Category: Professional Posters
Purpose: The rising prevalence of carbapenem-resistant organisms have rendered previous gold-standard drugs ineffective. A beta-lactamase inhibitor (BLI) is used in an attempt to restore activity of beta-lactams against some of these resistant isolates. Several cephalosporin/BLI combinations have been marketed recently, thus, a comparative evaluation to assess their potential clinical utility is needed. We used Monte Carlo Analysis (MCA) to analyze three cephalosporin/BLI combinations against carbapenem-resistant Enterobacteriaceae (CRE): cefepime-zidebactam (FEP-ZID), ceftazidime-avibactam (CAZ-AVI), and ceftolozane-tazobactam (TOL-TAZ). As part of the analysis, an assessment of the susceptibility breakpoints was also performed.
Methods: Data for all three combinations were collected from peer-reviewed literature. MICs were selected from a global study that compared them against carbapenem-resistant Enterobacteriaceae (CRE, n = 1018). Pharmacokinetic (PK) parameters (volume of distribution, protein binding, and a CrCl vs. Cl regression) were collected. Two volumes of distribution were selected for each drug, the first representing infected patients in which the volume was similar to that of normal volunteers and the second representing patients with severe infections likely to increase the volume. Dosage regimens were selected from the product labels with the exception of cefepime-zidebactam which is still in development. Using our inpatient CrCl distribution, the PK parameters, and the dosage regimens, steady-state serum PK profiles (n=10,000) were simulated using a one-compartment model and integrated with the MIC values to assess the pharmacodynamic (PD) profiles. Two %fT>MIC PD targets were used: stasis (no net bacterial killing) and 2-log bacterial killing. From this, percent target attainment (%TA) was calculated. EUCAST susceptibility breakpoints for CAZ-AVI (8 mg/L) and TOL-TAZ (1 mg/L) were used to assess if %TA reached a threshold of ≥90%. Although there are no official breakpoints yet for FEP-ZID, a similar strategy was used for proposed breakpoints.
Results: At the lower stasis PD target, %TA for FEP-ZID, CAZ-AVI, and TOL-TAZ was 99, 79, and 18 respectively. At the higher 2-log killing target, %TA was 98, 78, and 15, respectively. Overall variability in %TA due to different volumes of distribution and dosage regimens was minimal. It appears that the breakpoints for CAZ-AVI and TOL-TAZ are conservative and higher breakpoints may be warranted. Breakpoints of 16 mg/L for both drugs would result in >95 %TA. FEP-ZID had %TA=100 at a proposed breakpoint of 4 mg/L.
Conclusion: Of the cephalosporin/BLI combinations evaluated, FEP-ZID appears to be preferred for empiric therapy of suspected CRE infections; however, a substantial number of patients may respond to CAZ-AVI. Thus, CAZ-AVI may be useful in de-escalation or when patient-specific susceptibility results are known. Our results suggest that TOL-TAZ should not be considered for empiric coverage for CRE. Consideration should be given to alterations in susceptibility breakpoints for CAZ-AVI and TOL-TAZ.