Dalbavancin: a Novel Once-Weekly Lipoglycopeptide Antibiotic

Marianne Billeter 2 3 Marcus J. Zervos 0 1 2 Anne Y. Chen 0 1 2 Joseph R. Dalovisio () 2 3 Changa Kurukularatne 2 3 0 Wayne State University School of Medicine , Detroit, Michigan 1 Department of Internal Medicine, Division of Infectious Diseases, Henry Ford Hospital 2 Received 30 August 2007; accepted 20 October 2007; electronically published 16 January 2008. Clinic Foundation , 1514 Jefferson Hwy., New Orleans, LA 70121 3 Department of Infectious Diseases, Ochsner Clinic Foundation , New Orleans, Louisiana The increasing prevalence of drug-resistant gram-positive cocci, such as methicillin-resistant Staphylococcus aureus, has underscored the need for new agents for the treatment of this type of infection. Dalbavancin, a new lipoglycopeptide, has the desirable characteristics of increased in vitro activity, compared with vancomycin, for most gram-positive pathogenic bacteria, as well as an extremely long half-life, permitting once-weekly intravenous dosing. Clinical studies comparing linezolid with 2 doses of dalbavancin have shown comparable efficacy for the treatment of skin and soft-tissue infection. Dalbavancin has also proven to be effective for therapy of catheter-related bloodstream infections. It has an excellent safety profile in studies to date. Dalbavancin will likely have a significant role in outpatient intravenous therapy for patients with potentially serious drug-resistant gram-positive coccal infections. - positive workhorse antimicrobial for half a century. The emergence of vancomycin-resistant enterococci (VRE) and strains of S. aureus with reduced susceptibility or resistance to vancomycin has created an urgent need for antimicrobial agents with activity against drug-resistant gram-positive bacteria. The past few years have seen a surge in the development of antimicrobial agents with gram-positive bacterial activity, but these drugs are not without limitations. Although rare, linezolid resistance has already been documented. Regarding the treatment of bacteremia, daptomycin resistance has emerged during therapy, and strains with decreased susceptibility to vancomycin may also show decreased susceptibility to daptomycin [24]. Daptomycin cannot be used for the treatment of pneumonia because of likely drug inactivation by pulmonary surfactant. It is against this backdrop that we welcome a new addition to our antimicrobial armamentarium. Dalbavancin is a semisynthetic antibiotic derived from a teicoplanin-like glycopeptide agent (A-40926) by modifying the functional groups and sugar moieties of A-40926 while preserving the D-alanyl-Dalanine binding site required for antimicrobial activity (figure 1). The result is a lipoglycopeptide compound (di-[3-demethylaminopropyl] amide, N-alkylated at the aminoglucoronyl moiety). Dalbavancin inhibits bacterial cell wall synthesis by binding with the C-terminal D-alanyl-D alanine of the growing peptidoglycan chains [6], interfering with cross-linking and polymerization. Enhanced pharmacodynamic properties of the molecule, including lipophilic anchoring to the bacterial cell Figure 1. Chemical structure of dalbavancin. Reproduced from Lin et al. [5]. Reprinted with permission. membrane, has conferred more potent in vitro activity than vancomycin or teicoplanin [7, 8]. An unusually long terminal half-life, ranging from 149 to 250 h in human subjects, allows for once-weekly dosing, a characteristic that makes outpatient intravenous therapy feasible in a manner not possible with agents requiring more-frequent dosing [9]. MICROBIOLOGY The spectrum of in vitro activity of dalbavancin is similar to that of available glycopeptides, but dalbavancin is more potent than vancomycin against most pathogens (table 1) [7, 10, 14, 16, 2123]. Streit et al. [7] demonstrated dalbavancins superior in vitro activity in 16000 gram-positive pathogens collected from worldwide sites with MIC values ranging from 0.015 to 32 mg/mL. The MIC90 of dalbavancin was noted to be 0.06 mg/mL for S. aureus and coagulase-negative staphylococci resistant to multiple antimicrobial agents. Dalbavancin has potent in vitro activity against glycopeptide-intermediate S. aureus strains (dalbavancin MIC90, 0.061 mg/mL) [19] and linezolid-nonsusceptible S. aureus (MIC90, 0.030.06 mg/mL) and has demonstrated activity against 1 of the 2 vancomycinresistant S. aureus Hershey-Pennsylvania USA strains (MIC90, 0.5 mg/mL) [20]. The activity of dalbavancin against vancomycin-susceptible Enterococcus faecalis and Enterococcus faecium is similar to that of teicoplanin but more potent than that of vancomycin. Dalbavancin maintains activity against strains of VRE expressing vanB and vanC gene products but is inactive against VRE expressing vanA [10, 14, 16]. Dalbavancin is highly active against viridans group streptococci and penicillin-susceptible and penicillin-nonsusceptible Streptococcus pneumoniae [21]. Goldstein et al. [22] demonstrated dalbavancins excellent activity against a variety of gram-positive anaerobic species, fastidious aerobes, and Corynebacterium species, with the notable exceptions of Clostridium clostridioforme and certain Lactobacillus species. Dalbavancin, like other glycopeptides, is not active against gram-negative bacteria. Dalbavancin is bactericidal against S. aureus and coagulasenegative staphylococci at 4 times the MIC after 24 h; the lack of carry-over effect is shown to have little killing at earlier periods (312 h) [20]. PHARMACOKINETICS The pharmacokinetics and tissue distribution of dalbavancin were studied in a rat model in which a 20 mg/kg dose of dalbavancin or [3H] dalbavancin was administered and blood, urine, bile, feces, and tissue concentrations were determined [24]. The distribution of dalbavancin was consistent with a 3compartment model with elimination from the central compartment. The half-lives of the elimination phases were 0.18 h for the initial phase (t1/2a), 11.4 h for the intermediate phase (t1/2b), and 187.4 h (t1/2g) for the terminal phase [24]. The volume of distribution was 0.52 L/kg, with an area under the curve of 3194.2 L/mg/h and total plasma clearance of 6.3 mL/kg/h. Dalbavancin undergoes dual elimination via urine and feces. The distribution of dalbavancin was studied in 40 different tissues [24]. The highest concentrations were found in the kidney and liver 24 h after dosing. Most tissues continued to retain concentrations greater than that in plasma by day 3 after dosing; kidneys, liver, brown fat, skin, and skeletal muscle continued to have measurable concentrations at day 14. Dalbavancin was not selectively retained by any organ or tissue. The tolerability and pharmacokinetics of dalbavancin were studied in a group of healthy volunteers in a dose ranging study [25]. Volunteers were administered single doses of dalbavancin ranging from 140 mg to 1120 mg intravenously over 30 min or multiple doses with a loading dose to maintenance dose ratio of 10:1. The multiple-dose group received dosing regimens (...truncated)