P-1357. Comparative In Vitro Activity of Sulbactam-Durlobactam and Ampicillin-Sulbactam Against A. baumannii with and without PBP3 Mutation

TL;DR

This study compares the effectiveness of two antibiotic combinations against Acinetobacter baumannii, a difficult-to-treat bacteria, with and without a specific mutation.

Contribution

The study evaluates the in vitro activity of sulbactam-durlobactam versus ampicillin-sulbactam against A. baumannii with and without a PBP3 mutation.

Findings

Sulbactam-durlobactam showed activity against carbapenem-resistant A. baumannii with a PBP3 mutation.

Ampicillin-sulbactam caused MIC shifts and bacterial regrowth in susceptible strains.

Sulbactam-durlobactam performed similarly to meropenem against susceptible A. baumannii without MIC shifts.

Abstract

Treatment options for Acinetobacter baumannii are limited. The Infectious Diseases Society of America (IDSA) currently recommends the use of sulbactam-containing regimens whenever possible. We modeled serum concentrations of sulbactam-durlobactam (SUL-DUR), ampicillin-sulbactam (AMP-SUL), and meropenem (MER) to assist with combination treatment selection.Sulbactam-durlobactam and ampicillin-sulbactam dosing simulating humanized serum concentrations at steady state against carbapenem-resistant A. baumannii with a PBP3 mutationSulbactam-durlobactam, ampicillin-sulbactam, and meropenem dosing simulating humanized serum concentrations at steady state against carbapenem-susceptible A. baumannii

Sulbactam-durlobactam and ampicillin-sulbactam dosing simulating humanized serum concentrations at steady state against carbapenem-resistant A. baumannii with a PBP3 mutation

Sulbactam-durlobactam, ampicillin-sulbactam, and meropenem dosing simulating humanized serum concentrations at steady state against carbapenem-susceptible A. baumannii

Two A. baumannii isolates were evaluated, one carbapenem-susceptible (AR300) and, one carbapenem-resistant (ARC5950) with a penicillin binding protein-3 (PBP3) mutation. We conducted one compartment in vitro pharmacodynamic models using a starting inoculum of 6-log10 CFU/mL, simulating monotherapies with SUL-DUR or AMP-SUL with inflow media set to the respective antibiotic half-life. We additionally ran MER treatment models against the carbapenem-susceptible strain. Models were run in duplicate, simulating humanized serum concentrations targets selected based on free drug concentrations achievable in patients using 2024 IDSA dosing recommendations. Models were sampled for CFU/mL counts at 0, 4, 6, 8, 24, 32, 48, and 72h. Susceptibility changes were evaluated by E-test every 24h and compared to 0h.

Against AR300, all agents demonstrated initial bacteriostatic activity after 6h. Minimum inhibitory concentration (MIC) shifts were detected as early as 24h with AMP-SUL treatment and coincided with bacterial regrowth above the initial inoculum. There were no SUL-DUR MIC shifts seen for this isolate in any SUL-DUR or AMP-SUL treated models. Antibacterial activity was similar for both MER and SUL-DUR monotherapies through 72h. Against ARC5950, only SUL-DUR treatment produced a 1-log10 CFU reduction. Bacterial regrowth did occur with SUL-DUR treatment, accompanied by an increased MIC in one of the two models, and exceeded the initial inoculum after 48h of treatment. AMP-SUL monotherapy produced a slight initial reduction in colony count, however, after 6h, regrowth surpassed the starting inoculum. Treatment with AMP-SUL did not correspond with elevated SUL-DUR MICs.

SUL-DUR monotherapy was active against carbapenem-resistant A. baumannii with a PBP3 mutation and displayed similar activity to meropenem against carbapenem-susceptible A. baumannii with no MIC shifts.

Thomas Lavoie, PharmD, innoviva: Grant/Research Support|innoviva: Co-investogator|melinta: Grant/Research Support|pfizer: Grant/Research Support|shionogi: Grant/Research Support Kerry L. LaPlante, Pharm.D., FCCP, FIDSA, FIDP, Abbvie: Advisor/Consultant|Abbvie: Grant/Research Support|Innoviva: Advisor/Consultant|Innoviva: Grant/Research Support|Melinta: Grant/Research Support|Pfizer: Grant/Research Support|Shionogi: Advisor/Consultant|Shionogi: Grant/Research Support

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