P-1226. Dose Optimization of β-lactams against Carbapenem-Resistant Pseudomonas from Turkiye Defined as Susceptible to Ceftazidime, Cefepime or Piperacillin/Tazobactam
Authors: Buyukyanbolu Ecem , Gill Christian M , Genc Leyla , Karakus Mehmet , Comert Fusun , Otlu Barış , Aktas Elif , Nicolau David P 
Published: January 2025

Abstract

Background
Due to the increasing prevalence of carbapenem-Resistant Pseudomonas aeruginosa (CRPA), effective agents are needed to treat these serious infections. Although CRPA may test susceptible to other β-lactams such as ceftazidime (CAZ), cefepime (FEP), and piperacillin/tazobactam (TZP), reduced potency has been observed amongst CRPA. In this study, we used PKPD analysis to assess the adequacy of the EUCAST Susceptible (S) or Susceptible Increased Exposure (SIE)/(I) doses for CAZ, FEP, and TZP against CRPA clinical isolates.Figure 1.Probability of target attainment (PTA) of various ceftazidime different dosing regimens and the MIC distribution of carbapenem-resistant Pseudomonas aeruginosa (CR-PA).

Methods
CRPA isolates were collected from patients at three Turkish hospitals between January 2017-December 2021. CAZ, FEP, and TZP MICs were determined using broth microdilution according to CLSI methodology. Monte Carlo simulations were performed to determine the probability of target attainment (PTA) for a free time above the MIC (fT &gt;MIC) targets for various doses of each agent against isolates defined as susceptible. fT &gt;MIC targets were 70% for CAZ or FEP and 50% for TZP. Cumulative fraction of response (CFR) was calculated by integrating PTA with the MIC distribution of the isolates. Optimal PTA and CFR were defined as 90% target achievement.Figure 2.Probability of target attainment (PTA) of various cefepime different dosing regimens and the MIC distribution of carbapenem-resistant Pseudomonas aeruginosa (CR-PA).

Results
In the setting of CR-PA, the percentages of isolates susceptible to CAZ, FEP, and TZP were 49,8%, 47%, and 31,8%, respectively. Reduced potency was noted with 54,1% of CAZ-S isolates had MICs of 4 or 8 mg/L. Of the FEP and TZP-S isolates, MICs at the breakpoint (8 and 16 mg/L, respectively) were the mode with 45,2 and 53,9% of isolates for each, respectively. At an MIC of 8 mg/L for CAZ, the EUCAST standard dose was found to be insufficient with a CFR of 85%. 3-hour infusions of EUCAST SIE doses were required for 90% PTA at MIC of 8 mg/L and an optimized CFR of 100% (Figure 1). For FEP, the SIE dose of 2 g q8h 0.5 h infusion of was effective (CFR 96%), utilization of an extended 3h infusion further optimized the PTA at 8 mg/L (CFR 99%) (Figure 2).
For TZP, the standard dose of 4.5 q6h administered as a 0.5h infusion was inadequate (CFR 86%). A standard TZP dose with an extended infusion (4.5 g IV q8h over 4 h) and the SIE dose 4.5 g IV q6h 3 h inf resulted in CFRs &gt;95% (Figure 3).Figure 3.Probability of target attainment (PTA) of various piperacillin/tazobactam different dosing regimens and the MIC distribution of carbapenem-resistant Pseudomonas aeruginosa (CR-PA).

Conclusion
These data support the EUCAST SIE breakpoints for FEP and TZP. To optimize PTA at the SIE breakpoint for CAZ, prolonged infusion is required.

Disclosures
Christian M. Gill, PharmD, Cepheid: Grant/Research Support|Entasis: Grant/Research Support|Everest Medicines: Grant/Research Support|Shionogi: Grant/Research Support David P. Nicolau, PharmD, CARB-X: Grant/Research Support|Innoviva: Grant/Research Support|Innoviva: Honoraria|Merck: Advisor/Consultant|Merck: Grant/Research Support|Merck: Honoraria|Pfizer: Advisor/Consultant|Pfizer: Grant/Research Support|Pfizer: Honoraria|Shionogi: Advisor/Consultant|Shionogi: Grant/Research Support|Shionogi: Honoraria|Venatorx: Grant/Research Support