Characterization of sulopenem antimicrobial activity using <i>in vitro</i> time-kill kinetics, synergy, post-antibiotic effect, and sub-inhibitory MIC effect methods against <i>Escherichia coli</i> and <i>Klebsiella pneumoniae</i> isolates

Sulopenem is an oral and intravenous penem antibiotic in clinical development for treatment of urinary tract and intra-abdominal infections caused by multidrug-resistant pathogens. This study evaluated <i>in vitro</i> antimicrobial activity of sulopenem by post-antibiotic effect (PAE), sub-inhibitory minimal inhibitory concentration PAE effect (PAE-SME), checkerboard testing, and time-kill testing. Testing sulopenem at 1×, 5×, or 10× the baseline MIC resulted in a PAE interval of 0.0-0.7 hours. When exposed to 0.5× the sulopenem MIC following 5× MIC, all isolate/agent combinations had PAE-SME values of >4.8 hours. Checkerboard testing revealed no instances of antagonism between sulopenem and comparator agents-indifference was observed in most sulopenem checkerboard combinations. Sulopenem demonstrated bactericidal activity (≥3 log₁₀ [99.9%] reduction in viable organism counts) in all time-kill assays following 24 hours of incubation at 8× the baseline MIC (6/6), 5/6 displaying this activity within 8 hours. The present antimicrobial parameters seen at concentrations surrounding the MIC support optimization of sulopenem dosing and further development. The oral dosing regimen of sulopenem etzadroxil/probenecid 500 mg/500 mg administered every 12 hours was recently evaluated in two phase 3 clinical trials where sulopenem demonstrated efficacy against amoxicillin-clavulanate in uncomplicated urinary tract infection (uUTI) and against ciprofloxacin in fluoroquinolone-resistant uUTI.IMPORTANCESulopenem is an oral and intravenous penem antibiotic in clinical development for treatment of urinary tract and intra-abdominal infections caused by multidrug-resistant pathogens. This study evaluated sulopenem via broth microdilution susceptibility testing, PAE, sub-inhibitory MIC PAE effect, checkerboard testing, and time-kill testing. The results of this study-interpreted along with recent pharmacodynamic <i>in vitro</i> one-compartment and hollow-fiber infection model work-provide insight into the <i>in vitro</i> activity of sulopenem.