Dalbavancin and Oritavancin Each Have Similar Efficacy to Vancomycin in Patients with Serious Bacterial Skin and Skin Structure Infections

EBM Focus - Volume 9, Issue 24

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Reference: N Engl J Med 2014 Jun 5;370(23):2169, N Engl J Med 2014 Jun 5;370(23):2180 (level 1 [likely reliable] evidence)

Skin and skin-structure infections are common and represent a significant burden for hospitals and primary care practices. A recent population-based study in the United States estimated that there were 496 clinically diagnosed skin or soft tissue infections per 10,000 person-years, which translates to more than 15 million new cases annually in the U.S. (BMC Infect Dis 2013 May 30;13(1):252 full-text). Staphylococcus aureus is an important causative agent of these infections, and methicillin-resistant S. aureus, or MRSA, can be particularly difficult to treat. When MRSA is suspected among hospitalized patients with complicated skin and skin tissue infections, such as purulent cellulitis, the glycopeptide antibiotic vancomycin is a treatment option (Clin Infect Dis 2011 Feb;52(3):e18 full-text). Lipoglycopeptide analogs such as dalbavancin (an analog of teicoplanin) and oritavancin (an analog of vancomycin) share a similar mechanism to their glycopeptide counterparts, but have important differences in pharmacologic properties. Two recent studies, one evaluating dalbavancin and the other evaluating oritavancin, assessed whether these analogs were noninferior to vancomycin in patients with acute bacterial skin and skin-structure infections.

Dalbavancin was evaluated in a pooled analysis of 2 randomized noninferiority trials with a total of 1,312 adults (mean age 50 years) with acute bacterial skin and skin structure infections. Patients were randomized to dalbavancin 1 g IV on day 1 and 500 mg on day 8 vs. vancomycin 1 g or 15 mg/kg IV twice daily for ≥ 3 days and followed to 70 days. Patients in the vancomycin group had the option to switch to linezolid 600 mg orally twice daily to complete 10-14 days therapy. 54% of patients had cellulitis, 25% had major abscess, and 21% had a wound or surgical site infection. All patients had lesions with ≥ 75 cm2 of erythema plus systemic and symptomatic signs of infection. In patients with a pathogen isolated at baseline, 24% had MRSA and 53% had methicillin-susceptible S. aureus (MSSA). A total of 45 patients (3.4%) had Gram-positive bacteremia, including 20 patients with S. aureus bacteremia. The primary outcome was early clinical response, which was defined as cessation of spread of infection-related erythema plus absence of fever at 48-72 hours. The noninferiority criterion was defined as a lower limit of 95% CI ? 10% for differences between groups in early clinical response.

A total of 85% of patients were included in the per-protocol analysis, and 92% were included in the modified intention-to-treat analysis. Early clinical response was observed in 79.7% with dalbavancin vs. 79.8% with vancomycin-linezolid in the modified intention-to-treat analysis (noninferiority met). The overall clinical response rate at the end of treatment was 90.7% with dalbavancin vs. 92.1% with vancomycin-linezolid in the per-protocol analysis (not significant), with consistent results in the intention-to-treat analysis.

Oritavancin was evaluated in a randomized noninferiority trial of 968 adults (mean age 45 years) with acute bacterial skin and skin structure infections. Patients were randomized to a single dose of oritavancin 1,200 mg IV vs. vancomycin 1 g or 15 mg/kg IV twice daily for 7-10 days with serum trough monitoring, and followed to 60 days. 50% of patients had cellulitis, 30% had abscess, and 20% had wound infection. MRSA was isolated in 21% of patients, and MSSA was isolated in 23%. All patients had lesions surrounded by erythema, edema, or induration ? 75 cm2 plus signs and symptoms of systemic inflammation. The primary outcome was a composite of cessation of spreading or decrease in lesion size, absence of fever, and lack of need for rescue antibiotic at 48-72 hours. The noninferiority criterion was defined as a lower limit of 95% CI ≤ 10% for differences between groups in the primary outcome.

A total of 791 patients (82%) were clinically evaluable, and 954 patients (98.5%) were included in a modified intention-to-treat analysis. The primary outcome occurred in 82.3% with oritavancin vs. 78.9% with vancomycin (noninferiority met). An investigator-assessed clinical cure occurred in 79.6% with oritavancin vs. 80% with vancomycin (not significant). A decrease in lesion area of at least 20% at 48-72 hours was observed in 86.9% with oritavancin vs. 82.9% with vancomycin (not significant). There were no significant differences in the primary outcome in subgroup analyses separately evaluating patients with MRSA or MSSA.

The findings from these randomized trials demonstrate that dalbavancin and oritavancin have comparable clinical response rates compared to vancomycin in the management of acute bacterial skin and skin-structure infections. Dalbavancin has been approved by the U.S. Food and Drug Administration for treatment of adults with acute bacterial skin and skin structure infections caused by certain susceptible bacteria, including MRSA and MSSA (FDA Press Release 2014 May 23). Cost information was not reported for either agent, and pricing information does not yet appear to be available. In these trials, dalbavancin was administered once weekly and oritavancin was administered as a single dose, whereas vancomycin was administered every 12 hours. The less frequent administration required for dalbavancin and oritavancin, and the lack of need to monitor serum levels, may make it possible to treat some of these infections on an outpatient basis when they might otherwise have been treated in-hospital. This could dramatically reduce both the costs and risks of hospitalization. However, the longer duration of action may prove to be a safety concern as well, since any toxic effects may continue for weeks until the agents have been cleared. It is also important to keep in mind that these trials were designed to compare these lipoglycopeptide agents to vancomycin, and do not represent a comparison to standard practice in some cases. For example, in patients with MSSA bacteremia, retrospective cohort studies have demonstrated that nafcillin and cefazolin are associated with reduced mortality compared to vancomycin (BMC Infect Dis 2011 Oct 19;11:279 full-text, Antimicrob Agents Chemother 2008 Jan;52(1):192 full-text). For patients with bacteremia who are later shown to have MSSA, it’s not clear how these agents compare to standard practice, and the longer half-life of these agents may make switching to optimal treatment more difficult. In addition, it’s not clear that a full 14 days of therapy is warranted in all cases, and treatment with a long-acting agent might expose a patient to antibiotics for longer than needed. Longer duration of therapy may also augment the emergence of vancomycin-intermediate S. aureus and vancomycin-resistant S. aureus.

For more information see the Cellulitis, Skin abscess, and Treatment of MRSA skin and soft tissue infections topics in DynaMed.