Gatti Milo, Campoli Caterina, Latrofa Maria Elena, Ramirez Stefania, Sasso Tommaso, Mancini Rita, Caramelli Fabio, Viale Pierluigi, Pea Federico
From the Department of Medical and Surgical Sciences, Alma Mater Studiorum, University of Bologna, Bologna, Italy.
Clinical Pharmacology Unit, Department for Integrated Infectious Risk Management, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.
Pediatr Infect Dis J. 2023 Nov 1;42(11):975-982. doi: 10.1097/INF.0000000000004054. Epub 2023 Jul 24.
To explore the relationship between real-time therapeutic drug monitoring (TDM)-guided pharmacodynamic target attainment of continuous infusion (CI) beta-lactam monotherapy and microbiological outcome in the treatment of critically ill children with severe documented Gram-negative infections.
Observational, monocentric, retrospective study of critically ill patients receiving CI piperacillin-tazobactam, ceftazidime, or meropenem in monotherapy for documented Gram-negative infections optimized by means of a real-time TDM-guided strategy. Average steady-state beta-lactam concentrations (C ss ) were calculated for each patient, and the beta-lactam C ss /minimum inhibitory concentration (MIC) ratio was selected as a pharmacodynamic parameter of efficacy. The C ss /MIC ratio was defined as optimal if ≥4, quasi-optimal if between 1 and 4, and suboptimal if <1. The relationship between C ss /MIC and microbiological outcome was assessed.
Forty-six TDM assessments were carried out in 21 patients [median age 2 (interquartile range: 1-8) years]. C ss /MIC ratios were optimal in 76.2% of cases. Patients with optimal C ss /MIC ratios had both a significantly higher microbiological eradication rate (75.0% vs. 0.0%; P = 0.006) and lower resistance development rate (25.0% vs. 80.0%; P = 0.047) than those with quasi-optimal or suboptimal C ss /MIC ratios. Quasi-optimal/suboptimal C ss /MIC ratio occurred more frequently when patients had infections caused by pathogens with MIC values above the European Committee on Antimicrobial Susceptibility Testing clinical breakpoint (100.0% vs. 6.3%; P < 0.001).
Real-time TDM-guided pharmacodynamic target attainment of CI beta-lactam monotherapy allowed to maximize treatment efficacy in most critically ill children with severe Gram-negative infections. Attaining early optimal C ss /MIC ratios of CI beta-lactams could be a key determinant associated with microbiologic eradication during the treatment of Gram-negative infections. Larger prospective studies are warranted for confirming our findings.
探讨实时治疗药物监测（TDM）指导下的持续输注（CI）β-内酰胺类单药治疗的药效学目标达成情况与确诊为革兰氏阴性菌严重感染的重症儿童微生物学治疗结果之间的关系。
对接受CI哌拉西林-他唑巴坦、头孢他啶或美罗培南单药治疗确诊革兰氏阴性菌感染的重症患者进行观察性、单中心、回顾性研究，采用实时TDM指导策略优化治疗。计算每位患者的平均稳态β-内酰胺浓度（Css），并选择β-内酰胺Css/最低抑菌浓度（MIC）比值作为疗效的药效学参数。Css/MIC比值≥4定义为最佳，1至4之间为次优，<1为非最佳。评估Css/MIC与微生物学治疗结果之间的关系。
对21例患者进行了46次TDM评估[中位年龄2岁（四分位间距：1 - 8岁）]。76.2%的病例Css/MIC比值为最佳。Css/MIC比值最佳的患者与Css/MIC比值次优或非最佳的患者相比，微生物学根除率显著更高（75.0%对0.0%；P = 0.006），耐药发生率更低（25.0%对80.0%；P = 0.047）。当患者感染由MIC值高于欧洲抗菌药物敏感性试验委员会临床界值的病原体引起时，Css/MIC比值次优/非最佳的情况更频繁发生（100.0%对6.3%；P < 0.001）。
实时TDM指导下的CIβ-内酰胺类单药治疗的药效学目标达成可使大多数确诊为革兰氏阴性菌严重感染的重症儿童的治疗效果最大化。在革兰氏阴性菌感染治疗期间，实现CIβ-内酰胺类药物早期最佳Css/MIC比值可能是与微生物学根除相关的关键决定因素。需要开展更大规模的前瞻性研究来证实我们的发现。
