In vivo pharmacodynamics of a new XXXX ( @entity5136 ).

@entity3256 @entity22461 @entity19 @entity114 @entity2260 @entity794 @entity5136 @entity328
@entity5136 is a new @entity22461 with activity against gram-positive cocci. We determined the in vivo activity of @entity5136 against four strains of @entity794 (two @entity3256 -susceptible @entity794 [MSSA] strains and two @entity3256 -resistant @entity794 strains) and one @entity114 -susceptible @entity328 (PSSP) strain, two @entity114 -intermediate @entity2260 strains, and five @entity114 -resistant @entity2260 strains. The @entity19 had 10(6.3) to 10(7.7) CFU/thigh before therapy and were then treated for 24 h with 5 to 1,280 mg of @entity5136 /kg divided into 1, 2, 4, 8, or 16 doses. The killing activities after 4 h of therapy ranged from 2.4 to 5.0 log(10) CFU/thigh against @entity2260 and 1.35 to 2.2 log(10) CFU/thigh against @entity794 . Increasing doses produced minimal concentration-dependent killing; doses of 20 and 80 mg/kg produced no in vivo postantibiotic effects (PAEs) with PSSP and modest PAEs (3.4 and 3.2 h) with MSSA. Pharmacokinetic studies at doses of 20 and 80 mg/kg by high-pressure liquid chromatography analysis exhibited peak dose values of 0.68 and 0.71 and elimination half-lives of 1.02 and 1.00 h. @entity5136 MICs ranged from 0.5 to 1.0 micro g/ml for @entity2260 and from 1.0 to 4.0 micro g/ml for @entity794 . A sigmoid dose-response model was used to estimate the dose required to achieve a net bacteriostatic effect over 24 h. Static doses against @entity2260 ranged from 22.2 to 97.1 mg/kg/24 h and from 133 to 167 mg/kg/24 h for @entity794 . The 24-h area under the concentration-time curve (AUC)/MIC ratio was the major parameter determining the efficacy of @entity5136 against PSSP (R(2) = 82% for AUC/MIC versus 57% for T>MIC and 59% for the peak level in serum/MIC [peak/MIC]). It was difficult to determine the most relevant pharmacokinetic/pharmacodynamic parameter with @entity794 , although the outcomes correlated slightly better with the 24-h AUC/MIC ratio (R(2) = 75%) than with the other parameters (T>MIC R(2) = 75% and peak/MIC R(2) = 65%). The 24-h AUC/MIC ratio required for a bacteriostatic effect with @entity5136 varied from 22 to 97 (mean = 48) for pneumococci and from 39 to 167 (mean = 83) for staphylococci. Based upon a pharmacokinetic goal of a 24-h AUC/MIC of 50 to 100, a dosage regimen of 600 mg given either intravenously or orally twice daily would achieve success against organisms with MICs as high as 2 to 4 micro g/ml.
