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
