Oritavancin

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Oritavancin
File:Oritavancin.svg
Systematic (IUPAC) name
(4R)-22-O-(3-Amino-2,3,6-trideoxy-3-C-methyl-α-L-arabinohexopyranosyl)-N3-(p-(p-chlorophenyl)benzyl)vancomycin
Clinical data
Trade names Orbactiv
Routes of
administration		 Intravenous
Identifiers
CAS Number 171099-57-3 YesY
ATC code J01XA05 (WHO)
PubChem CID: 16131319
ChemSpider 31149229 N
UNII PUG62FRZ2E YesY
ChEBI CHEBI:82699 N
Chemical data
Formula C86H97Cl3N10O26
Molecular mass 1793.1 g/mol
  • 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 N
  • Key:VHFGEBVPHAGQPI-MYYQHNLBSA-N N
 NYesY (what is this?)  (verify)

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] In August 2014, the United States FDA approved oritavancin for treatment of skin infections.[2]

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.[3] 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.[4] Oritavancin was more active than either metronidazole or vancomycin against strains of Clostridium difficile tested.[5]

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.[6]

Mechanism

The 4'-chlorobiphenylmethyl group disrupts the cell membrane of Gram-positive bacteria.[7] It also acts by inhibition of transglycosylation and inhibition of transpeptidation.[8]

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.[9]

History

Originally discovered and developed by Eli Lilly, oritavancin was acquired by InterMune in 2001 and then by Targanta Therapeutics in late 2005.[10] 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.[11] On August 6, 2014, the United States FDA approved oritavancin to treat skin infections.[12]

References

  1. ↑ "Interactions of oritavancin, a new lipoglycopeptide derived from vancomycin, with phospholipid bilayers: Effect on membrane permeability and nanoscale lipid membrane organization" 2009
  2. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  3. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  4. ↑ 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
  5. ↑ 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
  6. ↑ ASM 2007 Poster: “Efficacy of Oritavancin in a Murine Model of Bacillus anthracis Spore Inhalation Anthrax” / Targanta Press Release May 24, 2007
  7. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  8. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  9. ↑ 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[dead link]
  10. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  11. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  12. ↑ Lua error in package.lua at line 80: module 'strict' not found.

External links

  • Lua error in package.lua at line 80: module 'strict' not found.
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