1565. Characterization of Tebipenem (SPR859) Pharmacokinetics–Pharmacodynamics (PK-PD) for Efficacy Against Enterobacteriaceae in a One-Compartment In Vitro Infection Model

Abstract

BackgroundSPR859 (tebipenem) is the active form of the orally bioavailable prodrug SPR994. Tebipenem is an oral carbapenem with a broad-spectrum activity against Gram-positive and -negative bacteria. SPR994 is being developed as an oral option for the treatment of complicated urinary tract infections (cUTI). The goal of these studies was to characterize the PK-PD of tebipenem against a diverse panel of Enterobacteriaceae.Methods24-hour dose-fractionation and dose-ranging studies were carried out utilizing the one-compartment in vitro infection model. Bacteria (1 × 106 CFU/mL) were exposed to tebipenem concentrations that mimicked human healthy volunteer free-drug plasma (f) concentration–time profiles following oral drug administration. For the dose-fractionation studies, 7 total daily dose levels (fAUC range, 0.11 to 19.0 mg hours/L) were fractionated in equal divided doses administered every 4, 8 or 12 hours (q4h, q8h and q12h, respectively). A single challenge isolate, E. coli ATCC 25922 (MIC = 0.015 mg/L), was evaluated in the dose-fractionation studies. In the dose-ranging studies, 13 Enterobacteriaceae clinical isolates (MIC values from 0.008 to 0.25 mg/L) were exposed to doses ranging from 4.69 to 1200 mg administered q8h (fAUC ranging from 0.14 to 37.2 mg hours/L). Relationships between change in log10 CFU from baseline at 24 h and each of fCmax:MIC ratio, f%T>MIC, and fAUC:MIC ratio, with and without adjustment for dosing interval tau for the latter (fAUC:MIC ratio·1/τ), were fit using Hill-type models.ResultsDose-fractionation study results demonstrated the activity of tebipenem to be time-dependent, with both f%T>MIC and fAUC:MIC ratio·1/τ similarly describing the PK-PD of tebipenem. The relationship between change in log10 CFU from baseline at 24 hours and fAUC:MIC ratio·1/τ, as assessed using pooled data for 13 Enterobacteriaceae isolates evaluated in the dose-ranging studies, described the PK-PD of tebipenem well (Figure 1). The magnitude of fAUC:MIC ratio·1/τ associated with net bacterial stasis and 1- and 2-log10 CFU reductions from baseline was 7.23, 13.1, and 32.4, respectively.ConclusionThese data will be useful to design other pre-clinical studies and support tebipenem dose selection for clinical studies in patients with cUTI. Disclosures All authors: No reported disclosures.