Dalbavancin, Oritavancin Safe, Effective for Skin Infection

Veronica Hackethal, MD

June 06, 2014

Patients with skin or skin structure infections may have two 2 new antibiotic options, both of which had similar efficacy and safety profiles as vancomycin in phase 3, randomized controlled trials (RCTs).

The trial data were published in the June 5 issue of the New England Journal of Medicine.

The first study, by Helen W. Boucher, MD, from the Division of Infectious Diseases and Geographic Medicine, Tufts Medical Center and Tufts University School of Medicine, Boston, Massachusetts, and colleagues looked at dalbavancin, a synthetic analog of teicoplanin with activity against gram-positive organisms. Dalbavancin's 2-week half-life enables once-weekly intravenous dosing.

The authors pooled data from 2 double-blind clinical trials, Efficacy and Safety of Dalbavancin for the Treatment of Acute Bacterial Skin and Skin Structure Infections 1 and 2 (DISCOVER 1 and DISCOVER 2). The studies, which served as the basis for US Food and Drug Administration approval of the antibiotic agent earlier this year, looked at clinical outcomes (lesion stabilization and fever resolution) in patients with serious skin or skin structure infections.

In both studies, investigators randomly assigned patients to either once-weekly intravenous dalbavancin or twice-daily intravenous vancomycin. Patients in the vancomycin group had the option to switch to oral linezolid, after 3 days of vancomycin, for the remaining 10 to 14 days of treatment.

Results showed that 79.7% of the dalbavancin group experienced early treatment success, as did 79.8% of the vancomycin-linezolid group. Among patients infected with Staphylococcus aureus, including methicillin-resistant S aureus (MRSA), 90.6% of the dalbavancin group and 93.8% of the vancomycin-linezolid group experienced treatment success.

Serious adverse events were reported in 2.6% of the dalbavancin group and 4.0% of the vancomycin-linezolid group. One patient in the dalbavancin group died, as did 7 patients in the vancomycin group.

"Once-weekly intravenous dalbavancin was not inferior to twice-daily intravenous vancomycin followed by oral linezolid for the treatment of acute bacterial skin and skin-structure infection," the authors conclude.

"[Our] results were robust in patients with major abscess, cellulitis, or wound infection; in those with S. aureus, including MRSA, or Strep Pyogenes infection; and in those treated as an outpatient."

The second study, by G. Ralph Corey, MD, from the Duke University Medical Center, Durham, North Carolina, and colleagues looked at oritavancin, a synthetic analog of vancomycin that also has activity against gram-positive bacteria. Oritavancin's long half-life enables single-dose therapy. In this double-blind, placebo-controlled study, the Oritavancin Versus IV Vancomycin for the Treatment of Patients With Acute Bacterial Skin and Skin Structure Infection (SOLO I) trial, patients were randomly assigned to receive either single-dose intravenous oritavancin or intravenous vancomycin twice daily. The study used similar definitions of efficacy as the trials by Dr. Boucher and colleagues, with the additional criteria of whether treatment success required rescue antibiotics.

Treatment was successful among 82.3% of the oritavancin group and 78.9% of the vancomycin group. Clinical cure after treatment, a secondary endpoint in the trial, occurred in 79% of the oritavancin group and 80% of the vancomycin group. Likewise, 86.9% of the oritavancin group vs 82.9% of the vancomycin group had a 20% or more reduction in lesion size within 48 to 72 hours of initiating therapy, which was also a predetermined secondary endpoint. Both treatment groups had similar efficacy outcomes by type of pathogen, including MRSA, Enterococcus faecalis, and 4 Streptococcus species.

Both groups also had similar rates of serious adverse events (7.4% for oritavancin vs 7.3% for vancomycin). One patient died in the oritavancin group (from sepsis and septic shock), and 2 patients died in the vancomycin group (1 from sepsis and 1 from advanced dementia with Parkinsonism).

"[T]reatment with a single dose of oritavancin was noninferior to 7 to 10 days of vancomycin in adults with acute bacterial skin and skin-structure infections caused by gram-positive pathogens, including MRSA," the authors conclude, "No significant differences in safety between the two treatment regimens were observed."

Outpatient Treatment May Be an Option

In an accompanying editorial, Henry F. Chambers, MD, from the Division of Infectious Disease at the University of California San Francisco, School of Medicine, commented on the advantages of dalbavancin and oritavancin, which include similar spectrums of activity, improved activity against some vancomycin-resistant strains, possible lower likelihood of inducing bacterial resistance, and concentration-dependent killing.

Dr. Chambers remained cautious, however, about using these antibiotics in other serious infections, such as pneumonia or bacteremia. He also warned about the possibility of serious consequences, including death, in allergic or toxic reactions to these drugs.

"These agents make it possible to treat patients with complicated skin and skin-structure infections, who might otherwise require hospitalization, on an outpatient basis without compromising efficacy and without the need for laboratory monitoring or an indwelling intravenous catheter," Dr. Chambers writes. "This approach could profoundly affect how these infections are managed, by reducing or in some cases eliminating costs and risks of hospitalization."

Anne-Catrin Uhlemann, MD, PhD, assistant professor of medicine in the Division of Infectious Diseases at Columbia University Medical Center in New York City, told Medscape Medical News that she was similarly optimistic.

"The great advantage of these drugs appears to be their relative ease of use. This is due to their long half-lives: oritavancin only needs to be dosed once, and dalbavancin needs to be dosed twice, which can be done in an outpatient setting. In contrast, vancomycin needs to be administered twice daily and requires careful dose adjusting," Dr. Uhlemann commented.

The flip side is that longer half-lives mean it takes longer for the body to clear these drugs, according to Dr. Uhlemann, which can raise concerns about allergic reactions and how to treat them. She explained, however, that in past clinical trials, these drugs seem to have had good safety profiles.

"Based on the data in these studies, I would consider both drugs for treatment of patients with severe skin and soft tissue infections who require intravenous therapy," Dr. Uhlemann concluded. "With these new drugs, patients don't need to be admitted to the hospital; don't need prolonged [intravenous] access, which has associated risk for adverse events or infections; and don't need frequent blood draws for monitoring drug levels, all of which should result in decreased cost of treatment."

The first study was supported by Durata Therapeutics. Multiple authors report serving on advisory boards, receiving fees, grant support, and having stock or stock options for 1 or more of the following companies: Basilea Pharmaceutica, Durata Therapeutics, Merck, Paratek Pharmaceuticals, Rib-X Pharmaceuticals, Theravance, Hospira/TheraDoc, Actelion Pharmaceuticals, Astellas Pharma, AstraZeneca, Cerexa, Nabriva Therapeutics, Novacta Biosystems, Novartis, Optimer Pharmaceuticals, Pfizer, Roche, Sanofi Pasteur, Summit, the Medicines Company, VHsquared, Abbott Laboratories, bioMérieux, the European Tissue Symposium, Alere, Summit, Da Volterra, Talbot Advisors, Cubist Pharmaceuticals, FAB Pharma, GlaxoSmithKline, Kalyra Pharmaceuticals, Achaogen, Cempra Pharmaceuticals, FujiFilm Pharmaceuticals, Johnson & Johnson, Kalidex Pharmaceuticals, Merada Pharmaceuticals, Sentinella, Shionogi, Bayer, Calixa Therapeutics, and Trius Therapeutics. Two coauthors are employees of Durata Therapeutics. The second study was supported by The Medicines Company. Dr. Corey reports receiving personal fees from The Medicines Company, Cerexa, Theravance, Pfizer, Cempra, Cubist, GlaxoSmithKline, DRL, Merck, Trius, and TMCo and other support from Seachaid. The other authors report having various relationships with The Medicines Company, Merck, and eStudySite. Dr. Chambers has reported receiving personal fees from Cubist Pharmaceuticals, Pfizer, AstraZeneca, and Theravance and personal fees and other support from Trius. Dr. Uhlemann has disclosed no relevant financial relationships.

N Engl J Med. 2014;370:2169-2190; 2238-2239. Boucher abstract, Corey abstract, Editorial extract

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