@article{WichaHuisingaKloft2017,
  author    = {Wicha, Sebastian G. and Huisinga, Wilhelm and Kloft, Charlotte},
  title     = {Translational pharmacometric evaluation of typical antibiotic broad-spectrum combination therapies against staphylococcus aureus exploiting in vitro information},
  series = {CPT: pharmacometrics \& systems pharmacology},
  volume    = {6},
  journal   = {CPT: pharmacometrics \& systems pharmacology},
  publisher = {Wiley},
  address   = {Hoboken},
  issn      = {2163-8306},
  doi       = {10.1002/psp4.12197},
  pages     = {512 -- 522},
  year      = {2017},
  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.},
  language  = {en}
}