2532. Pharmacokinetic-Pharmacodynamic Analyses for Ceftobiprole Efficacy Based on Phase 3 Data from Patients with Staphylococcus aureus Bacteremia

Abstract Background Ceftobiprole medocaril is an intravenously (IV) administered cephalosporin prodrug that is rapidly converted in vivo to ceftobiprole, which has activity against Gram-positive and Gram-negative organisms. Ceftobiprole is being developed for the treatment of patients with S. aureus bacteremia (SAB). Pharmacokinetic-pharmacodynamic (PK-PD) relationships for efficacy were evaluated using data from ceftobiprole-treated patients with SAB from the ERADICATE Phase 3 study [IDWeek 2022, LB202]. Methods Ceftobiprole-treated patients in the modified Intent-to-Treat (mITT) populations of Cohorts 1 and 2 (maximum treatment duration of 28 and 42 days, respectively) with an MIC value for the baseline S. aureus and PK data were considered. On Days 1-8, patients received ceftobiprole 500 mg IV every 6 hours followed by 500 mg IV every 8 hours on Day 9 and onwards with dose adjustment for renal impairment. Using a population PK model and PK data from patients, ceftobiprole free-drug plasma %T >MIC on Days 1 and 10 were determined. Univariable relationships between the dichotomous or time-to-event efficacy endpoints summarized in Table 1 and each of Days 1 or 10 free-drug plasma %T >MIC and baseline MIC were evaluated. Results A summary of response for efficacy endpoints among the 172 evaluable patients with SAB is provided in Table 2. As shown in Table 3, nearly all patients achieved Days 1 and 10 ceftobiprole free-drug plasma %T > MIC ≥ 97.9%. Given this distribution, the evaluation of associations with efficacy endpoints was limited. There was no substantial evidence of relationships between either increased free-drug plasma %T > MIC or reduced baseline MIC and increased efficacy among the endpoints assessed. All patients achieved free-drug plasma %T > MIC that exceeded the non-clinical free-drug plasma %T > MIC target of 24.7% associated with a 1-log10 CFU reduction from baseline for S. aureus. Conclusion Results of these analyses did not demonstrate relationships between either ceftobiprole free-drug plasma %T > MIC or baseline MIC and response. Given the favorable Phase 3 ERADICATE study findings of ceftobiprole non-inferiority relative to daptomycin, these data suggested that ceftobiprole exposures were efficacious and provide support for the ceftobiprole dosing regimens evaluated. Disclosures Sujata M. Bhavnani, PharmD; MS; FIDSA, Adagio Therapeutics, Inc.: Grant/Research Support|Albany Medical Center: Grant/Research Support|Amplyx Pharmaceuticals