Oritavancin: a novel lipoglycopeptide active against Gram-positive pathogens including multiresistant strains

Abstract

Oritavancin is a lipoglycopeptide antibiotic under investigation for the treatment of serious infections caused by Gram-positive bacteria. Oritavancin has demonstrated rapid dose-dependent bactericidal activity towards vancomycin-susceptible and -resistant enterococci, meticillin-susceptible and -resistant Staphylococcus aureus, vancomycin-intermediate S. aureus (VISA), heteroresistant VISA (hVISA), vancomycin-resistant S. aureus (VRSA) and small-colony variants of S. aureus. It is also active against Clostridium difficile. Upon intravenous administration, oritavancin displays a three-compartment pharmacokinetic model, dose proportionality, a distribution volume of ca. 110 L, a terminal elimination half-life in excess of 2 weeks and it is not metabolised. Its pharmacodynamic properties make it an ideal antibiotic for a once-daily or even single-dose regimen. Oritavancin is currently under review by the US Food and Drug Administration. So far, oritavancin has demonstrated efficacy in two pivotal Phase III trials conducted in patients with complicated skin and skin-structure infections in which oritavancin was compared with vancomycin plus cefalexin. In both trials, the primary endpoint (clinical cure in clinically evaluable patients at first follow-up with a 10% non-inferiority margin) was met, with the advantages of shorter duration of therapy and fewer adverse events. Further results indicating its activity against bacteria growing in biofilms as well as stationary-phase bacteria open the way for its use to treat prosthetic device infections, which is to be investigated in upcoming trials.

Progress in the Discovery of Treatments for C. difficile Infection: A Clinical and Medicinal Chemistry Review

“…Oritavancin is a novel structural analog of VAN, which belongs to the lipoglycopeptide antibiotic family [160]. Although the major indication of oritavancin in completed phase 3 trials was not for the treatment of CDI, recent studies demonstrated high therapeutic potential of oritavancin as a novel anti-difficile agent.…”

Oritavancin: An investigational lipoglycopeptide antibiotic

“…However, it should be noted that the resolution of an oritavancin-induced severe allergic reaction (if one were to occur) may be delayed due to the drug's long half-life. 3 In another pharmacokinetic study, adverse events reported among patients receiving oritavancin were mild; two volunteers experienced injection-site thrombosis and muscle spasm. 59 Details and recommendations on infusion rates for oritavancin are currently not available.…”

“…However, based on laboratory data, moderate-level resistance (as indicated by an MIC of ≤16 mg/L) can develop in VRE isolates exhibiting the VanA or VanB phenotype by a single-step mutation that can occur through a variety of mechanisms. 2,3,5,8 …”

“…concentration of 1.7 ± 0.8 mg/mL 2 ; this observation suggests that oritavancin (if approved for marketing) may need to be aggressively dosed for the treatment of pneumonia. 3 Oritavancin displays concentrationdependent killing activity against staphylococci including methicillinand vancomycin-resistant strains, as well as enterococci including vancomycin-resistant strains, which means that bacterial killing is correlated with the concentration of oritavancin rather than the time above the MIC. 39,40 In vitro studies have shown that oritavancin is more rapidly bactericidal against both methicillinsensitive and methicillin-resistant staphylococci relative to daptomycin, linezolid, teicoplanin, and vancomycin 41 and demonstrates more rapid and complete killing of streptococci, including MDR strains of S. pneumoniae 42 and erythromycin-resistant strains of S. pyogenes.…”

“…In January 2009, The Medicines Company (Parsipanny, NJ) acquired Targanta and planned to conduct further trials of oritavancin in patients with MRSA, the results of which are expected within two years. 3 In August 2009, The Medicines Company announced the withdrawal of the application for European marketing authorization for oritavancin after the European Medicines Agency recommended further studies of the agent. 4 The rampant emergence of MDR gram-positive pathogens and the inherent limitations of vancomycin therapy underline the need for novel rapidly acting bactericidal agents like oritavancin.…”