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{{Short description|Pharmaceutical drug}}
{{Drugbox
{{Use dmy dates|date=June 2024}}
| verifiedrevid = 443330841
{{cs1 config|name-list-style=vanc|display-authors=6}}
| IUPAC_name = (4''R'')-22-O-(3-Amino-2,3,6-trideoxy-3-C-methyl-alpha-L-arabinohexopyranosyl)-N3-(p-(p-chlorophenyl)benzyl)vancomycin
{{Infobox drug
| Verifiedfields = changed
| Watchedfields = changed
| verifiedrevid = 447756219
| image = Oritavancin.svg | image = Oritavancin.svg
| alt =

<!-- Clinical data -->
| pronounce = {{IPAc-en|oʊ|ˌ|r|ɪ|t|ə|ˈ|v|æ|n|s|ɪ|n}}<br />{{respell|oh|RIT|ə|VAN|sin}}
| tradename = Orbactiv, Kimyrsa
| Drugs.com = {{drugs.com|monograph|oritavancin}}
| MedlinePlus = a614042
| licence_EU = yes
| DailyMedID = Oritavancin
| licence_US = <!-- FDA may use generic or brand name (generic name preferred) -->
| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X -->
| pregnancy_AU_comment =
| pregnancy_category=
| routes_of_administration = ]
| ATC_prefix = J01
| ATC_suffix = XA05


<!--Clinical data-->
| tradename =
| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X -->
| pregnancy_US = <!-- A / B / C / D / X -->
| pregnancy_category =
| legal_AU = <!-- Unscheduled / S2 / S3 / S4 / S5 / S6 / S7 / S8 / S9 --> | legal_AU = <!-- Unscheduled / S2 / S3 / S4 / S5 / S6 / S7 / S8 / S9 -->
| legal_CA = <!-- / Schedule I, II, III, IV, V, VI, VII, VIII --> | legal_CA = <!-- / Schedule I, II, III, IV, V, VI, VII, VIII -->
| legal_UK = <!-- GSL / P / POM / CD / Class A, B, C --> | legal_UK = <!-- GSL / P / POM / CD / Class A, B, C -->
| legal_US = <!-- OTC / Rx-only / Schedule I, II, III, IV, V --> | legal_US = Rx-only
| legal_US_comment = <ref>{{cite web | title=Orbactiv- oritavancin injection, powder, lyophilized, for solution | website=DailyMed | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ff09a726-9f9b-4e30-b509-396781293220 | access-date=18 December 2020}}</ref><ref>{{cite web | title=Kimyrsa- oritavancin diphosphate injection, powder, lyophilized, for solution | website=DailyMed | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=5e755c40-6e73-4572-b474-4d8a131693d1 | access-date=31 March 2021}}</ref>
| legal_status =
| legal_EU = Rx-only
| routes_of_administration = intravenous
| legal_EU_comment = <ref name="Orbactiv EPAR" />
| legal_status =


<!--Pharmacokinetic data--> <!-- Pharmacokinetic data -->
| bioavailability = | bioavailability =
| protein_bound = | protein_bound =
| metabolism = | metabolism =
| elimination_half-life = | elimination_half-life = {{Val|16|u=day}})<ref name="pmid38075413"/>
| excretion = | excretion =


<!--Identifiers--> <!-- Identifiers -->
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 171099-57-3 | CAS_number = 171099-57-3
| ATC_prefix = J01
| ATC_suffix = XA05
| PubChem = 16131319 | PubChem = 16131319
| DrugBank_Ref = {{drugbankcite|correct|drugbank}} | DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = | DrugBank = DB04911
| UNII_Ref = {{fdacite|correct|FDA}} | UNII_Ref = {{fdacite|correct|FDA}}
| UNII = PUG62FRZ2E | UNII = PUG62FRZ2E
| ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}}
| ChemSpiderID = 31149229
| ChEBI_Ref = {{ebicite|changed|EBI}}
| ChEBI = 82699
| KEGG = D05271
| synonyms = LY333328


<!--Chemical data--> <!-- Chemical data -->
| IUPAC_name = (4''R'')-22-''O''-(3-Amino-2,3,6-trideoxy-3-''C''-methyl-α-<small>L</small>-arabinohexopyranosyl)-''N3''-(''p''-(''p''-chlorophenyl)benzyl)vancomycin
| C=86 | H=97 | Cl=3 | N=10 | O=26
| C=86 | H=97 | Cl=3 | N=10 | O=26
| molecular_weight = 1793.1 g/mol
| smiles = C1((C(O1)O23C(=O)N(C4=C(C(=CC(=C4)O)O)C5=C(C=CC(=C5)(C(=O)N3)NC(=O)6C7=CC(=C(C(=C7)OC8=C(C=C(C=C8)((C(=O)N(C(=O)N6)CC(=O)N)NC(=O)(CC(C)C)NC)O)Cl)O9((((O9)CO)O)O)O1C(((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
| StdInChI_Ref = {{stdinchicite|changed|chemspider}}
| StdInChI = 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
| StdInChIKey_Ref = {{stdinchicite|changed|chemspider}}
| StdInChIKey = VHFGEBVPHAGQPI-MYYQHNLBSA-N
}} }}
'''Oritavancin''' (], also known as '''LY333328''') is a novel semi-synthetic ] being developed for the treatment of serious ] infections. Originally discovered and developed by ], oritavancin was acquired by InterMune in 2001 and then by ] in late 2005.<ref></ref>


'''Oritavancin''', sold under the brand name '''Orbactiv''' (by Melinta Therapeutics) among others, is a ] ] medication for the treatment of serious ]s. Its chemical structure as a ] is similar to ].<ref>{{cite journal | vauthors = Domenech O, Francius G, Tulkens PM, Van Bambeke F, Dufrêne Y, Mingeot-Leclercq MP | title = Interactions of oritavancin, a new lipoglycopeptide derived from vancomycin, with phospholipid bilayers: Effect on membrane permeability and nanoscale lipid membrane organization | journal = Biochimica et Biophysica Acta (BBA) - Biomembranes | volume = 1788 | issue = 9 | pages = 1832–1840 | date = September 2009 | pmid = 19450541 | doi = 10.1016/j.bbamem.2009.05.003 | doi-access = free }}</ref>
In Dec 2008 the FDA declined to approve it, and an EU application was withdrawn.


The U.S. ] (FDA) and the ] (EMA) have approved oritavancin for treatment of acute bacterial ].<ref>{{cite press release |url=https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm408475.htm|archive-url=https://web.archive.org/web/20140808234620/http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm408475.htm|url-status=dead|archive-date=8 August 2014|title=FDA approves Orbactiv to treat skin infections|publisher=U.S. ] (FDA)|date=6 August 2014}}</ref><ref name="Orbactiv EPAR">{{cite web | url=https://www.ema.europa.eu/en/medicines/human/EPAR/orbactiv |title = Orbactiv EPAR |date = 17 September 2018 }}</ref>
In 2009 the development rights were acquired by ] who are running clinical trials for a possible new FDA application in 2013.<ref>{{cite news |url=http://www.fiercebiotech.com/story/biotechs-pick-slack-antibiotics-development/2011-05-17 |title=Biotechs pick up slack in antibiotics development |date=17 May 2011 }}</ref>


== Medical uses ==
Its structure is similar to ]<ref>http://www.farm.ucl.ac.be/Full-texts-FARM/Domenech-2009-1.pdf "Interactions of oritavancin, a new lipoglycopeptide derived from vancomycin, with
Oritavancin is considered a long-lasting antibiotic due to its extended half-life (up to {{Val|16|u=day}}), high protein binding capacity, and ability to penetrate tissues effectively. It binds strongly to plasma proteins (around 85%), resulting in prolonged release into surrounding tissues. Furthermore, oritavancin exhibits excellent tissue penetration and distribution throughout various sites, including skin structures, ] (found in joints), bone tissue, and macrophages. Less frequent dosing requirements still keep efficacy against gram-positive infections, which is convenient for prolonged treatment courses such as osteoarticular infections and endocarditis, making it an option for outpatient antibiotic therapy in difficult-to-treat populations where adherence may be challenging and those with limited access to healthcare facilities.<ref name="pmid38075413">{{cite journal |vauthors=Micheli G, Chiuchiarelli M, Taccari F, Fantoni M |title=The role of long-acting antibiotics in the clinical practice: a narrative review |journal=Infez Med |volume=31 |issue=4 |pages=449–465 |date=2023 |pmid=38075413 |pmc=10705857 |doi=10.53854/liim-3104-4 |url=}}</ref>
phospholipid bilayers: Effect on membrane permeability and nanoscale lipid
membrane organization" 2009</ref> It is a ].


==''In vitro'' activity== == ''In vitro'' activity ==


Oritavancin shares certain properties with other members of the glycopeptide class of antibiotics, which includes ], the current standard of care for serious Gram-positive infections in the United States and Europe<ref>{{cite journal |author=Scheinfeld, N |title=A comparison of available and investigational antibiotics for complicated skin infections and treatment-resistant ''Staphylococcus aureus'' and ''enterococcus'' |journal= J Drugs Dermatol. |volume=6 |issue=4 |pages=97&ndash;103 |year=2007 |pmid=17373167}}</ref>. Data presented at the 47th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) in September 2007 demonstrated that oritavancin possesses potent and rapid bactericidal activity ''in vitro'' against a broad spectrum of both resistant and susceptible Gram positive bacteria, including ], ], ], and ]<ref>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''.” / </ref>. Two posters presented at the meeting also demonstrated that oritavancin was more active than either metronidazole or vancomycin against strains of ] tested<ref>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” / </ref>. Oritavancin shares certain properties with other members of the glycopeptide class of antibiotics, which includes ], the current standard of care for serious Gram-positive infections in the United States and Europe.<ref>{{cite journal | vauthors = Scheinfeld N | title = A comparison of available and investigational antibiotics for complicated skin infections and treatment-resistant Staphylococcus aureus and enterococcus | journal = Journal of Drugs in Dermatology | volume = 6 | issue = 1 | pages = 97–103 | date = January 2007 | pmid = 17373167 }}</ref> It possesses potent and rapid bactericidal activity ''in vitro'' against a broad spectrum of both resistant and susceptible Gram-positive bacteria, including '']'', ], ], and ].<ref name="pmid18505390">{{cite journal | vauthors = Crandon J, Nicolau DP | title = Oritavancin: a potential weapon in the battle against serious Gram-positive pathogens | journal = Future Microbiology | volume = 3 | issue = 3 | pages = 251–263 | date = June 2008 | pmid = 18505390 | doi = 10.2217/17460913.3.3.251 }}</ref><ref name="pmid26831328">{{cite journal | vauthors = Brade KD, Rybak JM, Rybak MJ | title = Oritavancin: A New Lipoglycopeptide Antibiotic in the Treatment of Gram-Positive Infections | journal = Infectious Diseases and Therapy | volume = 5 | issue = 1 | pages = 1–15 | date = March 2016 | pmid = 26831328 | pmc = 4811835 | doi = 10.1007/s40121-016-0103-4 }}</ref>


Oritavancin has potential use as a therapy for exposure to '']'', the Gram-positive bacterium that causes ], having demonstrated efficacy in a mouse model both before and after exposure to the bacterium.<ref name="pmid18606841">{{cite journal | vauthors = Heine HS, Bassett J, Miller L, Bassett A, Ivins BE, Lehoux D, Arhin FF, Parr TR, Moeck G | title = Efficacy of oritavancin in a murine model of Bacillus anthracis spore inhalation anthrax | journal = Antimicrobial Agents and Chemotherapy | volume = 52 | issue = 9 | pages = 3350–3357 | date = September 2008 | pmid = 18606841 | pmc = 2533456 | doi = 10.1128/AAC.00360-08 }}</ref> 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 ]s (MIC) values.<ref name="pmid29885758">{{cite journal | vauthors = Yan Q, Karau MJ, Patel R | title = In vitro activity of oritavancin against biofilms of staphylococci isolated from prosthetic joint infection | journal = Diagnostic Microbiology and Infectious Disease | volume = 92 | issue = 2 | pages = 155–157 | date = October 2018 | pmid = 29885758 | doi = 10.1016/j.diagmicrobio.2018.05.010 | s2cid = 47010590 }}</ref> Moreover oritavancin has demonstrated activity against in vitro to vancomycin-susceptible enterococci (VSE) and vancomycin-resistant enterococci (VRE) in both planktonic and biofilm states.<ref name="pmid29678300">{{cite journal | vauthors = Yan Q, Karau MJ, Patel R | title = In vitro activity of oritavancin against planktonic and biofilm states of vancomycin-susceptible and vancomycin-resistant enterococci | journal = Diagnostic Microbiology and Infectious Disease | volume = 91 | issue = 4 | pages = 348–350 | date = August 2018 | pmid = 29678300 | doi = 10.1016/j.diagmicrobio.2018.03.008 | s2cid = 5021157 }}</ref>
Anthrax : Research presented at the ] 107th Annual General Meeting in May 2007, suggested oritavancin’s potential utility as a therapy for exposure to '']'', the gram-positive bacterium that causes ], having demonstrated efficacy in a mouse model both pre- and post-exposure to the bacterium<ref>ASM 2007 Poster: “Efficacy of Oritavancin in a Murine Model of ''Bacillus anthracis'' Spore Inhalation Anthrax” / </ref>


===Mechanism=== === Mechanism ===
The 4'-chloro]methyl group disrupts the cell membrane of gram positive bacteria.<ref>{{cite journal |doi=10.1128/AAC.00760-10 |url=http://aac.asm.org/cgi/content/short/54/12/5369?rss=1 |journal=Antimicrobial agents and chemotherapy |title=Oritavancin Disrupts Membrane Integrity of Staphylococcus aureus and Vancomycin-Resistant Enterococci To Effect Rapid Bacterial Killing |first8=G |last8=Moeck |first7=TR |last7=Parr Jr |first6=I |last6=Fadhil |first5=S |last5=Beaulieu |first4=I |last4=Sarmiento |first3=FF |last3=Arhin |first2=GA |volume=54 |last2=McKay |author=Belley |issue=12 |pages=5369–71 |year=2010 |pmid=20876372 |pmc=2981232 }}</ref>


The 4'-chloro]methyl group disrupts the cell membrane of Gram-positive bacteria.<ref>{{cite journal | vauthors = Belley A, McKay GA, Arhin FF, Sarmiento I, Beaulieu S, Fadhil I, Parr TR, Moeck G | title = Oritavancin disrupts membrane integrity of Staphylococcus aureus and vancomycin-resistant enterococci to effect rapid bacterial killing | journal = Antimicrobial Agents and Chemotherapy | volume = 54 | issue = 12 | pages = 5369–5371 | date = December 2010 | pmid = 20876372 | pmc = 2981232 | doi = 10.1128/AAC.00760-10 }}</ref>
==Clinical progress==
It also acts by inhibition of transglycosylation and inhibition of transpeptidation.<ref>{{cite journal | vauthors = Zhanel GG, Schweizer F, Karlowsky JA | title = Oritavancin: mechanism of action | journal = Clinical Infectious Diseases | volume = 54 | issue = Suppl 3 | pages = S214–S219 | date = April 2012 | pmid = 22431851 | doi = 10.1093/cid/cir920 | doi-access = }}</ref>


=== Synergism ===
Results have been presented (in 2003) but possibly not yet published from two pivotal Phase 3 clinical trials testing the efficacy of daily intravenous oritavancin for the treatment of ] (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 (] followed by ]). In addition, oritavancin showed a significantly improved safety profile with a 19.2 percent relative reduction in the overall incidence of adverse events versus vancomycin/cephalexin (p<0.001) in the second and larger pivotal trial<ref>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)" / </ref>.


Several antibiotics have been tested as partner drugs of oritavancin.<ref>{{cite journal | vauthors = Smith JR, Barber KE, Raut A, Aboutaleb M, Sakoulas G, Rybak MJ | title = β-Lactam combinations with daptomycin provide synergy against vancomycin-resistant Enterococcus faecalis and Enterococcus faecium | journal = The Journal of Antimicrobial Chemotherapy | volume = 70 | issue = 6 | pages = 1738–1743 | date = 1 June 2015 | pmid = 25645208 | pmc = 4542582 | doi = 10.1093/jac/dkv007 }}</ref><ref>{{cite journal | vauthors = Wu T, Meyer K, Harrington AT, Danziger LH, Wenzler E | title = In vitro activity of oritavancin alone or in combination against vancomycin-susceptible and -resistant enterococci | journal = The Journal of Antimicrobial Chemotherapy | volume = 74 | issue = 5 | pages = 1300–1305 | date = May 2019 | pmid = 30753495 | doi = 10.1093/jac/dkz010 }}</ref> 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''), including biofilm-producing isolates.<ref>{{cite journal | vauthors = Lagatolla C, Mehat JW, La Ragione RM, Luzzati R, Di Bella S | title = In Vitro and In Vivo Studies of Oritavancin and Fosfomycin Synergism against Vancomycin-Resistant ''Enterococcus faecium'' | journal = Antibiotics | volume = 11 | issue = 10 | pages = 1334 | date = September 2022 | pmid = 36289992 | pmc = 9598191 | doi = 10.3390/antibiotics11101334 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Di Cecco C, Monticelli J, Di Bella S, Di Maso V, Luzzati R | title = Vancomycin-resistant enterococcus bloodstream infection successfully managed with oritavancin and fosfomycin as sequential treatment | journal = Journal of Chemotherapy | pages = 31–34 | date = August 2023 | volume = 36 | issue = 1 | pmid = 37602423 | doi = 10.1080/1120009X.2023.2247205 | s2cid = 261048377 }}</ref> This synergistic action has also been proposed for the prevention of vascular graft infections by impregnating prostheses with a combination of oritavancin and fosfomycin.<ref>{{Cite journal | vauthors = Cruz I, Di Bella S, D'Oria M, Lagatolla C, Martins MC, Monteiro C |date=2024-10-22 |title=Vascular Graft Impregnation with a Fosfomycin/Oritavancin Combination to Prevent Early Infection |journal=Pharmaceutics |language=en |volume=16 |issue=11 |pages=1348 |doi=10.3390/pharmaceutics16111348 |doi-access=free |issn=1999-4923|pmc=11597391 }}</ref>
A Phase 2 clinical study was planned to run until May 2008 entitled “Single or Infrequent Doses for the Treatment of Complicated Skin and Skin Structure Infections (SIMPLIFI),” evaluating the efficacy and safety of either a single dose of oritavancin or an infrequent dose of oritavancin compared to the previously studied dosing regimen of 200&nbsp;mg oritavancin given once daily for 3 to 7 days<ref></ref>. Results published May 2011.<ref>{{cite journal |url=http://aac.asm.org/cgi/content/abstract/AAC.00029-11v1 |title=Comparison of the Efficacy and Safety of Oritavancin Front-Loaded Dosing Regimens to Daily Dosing: An Analysis of the SIMPLIFI Trial |date=May 2011 |doi=10.1128/AAC.00029-11 }}</ref>


==Spectrum of Activity==
==Regulatory submissions==
===USA===
On February 11, 2008, Targanta submitted a ] (NDA) to the ] ] seeking approval of oritavancin;<ref>{{cite web |url=http://www.drugs.com/nda/oritavancin_080211.html |title=Drugs.com, Targanta Submits Oritavancin New Drug Application |accessdate=2008-02-12 |work= }}</ref> in April 2008, the FDA accepted the NDA submission for standard review.<ref>{{cite web |url=http://www.fdanews.com/newsletter/article?articleId=105717&issueId=11481 |title=FDA News, Targanta to Get FDA Decision by December |accessdate=2008-04-10 |format= |work= }}</ref> On 9 Dec 2008 the FDA said insufficient data for approval of oritavancin had been provided and they requested a further phase 3 clinical study to include more patients with ].<ref>http://www.fiercebiotech.com/press-releases/fda-issues-complete-response-letter-oritavancin Dec 2008.</ref>


Oritavancin is active against gram-positive aerobic bacteria such as enterococci, staphylococci, streptococci, and anaerobic bacteria such as '']'' , '']'' , '']'' , and '']''<ref>{{cite journal | vauthors = Mendes RE, Woosley LN, Farrell DJ, Sader HS, Jones RN | title = Oritavancin activity against vancomycin-susceptible and vancomycin-resistant Enterococci with molecularly characterized glycopeptide resistance genes recovered from bacteremic patients, 2009-2010 | journal = Antimicrobial Agents and Chemotherapy | volume = 56 | issue = 3 | pages = 1639–1642 | date = March 2012 | pmid = 22183169 | pmc = 3294904 | doi = 10.1128/AAC.06067-11 }}</ref><ref>{{cite journal | vauthors = Mendes RE, Sader HS, Flamm RK, Jones RN | title = Activity of oritavancin tested against uncommonly isolated Gram-positive pathogens responsible for documented infections in hospitals worldwide | journal = The Journal of Antimicrobial Chemotherapy | volume = 69 | issue = 6 | pages = 1579–1581 | date = June 2014 | pmid = 24505091 | doi = 10.1093/jac/dku016 | doi-access = free }}</ref> Oritavancin's spectrum of activity shows similarities to vancomycin, but with lower minimum inhibitory concentrations (MIC).<ref>{{cite journal | vauthors = Arhin FF, Draghi DC, Pillar CM, Parr TR, Moeck G, Sahm DF | title = Comparative in vitro activity profile of oritavancin against recent gram-positive clinical isolates | journal = Antimicrobial Agents and Chemotherapy | volume = 53 | issue = 11 | pages = 4762–4771 | date = November 2009 | pmid = 19738026 | pmc = 2772347 | doi = 10.1128/AAC.00952-09 }}</ref>
===Europe===

June 2008, Targanta’s ] (MAA) for oritavancin was submitted and accepted for review by the ] (EMEA)<ref>{{cite web |url=http://www.pharmaceutical-business-review.com/article_news.asp?guid=BBD6223C-8695-4173-8E37-F4463C61A20E |title=Pharmaceutical Business Review, EMEA accepts Targanta's oritavancin MAA for review |accessdate=2008-06-26 |format= |work= }} {{Dead link|date=October 2010|bot=H3llBot}}</ref>, but the company later withdrew the application in Aug 2009<ref>http://www.nelm.nhs.uk/en/NeLM-Area/News/2009---August/24/European-application-for-investigational-antibiotic-oritavancin-withdrawn-/</ref>.
== 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 ]s (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 ]. Oritavancin showed a statistically significant improved safety profile with a 19% relative reduction in the overall incidence of adverse events versus vancomycin/cephalexin <!-- (p<0.001) --> in the second and larger pivotal trial.<ref name="pmid25709561">{{cite journal | vauthors = Kmeid J, Kanafani ZA | title = Oritavancin for the treatment of acute bacterial skin and skin structure infections: an evidence-based review | journal = Core Evidence | volume = 10 | issue = | pages = 39–47 | date = 2015 | pmid = 25709561 | pmc = 4334198 | doi = 10.2147/CE.S51284 | doi-access = free }}</ref>
<!-- out of date A phase-II clinical study was planned to run until May 2008 entitled "Single or Infrequent Doses for the Treatment of Complicated Skin and Skin Structure Infections (SIMPLIFI)," evaluating the efficacy and safety of either a single dose of oritavancin or an infrequent dose of oritavancin compared to the previously studied dosing regimen of 200&nbsp;mg oritavancin given once daily for 3 to 7 days.<ref>{{ClinicalTrialsGov|NCT00514527|A Study for Patients With Complicated Skin and Skin Structure Infections (SIMPLIFI)}}</ref> Results were published May 2011.<ref>{{cite journal | vauthors = Dunbar LM, Milata J, McClure T, Wasilewski MM | title = Comparison of the efficacy and safety of oritavancin front-loaded dosing regimens to daily dosing: an analysis of the SIMPLIFI trial | journal = Antimicrobial Agents and Chemotherapy | volume = 55 | issue = 7 | pages = 3476–3484 | date = July 2011 | pmid = 21537018 | pmc = 3122413 | doi = 10.1128/AAC.00029-11 }}</ref> -->

] remains a formidable foe in an era of increasing incidence of ] (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.<ref name="pmid30537532">{{cite journal | vauthors = Chastain DB, Davis A | title = Treatment of chronic osteomyelitis with multidose oritavancin: A case series and literature review | journal = International Journal of Antimicrobial Agents | volume = 53 | issue = 4 | pages = 429–434 | date = April 2019 | pmid = 30537532 | doi = 10.1016/j.ijantimicag.2018.11.023 | s2cid = 54475167 }}</ref>

==History==
Originally discovered and developed by ], oritavancin was acquired by InterMune in 2001 and then by ] in late 2005.<ref>{{cite web| vauthors = Okudaira T |url=http://www.bioworld.com/servlet/com.accumedia.web.Dispatcher?next=bioWorldHeadlines_article&forceid=46239 |title=The Daily Biopharmaceutical News Source |publisher=BioWorld |date=9 May 2014 |access-date=6 June 2014}}</ref>
In December 2008, the U.S. ] (FDA) declined to approve oritavancin without additional studies, and an EU application was withdrawn.{{citation needed|date=March 2023}}

In 2009, The Medicines Company acquired the development rights, completed clinical trials and submitted a ] to the FDA in February 2014.<ref>{{cite news |url=http://www.fiercebiotech.com/story/biotechs-pick-slack-antibiotics-development/2011-05-17 |title=Biotechs pick up slack in antibiotics development |date=17 May 2011 }}</ref> On 6 August 2014, the United States FDA approved oritavancin to treat ].<ref>{{cite press release|url= https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm408475.htm|archive-url= https://web.archive.org/web/20140808234620/http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm408475.htm|url-status= dead|archive-date= 8 August 2014|title=FDA approves Orbactiv to treat skin infections |publisher=U.S. ] (FDA) |date=6 August 2014}}</ref>

A marketing authorization valid throughout the European Union was granted in March 2015, for the treatment of acute bacterial skin and skin structure infections in adults.<ref>{{cite web | title = EPAR summary: Orbactiv | url = http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Summary_for_the_public/human/003785/WC500186346.pdf | work = European Medicines Agency | access-date = 12 February 2017 | archive-date = 19 June 2018 | archive-url = https://web.archive.org/web/20180619080140/http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Summary_for_the_public/human/003785/WC500186346.pdf | url-status = dead }}</ref>


== References == == References ==
{{reflist|2}} {{reflist}}


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Latest revision as of 04:03, 2 December 2024

Pharmaceutical drug

Pharmaceutical compound
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
Pharmacokinetic data
Elimination half-life16 d)
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
3D model (JSmol)
SMILES
  • C1((C(O1)O23C(=O)N(C4=C(C(=CC(=C4)O)O)C5=C(C=CC(=C5)(C(=O)N3)NC(=O)6C7=CC(=C(C(=C7)OC8=C(C=C(C=C8)((C(=O)N(C(=O)N6)CC(=O)N)NC(=O)(CC(C)C)NC)O)Cl)O9((((O9)CO)O)O)O1C(((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
  • Key:VHFGEBVPHAGQPI-MYYQHNLBSA-N
  (what is this?)  (verify)

Oritavancin, sold under the brand name Orbactiv (by Melinta Therapeutics) 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.

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.

Medical uses

Oritavancin is considered a long-lasting antibiotic due to its extended half-life (up to 16 d), high protein binding capacity, and ability to penetrate tissues effectively. It binds strongly to plasma proteins (around 85%), resulting in prolonged release into surrounding tissues. Furthermore, oritavancin exhibits excellent tissue penetration and distribution throughout various sites, including skin structures, synovial fluid (found in joints), bone tissue, and macrophages. Less frequent dosing requirements still keep efficacy against gram-positive infections, which is convenient for prolonged treatment courses such as osteoarticular infections and endocarditis, making it an option for outpatient antibiotic therapy in difficult-to-treat populations where adherence may be challenging and those with limited access to healthcare facilities.

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. 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.

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. 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. Moreover oritavancin has demonstrated activity against in vitro to vancomycin-susceptible enterococci (VSE) and vancomycin-resistant enterococci (VRE) in both planktonic and biofilm states.

Mechanism

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

Synergism

Several antibiotics have been tested as partner drugs of oritavancin. 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), including biofilm-producing isolates. This synergistic action has also been proposed for the prevention of vascular graft infections by impregnating prostheses with a combination of oritavancin and fosfomycin.

Spectrum of Activity

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

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.

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.

History

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

A marketing authorization valid throughout the European Union was granted in March 2015, for the treatment of acute bacterial skin and skin structure infections in adults.

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". 17 September 2018.
  4. ^ Micheli G, Chiuchiarelli M, Taccari F, Fantoni M (2023). "The role of long-acting antibiotics in the clinical practice: a narrative review". Infez Med. 31 (4): 449–465. doi:10.53854/liim-3104-4. PMC 10705857. PMID 38075413.
  5. 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". Biochimica et Biophysica Acta (BBA) - Biomembranes. 1788 (9): 1832–1840. doi:10.1016/j.bbamem.2009.05.003. PMID 19450541.
  6. "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.
  7. 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.
  8. Crandon J, Nicolau DP (June 2008). "Oritavancin: a potential weapon in the battle against serious Gram-positive pathogens". Future Microbiology. 3 (3): 251–263. doi:10.2217/17460913.3.3.251. PMID 18505390.
  9. Brade KD, Rybak JM, Rybak MJ (March 2016). "Oritavancin: A New Lipoglycopeptide Antibiotic in the Treatment of Gram-Positive Infections". Infectious Diseases and Therapy. 5 (1): 1–15. doi:10.1007/s40121-016-0103-4. PMC 4811835. PMID 26831328.
  10. Heine HS, Bassett J, Miller L, Bassett A, Ivins BE, Lehoux D, et al. (September 2008). "Efficacy of oritavancin in a murine model of Bacillus anthracis spore inhalation anthrax". Antimicrobial Agents and Chemotherapy. 52 (9): 3350–3357. doi:10.1128/AAC.00360-08. PMC 2533456. PMID 18606841.
  11. Yan Q, Karau MJ, Patel R (October 2018). "In vitro activity of oritavancin against biofilms of staphylococci isolated from prosthetic joint infection". Diagnostic Microbiology and Infectious Disease. 92 (2): 155–157. doi:10.1016/j.diagmicrobio.2018.05.010. PMID 29885758. S2CID 47010590.
  12. Yan Q, Karau MJ, Patel R (August 2018). "In vitro activity of oritavancin against planktonic and biofilm states of vancomycin-susceptible and vancomycin-resistant enterococci". Diagnostic Microbiology and Infectious Disease. 91 (4): 348–350. doi:10.1016/j.diagmicrobio.2018.03.008. PMID 29678300. S2CID 5021157.
  13. 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): 5369–5371. doi:10.1128/AAC.00760-10. PMC 2981232. PMID 20876372.
  14. Zhanel GG, Schweizer F, Karlowsky JA (April 2012). "Oritavancin: mechanism of action". Clinical Infectious Diseases. 54 (Suppl 3): S214 – S219. doi:10.1093/cid/cir920. PMID 22431851.
  15. Smith JR, Barber KE, Raut A, Aboutaleb M, Sakoulas G, Rybak MJ (1 June 2015). "β-Lactam combinations with daptomycin provide synergy against vancomycin-resistant Enterococcus faecalis and Enterococcus faecium". The Journal of Antimicrobial Chemotherapy. 70 (6): 1738–1743. doi:10.1093/jac/dkv007. PMC 4542582. PMID 25645208.
  16. Wu T, Meyer K, Harrington AT, Danziger LH, Wenzler E (May 2019). "In vitro activity of oritavancin alone or in combination against vancomycin-susceptible and -resistant enterococci". The Journal of Antimicrobial Chemotherapy. 74 (5): 1300–1305. doi:10.1093/jac/dkz010. PMID 30753495.
  17. Lagatolla C, Mehat JW, La Ragione RM, Luzzati R, Di Bella S (September 2022). "In Vitro and In Vivo Studies of Oritavancin and Fosfomycin Synergism against Vancomycin-Resistant Enterococcus faecium". Antibiotics. 11 (10): 1334. doi:10.3390/antibiotics11101334. PMC 9598191. PMID 36289992.
  18. Di Cecco C, Monticelli J, Di Bella S, Di Maso V, Luzzati R (August 2023). "Vancomycin-resistant enterococcus bloodstream infection successfully managed with oritavancin and fosfomycin as sequential treatment". Journal of Chemotherapy. 36 (1): 31–34. doi:10.1080/1120009X.2023.2247205. PMID 37602423. S2CID 261048377.
  19. Cruz I, Di Bella S, D'Oria M, Lagatolla C, Martins MC, Monteiro C (22 October 2024). "Vascular Graft Impregnation with a Fosfomycin/Oritavancin Combination to Prevent Early Infection". Pharmaceutics. 16 (11): 1348. doi:10.3390/pharmaceutics16111348. ISSN 1999-4923. PMC 11597391.
  20. 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): 1639–1642. doi:10.1128/AAC.06067-11. PMC 3294904. PMID 22183169.
  21. 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): 1579–1581. doi:10.1093/jac/dku016. PMID 24505091.
  22. 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): 4762–4771. doi:10.1128/AAC.00952-09. PMC 2772347. PMID 19738026.
  23. Kmeid J, Kanafani ZA (2015). "Oritavancin for the treatment of acute bacterial skin and skin structure infections: an evidence-based review". Core Evidence. 10: 39–47. doi:10.2147/CE.S51284. PMC 4334198. PMID 25709561.
  24. Chastain DB, Davis A (April 2019). "Treatment of chronic osteomyelitis with multidose oritavancin: A case series and literature review". International Journal of Antimicrobial Agents. 53 (4): 429–434. doi:10.1016/j.ijantimicag.2018.11.023. PMID 30537532. S2CID 54475167.
  25. Okudaira T (9 May 2014). "The Daily Biopharmaceutical News Source". BioWorld. Retrieved 6 June 2014.
  26. "Biotechs pick up slack in antibiotics development". 17 May 2011.
  27. "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.
  28. "EPAR summary: Orbactiv" (PDF). European Medicines Agency. Archived from the original (PDF) on 19 June 2018. Retrieved 12 February 2017.
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