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

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.