Oritavancin

Oritavancin, sold under the brand name Orbactiv among others, is a semisynthetic glycopeptide antibiotic medication for the treatment of serious Gram-positive bacterial infections. Its chemical structure as a lipoglycopeptide is similar to vancomycin.[4]

Oritavancin
Clinical data
Pronunciation/oʊˌrɪtəˈvænsɪn/
oh-RIT-ə-VAN-sin
Trade namesOrbactiv, Kimyrsa
Other namesLY333328
AHFS/Drugs.comMonograph
MedlinePlusa614042
License data
Routes of
administration		Intravenous
ATC code
Legal status
Legal status
Identifiers
IUPAC name
  • (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
DrugBank
ChemSpider
UNII
KEGG
ChEBI
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC86H97Cl3N10O26
Molar mass1793.12 g·mol−1
3D model (JSmol)
SMILES
  • 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
  • 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
 NY (what is this?)  (verify)

The U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have approved oritavancin for treatment of acute bacterial skin and skin structure infections.[5][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.[6] It 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]

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]

oritavancin demonstrates in vitro activity against both the planktonic and biofilmstates of staphylococci associated with Prosthetic joint infection (PJI), albeit with increased minimum biofilm bactericidal concentration (MBBC) compared to Minimum inhibitory concentrations (MIC) values.[10] Moreever oritavancin has demonstrated activity against in vitro to vancomycin-susceptible enterococci (VSE) and vancomycin-resistant enterococci (VRE) in both planktonic and biofilm states.[11]

Mechanism

The 4'-chlorobiphenylmethyl group disrupts the cell membrane of Gram-positive bacteria.[12] It also acts by inhibition of transglycosylation and inhibition of transpeptidation.[13]

Synergism

Several antibiotics have been tested as partner drugs of oritavancin.[14][15] Among these "companions" drugs, fosfomycin displayed (in vitro and in vivo) synergistic activity when administered together with oritavancin against VRE strains (both vanA and vanB).[16]

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.[17][18] Oritavancin's spectrum of activity shows similarities to vancomycin, but with lower minimum inhibitory concentrations (MIC).[19]

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.[20]

Osteomyelitis remains a formidable foe in an era of increasing incidence of Methicillin-resistant Staphylococcus aureus (MRSA) with limited guidance for treatment optimization. The success observed in many patients suggests multi-dose oritavancin may prove advantageous for chronic osteomyelitis but further research is needed to define the optimal dose and frequency of oritavancin for the treatment of chronic osteomyelitis.[21]

History

Originally discovered and developed by Eli Lilly, oritavancin was acquired by InterMune in 2001 and then by Targanta Therapeutics in late 2005.[22] In December 2008, the U.S. Food and Drug Administration (FDA) 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.[23] On August 6, 2014, the United States FDA approved oritavancin to treat skin infections.[24]

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.[25]

References
  1. "Orbactiv- oritavancin injection, powder, lyophilized, for solution". DailyMed. Retrieved 18 December 2020.
  2. "Kimyrsa- oritavancin diphosphate injection, powder, lyophilized, for solution". DailyMed. Retrieved 31 March 2021.
  3. "Orbactiv EPAR".
  4. Domenech O, Francius G, Tulkens PM, Van Bambeke F, Dufrêne Y, Mingeot-Leclercq MP (September 2009). "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 (BBA) - Biomembranes. 1788 (9): 1832–40. doi:10.1016/j.bbamem.2009.05.003. PMID 19450541.
  5. "FDA approves Orbactiv to treat skin infections" (Press release). U.S. Food and Drug Administration (FDA). 6 August 2014. Archived from the original on 8 August 2014.
  6. Scheinfeld N (January 2007). "A comparison of available and investigational antibiotics for complicated skin infections and treatment-resistant Staphylococcus aureus and enterococcus". Journal of Drugs in Dermatology. 6 (1): 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 Archived July 13, 2011, at the Wayback Machine
  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 Archived July 13, 2011, at the Wayback Machine
  9. ASM 2007 Poster: “Efficacy of Oritavancin in a Murine Model of Bacillus anthracis Spore Inhalation Anthrax” / Targanta Press Release May 24, 2007 Archived July 13, 2011, at the Wayback Machine
  10. Yan, Qun, Melissa J. Karau, and Robin Patel. “In Vitro Activity of Oritavancin against Biofilms of Staphylococci Isolated from Prosthetic Joint Infection.” Diagnostic Microbiology and Infectious Disease 92, no. 2 (October 2018): 155–57. https://doi.org/10.1016/j.diagmicrobio.2018.05.010.
  11. Yan, Qun, Melissa J. Karau, and Robin Patel. “In Vitro Activity of Oritavancin against Planktonic and Biofilm States of Vancomycin-Susceptible and Vancomycin-Resistant Enterococci.” Diagnostic Microbiology and Infectious Disease 91, no. 4 (August 2018): 348–50. https://doi.org/10.1016/j.diagmicrobio.2018.03.008.
  12. Belley A, McKay GA, Arhin FF, Sarmiento I, Beaulieu S, Fadhil I, et al. (December 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.
  13. Zhanel GG, Schweizer F, Karlowsky JA (April 2012). "Oritavancin: mechanism of action". Clinical Infectious Diseases. 54 Suppl 3: S214-9. doi:10.1093/cid/cir920. PMID 22431851.
  14. Smith, Jordan R.; Barber, Katie E.; Raut, Animesh; Aboutaleb, Mostafa; Sakoulas, George; Rybak, Michael J. (2015-06-01). "β-Lactam combinations with daptomycin provide synergy against vancomycin-resistant Enterococcus faecalis and Enterococcus faecium". Journal of Antimicrobial Chemotherapy. 70 (6): 1738–1743. doi:10.1093/jac/dkv007. ISSN 1460-2091. PMC 4542582. PMID 25645208.
  15. Wu, T; Meyer, K; Harrington, A T; Danziger, L H; Wenzler, E (2019-05-01). "In vitro activity of oritavancin alone or in combination against vancomycin-susceptible and -resistant enterococci". Journal of Antimicrobial Chemotherapy. 74 (5): 1300–1305. doi:10.1093/jac/dkz010. ISSN 0305-7453. PMID 30753495.
  16. Lagatolla, Cristina; Mehat, Jai W.; La Ragione, Roberto Marcello; Luzzati, Roberto; Di Bella, Stefano (2022-09-29). "In Vitro and In Vivo Studies of Oritavancin and Fosfomycin Synergism against Vancomycin-Resistant Enterococcus faecium". Antibiotics. 11 (10): 1334. doi:10.3390/antibiotics11101334. ISSN 2079-6382.
  17. Mendes RE, Woosley LN, Farrell DJ, Sader HS, Jones RN (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): 1639–42. doi:10.1128/AAC.06067-11. PMC 3294904. PMID 22183169.
  18. Mendes RE, Sader HS, Flamm RK, Jones RN (June 2014). "Activity of oritavancin tested against uncommonly isolated Gram-positive pathogens responsible for documented infections in hospitals worldwide". The Journal of Antimicrobial Chemotherapy. 69 (6): 1579–81. doi:10.1093/jac/dku016. PMID 24505091.
  19. Arhin FF, Draghi DC, Pillar CM, Parr TR, Moeck G, Sahm DF (November 2009). "Comparative in vitro activity profile of oritavancin against recent gram-positive clinical isolates". Antimicrobial Agents and Chemotherapy. 53 (11): 4762–71. doi:10.1128/AAC.00952-09. PMC 2772347. PMID 19738026.
  20. 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
  21. Chastain, Daniel B., and Anthony Davis. “Treatment of Chronic Osteomyelitis with Multidose Oritavancin: A Case Series and Literature Review.” International Journal of Antimicrobial Agents 53, no. 4 (April 2019): 429–34. https://doi.org/10.1016/j.ijantimicag.2018.11.023.
  22. Tomoko Okudaira (2014-05-09). "The Daily Biopharmaceutical News Source". BioWorld. Retrieved 2014-06-06.
  23. "Biotechs pick up slack in antibiotics development". 17 May 2011.
  24. "FDA approves Orbactiv to treat skin infections" (Press release). U.S. Food and Drug Administration (FDA). 6 August 2014. Archived from the original on 8 August 2014.
  25. "EPAR summary: Orbactiv" (PDF). European Medicines Agency.
  • "Oritavancin". Drug Information Portal. U.S. National Library of Medicine.
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