Pharmacodynamics of glycopeptides in the mouse peritonitis model of Streptococcus pneumoniae or Staphylococcus aureus infection

The emergence of resistance to various antibiotics in pneumococci leaves th e glycopeptides as the only antibiotics against which pneumococci have no r esistance mechanism. This situation has led to a renewed interest in the us e of glycopeptides. It has not yet been possible to conclude which one or m ore of the pharmacokinetic or pharmacodynamic (PK/PD) parameters are the mo st important and best predictors for the effects of treatment with glycopep tides in animal models or in humans. We used the mouse peritonitis model wi th immunocompetent mice and with Staphylococcus aureus and Streptococcus pn eumoniae as infective organisms. A wide spectrum of different treatment reg imens with vancomycin and teicoplanin was tested to study the pharmacodynam ics of these drugs. In studies in which the single dose that protected 50% of lethally infected mice (ED50) was given as one dose or was divided into two doses, survival was significantly decreased when the dose was divided. The only statistically significant correlations between the percentage of s urvival of the mice after 6 days and each of the PK/PD parameters were for peak concentration (C-max)/MIC and S. aureus and for the free fraction of C -max (Cmax-free)/MIC and S. pneumoniae. For S. pneumoniae, the ED50 for dif ferent dosing regimens increased with the number of doses given; e.g., the single-dose ED(50)s for vancomycin and teicoplanin were 0.65 and 0.45 mg/kg , respectively, but the ED(50)s for dosing regimens with 2-h doses given fo r 48 h were 6.79 and 5.67 mg/kg, respectively. In experiments with 39 diffe rent vancomycin dosing regimens and 40 different teicoplanin dosing regimen s against S. pneumoniae, the different PK/PD parameters were analyzed using logistic regression. The Cmax-free/MIC was one of two parameters that best explained the effect for both drugs; for vancomycin, the other important p arameter was the AUC/ MIC, and for teicoplanin, the other parameter was the time the free fraction of the drug is above the MIC. The effect analyzed a s a function of Cmax-free/MIC disclosed thresholds with shifts from almost no effect to full effect at ratios of five to six for vancomycin and two to three for teicoplanin.