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Dalbavancin

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Dalbavancin
Clinical data
Trade namesDalvance, Xydalba
License data
Routes of
administration		Intravenous
ATC code
Identifiers
  • 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]benzoxadiazacyclotetracosin-56-yl]-2-[(10-methylundecanoyl)amino]-β-D-glucopyranuronic acid [1]
CAS Number
PubChem CID
ChemSpider
UNII
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.308.391 Edit this at Wikidata
Chemical and physical data
FormulaC88H100Cl2N10O28
Molar mass1816.7 g/mol g·mol−1
3D model (JSmol)
  • 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=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
 ☒NcheckY (what is this?)  (verify)

Dalbavancin (INN, trade names Dalvance in the US and Xydalba in Europe) is a novel second-generation lipoglycopeptide antibiotic. It belongs to the same class as vancomycin, the most widely used and one of the few treatments available to patients infected with methicillin-resistant Staphylococcus aureus (MRSA).[2]

Dalbavancin is a semisynthetic lipoglycopeptide that was designed to improve upon the natural glycopeptides currently available, vancomycin and teicoplanin.[3]

It possesses in vitro activity against a variety of Gram-positive pathogens[4][5] including MRSA and methicillin-resistant Staphylococcus epidermidis (MRSE).[6] It is a once-weekly, two-dose antibiotic, the rights to which Actavis acquired when it bought Durata Therapeutics in 2014.[7]

The Food and Drug Administration approved dalbavancin in May 2014 for the treatment of acute bacterial skin and skin structure infections (ABSSSIs) caused by certain susceptible bacteria such as Staphylococcus aureus including methicillin-susceptible and methicillin-resistant strains of Streptococcus pyogenes, in intravenous dosage form.[8]

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.[9] 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.[10]

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.[11] Based on MIC data and other studies, dalbavancin is more potent and bactericidal and therefore requires lower concentrations than vancomycin against these organisms.[12] Dalbavancin also shows in vitro activity against vancomycin-susceptible Enterococcus faecium and Enterococcus faecalis.[11] 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.[12][13] There is no clinically significant activity against Gram-negative bacteria.[12]

Two trials, DISCOVER 1 and DISCOVER 2, demonstrated noninferiority of dalbavancin compared to vancomycin/linezolid in the treatment of ABSSSI. Patients were randomly assigned to receive two doses of dalbavancin on days 1 and 8, or to receive intravenous vancomyin for at least 3 days with the option of switching to oral linezolid to complete 10 to 14 days of therapy. Investigators assessed the cessation of spread of infection-related erythema and the absence of fever at 48 to 72 hours as the primary endpoint and found that once-weekly dalbavancin was as effective as twice-daily intravenous vancomycin followed by oral linezolid.[14] This once-weekly dosing regimen may offer an advantageous treatment option compared to daily or twice-daily dosing.[10]

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 vancomyin.[11]

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.[11] 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.[12] 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.[11] There is no evidence of ototoxicity associated with dalbavancin.[13]

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.[11]

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.[11] There is no evidence in animals of teratogenicity.[13]

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.[15] 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%.[15]

Dalbavancin homologs
Core structure of dalbavancin
Core structure of dalbavancin
Homolog Alkyl sidechain of N-acylaminoglucuronic acid (R1) Amino-terminal substituent (R2)
A0 CH(CH3)2 H
A1 CH2CH2CH3 H
B0 CH2CH(CH3)2 H
B1 CH2CH2CH2CH3 H
B2 CH2CH(CH3)2 CH3

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.[12]

Antimicrobial activity correlates with the ratio of area under the concentration-time curve to minimum inhibitory concentration for Staphylococcus aureus.[11]

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.[7] 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.

References

  1. ^ a b 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
  2. ^ Vicuron Pharmaceuticals Submits New Drug Application for Dalbavancin to U.S. Food and Drug Administration
  3. ^ Scheinfeld NS. (May 2006). "Dalbavancin: A review for dermatologists". Dermatology Online Journal. 12 (6). PMID 17083861.
  4. ^ Chen AY; Zervos MJ; Vazquez JA (2007). "Dalbavancin: a novel antimicrobial". Int. J. Clin. Pract. 61 (5): 853–63. doi:10.1111/j.1742-1241.2007.01318.x. PMC 1890846. PMID 17362476.
  5. ^ Das B; Sarkar C; Biswas R; Pandey S (2008). "Review: dalbavancin-a novel lipoglycopeptide antimicrobial for gram positive pathogens". Pak J Pharm Sci. 21 (1): 78–88. PMID 18166524.
  6. ^ Dalbavancin: A Novel Lipoglycopeptide Antibacterial
  7. ^ a b UPDATE 1-Pfizer says US FDA wants more data on antibiotic. Dec 2007
  8. ^ US FDA approves drug Dalvance containing Dalbavancin
  9. ^ Centers for Disease Control and Prevention - Methicillin-Resistant Staphylococcus aureus (MRSA) infections. https://www.cdc.gov/mrsa/
  10. ^ a b Dalbavancin: First I.V. antibiotic for acute bacterial skin infections. http://www.pharmacist.com/dalbavancin-first-iv-antibiotic-acute-bacterial-skin-infections
  11. ^ a b c d e f g h Dalvance (dalbavancin) for injection Full Prescribing Information. http://content.stockpr.com/duratatherapeutics/files/docs/Dalvance+APPROVED+USPI.PDF
  12. ^ a b c d e 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.
  13. ^ a b c FDA Briefing Document: Anti-Infective Drugs Advisory Committee Meeting. NDA 21-883: Dalvance (Dalbavancin) for Injection. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Anti-InfectiveDrugsAdvisoryCommittee/UCM390792.pdf
  14. ^ Boucher, HW; Wilcox, M; Talbot, GH; Puttagunta, S; Das, AF; Dunne, MW (2014). "Once-Weekly Dalbavancin versus Daily Conventional Therapy for Skin Infection". New England Journal of Medicine. 370: 2169–2179. doi:10.1056/NEJMoa1310480. PMID 24897082.
  15. ^ a b US patent 7119061 
  16. ^ "Pfizer Will Withdraw Global Marketing Applications for Dalbavancin to Conduct a New Trial" (Press release). Pfizer Inc. 2008-09-09. Retrieved 2008-09-11.
  17. ^ Durata Begins Dalbavancin Study Enrollment. Drug Discovery & Development - October 05, 2011.
  18. ^ Durata Therapeutics Announces Phase 3 Clinical Trial Results for Dalbavancin in the Treatment of ABSSSI
  19. ^ Dalvance’s safety and efficacy clinical trial ABSSSI, Results showed Dalvance was as effective as vancomycin
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