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A single 1200mg human equivalent dose of oritavancin is highly efficacious in the neutropenic mouse thigh infection model

Abstract number: P1568

Lehoux D., Laquerre K., Ostiguy V., Fadhil I., Malouin M., Cadieux C., Goyette N., Fournier S., Sarmiento I., Arhin F., Moeck G., Parr Jr. T.

Objectives: Oritavancin (ORI) is a lipoglycopeptide active against Gram-positive bacteria including streptococci, staphylococci, enterococci, and clostridia irrespective of their vancomycin- or oxacillin-resistance phenotype. Previous animal studies and a Phase 2 clinical study demonstrated that single and infrequent doses of ORI are efficacious dosing regimens. In this study, we compared the efficacy of several ORI human equivalent (HEQ) doses including a single dose in a neutropenic murine thigh infection model using 14 Staphylococcus aureus (SA) clinical isolates.

Methods: Thigh infection was established in neutropenic female CD-1 mice (19–21g; n = 3/group). Mice were made neutropenic by intraperitoneal injection of cyclophosphamide 4 days (150 mg/kg) and 1 day (100 mg/kg) before the infection. Each inoculum consisted of one of 14 clinical isolates (3 methicillin-susceptible SA [MSSA], 11 methicillin-resistant SA [MRSA]; ORI MICs 0.015 to 2 mg/L). The mice were infected with the inoculum containing 105 colony forming units (CFU) into each thigh. Efficacy of ORI doses simulating human exposure (i.e. 24 h AUC-matched) of 100, 200, or 400 mg daily x 3 days, or a single 1200 mg HEQ dose was evaluated. Both thighs were harvested and CFU were counted after 72 h treatment. Mean Log CFU/thigh changes from baseline were calculated, and correlation between the efficacy and MIC of tested strains was evaluated.

Results: ORI efficacy was HEQ dose-dependent. Treatment with 100, 200, or 400 mg daily x 3 days, or a single 1200 mg HEQ dose generated 1.5, -0.1, -1.6, and -2.7 log CFU/thigh changes from baseline against MSSA, and 0.8, -0.9, -2.8, -2.8 Log CFU/thigh changes from baseline against MRSA, respectively. Bacterial load reduction was significantly greater (pleqslant R: less-than-or-eq, slant0.05) for the single 1200 mg dose compared to the 200 mg daily dose for both MRSA and MSSA. The log CFU reduction observed with the 200 mg daily dose x 3 remained similar for all tested strains independent of their MIC, as it did with the single 1200 mg HEQ dose.

Conclusion: Front loading of ORI exposure was the most effective dosing regimen in this model. The more rapid and profound bacterial killing that was achieved by the 1200 mg HEQ dose of ORI is consistent with its concentration-dependent bactericidal activity in vitro. The apparent lack of impact of ORI MIC on in vivo efficacy, for the strains evaluated here, suggests that the test strains fall within the wild-type ORI susceptibility distribution.

Session Details

Date: 10/04/2010
Time: 00:00-00:00
Session name: Abstracts 20th European Congress of Clinical Microbiology and Infectious Diseases
Subject:
Location: Vienna, Austria, 10 - 13 April 2010
Presentation type:
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