2569. Pharmacokinetic-Pharmacodynamic Evaluation of Sulopenem Using a Five-Day Hollow-Fiber In Vitro Infection Model
Abstract
Abstract Background Sulopenem etzadroxil, the oral (PO) prodrug of the active moiety sulopenem, is a thiopenem in development for the treatment of uncomplicated urinary tract infection (uUTI). Oral sulopenem is a bilayer tablet composed of sulopenem etzadroxil and probenecid, an organic anion transport inhibitor that delays renal excretion of sulopenem. The goal of these studies was to determine whether the chosen clinical PO dosing regimen of 500 mg q12h, based on murine thigh models, would induce resistance amplification in a hollow-fiber in vitro infection model over a clinically relevant time period. Methods Four Escherichia coli clinical isolates (fluoroquinolone-R, ESBL +, Sequence Type 131, sulopenem MIC 0.03 to 0.125 mg/L), at an initial burden of 106 CFU/mL, were subjected to sulopenem concentration-time profiles simulating total-drug urine concentrations following a 500 mg PO q12h regimen in a hollow-fiber in vitro infection model. Each isolate was additionally exposed to negative (levofloxacin 750 mg) and positive (meropenem 2 g) control regimens simulating free-drug plasma concentrations following intravenous (IV) dosing every 24 and 8 hours, respectively. Samples were collected for the enumeration of bacterial burdens and evaluation of the simulated pharmacokinetic profiles over the five-day study period. Each sample for bacterial enumeration was suspended onto agar plates, with and without supplementation of the respective antibiotic, to observe the density of…
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