Category: Professional Posters
Purpose: VNRX-5133, a novel cyclic boronate-based broad spectrum beta-lactamase inhibitor, enhances the activity of cefepime against difficult to treat pathogens, including cephalosporin and carbapenem-resistant Enterobacteriaceae (ENT) and Pseudomonas aeruginosa (PA) producing serine- and metallo-beta-lactamases from all Ambler Classes. Cefepime, in combination with VNRX-5133, began Phase 3 clinical trials in April 2019. A Monte Carlo Analysis (MCA) was performed on cefepime alone (FEP) and in combination with VNRX-5133 (FEP-VNRX) to assess their potential efficacy against resistant Gram-negative organisms.
Methods: MCA (n=10,000) was performed for FEP and FEP-VNRX using pharmacokinetic parameters, pharmacodynamic (PD) targets, and recent MIC distributions collected from peer-reviewed literature. Four resistant organisms were analyzed: cefepime non-susceptible PA (PA FEP NS), meropenem non-susceptible PA (PA MEM NS), NDM-producing Enterobacteriaceae (ENT NDM), and KPC-producing Enterobacteriaceae (ENT KPC). The MCA analyzed 2 volumes of distribution, representing normal (V1) and burn/septic (V2) patients, and 4 body weights (60, 70, 80, 90 kg). Total body clearance was estimated using a CrCl vs. Cl regression and simulated using our inpatient CrCl distribution. Two dosage regimens were assessed, both using a 2-hour infusion time and adjusted for renal function: cefepime product label (D1), and experimental regimen (D2). D1 had a slightly higher average daily drug exposure compared to D2. The PD target was the percentage of time the free serum concentration remains above the MIC in a dosing interval (%fT>MIC). Low (%fT>MIC ≥40%, LT) and high (%fT>MIC ≥70%, HT) PD targets (%fT>MIC), representing bacterial stasis (no net bacterial killing) and near maximal killing (2-logs of bacterial killing), respectively, were used. Target attainment (the percentage of simulated patients reaching each of these targets, %TA) was assessed.
Results: The following results with D1, V1, and an 80kg patient were: LT/HT %TA was 48/24 (FEP) and 82/76 (FEP-VNRX) for PA FEP NS, 60/47 (FEP) and 85/81 (FEP-VNRX) for PA MEM NS, 5/2 (FEP) and 96/88 (FEP-VNRX) for ENT NDM, and 22/15 (FEP) and 100/100 (FEP-VNRX) for ENT KPC. Across all variables, the median %TA ratio of FEP-VNRX to FEP for LT/HT was 1.7/2.7 for PA FEP NS, 1.4/1.7 for PA MEM NS, 19.0/30.7 for ENT NDM, and 4.5/6.1 for ENT KPC.
Overall, volume and body weight minimally affected %TA of both drugs and dosage regimens. Difference in %TA due to variables was low: ≤2% (LT) and ≤10% (HT) for volume, and ≤2% (LT) and ≤9% (HT) for body weight. Interestingly, D1 and D2 produced similar %TA across all 4 organisms, with D2 usually having the same or higher %TA than D1 (differing ≤1% for LT and ≤5% for HT). The largest differences in %TA due to volume, weight, or dosing regimen were observed for HT with PA FEP NS.
Conclusion: The high target attainment for FEP-VNRX for all four pathogens suggests that it may be useful for empiric therapy. FEP alone showed poor %TA for resistant Enterobacteriaceae species, thus, it should not be used against those organisms. Interestingly, for P. aeruginosa organisms identified as resistant to FEP, the results suggest that some patients may still respond to FEP therapy. Thus, it may be considered for de-escalation therapy, or to treat pathogens in which susceptibility is known.