P-1258. Unlocking Potentials: The Impact of Meropenem, Meropenem-vaborbactam, and Ceftazidime-avibactam in Combatting Carbapenem-Resistant <i>Enterobacter cloacae</i> in Epithelial Lining Fluid and Serum

Abstract Background Carbapenem-resistant Enterobacterales (CRE) are an urgent threat. We modeled epithelial lining fluid (ELF) and serum concentrations of meropenem (MER), meropenem-vaborbactam (MV), and ceftazidime-avibactam (CA) to assist in treatment selection. Meropenem, meropenem-vaborbactam, and ceftazidime-avibactam dosing simulating ELF concentrations with a non-CP-producing CRE Methods Two E. cloacae were evaluated, one a non-carbapenemase (CP) producing isolate with multiple porin mutations and blaACT-15, and one blaKPC-3 CP-producing isolate. One compartment IVPD models were run in duplicate for ELF and humanized serum concentration targets. Models were sampled for CFU/mL counts at 0, 4, 6, 8, 24, 32, 48, 72, 96, and 120h. Concentrations were extrapolated from population-pharmacokinetic data to reflect free drug concentrations in ELF and serum. Antibiotics were administered as a bolus, with serum models also run as an extended infusion (EI). Susceptibility changes, via E-test, were evaluated every 24h and compared to 0h. Bactericidal activity was defined as ≥3log10 CFU/mL reduction from the initial inoculum, and bacteriostatic activity as &amp;lt; 3 log10 CFU/mL reduction. Meropenem, meropenem-vaborbactam, and ceftazidime-avibactam dosing simulating serum concentrations at steady state with a CP-producing CRE Results BlaACT-15 isolate: ELF concentrations of MER and MV were bactericidal through 24h with MIC shifts in both treatments, including MER MIC shifts to &amp;gt;32μg/mL and MV MIC shifts to 16μg/mL. CA ELF concentrations were bacteriostatic through 48h before bacterial regrowth above the initial inoculum and MIC shifts to 64μg/mL. All bolus serum antimicrobial concentrations resulted in bactericidal activity, however, only MV remained bactericidal at 120h with no MIC shifts. EI-MER and EI-MV alternatively were bacteriostatic after 48h. BlaKPC-3 isolate: Bactericidal activity was only observed with MV, in ELF models with no MIC shift. CA and MER ELF concentrations had bacterial regrowth after 24h. MIC shifts included a change to &amp;gt;256μg/mL after CA exposure. Serum concentrations of CA and MV were bacteriostatic through 24h. CA and MV serum models had bacterial regrowth after 72h with MIC shifts to 16μg/mL for CA. No MIC shifts were observed with serum MV. Bolus and EI results were similar for all. Meropenem, meropenem-vaborbactam, and ceftazidime-avibactam dosing simulating serum concentrations at steady state with a non-CP-producing CRE Conclusion MV serum concentrations were the most active therapy, with no MIC shifts, for two CRE E. cloacae IVPD models. ELF concentrations should be considered as a contributing factor to treatment failure and resistance development. Meropenem, meropenem-vaborbactam, and ceftazidime-avibactam dosing simulating ELF concentrations with a CP-producing CRE Disclosures jason M. Pogue, PharmD, Entasis: Advisor/Consultant|GSK: Advisor/Consultant|Melinta: Advisor/Consultant|Melinta: Grant/Research Support|Merck: Advisor/Consultant|Merck: Grant/Research Support|Shionogi: Advisor/Consultant|Shionogi: Grant/Research Support|Venatorx: Advisor/Consultant Kerry L. LaPlante, Pharm.D., FCCP, FIDSA, FIDP, Abbive: Advisor/Consultant|Abbive: Grant/Research Support|Ferring: Advisor/Consultant|Gilead: Grant/Research Support|Melinta: Advisor/Consultant|Merck: Grant/Research Support|Pfizer: Grant/Research Support