Role of a Real-Time TDM-Based Expert Clinical Pharmacological Advice Program in Optimizing the Early Pharmacokinetic/Pharmacodynamic Target Attainment of Continuous Infusion Beta-Lactams among Orthotopic Liver Transplant Recipients with Documented or Suspected Gram-Negative Infections

Abstract

(1) Objectives: To describe the attainment of optimal pharmacokinetic/pharmacodynamic (PK/PD) targets in orthotopic liver transplant (OLT) recipients treated with continuous infusion (CI) beta-lactams optimized using a real-time therapeutic drug monitoring (TDM)-guided expert clinical pharmacological advice (ECPA) program during the early post-surgical period. (2) Methods: OLT recipients admitted to the post-transplant intensive care unit over the period of July 2021–September 2023, receiving empirical or targeted therapy with CI meropenem, piperacillin-tazobactam, meropenem-vaborbactam, or ceftazidime-avibactam optimized using a real-time TDM-guided ECPA program, were retrospectively retrieved. Steady-state beta-lactam (BL) and/or beta-lactamase inhibitor (BLI) plasma concentrations (Css) were measured, and the Css/MIC ratio was selected as the best PK/PD target for beta-lactam efficacy. The PK/PD target of meropenem was defined as being optimal when attaining a fCss/MIC ratio > 4. The joint PK/PD target of the BL/BLI combinations (namely piperacillin-tazobactam, ceftazidime-avibactam, and meropenem-vaborbactam) was defined as being optimal when the fCss/MIC ratio > 4 of the BL and the fCss/target concentration (CT) ratio > 1 of tazobactam or avibactam, or the fAUC/CT ratio > 24 of vaborbactam were simultaneously attained. Multivariate logistic regression analysis was performed for testing potential variables that were associated with a failure in attaining early (i.e., at first TDM assessment) optimal PK/PD targets. (3) Results: Overall, 77 critically ill OLT recipients (median age, 57 years; male, 63.6%; median MELD score at transplantation, 17 points) receiving a total of 100 beta-lactam treatment courses, were included. Beta-lactam therapy was targeted in 43% of cases. Beta-lactam dosing adjustments were provided in 76 out of 100 first TDM assessments (76.0%; 69.0% decreases and 7.0% increases), and overall, in 134 out of 245 total ECPAs (54.7%). Optimal PK/PD target was attained early in 88% of treatment courses, and throughout beta-lactam therapy in 89% of cases. Augmented renal clearance (ARC; OR 7.64; 95%CI 1.32–44.13) and MIC values above the EUCAST clinical breakpoint (OR 91.55; 95%CI 7.12–1177.12) emerged as independent predictors of failure in attaining early optimal beta-lactam PK/PD targets. (4) Conclusion: A real-time TDM-guided ECPA program allowed for the attainment of optimal beta-lactam PK/PD targets in approximately 90% of critically ill OLT recipients treated with CI beta-lactams during the early post-transplant period. OLT recipients having ARC or being affected by pathogens with MIC values above the EUCAST clinical breakpoint were at high risk for failure in attaining early optimal beta-lactam PK/PD targets. Larger prospective studies are warranted for confirming our findings.

Impact of attaining aggressive vs. conservative PK/PD target on the clinical efficacy of beta-lactams for the treatment of Gram-negative infections in the critically ill patients: a systematic review and meta-analysis

“…The 21 observational studies included had a design that was prospective in 9 cases and retrospective in the other 12 (Table 1 ) [ 6 , 7 , 15 , 20 – 37 ]. Five were multicentric [ 22 , 25 , 32 , 35 , 36 ].…”

“…The aggressive beta-lactam PK/PD target selected in the different studies was a 100% f T >4x MIC and/or C ss or C min /MIC ratio > 4 in 18/21 studies [ 6 , 15 , 20 – 24 , 26 – 36 ], and a 100% f T >5x MIC and/or C ss or C min /MIC ratio > 5 in 3/21 studies [ 7 , 25 , 37 ]. Joint PK/PD target was assessed in three studies evaluating BL/BLIc (namely piperacillin-tazobactam, ceftazidime-avibactam, and meropenem-vaborbactam) [ 15 , 28 , 29 ]. In 11/21 studies, the assessment of aggressive PK/PD target attainment of beta-lactams was assessed first within 72 h from starting treatment.…”

“…The PK/PD target of beta-lactam was considered aggressive whenever the reported free beta-lactam trough (C min ) or steady-state concentrations (C ss ) to MIC ratio was > 4 (equivalent to 100% f T > 4xMIC ), in agreement with both preclinical/clinical studies and international guidance [ 4 , 14 ]. In studies assessing beta-lactam/beta lactamase inhibitor combinations (BL/BLIc), the definition of aggressive PK/PD target attainment was based on a joint PK/PD target attainment of both the BL and the BLI, in agreement with previous studies [ 15 ].…”

Comparative Impact of an Optimized PK/PD Target Attainment of Piperacillin-Tazobactam vs. Meropenem on the Trend over Time of SOFA Score and Inflammatory Biomarkers in Critically Ill Patients Receiving Continuous Infusion Monotherapy for Treating Documented Gram-Negative BSIs and/or VAP

“…MDR colonization at 90-days was defined as the finding at surveillance rectal swabs or urine culture of a novel difficult-to-treat resistant (DTR) Gram-negative pathogen in the absence of signs or symptoms of infection in the subsequent 90-days after starting piperacillin-tazobactam or meropenem treatment course. Targeted monotherapy with piperacillin-tazobactam or meropenem was always started with a loading dose followed by a CI maintenance dose with timing for solutions reconstitution depending on the selected agent, as previously detailed according to stability in aqueous solution [74].…”

“…Subsequent TDM-guided ECPA reassessments were performed every 48-72-h during the ICU stay. Free (f ) meropenem, piperacillin, and tazobactam C ss were calculated according to the plasma protein binding rate reported in the literature, as previously detailed [74].…”