Pharmacokinetic/Pharmacodynamic Target Attainment of Continuous Infusion Piperacillin–Tazobactam or Meropenem and Microbiological Outcome among Urologic Patients with Documented Gram-Negative Infections

Abstract

(1) Objectives: To describe the relationship between pharmacokinetic/pharmacodynamic (PK/PD) target attainment of continuous infusion (CI) piperacillin–tazobactam or meropenem monotherapy and microbiological outcome in a case series of urological patients with documented Gram-negative infections. (2) Methods: Patients admitted to the urology ward who were treated with CI piperacillin–tazobactam or meropenem monotherapy for documented Gram-negative infections and underwent real-time therapeutic drug monitoring (TDM)-guided expert clinical pharmacological advice (ECPA) program from June 2021 to May 2023 were retrospectively retrieved. Average steady-state (Css) piperacillin–tazobactam and meropenem concentrations were determined, and the free fractions (fCss) were calculated. Optimal PK/PD target attainments were defined as an fCss/MIC ratio >4 for CI meropenem and an fCss/MIC ratio of piperacillin >4 coupled with an fCss/CT ratio for tazobactam >1 for piperacillin–tazobactam (joint PK/PD target). The relationship between beta-lactam PK/PD targets and microbiological outcome was explored. (3) Results: Sixteen urologic patients with documented Gram-negative infections (62.5% complicated urinary tract infections (cUTI)) had 30 TDM-guided ECPAs. At first TDM assessment, beta-lactam dosing adjustments were recommended in 11 out of 16 cases (68.75%, of which 62.5% decreases and 6.25% increases). Overall, beta-lactam dosing adjustments were recommended in 14 out of 30 ECPAs (46.6%). Beta-lactam PK/PD target attainments were optimal in 100.0% of cases. Microbiological failure occurred in two patients, both developing beta-lactam resistance. (4) Conclusion: A TDM-guided ECPA program may allow for optimizing beta-lactam treatment in urologic patients with documented Gram-negative infections, ensuring microbiological eradication in most cases.

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

“…The PD determinant selected for assessing the efficacy of piperacillin–tazobactam monotherapy was a joint PK/PD target, as previously described [ 38 ]. Briefly, the joint PK/PD target was considered optimal whenever the piperacillin f C ss /MIC ratio was >4 and the tazobactam f C ss /target concentration (C T ) ratio was >1 (where C T is the fixed tazobactam target concentration of 4 mg/L proposed by the EUCAST for testing the in vitro susceptibility of the piperacillin–tazobactam combination); it was considered quasi-optimal whenever only one of the two thresholds was attained and suboptimal whenever none of the two was attained [ 38 ].…”

“…Some studies showed that when using beta-lactam/beta-lactamase inhibitor combinations (BL/BLIc), attaining optimal joint pharmacokinetic/pharmacodynamic (PK/PD) targets of both the BL and the BLI may be beneficial in terms of both maximizing the clinical/microbiological outcome and preventing resistance development [ 38 , 39 ]. In this scenario, implementing a real-time therapeutic drug monitoring (TDM)-based expert clinical pharmacological advice (ECPA) program may represent a valuable approach for assessing the optimal joint PK/PD target attainment of BL/BLIc administered by continuous infusion (CI) [ 40 ].…”

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?

“…The so-called joint PK/PD target was selected as best PD determinant of piperacillintazobactam efficacy. Specifically, the joint PK/PD target was defined as optimal when both the piperacillin f C ss /MIC ratio was >4 and the tazobactam f C ss /C T ratio was >1 (where C T corresponded to the fixed tazobactam target concentration used by the EUCAST for the in vitro standard susceptibility testing, namely, 4 mg/L), and quasi-optimal or suboptimal when only one or none of the two thresholds were attained, respectively [27]. Attainment of this aggressive PK/PD target with beta-lactams was previously associated with both maximal clinical efficacy and suppression of resistance emergence among Gram-negative pathogens [13][14][15][16][17][18][19].…”

“…All studies assessing aggressive PK/PD target attainment of piperacillin-tazobactam were based solely on piperacillin concentrations, without taking tazobactam exposure into account. Indeed, with regard to beta lactam (BL)-beta lactamase inhibitor (BLI) combinations, including piperacillin-tazobactam, the innovative concept of the so-called joint PK/PD target was recently proposed [27,28], in which optimal PK/PD target attainment should be achieved for both the BL and for the combined BLI simultaneously [27]. Additionally, it should not be overlooked that selecting the most appropriate dosing regimen may be extremely challenging in critically ill patients, considering that piperacillin-tazobactam pharmacokinetics may be significantly affected by sepsis-related pathophysiological changes [29][30][31][32].…”

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

“…With regard to meropenem, PK/PD target attainment was defined as being optimal when the f C ss /MIC ratio was >4 (equivalent to 100%f T > 4 × MIC ), and quasi-optimal or suboptimal when the f C ss /MIC ratio was 1-4 or <1 (equivalent to 100%f T 1-4 × MIC and to <100%f T 1 × MIC ), respectively, as previously reported [58]. With regard to the BL/BLI combinations, namely piperacillin-tazobactam, ceftazidime-avibactam, and meropenem-vaborbactam, a joint PK/PD target was considered [59,60]. With regard to piperacillin-tazobactam, the joint PK/PD target was defined as being optimal if both the piperacillin f C ss /MIC ratio was >4 and the tazobactam f C ss /target concentration (C T ) ratio was >1, and quasi-optimal or suboptimal if only one or none of the two thresholds was attained, respectively [59].…”