持续输注β-内酰胺类药物达到积极的药代动力学/药效学目标对重症肝移植受者移植后早期革兰氏阴性菌感染靶向治疗临床疗效的影响。一项为期3年的前瞻性观察性研究的中期分析。

Impact of attaining an aggressive PK/PD target with continuous infusion beta-lactams on the clinical efficacy of targeted therapy of early post-transplant Gram-negative infections in critically ill OLT recipients. An interim analysis of a 3-year prospective, observational, study.

作者信息

Gatti Milo, Rinaldi Matteo, Laici Cristiana, Bonazzetti Cecilia, Vizioli Luca, Ambretti Simone, Morelli Maria Cristina, Siniscalchi Antonio, Giannella Maddalena, Viale Pierluigi, Pea Federico

机构信息

Department of Medical and Surgical Sciences, Alma Mater Studiorum, University of Bologna, Italy.

Clinical Pharmacology Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.

出版信息

J Infect Dis. 2025 Jan 24. doi: 10.1093/infdis/jiaf048.

DOI:10.1093/infdis/jiaf048

PMID:39854631

Abstract

BACKGROUND

To assess the impact of attaining aggressive beta-lactam pharmacokinetic/pharmacodynamic (PK/PD) targets on clinical efficacy in critical orthotopic liver transplant (OLT) recipients with documented early Gram-negative infections.

METHODS

OLT recipients admitted to the post-transplant ICU between June 2021 and May 2024 having documented Gram-negative infections treated with targeted therapy continuous infusion (CI) beta-lactams, and undergoing therapeutic drug monitoring (TDM)-guided beta-lactam dosing adjustment in the first 72 hours were prospectively enrolled. Free steady-state concentrations (fCss) of beta-lactams (BL) and/or of beta-lactamase inhibitors (BLI) were calculated, and aggressive PK/PD target attainment was measured. Multivariate logistic regression analyses were performed for testing independent variables associated with 30-day resistance occurrence.

RESULTS

Fifty critical OLT recipients were treated with CI beta-lactam in mono- (n=34) or in combination (n=16) therapy for documented Gram-negative infections (46% hospital-acquired/ventilator-associated pneumonia). Combination therapy was selected more frequently for treating intraabdominal infections (P=0.03) and was associated with lower attainment of aggressive PK/PD target (P=0.03). No significant difference in clinical/microbiological outcome emerged between mono- and combination therapy. Four patients (8.0%) developed 30-day resistance occurrence. At multivariate analysis, failure in attaining an aggressive beta-lactam PK/PD target emerged as the only independent predictor of 30-day resistance development (OR 14.33; 95% CI 1.46-140.53; P=0.02).

CONCLUSIONS

Attaining an aggressive PK/PD target of CI beta-lactams in critical OLT recipients treated for documented Gram-negative infections could represent an effective strategy for minimizing the risk of 30-day resistance occurrence to the selected beta-lactam.

摘要

背景

评估在有记录的早期革兰氏阴性菌感染的重症原位肝移植（OLT）受者中，达到积极的β-内酰胺类药物药代动力学/药效学（PK/PD）目标对临床疗效的影响。

方法

前瞻性纳入2021年6月至2024年5月入住移植后重症监护病房、有记录的革兰氏阴性菌感染且接受靶向治疗持续输注（CI）β-内酰胺类药物治疗、并在最初72小时内接受治疗药物监测（TDM）指导的β-内酰胺类药物剂量调整的OLT受者。计算β-内酰胺类药物（BL）和/或β-内酰胺酶抑制剂（BLI）的游离稳态浓度（fCss），并衡量积极的PK/PD目标达成情况。进行多变量逻辑回归分析，以测试与30天耐药发生相关的独立变量。

结果

50例重症OLT受者因有记录的革兰氏阴性菌感染接受CIβ-内酰胺类药物单药治疗（n=34）或联合治疗（n=16）（46%为医院获得性/呼吸机相关性肺炎）。联合治疗更常用于治疗腹腔内感染（P=0.03），且与积极的PK/PD目标达成率较低相关（P=0.03）。单药治疗和联合治疗在临床/微生物学结果方面无显著差异。4例患者（8.0%）出现30天耐药。在多变量分析中，未达到积极的β-内酰胺类药物PK/PD目标是30天耐药发生的唯一独立预测因素（OR 14.33；95%CI 1.46-140.53；P=0.02）。