Could an Optimized Joint Pharmacokinetic/Pharmacodynamic Target Attainment of Continuous Infusion Piperacillin-Tazobactam Be a Valuable Innovative Approach for Maximizing the Effectiveness of Monotherapy Even in the Treatment of Critically Ill Patients with Documented Extended-Spectrum Beta-Lactamase-Producing Enterobacterales Bloodstream Infections and/or Ventilator-Associated Pneumonia?

Abstract

(1) Background: Piperacillin-tazobactam represents the first-line option for treating infections caused by full- or multi-susceptible Enterobacterales and/or Pseudomonas aeruginosa in critically ill patients. Several studies reported that attaining aggressive pharmacokinetic/pharmacodynamic (PK/PD) targets with beta-lactams is associated with an improved microbiological/clinical outcome. We aimed to assess the relationship between the joint PK/PD target attainment of continuous infusion (CI) piperacillin-tazobactam and the microbiological/clinical outcome of documented Gram-negative bloodstream infections (BSI) and/or ventilator-associated pneumonia (VAP) of critically ill patients treated with CI piperacillin-tazobactam monotherapy. (2) Methods: Critically ill patients admitted to the general and post-transplant intensive care unit in the period July 2021–September 2023 treated with CI piperacillin-tazobactam monotherapy optimized by means of a real-time therapeutic drug monitoring (TDM)-guided expert clinical pharmacological advice (ECPA) program for documented Gram-negative BSIs and/or VAP were retrospectively retrieved. Steady-state plasma concentrations (Css) of piperacillin and of tazobactam were measured, and the free fractions (f) were calculated according to respective plasma protein binding. The joint PK/PD target was defined as optimal whenever both the piperacillin fCss/MIC ratio was >4 and the tazobactam fCss/target concentration (CT) ratio was > 1 (quasi-optimal or suboptimal whenever only one or none of the two weas achieved, respectively). Multivariate logistic regression analysis was performed for testing variables potentially associated with microbiological outcome. (3) Results: Overall, 43 critically ill patients (median age 69 years; male 58.1%; median SOFA score at baseline 8) treated with CI piperacillin-tazobactam monotherapy were included. Optimal joint PK/PD target was attained in 36 cases (83.7%). At multivariate analysis, optimal attaining of joint PK/PD target was protective against microbiological failure (OR 0.03; 95%CI 0.003–0.27; p = 0.002), whereas quasi-optimal/suboptimal emerged as the only independent predictor of microbiological failure (OR 37.2; 95%CI 3.66–377.86; p = 0.002). (4) Conclusion: Optimized joint PK/PD target attainment of CI piperacillin-tazobactam could represent a valuable strategy for maximizing microbiological outcome in critically ill patients with documented Gram-negative BSI and/or VAP, even when sustained by extended-spectrum beta-lactamase (ESBL)-producing Enterobacterales. In this scenario, implementing a real-time TDM-guided ECPA program may be helpful in preventing failure in attaining optimal joint PK/PD targets among critically ill patients. Larger prospective studies are warranted to confirm 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

“…Importantly, previous preclinical studies showed that PK/PD target attainment of C min /MIC ratios ranging between 3.8 and 6.2 with beta-lactams was effective in preventing the emergenge of breakthrough resistance to beta-lactams among Gram-negatives [ 38 ]. This represented a first rationale for starting the adoption of an aggressive PK/PD target of 100% f T >4x MIC in clinical practice, as recently reported by several studies [ 6 , 28 , 29 ]. Scheduled timing for assessing aggressive PK/PD target attainment of beta-lactams may be crucial, especially in case of severe infections.…”

“…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.…”

“…Three studies (217 patients) provided data for assessing microbiological outcome [ 7 , 28 , 29 ]. Overall, failure in attaining aggressive beta-lactam PK/PD targets was significantly associated with higher risk of microbiological failure (OR 26.08; 95% CI 8.72–77.95; p < 0.001; Fig.…”

“…Three studies (365 patients) provided data for assessing beta-lactam resistance occurrence [ 7 , 23 , 29 ]. Overall, attaining aggressive PK/PD targets was significantly associated with lower risk of beta-lactam resistance development (OR 0.06; 95%CI 0.01–0.29; p < 0.001; Fig.…”

Real-Time TDM-Guided Optimal Joint PK/PD Target Attainment of Continuous Infusion Piperacillin–Tazobactam Monotherapy Is an Effective Carbapenem-Sparing Strategy for Treating Non-Severe ESBL-Producing Enterobacterales Secondary Bloodstream Infections: Findings from a Prospective Pilot Study

“…In a recent retrospective study carried out among 43 ICU critically ill patients having documented Gram-negative BSI and/or ventilator-associated pneumonia, we showed that the TDM-guided attainment of optimal joint PK/PD target of CI piperacillin–tazobactam monotherapy granted very high microbiological eradication rates (87.4%) and resulted in protection against microbiological failure (OR 0.03; 95%CI 0.003–0.27; p = 0.002) [ 53 ]. Although in that study the number of patients having ESBL-producing Enterobacterales infections was quite limited (only 6/43), the findings allowed us to hypothesize that this strategy could have been potentially effective even when dealing with ESBL producers [ 53 ].…”