Garreau Romain, Pham Truong-Thanh, Bourguignon Laurent, Millet Aurélien, Parant François, Bussy David, Desevre Marine, Franchi Victor, Ferry Tristan, Goutelle Sylvain
Hospices Civils de Lyon, Groupement Hospitalier Nord, Service de Pharmacie, Lyon, France.
LBBE-Laboratoire de Biométrie et Biologie Evolutive, CNRS, UMR 5558, Université Lyon 1, Villeurbanne, France.
Clin Infect Dis. 2023 Nov 17;77(10):1372-1380. doi: 10.1093/cid/ciad386.
High-dose daptomycin is increasingly used in patients with bone and joint infection (BJI). This raises concerns about a higher risk of adverse events (AEs), including daptomycin-induced eosinophilic pneumonia (DIEP) and myotoxicity. We aimed to examine pharmacokinetic and other potential determinants of DIEP and myotoxicity in patients with BJI receiving daptomycin.
All patients receiving daptomycin for BJI were identified in a prospective cohort study. Cases were matched at a 1:3 ratio, with controls randomly selected from the same cohort. Bayesian estimation of the daptomycin daily area under the concentration-time curve over 24 hours (AUC24h) was performed with the Monolix software based on therapeutic drug monitoring (TDM) data. Demographic and biological data were also collected. Risk factors of AEs were analyzed using Cox proportional hazards model.
From 1130 patients followed over 7 years, 9 with DIEP, 26 with myotoxicity, and 106 controls were included in the final analysis. Daptomycin AUC24h, C-reactive protein, and serum protein levels were associated with the risk of AEs. The adjusted hazard ratio of DIEP or myotoxicity was 3.1 (95% confidence interval [CI], 1.48-6.5; P < .001) for daptomycin AUC24h > 939 mg/h/L, 9.8 (95% CI, 3.94-24.5; P < .001) for C-reactive protein > 21.6 mg/L, and 2.4 (95% CI, 1.02-5.65; P = .04) for serum protein <72 g/L.
We identified common determinants of DIEP and myotoxicity in patients with BJI. Because the risk of AEs was associated with daptomycin exposure, daptomycin TDM and model-informed precision dosing may help optimize the efficacy and safety of daptomycin treatment in this setting. A target AUC24h range of 666 to 939 mg/h/L is suggested.
高剂量达托霉素在骨与关节感染（BJI）患者中的应用日益增多。这引发了人们对包括达托霉素诱导的嗜酸性粒细胞性肺炎（DIEP）和肌毒性在内的不良事件（AE）风险增加的担忧。我们旨在研究接受达托霉素治疗的BJI患者中DIEP和肌毒性的药代动力学及其他潜在决定因素。
在一项前瞻性队列研究中确定所有接受达托霉素治疗BJI的患者。病例与对照按1:3的比例匹配，对照从同一队列中随机选择。基于治疗药物监测（TDM）数据，使用Monolix软件对达托霉素24小时浓度 - 时间曲线下的每日面积（AUC24h）进行贝叶斯估计。还收集了人口统计学和生物学数据。使用Cox比例风险模型分析AE的危险因素。
在7年随访的1130例患者中，最终分析纳入了9例DIEP患者、26例肌毒性患者和106例对照。达托霉素AUC24h、C反应蛋白和血清蛋白水平与AE风险相关。当达托霉素AUC24h > 939 mg/h/L时，DIEP或肌毒性的调整后风险比为3.1（95%置信区间[CI]，1.48 - 6.5；P <.001）；当C反应蛋白> 21.6 mg/L时，为9.8（95% CI，3.94 - 24.5；P <.001）；当血清蛋白< 72 g/L时，为2.4（95% CI，1.02 - 5.65；P =.04）。
我们确定了BJI患者中DIEP和肌毒性的常见决定因素。由于AE风险与达托霉素暴露相关，达托霉素TDM和模型指导的精准给药可能有助于优化这种情况下达托霉素治疗的疗效和安全性。建议目标AUC24h范围为666至939 mg/h/L。
