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Antimicrobial Agents and Chemotherapy, May 2000, p. 1247-1254, Vol. 44, No. 5
Division of Microbiology, Statens Serum
Institut, Copenhagen, Denmark,1 and
Providence Medical Center, Portland, Oregon2
Received 25 March 1998/Returned for modification 18 September
1998/Accepted 8 February 2000
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 (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
survival of the mice after 6 days and each of the PK/PD parameters were
for peak concentration (Cmax)/MIC and S. aureus and for the free fraction of Cmax
(Cmax-free)/MIC and S. pneumoniae.
For S. pneumoniae, the ED50 for different
dosing regimens increased with the number of doses given; e.g., the
single-dose ED50s for vancomycin and teicoplanin were 0.65 and 0.45 mg/kg, respectively, but the ED50s 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 Cmax-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
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.
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
Pharmacodynamics of Glycopeptides in the Mouse
Peritonitis Model of Streptococcus pneumoniae or
Staphylococcus aureus Infection
*
Corresponding author. Mailing address: Microbiological
Research and Development, Division of Microbiology, Statens Serum
Institut, 5, Artillerivej, DK-2300 Copenhagen S, Denmark. Phone: 45 3268 3175. Fax: 45 3268 3887. E-mail: jdk{at}ssi.dk.
Antimicrobial Agents and Chemotherapy, May 2000, p. 1247-1254, Vol. 44, No. 5
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
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