Oritavancin, a semisynthetic lipoglycopeptide with activity against gram-positive bacteria, has multiple mechanisms of action, including the inhibition of cell wall synthesis and the perturbation of the membrane potential. Approved guidelines for broth microdilution 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 the recovery of [(14)C]oritavancin from susceptibility assay plates with and without polysorbate 80 and examined the effect of the presence of polysorbate 80 on the oritavancin MICs for 301 clinical isolates from the genera Staphylococcus, Enterococcus, and Streptococcus. In the absence of polysorbate 80, [(14)C]oritavancin was rapidly lost from solution in susceptibility assay test plates: 9% of the input drug was recovered in broth at 1 h when [(14)C]oritavancin was tested at 1 mug/ml. Furthermore, proportionately greater losses were observed at lower oritavancin concentrations, suggesting saturable binding of oritavancin to surfaces. The inclusion of 0.002% polysorbate 80 or 2% lysed horse blood permitted the recovery of 80 to 100% [(14)C]oritavancin at 24 h for all drug concentrations tested. Concordantly, oritavancin MIC(90)s 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 the oritavancin MIC(90)s 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 the MIC data for oritavancin in the current literature significantly underestimate the potency of oritavancin in vitro. Moreover, the combination of data from MIC and [(14)C]oritavancin recovery studies supports the revision of the oritavancin broth microdilution method to include polysorbate 80 throughout the assay.
OBJECTIVE: The objective was to conduct a systematic review and network meta-analysis (NMA) of existing treatments for ABSSSI focusing on the novel lipoglycopeptide oritavancin. METHODS: EMBASE, MEDLINE, MEDLINE in Process, CENTRAL (Cochrane), and select conferences were searched for randomized controlled trials investigating antimicrobial agents for the treatment of ABSSSI. NMA was used to estimate the odds ratios of the Test-Of-Cure (TOC) and Early Clinical Response (ECR) outcomes for treatments relative to vancomycin in the ITT populations. Sub-group analyses in MRSA and MSSA populations were conducted for TOC; sensitivity analyses investigated the use of the clinically evaluable (CE) populations and the restriction to trials following the recent FDA guidelines for clinical trials. RESULTS: The systematic review identified 52 trials. The most commonly investigated treatments were vancomycin and linezolid; most trials reported TOC, but not ECR. The posterior mean and 95% credible intervals for odds ratios of TOC for antimicrobial agents relative to vancomycin were: linezolid (1.55; 0.91-2.57), daptomycin (2.18; 0.90-5.42), and oritavancin 1200 mg (1.06; 0.80-1.43). The odds ratio of ECR for oritavancin 1200 mg was 1.02 (0.23-4.33). In the MRSA sub-group the odds ratios relative to vancomycin for TOC were: linezolid (1.55; 0.96-2.46), daptomycin (0.74; 0.13-3.66), and oritavancin 1200 mg (0.94; 0.44-2.02). In the MSSA sub-group they were linezolid (1.36; 0.15-13.34) and oritavancin 1200 mg (0.82; 0.08-7.83). These results were robust to the sensitivity analyses. CONCLUSIONS: This NMA provides a unified framework for the comparison of all available antimicrobial agents used in the treatment of ABSSSI and is the first to assess the ECR end-point. The results suggest equivalence of clinical efficacy between vancomycin, daptomycin, linezolid, and novel antimicrobial agents including oritavancin for the treatment of ABSSSI at TOC. The wide uncertainty margins indicate the heterogeneity of the available evidence and the need for further research.
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