Dalbavancin: A new antibacterial drug for Gram-positive infections

On May 23, 2014, FDA approved dalbavancin (Dalvance; Durata Therapeutics), an intravenous antibacterial agent indicated for acute bacterial skin and skin structure infections (ABSSSI) caused by susceptible strains of Gram-positive organisms. It is used to treat infections caused by Staphylococcus aureus (including methicillin-susceptible and methicillin-resistant strains), Streptococcus pyogenes, Streptococcus agalactiae, and the Streptococcus anginosus group (including S. anginosus, S. intermedius, S. constellatus).

Dalbavancin is the first drug to receive FDA approval as a qualified infectious disease product (QIDP), a designation granted because dalbavancin is intended to treat serious or life-threatening infections.

Efficacy

Dalbavancin is a semisynthetic lipoglycopeptide. It interferes with bacterial cell wall synthesis by binding to the D-alanyl-D-alanine terminus of the stem pentapeptide in nascent cell wall peptidoglycan, thus preventing cross-linking.

Two phase 3, randomized, double-blind, double-dummy (non-inferiority) clinical trials of identical design, titled DISCOVER 1 and DISCOVER 2, enrolled adult patients with ABSSSI. Patients were treated for two weeks with either a two-dose regimen of dalbavancin (1000 mg followed one week later by 500 mg) or intravenous vancomycin (1000 mg or 15 mg/kg every 12 hours, with the option to switch to oral linezolid after three days) to complete 10 to 14 days of therapy. Specific infections in these trials included cellulitis, major abscess, and wound infection. In addition to local signs and symptoms of infection, patients were also required to have at least one systemic sign of disease at baseline. Mean patient age was 50 years.

In both trials, the primary end point was early clinical response, defined as patients who had no increase from baseline in lesion area or infection-related erythema, along with the absence of fever at 48 to 72 hours. Analysis of clinical response rates showed noninferiority of dalbavancin in both DISCOVER 1 and DISCOVER 2.

In DISCOVER 1, dalbavancin had clinical response rates of 83.3% vs. 81.8% in the vancomycin/linezolid group (95% confidence interval, -4.6, 7.9). In DISCOVER 2, dalbavancin had clinical response rates of 76.8% vs. 78.3% in the vancomycin/linezolid group (95% CI, -7.4, 4.6). A pooled analysis of DISCOVER 1 and DISCOVER 2 showed that 525 of 659 patients (79.7%) in the dalbavancin group and 521 of 653 (79.8%) in the vancomycin/linezolid group had an early clinical response that indicated treatment success (95% CI, −4.5 to 4.2).

For patients who had an S. aureus infection, including methicillin-resistant S. aureus, treatment success was seen in 90.6% of the patients treated with dalbavancin and 93.8% of those treated with vancomycin/linezolid. The most common adverse events in either group were nausea, diarrhea, and pruritus.

Safety

The most common adverse reactions in patients treated with dalbavancin were nausea (5.5%), headache (4.7%), and diarrhea (4.4%).

Serious hypersensitivity and skin reactions to dalbavancin have been reported. Due to the potential for cross-sensitivity, it should be determined whether patients have had a previous hypersensitivity reaction to glycopeptides. Caution should be exercised in patients who have a history of glycopeptide allergy.

Dalbavancin is administered intravenously, and rapid infusions can cause reactions that resemble “Red-Man Syndrome.” Slowing the infusion may resolve these reactions.

In phase 2 and phase 3 clinical trials, more dalbavancin-treated subjects than comparator-treated subjects with normal baseline ALT levels had post-treatment ALT increases greater than three times the upper limit of normal (ULN), 12 (0.8%) versus two (0.2%), including three patients with post-treatment ALT elevations of greater than 10 times ULN. No comparator-treated subjects with normal baseline liver enzymes had ALT elevations greater than 10 times ULN.

As with most systemic antibacterial agents, Clostridium difficile-associated diarrhea has been reported by users of dalbavancin.

Dalbavancin is classified as a pregnancy category C. No adequate or well-controlled studies of dalbavancin have been conducted with pregnant women. Caution should be exercised when dalbavancin is given to a nursing woman. Pediatric safety and efficacy have not been established.

Dosing

Single-use glass vials supply a sterile powder, equivalent to 500 mg of dalbavancin. Recommended dosing to treat ABSSSI is 1,000 mg, followed one week later by 500 mg. Dalbavancin should be administered over 30 minutes by intravenous infusion.

In patients with renal impairment who have a known creatinine clearance less than 30 mL/min and who are not receiving regularly scheduled hemodialysis, the recommended dalbavancin dosing regimen is 750 mg followed by 375 mg administered one week later.

Kinjal Vakil Sidhpura is clinical assistant professor of Pharmacy Practice, PCOM School of Pharmacy, Suwanee, Ga. Contact her at kinjalsi@pcom.edu.