Date of Award

2026

Document Type

Dissertation

Degree Name

Doctor of Pharmaceutical Sciences - Pharmaceutics

Department

Pharmaceutical Sciences

Committee Chair and Members

David Taft, Chair

Jaclyn Cusumano

Glen Kowach

Kushal Shah

Keywords

Ceftaroline, Enterococcus faecalis, PBPK modeling, PBPK-PD modeling, Penicillin, Simcyp

Abstract

Bacterial resistance to antibiotics continues to be a global health problem, limiting antibacterial therapy against infective endocarditis caused by Enterococcus faecalis. To overcome increasing resistance, dual beta-lactam therapy has been advocated as an alternative regimen for treatment – the synergistic activity against E. faecalis demonstrated to be effective. Currently, ampicillin plus ceftriaxone is the standard of care, but the practical application of this therapy is limited by ampicillin’s poor stability in solution at room temperature. A synergistic combination of penicillin plus ceftriaxone shows promise due to penicillin’s superior stability at ambient temperature, but ceftriaxone’s potential to cause hepatoxicity further limits this therapy. Additionally, ceftriaxone can increase the risk for vancomycin resistant enterococcus (VRE) colonization and Clostridioides difficile infections. An alternative therapy is tested in this dissertation – penicillin plus ceftaroline. Penicillin plus ceftaroline combination demonstrated greater synergistic and bactericidal activity through time-kill assays, against penicillin-susceptible (minimum inhibitory concentration [MIC] = 2 μg/ml) and borderline penicillin-resistant, ampicillin-susceptible E. faecalis (PRASEF) (MIC = 4 μg/ml) strains as compared to penicillin plus ceftriaxone combination therapy.

A model-based approach was utilized to predict the impact of dual beta-lactam therapy on antibiotic-resistant bacteria in healthy and severe renal impairment populations. A physiologically based pharmacokinetic pharmacodynamic (PBPK-PD) model was developed for penicillin plus ceftaroline combination therapy against E. faecalis utilizing two steps: initial construction of PBPK models for penicillin and ceftaroline to simulate systemic exposure of both medications, and incorporation of PD parameters describing E. faecalis bacterial growth in the absence and presence of antibiotics. Initial PBPK models of penicillin and ceftaroline were validated in a healthy volunteer population with normal renal function using literature data. PBPK models were extended to a severe renal impairment population (GFR = 15-30 ml/min) and validated to demonstrate that the constructed models could be successfully extended to this special target population. PD parameters were acquired from penicillin-susceptible (e.2122) and borderline-PRASEF (e.2095) strains.

The final PBPK-PD model of penicillin plus ceftaroline combination therapy against penicillin-susceptible and borderline-PRASEF strains was applied to Healthy Volunteer and Severe Renal Impairment populations. The model-simulated bacterial reduction versus time profiles of combination therapy against E. faecalis exhibited greater reduction against isolate e.2122 than isolate e.2095. This was consistent with the entirety of this study, with less bacterial reduction resulting in borderline-PRASEF strains, from time-kill assays to bacterial growth kinetics, and finally, bacterial reduction profiles of penicillin plus ceftaroline against E. faecalis. This study not only validates penicillin plus ceftaroline as an alternative combination therapy but demonstrates its superior activity against borderline-PRASEF. This also supports the clinical application of penicillin susceptibility testing in patients with E. faecalis infective endocarditis in order to provide safe and effective dosing regimens. In this research, the least but most effective dose against E. faecalis in severe renal impairment population was found to be 3MU q8H for penicillin plus 0.5xMIC for ceftaroline.

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