Oritavancin

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Oritavancin
Oritavancin.svg
Clinical data
Pronunciation /oʊˌrɪtəˈvænsɪn/
oh-RIT-ə-VAN-sin
Trade names Orbactiv, Kimyrsa
Other namesLY333328
AHFS/Drugs.com Monograph
MedlinePlus a614042
License data
Routes of
administration 		Intravenous
ATC code
Legal status
Legal status
Pharmacokinetic data
Elimination half-life 16 d) [4]
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
DrugBank
ChemSpider
UNII
KEGG
ChEBI
CompTox Dashboard (EPA)
Chemical and physical data
Formula C86H97Cl3N10O26
Molar mass 1793.12 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 X mark.svgN
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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. [5]

Contents

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. [6] [3]

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. [4]

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. [7] 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. [8] [9]

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. [10] 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. [11] Moreover oritavancin has demonstrated activity against in vitro to vancomycin-susceptible enterococci (VSE) and vancomycin-resistant enterococci (VRE) in both planktonic and biofilm states. [12]

Mechanism

The 4'-chlorobiphenylmethyl group disrupts the cell membrane of Gram-positive bacteria. [13] It also acts by inhibition of transglycosylation and inhibition of transpeptidation. [14]

Synergism

Several antibiotics have been tested as partner drugs of oritavancin. [15] [16] 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. [17] [18]

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. [19] [20] Oritavancin's spectrum of activity shows similarities to vancomycin, but with lower minimum inhibitory concentrations (MIC). [21]

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. [22]

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. [23]

History

Originally discovered and developed by Eli Lilly, oritavancin was acquired by InterMune in 2001 and then by Targanta Therapeutics in late 2005. [24] 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 ]

In 2009, The Medicines Company acquired the development rights, completed clinical trials and submitted a new drug application to the FDA in February 2014. [25] On August 6, 2014, the United States FDA approved oritavancin to treat skin infections. [26]

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. [27]

Related Research Articles

<span class="mw-page-title-main">Vancomycin</span> Antibiotic medication

Vancomycin is a glycopeptide antibiotic medication used to treat a number of bacterial infections. It is used intravenously as a treatment for complicated skin infections, bloodstream infections, endocarditis, bone and joint infections, and meningitis caused by methicillin-resistant Staphylococcus aureus. Blood levels may be measured to determine the correct dose. Vancomycin is also taken orally as a treatment for severe Clostridium difficile colitis. When taken orally it is poorly absorbed.

<i>Enterococcus</i> Genus of bacteria

Enterococcus is a large genus of lactic acid bacteria of the phylum Bacillota. Enterococci are gram-positive cocci that often occur in pairs (diplococci) or short chains, and are difficult to distinguish from streptococci on physical characteristics alone. Two species are common commensal organisms in the intestines of humans: E. faecalis (90–95%) and E. faecium (5–10%). Rare clusters of infections occur with other species, including E. casseliflavus, E. gallinarum, and E. raffinosus.

<span class="mw-page-title-main">Linezolid</span> Antibiotic medication

Linezolid is an antibiotic used for the treatment of infections caused by Gram-positive bacteria that are resistant to other antibiotics. Linezolid is active against most Gram-positive bacteria that cause disease, including streptococci, vancomycin-resistant enterococci (VRE), and methicillin-resistant Staphylococcus aureus (MRSA). The main uses are infections of the skin and pneumonia although it may be used for a variety of other infections including drug-resistant tuberculosis. It is used either by injection into a vein or by mouth.

<span class="mw-page-title-main">Clindamycin</span> Antibiotic

Clindamycin is a lincosamide antibiotic medication used for the treatment of a number of bacterial infections, including osteomyelitis (bone) or joint infections, pelvic inflammatory disease, strep throat, pneumonia, acute otitis media, and endocarditis. It can also be used to treat acne, and some cases of methicillin-resistant Staphylococcus aureus (MRSA). In combination with quinine, it can be used to treat malaria. It is available by mouth, by injection into a vein, and as a cream or a gel to be applied to the skin or in the vagina.

Vancomycin-resistant <i>Staphylococcus aureus</i> Antibiotica resistant bacteria

Vancomycin-resistant Staphylococcus aureus (VRSA) are strains of Staphylococcus aureus that have acquired resistance to the glycopeptide antibiotic vancomycin. Bacteria can acquire resistant genes either by random mutation or through the transfer of DNA from one bacterium to another. Resistance genes interfere with the normal antibiotic function and allow a bacteria to grow in the presence of the antibiotic. Resistance in VRSA is conferred by the plasmid-mediated vanA gene and operon. Although VRSA infections are uncommon, VRSA is often resistant to other types of antibiotics and a potential threat to public health because treatment options are limited. VRSA is resistant to many of the standard drugs used to treat S. aureus infections. Furthermore, resistance can be transferred from one bacterium to another.

<span class="mw-page-title-main">Tigecycline</span> Chemical compound

Tigecycline, sold under the brand name Tygacil, is a tetracycline antibiotic medication for a number of bacterial infections. It is a glycylcycline administered intravenously. It was developed in response to the growing rate of antibiotic resistant bacteria such as Staphylococcus aureus, Acinetobacter baumannii, and E. coli. As a tetracycline derivative antibiotic, its structural modifications has expanded its therapeutic activity to include Gram-positive and Gram-negative organisms, including those of multi-drug resistance.

Vancomycin-resistant <i>Enterococcus</i> Bacterial strains of Enterococcus that are resistant to the antibiotic vancomycin

Vancomycin-resistant Enterococcus, or vancomycin-resistant enterococci (VRE), are bacterial strains of the genus Enterococcus that are resistant to the antibiotic vancomycin.

<i>Enterococcus faecalis</i> Species of bacterium

Enterococcus faecalis – formerly classified as part of the group D Streptococcus system – is a Gram-positive, commensal bacterium inhabiting the gastrointestinal tracts of humans. Like other species in the genus Enterococcus, E. faecalis is found in healthy humans and can be used as a probiotic. The probiotic strains such as Symbioflor1 and EF-2001 are characterized by the lack of specific genes related to drug resistance and pathogenesis. As an opportunistic pathogen, E. faecalis can cause life-threatening infections, especially in the nosocomial (hospital) environment, where the naturally high levels of antibiotic resistance found in E. faecalis contribute to its pathogenicity. E. faecalis has been frequently found in reinfected, root canal-treated teeth in prevalence values ranging from 30% to 90% of the cases. Re-infected root canal-treated teeth are about nine times more likely to harbor E. faecalis than cases of primary infections.

Enterococcus faecium is a Gram-positive, gamma-hemolytic or non-hemolytic bacterium in the genus Enterococcus. It can be commensal in the gastrointestinal tract of humans and animals, but it may also be pathogenic, causing diseases such as neonatal meningitis or endocarditis.

<span class="mw-page-title-main">Cefoxitin</span> Chemical compound

Cefoxitin is a second-generation cephamycin antibiotic developed by Merck & Co., Inc. from Cephamycin C in the year following its discovery, 1972. It was synthesized in order to create an antibiotic with a broader spectrum. It is often grouped with the second-generation cephalosporins. Cefoxitin requires a prescription and as of 2010 is sold under the brand name Mefoxin by Bioniche Pharma, LLC. The generic version of cefoxitin is known as cefoxitin sodium.

<span class="mw-page-title-main">Fosfomycin</span> Chemical compound

Fosfomycin, sold under the brand name Monurol among others, is an antibiotic primarily used to treat lower urinary tract infections. It is not indicated for kidney infections. Occasionally it is used for prostate infections. It is generally taken by mouth.

Targanta Therapeutics Corporation was a biopharmaceutical company headquartered in Cambridge, Massachusetts. The company also had operations in Indianapolis, Montreal and Toronto. Targanta completed its initial public offering on October 9, 2007 and traded on the Nasdaq market under the symbol: TARG. Targanta was acquired by The Medicines Company in 2009.

<span class="mw-page-title-main">Dalbavancin</span> Antibiotic used to treat MRSA

Dalbavancin, sold under the brand names Dalvance in the US and Xydalba in the EU among others, is a second-generation lipoglycopeptide antibiotic medication. It belongs to the same class as vancomycin, the most widely used and one of the treatments available to people infected with methicillin-resistant Staphylococcus aureus (MRSA).

<span class="mw-page-title-main">Tedizolid</span> Oxazolidinone-class antibiotic

Tedizolid, is an oxazolidinone-class antibiotic. Tedizolid phosphate is a phosphate ester prodrug of the active compound tedizolid. It was developed by Cubist Pharmaceuticals, following acquisition of Trius Therapeutics, and is marketed for the treatment of acute bacterial skin and skin structure infections.

<span class="mw-page-title-main">Ceftaroline fosamil</span> Chemical compound

Ceftaroline fosamil (INN), brand name Teflaro in the US and Zinforo in Europe, is a cephalosporin antibiotic with anti-MRSA activity. Ceftaroline fosamil is a prodrug of ceftaroline. It is active against methicillin-resistant Staphylococcus aureus (MRSA) and other Gram-positive bacteria. It retains some activity of later-generation cephalosporins having broad-spectrum activity against Gram-negative bacteria, but its effectiveness is relatively much weaker. It is currently being investigated for community-acquired pneumonia and complicated skin and skin structure infection.

<span class="mw-page-title-main">Lipoglycopeptide</span> Class of chemical compounds

Lipoglycopeptides are a class of antibiotic that have lipophilic side-chains linked to glycopeptides. The class includes oritavancin, telavancin and dalbavancin.

<span class="mw-page-title-main">Solithromycin</span> Chemical compound

Solithromycin is a ketolide antibiotic undergoing clinical development for the treatment of community-acquired pneumonia and other infections.

<span class="mw-page-title-main">Omadacycline</span> Chemical compound

Omadacycline, sold under the brand name Nuzyra, is a broad spectrum antibiotic medication belonging to the aminomethylcycline subclass of tetracycline antibiotics. In the United States, it was approved in October 2018, for the treatment of community-acquired bacterial pneumonia and acute skin and skin structure infections.

ESKAPE is an acronym comprising the scientific names of six highly virulent and antibiotic resistant bacterial pathogens including: Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp. The acronym is sometimes extended to ESKAPEE to include Escherichia coli. This group of Gram-positive and Gram-negative bacteria can evade or 'escape' commonly used antibiotics due to their increasing multi-drug resistance (MDR). As a result, throughout the world, they are the major cause of life-threatening nosocomial or hospital-acquired infections in immunocompromised and critically ill patients who are most at risk. P. aeruginosa and S. aureus are some of the most ubiquitous pathogens in biofilms found in healthcare. P. aeruginosa is a Gram-negative, rod-shaped bacterium, commonly found in the gut flora, soil, and water that can be spread directly or indirectly to patients in healthcare settings. The pathogen can also be spread in other locations through contamination, including surfaces, equipment, and hands. The opportunistic pathogen can cause hospitalized patients to have infections in the lungs, blood, urinary tract, and in other body regions after surgery. S. aureus is a Gram-positive, cocci-shaped bacterium, residing in the environment and on the skin and nose of many healthy individuals. The bacterium can cause skin and bone infections, pneumonia, and other types of potentially serious infections if it enters the body. S. aureus has also gained resistance to many antibiotic treatments, making healing difficult. Because of natural and unnatural selective pressures and factors, antibiotic resistance in bacteria usually emerges through genetic mutation or acquires antibiotic-resistant genes (ARGs) through horizontal gene transfer - a genetic exchange process by which antibiotic resistance can spread.

Kerry L. LaPlante is an American pharmacist, academic and researcher. She is the Dean at the University of Rhode Island College of Pharmacy. She is a Professor of Pharmacy and former department Chair of the Department of Pharmacy Practice at the University of Rhode Island, an Adjunct Professor of Medicine at Brown University, an Infectious Diseases Pharmacotherapy Specialist, and the Director of the Rhode Island Infectious Diseases Fellowship and Research Programs at the Veterans Affairs Medical Center in Providence, Rhode Island.

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. 1 2 "Orbactiv EPAR". 17 September 2018.
  4. 1 2 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 (2015-06-01). "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. ↑ 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.
  20. ↑ 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.
  21. ↑ 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.
  22. ↑ 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.
  23. ↑ 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.
  24. ↑ Tomoko Okudaira (2014-05-09). "The Daily Biopharmaceutical News Source". BioWorld. Retrieved 2014-06-06.
  25. ↑ "Biotechs pick up slack in antibiotics development". 17 May 2011.
  26. ↑ "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.
  27. ↑ "EPAR summary: Orbactiv" (PDF). European Medicines Agency. Archived from the original (PDF) on 2018-06-19. Retrieved 2017-02-12.
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