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Efficacy of oritavancin in a mouse model of Streptococcus pneumoniae pneumonia

Abstract number: 1733_1277

Lehoux D., McKay G., Fadhil I., Laquerre K., Malouin M., Ostiguy V., Moeck G., Parr Jr T.

Objective:Streptococcus pneumoniae is one of the leading causes of community-acquired bacterial infections such as pneumonia. Oritavancin (ORI) is a semi-synthetic glycopeptide with bactericidal activity against Gram-positive cocci. We investigated the activity of ORI in vitro in the presence of surfactant and in vivo in a mouse model of S. pneumoniae pneumonia.

Methods: 1) Broth microdilution assays with ORI, daptomycin (DAP) and ceftriaxone (CTX) used Staphylococcus aureus ATCC 29213 following CLSI guidelines either without modification or including 0.5 to 5% commercially-available surfactant in parallel. 2) In vivo efficacy studies were performed in an immunocompetent mouse pneumonia model. CD-1 mice (n = 10/group) were challenged intranasally with 106 colony-forming units (CFU) of penicillin-sensitive S. pneumoniae (PSSP) ATCC 6303. In a study to assess efficacy resulting from administration of two doses of ORI and comparators, agents were administered at 1 and 4 h post-infection as follows: ORI, 32 mg/kg, intravenously; DAP, 100 mg/kg subcutaneously; CTX, 50 mg/kg, subcutaneously. In a dose-ranging study, ORI was administered at 1 h post-infection in single intravenous doses ranging from 0.25 to 32 mg/kg. For both the single- and two-dose studies, lungs were harvested 24 h post-infection, homogenised, and plated for bacterial counts. A maximal effect (Emax) model was used to examine the relationship between dose and efficacy.

Results: (1) The addition of 5% surfactant resulted in a 2- to 4-fold increase in ORI MIC compared to a ≥64-fold increase for DAP MIC and no shift for CTX MIC. (2) ORI (2 × 32 mg/kg) was more active in the mouse pneumonia model than CTX (2 × 50 mg/kg) and DAP (2 × 100 mg/kg): no detectable CFU were recovered from the lungs of 100% of mice treated with ORI while 40% and 0% of mice treated with CTX and DAP, respectively, had sterile lungs. Single-dose dose-response studies of ORI yielded an Emax of 6.49±0.18 mg/kg and an ED50 (dose resulting in 50% of the maximal killing) of 2.76±0.3 mg/kg.

Conclusions: (1) Surfactant affected only minimally the antibacterial activity of ORI in vitro. (2) ORI is highly active in the mouse pneumonia model and it may have potential utility in the treatment of pneumonia caused by PSSP.

Session Details

Date: 31/03/2007
Time: 00:00-00:00
Session name: European Society of Clinical Microbiology and Infectious Diseases
Subject:
Location: ICC, Munich, Germany
Presentation type:
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