Oritavancin

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Oritavancin
Clinical data
Trade namesOrbactiv
Routes of
administration		intravenous
ATC code
Identifiers
  • (4R)-22-O-(3-Amino-2,3,6-trideoxy-3-C-methyl-α-L-arabinohexopyranosyl)-N3-(p-(p-chlorophenyl)benzyl)vancomycin
CAS Number
PubChem CID
ChemSpider
UNII
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC86H97Cl3N10O26
Molar mass1793.1 g/mol g·mol−1
3D model (JSmol)
  • C[C@H]1[C@@H]([C@@](C[C@@H](O1)O[C@H]2[C@H]3C(=O)N[C@H](C4=C(C(=CC(=C4)O)O)C5=C(C=CC(=C5)[C@H](C(=O)N3)NC(=O)[C@H]6C7=CC(=C(C(=C7)OC8=C(C=C(C=C8)[C@H]([C@H](C(=O)N[C@H](C(=O)N6)CC(=O)N)NC(=O)[C@@H](CC(C)C)NC)O)Cl)O[C@H]9[C@@H]([C@H]([C@@H]([C@H](O9)CO)O)O)O[C@H]1C[C@]([C@H]([C@@H](O1)C)O)(C)NCC1=CC=C(C=C1)C1=CC=C(C=C1)Cl)OC1=C(C=C2C=C1)Cl)O)C(=O)O)(C)N)O
  • InChI=1S/C86H97Cl3N10O26/c1-35(2)22-51(92-7)77(110)98-67-69(105)42-15-20-55(49(88)24-42)120-57-26-44-27-58(73(57)125-84-74(71(107)70(106)59(34-100)122-84)124-62-32-86(6,76(109)37(4)119-62)93-33-38-8-10-39(11-9-38)40-12-17-45(87)18-13-40)121-56-21-16-43(25-50(56)89)72(123-61-31-85(5,91)75(108)36(3)118-61)68-82(115)97-66(83(116)117)48-28-46(101)29-54(103)63(48)47-23-41(14-19-53(47)102)64(79(112)99-68)96-80(113)65(44)95-78(111)52(30-60(90)104)94-81(67)114/h8-21,23-29,35-37,51-52,59,61-62,64-72,74-76,84,92-93,100-103,105-109H,22,30-34,91H2,1-7H3,(H2,90,104)(H,94,114)(H,95,111)(H,96,113)(H,97,115)(H,98,110)(H,99,112)(H,116,117)/t36-,37-,51+,52-,59+,61-,62-,64+,65+,66+,67+,68-,69+,70+,71-,72+,74+,75-,76-,84-,85-,86-/m0/s1
  • Key:VHFGEBVPHAGQPI-MYYQHNLBSA-N
  (verify)

Oritavancin (INN, also known as LY333328, Orbactiv) is a novel semisynthetic glycopeptide antibiotic being developed for the treatment of serious Gram-positive bacterial infections. Originally discovered and developed by Eli Lilly, oritavancin was acquired by InterMune in 2001 and then by Targanta Therapeutics in late 2005.[1]

In December 2008, the US Food and Drug Administration declined to approve it without additional studies, and an EU application was withdrawn. In 2009, the development rights were acquired by The Medicines Company, which has completed clinical trials and submitted a new drug application to the FDA in February 2014.[2][3] On August 6, 2014, the FDA approved oritavancin for treatment of skin infections in the United States. [4]

Its chemical structure is similar to vancomycin.[5] It is a lipoglycopeptide.

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.[6] Oritavancin 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.[7] Oritavancin was more active than either metronidazole or vancomycin against strains of Clostridium difficile tested.[8]

Anthrax : 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.[9]

Mechanism

The 4'-chlorobiphenylmethyl group disrupts the cell membrane of Gram-positive bacteria.[10] It also acts by inhibition of transglycosylation and inhibition of transpeptidation.[11]

Clinical trial results

Results have been presented from two pivotal phase-III clinical trials testing the efficacy of daily intravenous oritavancin for the treatment of complicated skin and skin-structure infections (cSSSI) caused by Gram-positive bacteria. The primary endpoints of both studies were successfully met, with oritavancin achieving efficacy with fewer days of therapy than the comparator agents (vancomycin followed by cephalexin). In addition, oritavancin showed a significantly improved safety profile with a 19.2% relative reduction in the overall incidence of adverse events versus vancomycin/cephalexin in the second and larger pivotal trial.[12]

References

  1. ^ Tomoko Okudaira (2014-05-09). "The Daily Biopharmaceutical News Source". BioWorld. Retrieved 2014-06-06.
  2. ^ "Biotechs pick up slack in antibiotics development". 17 May 2011.
  3. ^ PBR Staff Writer. regulatoryaffairs.pharmaceutical-business-review.com/news/the-medicines-companys-oritavancin-nda-accepted-by-fda-200214-4181432 The Medicines Company's oritavancin NDA accepted by FDA. 20 February 2014
  4. ^ News Release (6 August 2014). "FDA approves Orbactiv to treat skin infections". FDA. {{cite web}}: Cite has empty unknown parameter: |1= (help)
  5. ^ "Interactions of oritavancin, a new lipoglycopeptide derived from vancomycin, with phospholipid bilayers: Effect on membrane permeability and nanoscale lipid membrane organization" 2009
  6. ^ 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.
  7. ^ 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
  8. ^ 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
  9. ^ ASM 2007 Poster: “Efficacy of Oritavancin in a Murine Model of Bacillus anthracis Spore Inhalation Anthrax” / Targanta Press Release May 24, 2007
  10. ^ 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.
  11. ^ Zhanel; et al. (2012). "Oritavancin: Mechanism of Action". Clin Infect Dis. doi:10.1093/cid/cir920. {{cite journal}}: Explicit use of et al. in: |author= (help)
  12. ^ 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

External links

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