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By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD
Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente; and Assistant Professor of Medicine, University of California, San Francisco. Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA
Drs. Elliott and Chan report no financial relationships relevant to this field of study.
The FDA has approved a once-weekly antibiotic for the treatment of serious skin infections. Dalbavancin is the first antibiotic with the designation of a Qualified Infectious Disease Product (QIDP).1 As part of this designation, the drug was given a priority and expedited review as well as an additional 5 years of marketing exclusivity. Dalbavancin is marketed by Durata Therapeutics as Dalvance.
Dalbavancin is indicated for the treatment of acute bacterial skin and skin structure infections (ABSSSI) caused by susceptible gram-positive microorganisms.2 These include Staphylococcus aureus (including methicillin-susceptible and methicillin-resistant strains), Streptococcus pyogenes, Streptococcus agalactiase, and Streptococcus anginosus group.
The recommended dose in adults is 1000 mg (by intravenous infusion over 30 minutes) followed by 500 mg 1 week later.1 For patients with creatinine clearance < 30 mL/min (not receiving regularly scheduled hemodialysis), the dose is 750 mg and 375 mg. No dosage adjustment is needed for those on regularly scheduled dialysis. Dalbavancin is available as a 500 mg vial.
Dalbavancin has a very long elimination half-life (approximately 15 days), and thus is dosed once weekly. It is bactericidal in vitro against S. aureus and S. pyogenes.
Serious hypersensitivity (anaphylactic and skin)reactions have been reported.1 Rapid intravenous infusions can cause reactions that resemble "Red-Man Syndrome." A small percent of patients (0.8%) had elevations of ALT 3 × ULN.
Dalbavancin is a lipoglycoprotein antibiotic synthesized from a precursor fermentation product of Actinomycetes Nonomureaea species. It has a broad range of activity against gram-positive microorganisms. The safety and efficacy of dalbavancin was evaluated in two Phase 3, randomized, double-blind, noninferiority, double-dummy trials of similar design (DISCOVER 1 and DISCOVER 2).2,3 Subjects (n = 1312) were included if they had cellulitis, major abscess, or wound infection and at least 75 cm2 of erythema (medium lesion area at baseline was 341 cm2). They were randomized to dalbavancin (1 g IV followed by 500 mg 1 week later) or vancomycin (1 g or 15 mg/kg q 12 hour) with the option of switching to oral linezolide (600 mg q 12 hours) after 3 days, to complete 10-14 days of therapy. The dose of vancomycin and dalbavancin could be adjusted to ideal body weight for patients with renal insufficiency. The primary endpoint was measured at 48-72 hours of therapy. Treatment success was defined as cessation of spreading of erythema associated with the infection and a temperature of 37.6°C or less for three consecutive readings 6 hours apart. Noninferiority was achieved if the lower limit of the 95% confidence interval (CI) for the absolute difference between dalbavancin and vancomycin/linezolid was > -10%. Secondary endpoints were reduction in lesion area of 20% or more and clinical success at days 26-30. This study was based on the FDA guidance on the conduct of clinical trials for ABSSSI in 2010.4 The primary endpoint for the pooled results was 79.7% for dalbavancin and 79.8% for vancomycin (95% CI; -0.1 (-4.5%, 4.2). The lower limits were -4.6% in one study and -7.4% in the second. There does not appear to be any significant difference between treatments based on infection type (e.g., cellulitis or major abscess), baseline pathogen, presence or absence of diabetes mellitus, or systemic inflammatory response syndrome.3 Secondary endpoints were similar between treatments. Dalbavancin is generally well tolerated. Most common adverse events are nausea (5.5%), headache (4.7%), diarrhea (4.4%), vomiting (2.8%), and rash (2.7%).
Dalbavancin is the newest drug to be approved for ABSSSI based on the 2010 guidelines, using more objective endpoints. However, using lesion size as disease severity, cessation of lesion spread as success, and temperature as an endpoint have been a subject of debate.5,6 The role of this drug in actual clinical practice remains to be determined as well as how results from clinical studies for ABSSSI are interpreted and translated to actual clinical practice and specific disease entities. Inclusion criteria in the clinical trial could include a wide and varying range of lesions.7 Currently, the Infectious Diseases Society of America (IDSA) guidelines are by disease entity (e.g., nonprurulent cellulitis, purulent abscess, MSSA, MRSA SSTI, etc.).8 The convenience of once-a-week administration is offset by the need for a 30-minute infusion for each dose and the wholesale cost of nearly $4500 for a full 2 week course.
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