In vivo pharmacodynamic activities of two glycylcyclines (GAR-936 and WAY 152,288) against various gram-positive and gram-negative bacteria

The in vivo pharmacodynamic activities of two glycylcyclines (GAR-936 and W AY 152,288) were assessed in an experimental murine thigh infection model i n neutropenic mice. Mice were infected with one of several strains of Strep tococcus pneumoniae, Staphylococcus aureus, Escherichia coli, or Klebsiella pneumoniae. Most infections were treated with a twice-daily dosing schedul e, with administration of 0.75 to 192 mg of GAR-936 or WAY 152,288 per kg o f body weight, A maximum-effect dose-response model was used to calculate t he dose that produced a net bacteriostatic effect over 24 h of therapy. Thi s dose was called the bacteriostatic dose. More extensive dosing studies we re performed with S. pneumoniae 1199, E. coli ATCC 25922, and K. pneumoniae ATCC 43816, with doses being given as one, two, four, or eight equal doses over a period of 24 h. The dosing schedules were designed in order to mini mize the interrelationship between the various pharmacokinetic and pharmaco dynamic parameters studied. These parameters were time above 0.03 to 32 tim es the MIG, area under the concentration-time curve (AUC), and maximum conc entration of drug in serum (C-max). The bacteriostatic dose remained essent ially the same, irrespective of the dosing frequency, for S. pneumoniae 119 9 (0.3 to 0.9 mg/kg/day), For E. coli ATCC 25922 and K. pneumoniae ATCC 438 16, however, more frequent dosing led to lower bacteriostatic doses. Pharma cokinetic studies demonstrated dose-dependent elimination half-lives of 1.0 5 to 2.34 and 1.65 to 3.36 h and serum protein bindings of 59 and 71% for G AR-936 and WAY 152,288, respectively. GAR-936 and WAY 152,288 were similarl y effective against the microorganisms studied, with small differences in m aximum effect and 50% effective dose. The glycylcyclines were also similarl y effective against tetracycline-sensitive and tetracycline-resistant bacte ria. Time above a certain factor (range, 0.5 to 4 times) of the MIC was a b etter predictor of in vivo efficacy than C-max or AUC for most organism-dru g combinations. The results demonstrate that in order to achieve 80% maximu m efficacy, the concentration of unbound drug in serum should be maintained above the MIC for at least 50% of the time for GAR-936 and for at least 75 % of the time for WAY 152,288. The results of these experiments will aid in the rational design of dose-finding studies for these glycylcyclines in hu mans.