Once-Weekly Dalbavancin versus Standard-of-Care Antimicrobial Regimens for Treatment of Skin and Soft-Tissue Infections

MAJOR ARTICLE Once-Weekly Dalbavancin versus Standard-of-Care Antimicrobial Regimens for Treatment of Skin and Soft-Tissue Infections Elyse Seltzer, Mary Beth Dorr, Beth P. Goldstein, Marc Perry, James A. Dowell, Tim Henkel, and the Dalbavancin Skin and Soft-Tissue Infection Study Groupa Vicuron Pharmaceuticals, King of Prussia, Pennsylvania Dalbavancin, a novel glycopeptide with a long elimination half-life (∼9–12 days), was compared to standard antimicrobial therapy for skin and soft-tissue infections (SSTIs). In a randomized, controlled, open-label, phase 2 proof-of-concept trial, adults received 1100 mg of dalbavancin (as a single intravenous infusion), 1000 mg of dalbavancin intravenously and then 500 mg intravenously 1 week later, or a prospectively defined standardof-care regimen. A gram-positive pathogen was isolated from samples obtained from 41 (66%) of 62 patients at baseline; Staphylococcus aureus was the most prevalent species (83% of pathogens). Clinical success rates at a follow-up visit (test of cure) were 94.1% among patients treated with 2 doses of dalbavancin, 61.5% among patients treated with 1 dose of dalbavancin, and 76.2% among patients treated with a standard-of-care regimen. All treatment regimens were well tolerated; drug-related adverse reaction rates were similar across the 3 groups. These findings suggest that a regimen of 2 doses of dalbavancin administered 1 week apart is effective in the treatment of complicated, gram-positive bacterial SSTIs and warrants further study. Dalbavancin is a semisynthetic intravenous glycopeptide antibiotic in clinical development. Dalbavancin is active against gram-positive bacteria (staphylococci, streptococci, enterococci, corynebacteria, and anaerobes) [1–3]. Dalbavancin MIC90 values for staphylococci, including Staphylococcus aureus and coagulase-negative staphylococci of various species (both methicillin susceptible and methicillin resistant), range from ⭐0.13 to 0.5 mg/L; dalbavancin MIC90 values for streptococci range from ⭐0.03 to 0.13 mg/L [1]. MICs of dalbavancin are usually lower than those of vancomycin, teicoplanin, linezolid, and quinupristin-dalfopristin, and dalbavancin is generally more bactericidal than vancomycin or teicoplanin Received 27 March 2003; accepted 5 July 2003; electronically published 17 October 2003. a Study group members are listed at the end of the text. Reprints or correspondence: Dr. Elyse Seltzer, 455 S. Gulph Rd., Ste. 310, King of Prussia, PA 19406 (). Clinical Infectious Diseases 2003; 37:1298–1303  2003 by the Infectious Diseases Society of America. All rights reserved. 1058-4838/2003/3710-0003$15.00 1298 • CID 2003:37 (15 November) • Seltzer et al. [1]. Although dalbavancin has the same mechanism of action as other glycopeptides (i.e., inhibition of cell-wall peptidoglycan cross-linking), it is not completely crossresistant with vancomycin. For example, dalbavancin is active against certain vancomycin-resistant enterococci (including VanB and VanC strains) [2] and is also active in vitro and in animal infection models against vancomycin-intermediate S. aureus strains [4]. Dalbavancin MICs for target organisms are greatly exceeded during the entire treatment interval, because a unique feature of dalbavancin is its long elimination half-life (∼9–12 days in humans) [5–7]. This long halflife is the result of extensive, reversible binding of dalbavancin to plasma proteins, primarily albumin. The degree of plasma protein binding is constant through concentrations observed in clinical studies and has been estimated to be 195% by means of a number of quantitative methods [8]. After a single intravenous infusion of 1 g of dalbavancin, mean plasma concentrations were found to be 135 mg/L for 7 days. This dose was chosen for investigation of the dose needed to maintain con- centrations that exceed the MICs of target skin and soft-tissue infection (SSTI) pathogens for at least 1 week. These concentrations have been shown to be bactericidal for staphylococci [5]. We report on the safety and efficacy of dalbavancin in a study of 1- and 2-dose regimens of dalbavancin versus standardof-care therapy in adults with SSTIs caused by gram-positive pathogens. PATIENTS AND METHODS Patient Population Men and nonpregnant women ⭓18 years of age who had an SSTI that was suspected or known to be caused by gram-positive bacteria (based on Gram staining or culture results) were eligible for enrollment. Eligible SSTIs were those that involved deep soft tissue and/or required significant surgical intervention, such as a major abscess, an infected ulcer, a major burn (⭐20% body surface area), or deep and extensive cellulitis. In addition, to be eligible for study inclusion, patients had to have at least 2 symptoms consistent with SSTI, including drainage, erythema, fluctuance, heat, tenderness to palpation, or swelling. Exclusion criteria for this study included creatinine clearance !50 mL/min, receipt of recent antimicrobial treatment for SSTI (a regimen lasting 124 h within 7 days before study entry), self-limited infection, SSTI with compromised vascularity, and documented osteomyelitis. Because no information exists about vancomycin allergies and cross-reactivity with dalbavancin, patients with a history of glycopeptide hypersensitivity were excluded. Study Design and Antimicrobial Regimens The study, a randomized, controlled, open-label, phase 2 proofof-concept trial, was conducted at 10 centers in the United States from 31 July 2001 through 30 May 2002. Each center received protocol approval from its institutional review board, and written consent was obtained from each patient before receipt of study drug. In this dose-ranging study, only descriptive statistics were prospectively planned. Assuming 80%–85% success rates, it was estimated that a treatment group size of ∼20 patients would provide 95% CIs for the true success rates, with the bounds of 95% CIs not 117.5%. Sixty patients ⭓18 years of age were to be enrolled. Before randomization, investigators determined the antimicrobial therapy that each patient would receive if he or she were randomized to the comparator arm. Subjects were then randomly assigned to 1 of 3 groups: 1-dose dalbavancin (a single 1100-mg dose of dalbavancin [Vicuron Pharmaceuticals] administered intravenously as a single dose), 2-dose dalbavancin (1 intravenous dose of 1000 mg of dalbavancin, followed by a second intravenous dose of 500 mg 1 week later [study day 8]), or a comparator regimen (determined by the investigator before randomization). Dalbavancin was administered intravenously over the course of a 30-min period. For study purposes, the end of therapy (EOT) was considered to be 10–12 days after the last dalbavancin dose, which is consistent with the drug’s pharmacokinetics. The comparator antimicrobial regimens were administered for 7–21 days, and patients could be switched to oral therapy at the investigator’s discretion. The investigator (...truncated)