Translational Pharmacometric Evaluation of Typical Antibiotic Broad‐Spectrum Combination Therapies Against Staphylococcus Aureus Exploiting In Vitro Information

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.