Pharmacodynamics of a new streptogramin, XRP 2868, in murine thigh and lung infection models.
XRP 2868 is a new streptogramin antibiotic with broad-spectrum activity against gram-positive cocci. We used the neutropenic murine thigh and lung infection models to characterize the time course of antimicrobial activity of XRP 2868 and determine which pharmacokinetic/pharmacodynamic (PK/PD) parameter and magnitude best correlated with efficacy. Serum levels following four two- to fourfold-escalating single-dose levels of XRP 2868 were measured by liquid chromatography mass spectrometry assay. In vivo postantibiotic effects (PAEs) were determined after doses of 2.5, 10, and 40 mg/kg. Mice had 10(6.8) to 10(8.4) CFU/thigh of strains of Streptococcus pneumoniae ATCC 10813 or Staphylococcus aureus ATCC 29213 at the start of therapy when treated for 24 h with 2.5 to 640 mg/kg/day of XRP 2868 fractionated for 3-, 6-, 12-, and 24-h dosing regimens. Nonlinear regression analysis was used to determine which PK/PD parameter best correlated with CFU/thigh at 24 h. Pharmacokinetic studies exhibited peak dose values of 0.03 to 0.07, area under the concentration-time curve (AUC) dose values of 0.02 to 0.07, and half-lives of 0.35 to 1.27 h. XRP 2868 produced in vivo PAEs of 0.5 to 3.4 h with S. pneumoniae strain ATCC 10813 and -1.5 to 10.7 h with S. aureus strain ATCC 29213. The 24-h AUC/MIC was the PK/PD parameter that best correlated with efficacy. In subsequent studies, we used the neutropenic murine thigh infection model to determine if the magnitude of the AUC/MIC needed for the efficacy of XRP 2868 varied among pathogens (including resistant strains). Mice had 10(6.1) to 10(7.8) CFU/thigh of four isolates of S. aureus (three methicillin-susceptible and one methicillin-resistant strain) and nine isolates of S. pneumoniae (one penicillin-susceptible, four penicillin-intermediate, and four penicillin-resistant strains) when treated for 24 h with 0.16 to 640 mg/kg of XRP 2868 every 6 h. A sigmoid dose-response model was used to estimate the doses (mg/kg/24 h) required to achieve a net bacteriostatic affect over 24 h. MICs ranged from 0.06 to 0.25 microg/ml. The 24-h AUC/MICs for each static dose (20.7 to 252 mg/kg/day) varied from 3 to 70. Mean 24-h AUC/MICs +/- standard deviations (SDs) for S. pneumoniae and S. aureus isolates were 14 +/- 10 and 31 +/- 16, respectively. Beta-lactam and macrolide resistance did not alter the magnitude of AUC/MIC required for efficacy.
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Department of Medicine, Section of Infectious Diseases, University of Wisconsin School of Medicine, Room H4/570, 600 Highland Ave., Madison, Wisconsin 53792, USA. dra@medicine.wisc.edu
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D000818:Animals; D000890:Anti-Infective Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019540:Area Under Curve; D001419:Bacteria / Q000187:drug effects; D001424:Bacterial Infections / Q000188:drug therapy* / Q000378:metabolism / Q000382:microbiology; D004195:Disease Models, Animal; D004338:Drug Combinations; D004341:Drug Evaluation; D008168:Lung / Q000382:microbiology; D051379:Mice; D008813:Mice, Inbred ICR; D008826:Microbial Sensitivity Tests; D025364:Streptogramin A / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D025381:Streptogramin B / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D025361:Streptogramins / Q000493:pharmacokinetics / Q000627:therapeutic use; D013848:Thigh / Q000382:microbiology
D000890:Anti-Infective Agents; D004338:Drug Combinations; D025361:Streptogramins; C509060:flopristin, linopristin drug combination; D025381:Streptogramin B; D025364:Streptogramin A