Department of Medical and Surgical Sciences, Alma Mater Studiorum, University of Bologna, Via Massarenti 9, 40138, Bologna, Italy.
Clinical Pharmacology Unit, Department for Integrated Infectious Risk Management, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.
Clin Pharmacokinet. 2024 Nov;63(11):1573-1583. doi: 10.1007/s40262-024-01436-6. Epub 2024 Oct 25.
Population pharmacokinetic/pharmacodynamic (PK/PD) modelling of antibiotics including C-reactive protein (C-RP) dynamics could be helpful in predicting the efficacy of antimicrobials. We developed a PK/PD model for assessing the impact of continuous infusion (CI) meropenem PK/PD target attainment on C-RP dynamics in critically ill patients with documented Gram-negative hospital- (HAP) or ventilator-acquired pneumonia (VAP).
Patients were grouped according to the type of antibiotic treatment received [meropenem monotherapy; meropenem plus empirical anti-MRSA (methicillin-resistant Staphylococcus aureus) therapy; meropenem in combination with another anti-Gram-negative active agent; meropenem plus a targeted anti-MRSA therapy]. A one-compartment population PK model of CI meropenem was developed by including all patients. A full C-RP production inhibition model was developed for fitting the PD data by including only patients receiving meropenem monotherapy or meropenem plus empirical anti-MRSA therapy. Monte Carlo simulations explored the relationship between the type of PK/PD target attainment of CI meropenem, defined as optimal (steady-state plasma concentration [C] to minimum inhibitory concentration [MIC] ratio = 4-8), quasi-optimal (C/MIC = 1-4) and sub-optimal (C/MIC < 1) and the magnitude of C-RP production inhibition over time.
A total of 64 patients providing 211 meropenem concentrations were included in the PK analysis, whereas 47 patients providing 328 C-RP data were included in the PD model. Simulations showed that optimal PK/PD target attainment was associated with the highest and most rapid C-RP production inhibition (44% and 56% at days 2 and 4, respectively). Conversely, sub-optimal PK/PD target attainment was shown to be almost ineffective (< 5% at day 4 and < 10% at day 10).
Our PK/PD model predicted that attaining optimal PK/PD target with CI meropenem may grant prompt and intense C-RP decrease among critically ill patients receiving targeted monotherapy for Gram-negative HAP/VAP, thus anticipating efficacy.
包括 C 反应蛋白（C-RP）动力学在内的抗生素群体药代动力学/药效学（PK/PD）模型有助于预测抗菌药物的疗效。我们开发了一个 PK/PD 模型，用于评估连续输注（CI）美罗培南 PK/PD 目标达标对有记录的革兰氏阴性医院获得性肺炎（HAP）或呼吸机相关性肺炎（VAP）患者 C-RP 动力学的影响。
根据接受的抗生素治疗类型将患者分组[美罗培南单药治疗；美罗培南加经验性抗耐甲氧西林金黄色葡萄球菌（MRSA）治疗；美罗培南联合另一种抗革兰氏阴性活性药物；美罗培南加靶向抗 MRSA 治疗]。通过纳入所有患者，开发了 CI 美罗培南的单室群体 PK 模型。通过纳入仅接受美罗培南单药或美罗培南加经验性抗 MRSA 治疗的患者，开发了一个完整的 C-RP 生产抑制模型来拟合 PD 数据。蒙特卡罗模拟探索了 CI 美罗培南 PK/PD 目标达成的类型（定义为最佳[稳态血浆浓度[C]与最小抑菌浓度 [MIC]比值= 4-8]、准最佳 [C/MIC = 1-4] 和次最佳 [C/MIC < 1]）与 C-RP 生产抑制随时间的关系。
共有 64 名患者提供了 211 次美罗培南浓度，纳入 PK 分析，而 47 名患者提供了 328 次 C-RP 数据，纳入 PD 模型。模拟结果表明，最佳 PK/PD 目标达成与最高和最快的 C-RP 生产抑制相关（第 2 天和第 4 天分别为 44%和 56%）。相反，次优 PK/PD 目标达成几乎无效（第 4 天<5%，第 10 天<10%）。
我们的 PK/PD 模型预测，通过 CI 美罗培南实现最佳 PK/PD 目标可能会使接受革兰氏阴性 HAP/VAP 靶向单药治疗的危重症患者迅速而强烈地降低 C-RP，从而预测疗效。
