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Antimicrobial Agents and Chemotherapy, March 2006, p. 994-1000, Vol. 50, No. 3
0066-4804/06/$08.00+0     doi:10.1128/AAC.50.3.994-1000.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Pharmacokinetic-Pharmacodynamic Relationships Describing the Efficacy of Oritavancin in Patients with Staphylococcus aureus Bacteremia

Sujata M. Bhavnani,^1,2* Julie A. Passarell,¹ Joel S. Owen,^1,3 Jeffrey S. Loutit,⁴ Steven B. Porter,⁴ and Paul G. Ambrose^1,2,

Cognigen Corporation, Buffalo, New York,¹ School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, New York,² Harrison School of Pharmacy, Auburn University, Auburn, Alabama,³ InterMune, Inc., Brisbane, California⁴

Received 14 July 2005/ Returned for modification 17 September 2005/ Accepted 4 December 2005

Bloodstream infections due to antimicrobial-resistant Staphylococcus aureus occur with increasing frequency and represent an important cause of morbidity and mortality. To date, the evaluation of pharmacokinetic-pharmacodynamic relationships for efficacy among patients with bacteremia has been limited. The objectives of these analyses were to evaluate relationships between microbiological and clinical responses for patients with S. aureus bacteremia and exposures for oritavancin, a novel bactericidal glycopeptide in development. Bayesian oritavancin exposure predictions, following treatment with 5, 6.5, 8, or 10 mg/kg of body weight/day, were derived using a validated population pharmacokinetic model for 55 patients with S. aureus bacteremia. Using classification and regression tree analysis, a breakpoint of the percentage of the dosing interval duration for which free-drug concentrations were above the MIC (free-drug % time > MIC) of 22% was identified for microbiological response; the probabilities of success greater than or equal to and less than this value were 93% and 76%, respectively. Using logistic regression, a relationship was found between microbiological response and free-drug % time > MIC (odds ratio = 4.42, P = 0.09, and odds ratio = 8.84, P = 0.05, when one patient, a medical outlier, was excluded). A similar relationship was found for clinical response. These results will be valuable in supporting dose selection of oritavancin for patients with S. aureus bacteremia.

Present address: Institute for Clinical Pharmacodynamics, Ordway Research Institute, Albany, NY 12208.