Pharmacodynamics of Glycopeptides in the Mouse Peritonitis Model ofStreptococcus pneumoniaeorStaphylococcus aureusInfection

Abstract

The emergence of resistance to various antibiotics in pneumococci leaves the glycopeptides as the only antibiotics against which pneumococci have no resistance mechanism. This situation has led to a renewed interest in the use of glycopeptides. It has not yet been possible to conclude which one or more of the pharmacokinetic or pharmacodynamic (PK/PD) parameters are the most important and best predictors for the effects of treatment with glycopeptides in animal models or in humans. We used the mouse peritonitis model with immunocompetent mice and with Staphylococcus aureus and Streptococcus pneumoniae as infective organisms. A wide spectrum of different treatment regimens with vancomycin and teicoplanin was tested to study the pharmacodynamics of these drugs. In studies in which the single dose that protected 50% of lethally infected mice (ED 50 ) 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 survival 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 (C max-free )/MIC and S. pneumoniae. For S. pneumoniae, the ED 50 for different 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 for 48 h were 6.79 and 5.67 mg/kg, respectively. In experiments with 39 different vancomycin dosing regimens and 40 different teicoplanin dosing regimens against S. pneumoniae, the different PK/PD parameters were analyzed using logistic regression. The C max-free /MIC was one of two parameters that best explained the effect for both drugs; for vancomycin, the other important parameter 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 as a function of C max-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.

Pharmacokinetic/pharmacodynamic (PK/PD) considerations in the management of Gram-positive bacteraemia

“…T >MIC was thus initially pneumoniae as infective organisms [24]. The data showed that C max-free was of major importance in the one-and two-dose trials, but this parameter alone could not explain the effects achieved in the multidose trials.…”

A higher dose of vancomycin in continuous infusion is needed in critically ill patients

“…However, experimental models in neutropenic mice have shown some concentration-dependent activity [maximum drug concentration/minimum inhibitory concentration ratio (C max /MIC)], with advantages also evident when the area under the concentration-time curve (AUC) to MIC ratio (AUC/MIC) is maximised [2]. Therefore, the question remains whether intermittent dosing or continuous infusion is preferred.…”

A Mouse Peritonitis Model for the Study of Glycopeptide Efficacy in GISA Infections

“…The parameters calculated were: peak drug concentration in serum (C max ), elimination half-life (T 1/2 ), area under the concentration-time curve (AUC), inhibitory quotient (IQ; IQ ϭ C max /MIC), and time above the MIC of the drug concentration in serum (T Ͼ MIC). Based on previous studies, 6,15,16 human data, 7,21,30 and …”

“…Different time points were tested to study the evolution of the infection and appropriate time points were set for starting therapy. Groups of mice were killed at 4,8,16, and 24 hr postinoculation to obtain blood and peritoneal fluid (PF) samples as described below. Bacterial counts and bacteremia were determined for each mouse and time point.…”

“…To evaluate effortlessly the in vivo efficacy of different antimicrobial treatments for MRSA and GISA infections, we have developed a modified model of mouse peritonitis, using clinical strains of S. aureus with different susceptibilities to ␤-lactams and glycopeptides. The mouse peritonitis model is straightforward, rapid, and easily reproducible, and has been widely used in testing antibiotics in vivo 8,11,[13][14][15][16]18,23,26 ; however, although it has been used for the study of S. aureus infections, 11,16,18,23,26 only a few comparative therapeutic studies have been reported. In this particular study, we performed the standardization of the model and assessed the comparative efficacy of monotherapy with cloxacillin, cefotaxime, vancomycin, and teicoplanin against the infection caused by four S. aureus strains.…”