Oritavancin microbiologic features and activity results from the surveillance program in the United States.

Clin Infect Dis. 2012 Apr;54 Suppl 3:S203-13

Authors: Mendes RE, Farrell DJ, Sader HS, Jones RN

Abstract
Oritavancin is in the final stages of clinical development for treatment of acute bacterial skin and skin structure infections. This drug has demonstrated potent activity against staphylococci (minimum inhibitory concentration [MIC] for which 90% of isolates are inhibited [MIC(90)], 0.06 ?g/mL), enterococci (MIC(90), ?0.008 to 0.5 ?g/mL), and streptococci (MIC(90), ?0.008 to 0.12 ?g/mL), including enhanced potency against vancomycin-resistant enterococci. During the clinical development of oritavancin, it was demonstrated that this molecule binds to plastic labware surfaces and that this feature was likely responsible for interlaboratory variability observed from in vitro investigations before 2006. Therefore, reference broth microdilution methods and MIC ranges for quality control strains were reestablished using media supplemented with a surfactant (polysorbate-80, 0.002%). These were followed by numerous experiments to reassess the in vitro characteristics of oritavancin; the results originating from those studies are summarized here. The oritavancin activity tested against a resistance surveillance collection of 12?367 Gram-positive clinical pathogens and resistant subsets from the United States (2008-2009) is also presented, with the highest MIC among staphylococci at only 0.25 ?g/mL. In vitro results for oritavancin indicate wide potential use against Gram-positive pathogens.

PMID: 22431850 [PubMed - in process]

Oritavancin: mechanism of action.

Clin Infect Dis. 2012 Apr;54 Suppl 3:S214-9

Authors: Zhanel GG, Schweizer F, Karlowsky JA

Abstract
Oritavancin is a semisynthetic lipoglycopeptide analogue of vancomycin that contains the heptapeptide core common to all glycopeptides. It differs from vancomycin by the presence of a hydrophobic N-4-(4-chlorophenyl)benzyl (also referred to as 4'-chlorobiphenylmethyl) substituent on the disaccharide sugar, the addition of a 4-epi-vancosamine monosaccharide to the amino acid residue in ring 6, and the replacement of the vancosamine moiety by 4-epi-vancosamine. One mechanism of action of oritavancin is inhibition of transglycosylation (important in peptidoglycan synthesis) by binding to D-alanyl-D-alanine stem termini in Gram-positive bacteria. The inhibition of peptidoglycan synthesis via inhibition of transglycosylation is common to all glycopeptides (vancomycin) and lipoglycopeptides. Secondary binding of oritavancin to the pentaglycyl (Asp/Asn) bridging segment in peptidoglycan also occurs, which distinguishes it from vancomycin and contributes to oritavancin's activity versus vancomycin-resistant organisms. The presence of the hydrophobic 4'-chlorobiphenylmethyl group allows for interaction and disruption of the cell membrane, resulting in depolarization, permeabilization, and concentration-dependent, rapid cell death. This mechanism is shared with telavancin but not vancomycin and results in activity against daptomycin-nonsusceptible organisms. In conclusion, oritavancin's mechanism of action involves at least 3 known mechanisms: inhibition of transglycosylation, inhibition of transpeptidation, and cell membrane interaction/disruption. Oritavancin's multiple mechanisms of action confer activity against vancomycin-susceptible and -resistant organisms, as well as rapid, concentration-dependent killing versus actively growing, stationary phase, and biofilm-producing Gram-positive bacteria.

PMID: 22431851 [PubMed - in process]