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Antimicrob. Agents Chemother. doi:10.1128/AAC.01513-07
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Effect of Polysorbate-80 on Oritavancin Binding to Plastic Surfaces – Implications for Susceptibility Testing

Targanta Therapeutics, Saint Laurent, Québec, Canada; and Eurofins Medinet, Herndon, Virginia, USA

^* To whom correspondence should be addressed. Email: gmoeck{at}targanta.com.

	Abstract

Oritavancin, a semi-synthetic lipoglycopeptide with activity against gram-positive bacteria, has multiple mechanisms of action including inhibition of cell wall synthesis and perturbation of membrane potential. Approved guidelines for broth microdilution minimum inhibitory concentration (MIC) assays with dalbavancin, another lipoglycopeptide, require inclusion of 0.002% polysorbate-80. To investigate the potential impact of polysorbate-80 on oritavancin susceptibility assays, we quantified [¹⁴C]oritavancin recovery from susceptibility assay plates with and without polysorbate-80 and examined the effect of the presence of polysorbate-80 on oritavancin MICs for 301 clinical isolates from the genera Staphylococcus, Enterococcus and Streptococcus. In the absence of polysorbate-80, [¹⁴C]oritavancin was rapidly lost from solution in susceptibility assay test plates: 9% of input drug was recovered in broth at 1 h when [¹⁴C]oritavancin was tested at 1 µg/mL. Furthermore, proportionately greater losses were observed at lower oritavancin concentrations, suggesting saturable binding of oritavancin to surfaces. Inclusion of 0.002% polysorbate-80 or 2% lysed horse blood permitted 24 h recovery of 80-100% of [¹⁴C]oritavancin at all drug concentrations tested. Concordantly, oritavancin MIC₉₀s for streptococcal isolates, as determined in medium containing 2% lysed horse blood, were identical with and without polysorbate-80. In stark contrast, polysorbate-80 reduced oritavancin MIC₉₀s by 16- to 32-fold for clinical isolates of enterococci and staphylococci, which are typically cultured without blood. The results presented here provide evidence that current literature MIC data for oritavancin significantly underestimate oritavancin in vitro potency. Moreover, the combination of data from MIC and [¹⁴C]oritavancin recovery studies supports revision of the oritavancin broth microdilution method to include polysorbate-80 throughout the assay.

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