Rubin Institute for Advanced Orthopedics, Sinai Hospital of Baltimore, LifeBridge Health, Baltimore, Maryland.
University of California Los Angeles, Los Angeles, California, USA.
Antimicrob Agents Chemother. 2024 Aug 7;68(8):e0065524. doi: 10.1128/aac.00655-24. Epub 2024 Jul 16.
We report the results of a first-in-human phase 1 clinical study to evaluate TRL1068, a native human monoclonal antibody that disrupts bacterial biofilms with broad-spectrum activity against both Gram-positive and Gram-negative species. The study population consisted of patients with chronic periprosthetic joint infections (PJIs) of the knee or hip, including both monomicrobial and polymicrobial infections, that are highly resistant to antibiotics due to biofilm formation. TRL1068 was administered via a single pre-surgical intravenous infusion in three sequentially ascending dose groups (6, 15, and 30 mg/kg). Concomitant perioperative antibiotics were pathogen-targeted as prescribed by the treating physician. In this double-blinded study, 4 patients were randomized to receive placebo and 11 patients to receive TRL1068 on day 1, as well as targeted antibiotics for 7 days prior to the scheduled removal of the infected implant and placement of an antibiotic-eluting spacer as the first stage of the standard of care two-stage exchange arthroplasty. No adverse events attributable to TRL1068 were reported. TRL1068 serum half-life was 15-18 days. At day 8, the concentration in synovial fluid was approximately 60% of the blood level and thus at least 15-fold above the threshold for biofilm-disrupting activity . Explanted prostheses were sonicated to release adherent bacteria for culture, with elimination of the implant bacteria observed in 3 of the 11 patients who received TRL1068, which compares favorably to prior PJI treatments. None of the patients who received TRL1068 had a relapse of the original infection by the end of the study (day 169).
This study is registered with ClinicalTrials.gov as NCT04763759.
我们报告了一项首次人体 1 期临床研究的结果，该研究评估了 TRL1068，这是一种天然的人源单克隆抗体，可破坏细菌生物膜，对革兰氏阳性和革兰氏阴性物种均具有广谱活性。研究人群包括患有慢性人工关节周围感染（PJI）的膝关节或髋关节患者，包括单微生物和多微生物感染，由于生物膜形成，这些感染对抗生素高度耐药。TRL1068 通过单次术前静脉输注，在三个连续递增剂量组（6、15 和 30mg/kg）中给药。根据治疗医生的规定，同时给予围手术期抗生素，针对病原体。在这项双盲研究中，4 名患者随机接受安慰剂，11 名患者在第 1 天接受 TRL1068，以及在计划取出感染植入物并放置抗生素洗脱间隔物之前 7 天给予靶向抗生素，这是标准护理两阶段关节置换术的第一阶段。没有报告与 TRL1068 相关的不良事件。TRL1068 血清半衰期为 15-18 天。在第 8 天，滑液中的浓度约为血液水平的 60%，因此至少是破坏生物膜活性的阈值的 15 倍以上。取出的假体进行超声处理以释放附着的细菌进行培养，在接受 TRL1068 的 11 名患者中，有 3 名观察到植入物细菌消除，与先前的 PJI 治疗相比效果较好。在研究结束时（第 169 天），接受 TRL1068 的患者均未出现原始感染复发。
这项研究在 ClinicalTrials.gov 上注册为 NCT04763759。
