Dalbavancin

Dalbavancin
Names
Trade namesDalvance, Xydalba, Zeven, other
IUPAC name
  • 2-deoxy-1-O-[(3S,15R,18R,34R,35S,38S,48R,50aR)-5,31-dichloro-38-{[3-(dimethylamino)propyl]carbamoyl}-6,11,34,40,44-pentahydroxy-42-(α-D-mannopyranosyloxy)-15-(methylamino)-2,16,36,50,51,59-hexaoxo-2,3,16,17,18,19,35,36,37,38,48,49,50,50a-tetradecahydro-1H,15H,34H-20,23:30,33-dietheno-3,18:35,48-bis(iminomethano) 4,8:10,14:25,28:43,47-tetrametheno[1,14,6,22]dioxadiazacyclooctacosino[4,5-m][10,2,16]benzoxadiazacyclohexacosin-56-yl]-2-[(10-methylundecanoyl)amino]-β-D-glucopyranuronic acid [1]
Clinical data
Pregnancy
category
  • US: C (Risk not ruled out)
    Routes of
    use    		Intravenous
    External links
    AHFS/Drugs.comMonograph
    US NLMDalbavancin
    MedlinePlusa614036
    Legal
    License data
    Legal status
    Chemical and physical data
    FormulaC88H100Cl2N10O28
    Molar mass1816.71 g·mol−1
    3D model (JSmol)
    SMILES
    • CC(C)CCCCCCCCC(=O)N[C@@H]1[C@H]([C@@H]([C@H](O[C@H]1Oc2c3cc4cc2Oc5ccc(cc5Cl)[C@H]([C@H]6C(=O)N[C@@H](c7cc(cc(c7-c8cc(ccc8O)[C@H](C(=O)N6)NC(=O)[C@@H]4NC(=O)[C@@H]9c1cc(cc(c1Cl)O)Oc1ccc(cc1O)[C@H](C(=O)N[C@H](Cc1ccc(cc1)O3)C(=O)N9)NC)O[C@@H]1[C@H]([C@H]([C@@H]([C@H](O1)CO)O)O)O)O)C(=O)NCCCN(C)C)O)C(=O)O)O)O
    InChI
    • InChI=1S/C88H100Cl2N10O28/c1-38(2)13-10-8-6-7-9-11-14-61(106)94-70-73(109)75(111)78(86(120)121)128-87(70)127-77-58-31-43-32-59(77)124-55-23-19-42(29-50(55)89)71(107)69-85(119)98-67(80(114)92-25-12-26-100(4)5)48-33-44(102)34-57(125-88-76(112)74(110)72(108)60(37-101)126-88)62(48)47-28-40(17-22-52(47)103)65(82(116)99-69)95-83(117)66(43)96-84(118)68-49-35-46(36-54(105)63(49)90)123-56-24-18-41(30-53(56)104)64(91-3)81(115)93-51(79(113)97-68)27-39-15-20-45(122-58)21-16-39/h15-24,28-36,38,51,60,64-76,78,87-88,91,101-105,107-112H,6-14,25-27,37H2,1-5H3,(H,92,114)(H,93,115)(H,94,106)(H,95,117)(H,96,118)(H,97,113)(H,98,119)(H,99,116)(H,120,121)/t51-,60-,64-,65-,66-,67+,68+,69+,70-,71-,72-,73-,74+,75+,76+,78+,87-,88+/m1/s1 ☒N
    • Key:IZJRUXNZMRDQJI-SZUNQUCBSA-N ☒N

    Dalbavancin, sold under the trade names Dalvance among others, is an antibiotic used to treat bacterial skin infections, including those caused by methicillin-resistant Staphylococcus aureus (MRSA).[2] It is give by injection into a vein either as a single dose or two doses one week apart.[2][3]

    Common side effects include nausea, diarrhea, rash, and headache.[2] Other side effects may include antibiotic associated colitis, constipation, and low white blood cells.[3] It is unclear if use is safe in pregnancy or breastfeeding.[4] It is in the lipoglycopeptide class of medications, along with vancomycin.[2]

    Dalbavancin was approved for medical use in the United States in 2014 and Europe in 2015.[2][5] In the United States the a course of medication costs about 4,800 USD as of 2021.[6] In the United Kingdom this amount costs the NHS about £1,700.[3]

    Medical uses

    Dalbavancin is an antibiotic used to treat acute bacterial skin and skin structure infections (ABSSSI) in adults caused by susceptible Gram-positive organisms, including methicillin-resistant Staphylococcus aureus (MRSA). MRSA infections have become problematic in the community and in healthcare settings due to resistance to many available antibiotics.[7] Because dalbavancin has demonstrated efficacy against MRSA and other microorganisms to treat serious or life-threatening infections, it was the first drug approved as a Qualified Infectious Disease Product under the Generating Antibiotic Incentives Now (GAIN) act, which is part of the FDA Safety and Innovation Act.[8]

    It has strong activity against many Gram-positive bacteria, including methicillin-sensitive and methicillin-resistant Staphylococcus aureus, Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus anginosus, Streptococcus intermedius, and Streptococcus constellatus.[9] Based on MIC data and other studies, dalbavancin is more potent and bactericidal and therefore requires lower concentrations than vancomycin against these organisms.[10] Dalbavancin also shows in vitro activity against vancomycin-susceptible Enterococcus faecium and Enterococcus faecalis.[9] Other Gram-positive organisms belonging to the Bacillus spp., Listeria spp., and Corynebacterium spp. may show in vitro susceptibility, and dalbavancin may exhibit activity against enterococci expressing the VanB or VanC phenotype of acquired resistance against vancomycin.[10][11] There is no clinically significant activity against Gram-negative bacteria.[10]

    Two trials demonstrated noninferiority of dalbavancin compared to vancomycin/linezolid in the treatment of ABSSSI.[12] This once-weekly dosing regimen may offer an advantageous treatment option compared to daily or twice-daily dosing.[8]

    Dosage

    It is given as 1 gram and than 500 mg seven days later.[2] It may also be given as 1.5 gram as a single dose.[3]

    Contraindications

    Dalbavancin is contraindicated in patients with hypersensitivity to dalbavancin, such as skin reactions or anaphylaxis, and caution is advised for patients with known hypersensitivity to other glycopeptides. There is currently no data on cross-reactivity between dalbavancin and vancomycin.[9]

    Side effects

    The most common adverse reactions encountered in Phase II and Phase III trials were nausea (5.5%), headache (4.7%), and diarrhea (4.4%), as well as rash (2.7%) and itchiness (2.1%). Other less frequent but serious adverse reactions included hematologic disorders, hepatotoxicity, Clostridium difficile colitis, bronchospasm, infusion-related reactions including Red Man Syndrome, and anaphylactic shock.[9] In trials, dalbavancin was associated with higher rates of hemorrhagic events compared to comparator groups and should be a precaution in patients undergoing surgery or taking anticoagulants.[10] Patients on dalbavancin also had post-baseline alanine aminotransferase (ALT) levels that were 3 times the upper normal limit, some even having elevations 10 times the upper normal limit; however, eight of the twelve dalbavancin-treated patients had comorbid conditions that could affect their ALT, compared to only one patient in the comparator group.[9] There is no evidence of ototoxicity associated with dalbavancin.[11]

    Drug interactions

    Clinical drug-drug interactions with dalbavancin have not been studied, and dalbavancin does not appear to interact with cytochrome P450 substrates, inhibitors, or inducers. It was found to have an in vitro synergistic interaction with the antimicrobial oxacillin, but the clinical significance of this interaction has yet to be established.[9]

    Pregnancy and lactation

    Use of dalbavancin in pregnant women has not been studied sufficiently and should only occur when the potential benefit outweighs the potential risk to the fetus. Animal studies did not show embryo or fetal toxicity at doses that were 1.2 and 0.7 times the human dose. However, delayed fetal maturation was observed at a dose that was 3.5 times the human dose. While dalbavancin is excreted in rat milk, it is unknown if it is excreted in human milk. It should be used in nursing mothers only when the potential benefit exceeds the potential risk.[9] There is no evidence in animals of teratogenicity.[11]

    Mechanism of action

    Dalbavancin is a lipoglycopeptide belonging in the same glycopeptide class as vancomycin. Similar to other glycopeptides, dalbavancin exerts its bactericidal effect by disrupting cell wall biosynthesis. It binds to the D-alanyl-D-alanyl residue on growing peptidoglycan chains and prevents transpeptidation from occurring, preventing peptidoglycan elongation and cell wall formation. Dalbavancin also dimerizes and anchors itself in the lipophilic bacterial membrane, thereby increasing its stability in the target environment and its affinity for peptidoglycan.[10]

    Antimicrobial activity correlates with the ratio of area under the concentration-time curve to minimum inhibitory concentration for Staphylococcus aureus.[9]

    Metabolism

    When evaluated by in vitro studies, the metabolism of dalbavancin was minimally impacted by the human hepatic CYP450 system.[13] Further investigations with either inducers or inhibitors of this enzyme system demonstrated no changes in the elimination or clearance of dalbavancin, and the metabolism of model compounds of these CYP systems was not altered by the dalbavancin. Hydroxy-dalbavancin, a minor metabolite that has only been identified in urine, was also not changed in its formation or elimination with these enzyme models.[13][14]

    History

    Dalbavancin has undergone a phase-III clinical trial for adults with complicated skin infections, but in December 2007, the FDA said more data were needed before approval.[15] On September 9, 2008, Pfizer announced it will withdraw all marketing applications to conduct another phase-III clinical trial.[16] Durata Therapeutics acquired the rights to dalbavancin in December 2009, and has initiated two new phase-III clinical trials for treatment of ABSSSIs.[17] Preliminary results in 2012 were promising.[18]

    About 1,289 adults with ABSSSI were given dalbavancin or vancomycin randomly, and dalbavancin was found to exhibit efficacy comparable to vancomycin.[19]

    In May 2014, dalbavancin was approved by the FDA for use in the US for ABSSSIs, including MRSA and Streptococcus pyogenes infections.

    Society and culture

    Terminology

    Dalbavancin has been referred to in the scientific literature by a series of names: MDL-63397, A-!-1, BI-397, VER-001. These different labels reflected where the research had been carried out: MDL representing Merrell-Dow-Lepetit, where the initial complex was discovered; BI referring to BioSearch Italia where Dalbavancin itself was first synthesized; VER referring to Versicor (which Biosearch Italia merged with to create Vicuron Pharmaceuticals). The phase 1, 2 and 3 clinical trials were carried out of by Vicuron and the initial NDA filed. Vicuron was acquired by Pfizer in 2005, which decided to not further develop Dalbavancin at that time, subsequently selling the rights to Durata Therapeutics in 2009.

    Production and composition

    Dalbavancin is manufactured by fermentation of a selected Nonomuraea strain to generate the natural glycopeptide complex A-40926. This precursor is then selectively esterified at the carboxyl group of its sugar moiety, its peptidyl carboxyl group is amidated and the ester of the N-acylaminoglucuronic acid carboxyl group is saponified.[20] The outcome is a compound mixture of two closely related structural families — A and B — that can be further subdivided into a total of five subtypes (see table below).[1] At least ten different dalbavancin components have been described, of which the B0 component makes up around 80–98 wt%.[20]

    Dalbavancin homologs
    Core structure of dalbavancin
    Core structure of dalbavancin
    HomologAlkyl sidechain of N-acylaminoglucuronic acid (R1)Amino-terminal substituent (R2)
    A0CH(CH3)2H
    A1CH2CH2CH3H
    B0CH2CH(CH3)2H
    B1CH2CH2CH2CH3H
    B2CH2CH(CH3)2CH3

    References

    1. 1 2 European Medicines Agency (EMA) assessment of Dalbavancin http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/002840/WC500183871.pdf Archived 2018-06-19 at the Wayback Machine
    2. 1 2 3 4 5 6 "Dalbavancin Monograph for Professionals". Drugs.com. Archived from the original on 5 March 2021. Retrieved 21 July 2021.
    3. 1 2 3 4 BNF (80 ed.). BMJ Group and the Pharmaceutical Press. September 2020 – March 2021. p. 561. ISBN 978-0-85711-369-6.{{cite book}}: CS1 maint: date format (link)
    4. ↑ "Dalbavancin (Dalvance) Use During Pregnancy". Drugs.com. Archived from the original on 28 November 2020. Retrieved 21 July 2021.
    5. ↑ "Xydalba". Archived from the original on 20 January 2021. Retrieved 21 July 2021.
    6. ↑ "Dalbavancin Prices, Coupons & Savings Tips - GoodRx". GoodRx. Retrieved 21 July 2021.
    7. ↑ Centers for Disease Control and Prevention - Methicillin-Resistant Staphylococcus aureus (MRSA) infections. https://www.cdc.gov/mrsa/ Archived 2021-07-12 at the Wayback Machine
    8. 1 2 Dalbavancin: First I.V. antibiotic for acute bacterial skin infections. http://www.pharmacist.com/dalbavancin-first-iv-antibiotic-acute-bacterial-skin-infections Archived 2018-02-14 at the Wayback Machine
    9. 1 2 3 4 5 6 7 8 Dalvance (dalbavancin) for injection Full Prescribing Information. http://content.stockpr.com/duratatherapeutics/files/docs/Dalvance+APPROVED+USPI.PDF Archived 2021-01-24 at the Wayback Machine
    10. 1 2 3 4 5 Bennet JW, Lewis JS, Ellis MW (2008). "Dalbavancin in the treatment of complicated skin and soft-tissue infections: a review." Therapeutics and Clinical Risk Management 4 (1): 31-40. PMC 2503664 Archived 2021-08-28 at the Wayback Machine.
    11. 1 2 3 FDA Briefing Document: Anti-Infective Drugs Advisory Committee Meeting. NDA 21-883: Dalvance (Dalbavancin) for Injection. https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Anti-InfectiveDrugsAdvisoryCommittee/UCM390792.pdf Archived 2017-06-23 at the Wayback Machine
    12. ↑ Boucher HW, Wilcox M, Talbot GH, Puttagunta S, Das AF, Dunne MW (June 2014). "Once-weekly dalbavancin versus daily conventional therapy for skin infection". The New England Journal of Medicine. 370 (23): 2169–79. doi:10.1056/NEJMoa1310480. PMID 24897082.
    13. 1 2 Leuthner KD, Buechler KA, Kogan D, Saguros A, Lee HS (June 2016). "Clinical efficacy of dalbavancin for the treatment of acute bacterial skin and skin structure infections (ABSSSI)". Therapeutics and Clinical Risk Management. 12: 931–40. doi:10.2147/TCRM.S86330. PMC 4907732. PMID 27354809.
    14. ↑ Buckwalter M, Dowell JA (November 2005). "Population pharmacokinetic analysis of dalbavancin, a novel lipoglycopeptide". Journal of Clinical Pharmacology. 45 (11): 1279–87. doi:10.1177/0091270005280378. PMID 16239361. S2CID 42875399.
    15. ↑ "UPDATE 1-Pfizer says US FDA wants more data on antibiotic. Dec 2007". Archived from the original on 2008-04-22. Retrieved 2021-07-10.
    16. ↑ "Pfizer Will Withdraw Global Marketing Applications for Dalbavancin to Conduct a New Trial" (Press release). Pfizer Inc. 2008-09-09. Archived from the original on 2019-08-01. Retrieved 2008-09-11.
    17. ↑ Durata Begins Dalbavancin Study Enrollment. Archived 2011-10-20 at the Wayback Machine Drug Discovery & Development - October 05, 2011.
    18. ↑ "Durata Therapeutics Announces Phase 3 Clinical Trial Results for Dalbavancin in the Treatment of ABSSSI". Archived from the original on 2015-09-23. Retrieved 2021-07-10.
    19. ↑ Dalvance’s safety and efficacy clinical trial ABSSSI, Results showed Dalvance was as effective as vancomycin
    20. 1 2 US patent 7119061 
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