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Dalbavancin

dalbavancin, dalbavancin for osteomyelitis
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

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

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

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

Contents

  • 1 Medical uses
  • 2 Contraindications
  • 3 Side effects
    • 31 Drug interactions
    • 32 Pregnancy and lactation
  • 4 Mechanism of action
  • 5 History
  • 6 References

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 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

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

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 This once-weekly dosing regimen may offer an advantageous treatment option compared to daily or twice-daily dosing

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

Side effects

The most common adverse reactions encountered in Phase II and Phase III trials were nausea 55%, headache 47%, and diarrhea 44%, as well as rash 27% and itchiness 21% 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 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 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 There is no evidence of ototoxicity associated with dalbavancin

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

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 12 and 07 times the human dose However, delayed fetal maturation was observed at a dose that was 35 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 There is no evidence in animals of teratogenicity

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

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

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 On September 9, 2008, Pfizer announced it will withdraw all marketing applications to conduct another phase-III clinical trial Durata Therapeutics acquired the rights to dalbavancin in December 2009, and has initiated two new phase-III clinical trials for treatment of ABSSSIs Preliminary results in 2012 were promising

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

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

References

  1. ^ Vicuron Pharmaceuticals Submits New Drug Application for Dalbavancin to US Food and Drug Administration
  2. ^ Scheinfeld NS May 2006 "Dalbavancin: A review for dermatologists" Dermatology Online Journal 12 6 PMID 17083861 
  3. ^ Chen AY; Zervos MJ; Vazquez JA 2007 "Dalbavancin: a novel antimicrobial" Int J Clin Pract 61 5: 853–63 doi:101111/j1742-1241200701318x PMC 1890846  PMID 17362476 
  4. ^ 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 
  5. ^ Dalbavancin: A Novel Lipoglycopeptide Antibacterial
  6. ^ a b UPDATE 1-Pfizer says US FDA wants more data on antibiotic Dec 2007
  7. ^ US FDA approves drug Dalvance containing Dalbavancin
  8. ^ Centers for Disease Control and Prevention - Methicillin-Resistant Staphylococcus aureus MRSA infections https://wwwcdcgov/mrsa/
  9. ^ a b Dalbavancin: First IV antibiotic for acute bacterial skin infections http://wwwpharmacistcom/dalbavancin-first-iv-antibiotic-acute-bacterial-skin-infections
  10. ^ a b c d e f g h Dalvance dalbavancin for injection Full Prescribing Information http://contentstockprcom/duratatherapeutics/files/docs/Dalvance+APPROVED+USPIPDF
  11. ^ 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
  12. ^ a b c FDA Briefing Document: Anti-Infective Drugs Advisory Committee Meeting NDA 21-883: Dalvance Dalbavancin for Injection http://wwwfdagov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Anti-InfectiveDrugsAdvisoryCommittee/UCM390792pdf
  13. ^ 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:101056/NEJMoa1310480 PMID 24897082 
  14. ^ "Pfizer Will Withdraw Global Marketing Applications for Dalbavancin to Conduct a New Trial" Press release Pfizer Inc 2008-09-09 Retrieved 2008-09-11 
  15. ^ Durata Begins Dalbavancin Study Enrollment Drug Discovery & Development - October 05, 2011
  16. ^ Durata Therapeutics Announces Phase 3 Clinical Trial Results for Dalbavancin in the Treatment of ABSSSI
  17. ^ Dalvance’s safety and efficacy clinical trial ABSSSI, Results showed Dalvance was as effective as vancomycin

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