oritavancin

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, 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.{{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=}}

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.{{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 }} 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.{{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 }}{{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 }}

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

The 4'-chlorobiphenylmethyl group disrupts the cell membrane of Gram-positive bacteria.{{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 }}

It also acts by inhibition of transglycosylation and inhibition of transpeptidation.{{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 = }}

Several antibiotics have been tested as partner drugs of oritavancin.{{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 }}{{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 }} 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.{{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 }}{{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 }} This synergistic action has also been proposed for the prevention of vascular graft infections by impregnating prostheses with a combination of oritavancin and fosfomycin.{{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 }}

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.{{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 }}{{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 }} Oritavancin's spectrum of activity shows similarities to vancomycin, but with lower minimum inhibitory concentrations (MIC).{{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 }}

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.{{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 }}

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.{{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 }}

Originally discovered and developed by Eli Lilly, oritavancin was acquired by InterMune in 2001 and then by Targanta Therapeutics in late 2005.{{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}}

In December 2008, the U.S. Food and Drug Administration (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 new drug application to the FDA in February 2014.{{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 }} On 6 August 2014, the United States FDA approved oritavancin to treat skin infections.{{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. Food and Drug Administration (FDA) |date=6 August 2014}}

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.{{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 }}

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Category:CYP3A4 inducers

Category:Drugs developed by Eli Lilly and Company

Category:Glycopeptide antibiotics