Relevance of the Alexander Project: pharmacodynamic considerations

Application of pharmacodynamic principles for interpretation of data generated by the Alexander Project is possible for beta-lactam, quinolone and macrolide antibiotics. For beta-lactams, the time that serum concentrations remain above the MIC of the pathogen (T > MIC) is the parameter most closely linked with outcome. It has been shown that T > MIC need be only 50-60% of a dose interval. Since the MIC has the greatest influence on this parameter, a conservative estimate of activity would use the MIC90. The only beta-lactam antibiotics in the Alexander Project for which T > MIC90 for the four major pathogens (Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis and Staphylococcus aureus) exceeded 50% of the dose interval were amoxycillin/clavulanate (500/125 mg) and ceftriaxone. For macrolides, T > MIC is relevant for erythromycin and clarithromycin, but not azithromycin, for which AUC is the parameter most closely linked to outcome. Erythromycin, clarithromycin and azithromycin showed efficacy against M. catarrhalis only at MIC90. Quinolones (ciprofloxacin and ofloxacin), for which AUC is also the relevant pharmacodynamic parameter, had the greatest activity against H. influenzae and M. catarrhalis at MIC90, but were less effective against S. pneumoniae and S. aureus. Susceptibility data such as those provided by the Alexander Project can aid clinicians in choosing appropriate treatment for LRTI based on pharmacodynamic principles.