title: Translational Pharmacometric Evaluation of Typical Antibiotic Broad-Spectrum Combination Therapies Against Staphylococcus Aureus Exploiting In Vitro Information.
abstract: Broad-spectrum antibiotic combination therapy is frequently applied due to increasing resistance development of infective pathogens. The objective of the present study was to evaluate two common empiric broad-spectrum combination therapies consisting of either linezolid (LZD) or vancomycin (VAN) combined with meropenem (MER) against Staphylococcus aureus (S. aureus) as the most frequent causative pathogen of severe infections. A semimechanistic pharmacokinetic-pharmacodynamic (PK-PD) model mimicking a simplified bacterial life-cycle of S. aureus was developed upon time-kill curve data to describe the effects of LZD, VAN, and MER alone and in dual combinations. The PK-PD model was successfully (i) evaluated with external data from two clinical S. aureus isolates and further drug combinations and (ii) challenged to predict common clinical PK-PD indices and breakpoints. Finally, clinical trial simulations were performed that revealed that the combination of VAN-MER might be favorable over LZD-MER due to an unfavorable antagonistic interaction between LZD and MER.
authors.affiliation: Department of Clinical Pharmacy and Biochemistry, Institute of Pharmacy, Freie Universitaet Berlin, Berlin, Germany.
authors.forename: S G
authors.initials: SG
authors.lastname: Wicha
authors.affiliation: Institute of Mathematics, University of Potsdam, Potsdam-Golm, Germany.
authors.forename: W
authors.initials: W
authors.lastname: Huisinga
authors.affiliation: Department of Clinical Pharmacy and Biochemistry, Institute of Pharmacy, Freie Universitaet Berlin, Berlin, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Kloft
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D003198:Computer Simulation; D004359:Drug Therapy, Combination; D066298:In Vitro Techniques; D000069349:Linezolid / Q000494:pharmacology*; D000077731:Meropenem; D008826:Microbial Sensitivity Tests; D008962:Models, Theoretical; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000302:isolation & purification; D013845:Thienamycins / Q000494:pharmacology*; D057170:Translational Research, Biomedical; D014640:Vancomycin / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D013845:Thienamycins; D014640:Vancomycin; D000077731:Meropenem; D000069349:Linezolid