Internal Medicine Service, Department of Medicine, Lausanne University Hospital (CHUV), Lausanne, Switzerland.
Infectious Diseases Service, Department of Medicine, Lausanne University Hospital (CHUV), Lausanne, Switzerland.
J Antimicrob Chemother. 2018 Dec 1;73(12):3413-3422. doi: 10.1093/jac/dky370.
Meropenem plasma concentration above a pathogen's MIC over the whole dosing interval (100% ƒT>MIC) is a determinant of outcome in severe infections. Significant variability of meropenem pharmacokinetics is reported in ICU patients.
To characterize meropenem pharmacokinetics in variable CLCR or renal replacement therapy and assess the appropriateness of recommended regimens for MIC coverage.
A pharmacokinetic analysis (NONMEM) was conducted with external model validation. Patient characteristics were tested on meropenem clearance estimates, differentiated according to the presence/absence of continuous renal replacement therapy (CRRT, CLCRRT or CLno-CRRT). Simulations evaluated the appropriateness of recommended dosing for achieving 100% fT>MIC in 90% of patients.
A total of 101 patients were studied: median 63 years (range 49-70), 56% male, SAPS II 38 (27-48). 32% had a CLCR >60 mL/min, 49% underwent CRRT and 32% presented severe sepsis or septic shock. A total of 127 pathogens were documented: 76% Gram-negatives, 24% Gram-positives (meropenem MIC90 2 mg/L, corresponding to EUCAST susceptibility breakpoint). Three hundred and eighty plasma and 129 filtrate-dialysate meropenem concentrations were analysed: two-compartment modelling best described the data. Predicted meropenem CLno-CRRT was 59% lower in impaired (CLCR 30 mL/min) compared to normal (CLCR 100 mL/min) renal function. Simulations showed that recommended regimens appropriately cover MIC90 in patients with CLCR <60 mL/min. Patients with CLCR of 60 to <90 mL/min need 6 g/day to achieve appropriate coverage. In patients with CLCR ≥90 mL/min, appropriate exposure is achieved with increased dose, frequency of administration and infusion duration, or continuous infusion.
Recommended meropenem regimens are suboptimal in ICU patients with normal or augmented renal clearance. Modified dosing or infusion modalities achieve appropriate MIC coverage for optimized antibacterial efficacy in meropenem-susceptible life-threatening infections.
美罗培南血药浓度超过全剂量给药间隔内致病菌 MIC 的时间百分比（100% ƒT>MIC）是严重感染患者临床转归的决定因素。重症监护病房（ICU）患者的美罗培南药代动力学存在显著的变异性。
研究不同肌酐清除率（CLCR）或肾脏替代治疗（RRT）患者的美罗培南药代动力学特征，并评估现有推荐方案对 MIC 覆盖度的适用性。
采用 NONMEM 法进行药代动力学分析，并进行外部模型验证。根据是否存在持续 RRT（CRRT、CLCRRT 或 CLno-CRRT）对患者美罗培南清除率进行分组，以检验患者特征对美罗培南清除率的影响。采用模拟方法评估了推荐剂量方案在实现 90%患者 100% ƒT>MIC 的适用性。
共纳入 101 例患者，中位年龄 63 岁（范围 49-70 岁），56%为男性，急性生理学与慢性健康状况评分系统 II （SAPS II）评分为 38 分（27-48 分）。32%的患者 CLCR＞60mL/min，49%的患者接受了 CRRT，32%的患者患有严重脓毒症或感染性休克。共检测到 127 种病原体，其中 76%为革兰氏阴性菌，24%为革兰氏阳性菌（美罗培南 MIC90 为 2mg/L，相当于 EUCAST 药敏折点）。共分析了 380 份血浆和 129 份滤过液-透析液美罗培南浓度，结果表明二室模型最能描述数据。与肾功能正常（CLCR 100mL/min）患者相比，CLCR 受损（CLCR 30mL/min）患者的美罗培南 CLno-CRRT 降低了 59%。模拟结果表明，在 CLCR＜60mL/min 的患者中，推荐方案能较好地覆盖 MIC90。CLCR 为 60-＜90mL/min 的患者需每天 6g 才能达到适当的覆盖度。CLCR≥90mL/min 的患者可通过增加剂量、给药频率和输注时间或持续输注来实现适当的暴露。
对于 CLCR 正常或增加的 ICU 患者，推荐的美罗培南方案并不理想。调整剂量或输注方式可以实现美罗培南敏感的危及生命感染的适当 MIC 覆盖，从而优化抗菌疗效。
