of care (1% sulfadiazine silver emulsion cream), both given as a daily topical treatment for 7 days, with 14 days of follow-up. Masking of treatment from clinicians was not possible because of the appearance of the two treatments (standard of care a thick cream, PP1131 a clear liquid applied via a dressing), but assignments were masked from microbiologists who analysed the samples and patients (treatment applied while patients were under general anaesthetic). The primary endpoint was median time to sustained reduction in bacterial burden by at least two quadrants via a four-quadrant method, assessed by use of daily swabs in all participants with a microbiologically documented infection at day 0 who were given at least one sulfadiazine silver or phage dressing (modified intention-to-treat population). Safety was assessed in all participants who received at least one dressing according to protocol. Ancillary studies were done in the per-protocol population (all PP1131 participants who completed 7 days of treatment) to assess the reasons for success or failure of phage therapy. This trial is registered with the European Clinical Trials database, number 2014-000714-65, and ClinicalTrials. gov, number NCT02116010, and is now closed.Findings Between July 22, 2015, and Jan 2, 2017, across two recruitment periods spanning 13 months, 27 patients were recruited and randomly assigned to receive phage therapy (n=13) or standard of care (n=14). One patient in the standard of care group was not exposed to treatment, giving a safety population of 26 patients (PP1131 n=13, standard of care n=13), and one patient in the PP1131 group did not have an infection at day 0, giving an efficacy population of 25 patients (PP1131 n=12, standard of care n=13). The trial was stopped on Jan 2, 2017, because of the insufficient efficacy of PP1131. The primary endpoint was reached in a median of 144 h (95% CI 48-not reached) in the PP1131 group versus a median of 47 h (23-122) in the standard of care group (hazard ratio 0.29, 95% CI 0.10-0.79; p= 0.018). In the PP1131 group, six (50%) of 12 analysable participants had a maximal bacterial burden versus two (15%) of 13 in the standard of care group. PP1131 titre decreased after manufacturing and participants were given a lower concentration of phages than expected (1 x 10 (2) PFU/mL per daily dose). In the PP1131 group, three (23%) of 13 analysable participants had adverse events versus seven (54%) of 13 in the standard of care group. One participant in each group died after follow-up and the deaths were determined to not be related to treatment. The ancillary study showed that the bacteria isolated from patients with failed PP1131 treatment were resistant to low phage doses.Interpretation At very low concentrations, PP1131 decreased bacterial burden in burn wounds at a slower pace than standard of care. Further studies using increased phage concentrations and phagograms in a larger sample of participants are warranted. Copyright (c) 2018 Elsevier Ltd. All rights reserved.