Oritavancin

Oritavancin (INN, also known as LY333328, Orbactiv) is a novel semisynthetic glycopeptide antibiotic for the treatment of serious Gram-positive bacterial infections. Its chemical structure as a lipoglycopeptide is similar to vancomycin.[1]

Oritavancin
Clinical data
Trade namesOrbactiv
License data
Routes of
administration		Intravenous
ATC code
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEBI
Chemical and physical data
FormulaC86H97Cl3N10O26
Molar mass1793.1 g/mol g·mol−1
3D model (JSmol)
 NY (what is this?)  (verify)

The US FDA and European Medicines Agency have approved oritavancin for treatment of acute bacterial skin and skin structure infections.[2][3]

In vitro activity

Oritavancin shares certain properties with other members of the glycopeptide class of antibiotics, which includes vancomycin, the current standard of care for serious Gram-positive infections in the United States and Europe.[4] , possesses potent and rapid bactericidal activity in vitro against a broad spectrum of both resistant and susceptible Gram-positive bacteria, including Staphylococcus aureus, MRSA, enterococci, and streptococci.[5] Oritavancin was more active than either metronidazole or vancomycin against strains of Clostridium difficile tested.[6]

Oritavancin has potential use as a therapy for exposure to Bacillus anthracis, the Gram-positive bacterium that causes anthrax, having demonstrated efficacy in a mouse model both before and after exposure to the bacterium.[7]

Mechanism

The 4'-chlorobiphenylmethyl group disrupts the cell membrane of Gram-positive bacteria.[8] It also acts by inhibition of transglycosylation and inhibition of transpeptidation.[9]

Spectrum of Activity

Oritavancin is active against gram-positive aerobic bacteria such as enterococci, staphylococci, streptococci, and anaerobic bacteria such as Clostridium difficile , Clostridium perfringens , Peptostreptococcus spp. , and Propionibacterium acnes.[10][11] Oritavancin’s spectrum of activity shows similarities to vancomycin, but with lower minimum inhibitory concentrations (MIC).[12]

Clinical trials

In 2003 results were presented from two pivotal phase-III clinical trials testing the efficacy of daily intravenous oritavancin for the treatment of acute bacterial skin and skin-structure infections (ABSSSI) caused by Gram-positive bacteria. The primary endpoints of both studies were met, with oritavancin achieving efficacy with fewer days of therapy than the comparator agents vancomycin followed by cephalexin. Oritavancin showed a statistically significant improved safety profile with a 19% relative reduction in the overall incidence of adverse events versus vancomycin/cephalexin in the second and larger pivotal trial.[13]

History

Originally discovered and developed by Eli Lilly, oritavancin was acquired by InterMune in 2001 and then by Targanta Therapeutics in late 2005.[14] In December 2008, the US Food and Drug Administration declined to approve oritavancin without additional studies, and an EU application was withdrawn.

In 2009, The Medicines Company acquired the development rights, completed clinical trials and submitted a new drug application to the FDA in February 2014.[15] On August 6, 2014, the United States FDA approved oritavancin to treat skin infections.[16]

A marketing authorisation valid throughout the European Union was granted on 19 March 2015 for the treatment of acute bacterial skin and skin structure infections in adults.[17]

References
  1. Domenech, Oscar; Francius, Grégory; Tulkens, Paul M.; Van Bambeke, Françoise; Dufrêne, Yves; Mingeot-Leclercq, Marie-Paule (2009-09-01). "Interactions of oritavancin, a new lipoglycopeptide derived from vancomycin, with phospholipid bilayers: Effect on membrane permeability and nanoscale lipid membrane organization" (PDF). Biochimica et Biophysica Acta. 1788 (9): 1832–1840. doi:10.1016/j.bbamem.2009.05.003. ISSN 0006-3002. PMID 19450541.
  2. News Release (6 August 2014). "FDA approves Orbactiv to treat skin infections". FDA.
  3. https://www.ema.europa.eu/en/medicines/human/EPAR/orbactiv
  4. Scheinfeld, N (2007). "A comparison of available and investigational antibiotics for complicated skin infections and treatment-resistant Staphylococcus aureus and enterococcus". J Drugs Dermatol. 6 (4): 97–103. PMID 17373167.
  5. 2007 ICAAC Posters: E-1612 “In Vitro Activity Profile of Oritavancin against a Broad Spectrum of Aerobic and Anaerobic Bacterial Pathogens”/E -1613 “In Vitro Activity Profile of Oritavancin (ORI) Against Organisms Demonstrating Key Resistance Profiles to Other Antimicrobial Agents”/E-1614 “In vitro Time Kill Studies of Oritavancin against Drug-resistant Isolates of Staphylococcus aureus and Enterococci”/E-1615 “Anti-Enterococcal Activity Profile of Oritavancin, a Potent Lipoglycopeptide under Development for Use Against Gram-Positive Infections”/E-1616 “Anti-Streptococcal Activity Profile of Oritavancin, a Potent Lipoglycopeptide under Development for Use Against Gram-Positive Infections”/E-1617 “In Vitro Activity Profile of Oritavancin (ORI) Against Resistant Staphylococcal Populations From a Recent Surveillance Initiative”/E-1620 “Pharmacokinetic Concentrations of Oritavancin Kill Stationary-Phase and Biofilm Staphylococcus aureus In Vitro.” / Targanta Press Release September 19, 2007
  6. ICAAC 2007 Posters: “In Vitro Susceptibility of Genotypically Distinct Clostridium difficile Strains to Oritavancin” and “Activity of Metronidazole, Vancomycin and Oritavancin Against Epidemic Clostridium difficile Spores” / Targanta Press Release September 19, 2007
  7. ASM 2007 Poster: “Efficacy of Oritavancin in a Murine Model of Bacillus anthracis Spore Inhalation Anthrax” / Targanta Press Release May 24, 2007
  8. Belley; McKay, GA; Arhin, FF; Sarmiento, I; Beaulieu, S; Fadhil, I; Parr Jr, TR; Moeck, G (2010). "Oritavancin Disrupts Membrane Integrity of Staphylococcus aureus and Vancomycin-resistant Enterococci to Effect Rapid Bacterial Killing". Antimicrobial Agents and Chemotherapy. 54 (12): 5369–71. doi:10.1128/AAC.00760-10. PMC 2981232. PMID 20876372.
  9. Zhanel; et al. (2012). "Oritavancin: Mechanism of Action". Clin Infect Dis. 54: S214–S219. doi:10.1093/cid/cir920. PMID 22431851.
  10. Mendes, Rodrigo E.; Woosley, Leah N.; Farrell, David J.; Sader, Helio S.; Jones, Ronald N. (March 2012). "Oritavancin Activity against Vancomycin-Susceptible and Vancomycin-Resistant Enterococci with Molecularly Characterized Glycopeptide Resistance Genes Recovered from Bacteremic Patients, 2009-2010". Antimicrobial Agents and Chemotherapy. 56 (3): 1639–1642. doi:10.1128/AAC.06067-11. ISSN 0066-4804. PMC 3294904. PMID 22183169.
  11. Mendes, R. E.; Sader, H. S.; Flamm, R. K.; Jones, R. N. (2014-06-01). "Activity of oritavancin tested against uncommonly isolated Gram-positive pathogens responsible for documented infections in hospitals worldwide". Journal of Antimicrobial Chemotherapy. 69 (6): 1579–1581. doi:10.1093/jac/dku016. ISSN 0305-7453. PMID 24505091.
  12. Arhin, F.F.; Draghi, D.C.; Pillar, C.M.; Parr, T.R.; Moeck, G.; Sahm, D.F. (2009). "Comparative in vitro activity profile or oritavancin against recent gram-positive clinical isolates". Antimicrob Agents Chemother. 53 (11): 4762–4771. doi:10.1128/AAC.00952-09. PMC 2772347. PMID 19738026.
  13. ICAAC 2003 Late-breaker poster: "Phase III Trial Comparing 3–7 days of Oritavancin vs. 10–14 days of Vancomycin/Cephalexin in the Treatment of Patients with Complicated Skin and Skin Structure Infections (cSSSI)" / InterMune Press Release September 15, 2003
  14. Tomoko Okudaira (2014-05-09). "The Daily Biopharmaceutical News Source". BioWorld. Retrieved 2014-06-06.
  15. "Biotechs pick up slack in antibiotics development". 17 May 2011.
  16. News Release (6 August 2014). "FDA approves Orbactiv to treat skin infections". FDA.
  17. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Summary_for_the_public/human/003785/WC500186346.pdf
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