Relationship Between Real-time TDM-guided Pharmacodynamic Target Attainment of Continuous Infusion Beta-lactam Monotherapy and Microbiologic Outcome in the Treatment of Critically Ill Children With Severe Documented Gram-negative Infections

OBJECTIVES: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.