Antistaphylococcal Activity of Dalbavancin, an Experimental Glycopeptide

Abstract

Dalbavancin, tested against 146 staphylococci, was more potent than other drugs tested, with an MIC at which 50% of staphylococci were inhibited of 0.03 g/ml and an MIC at which 90% of staphylococci were inhibited of 0.06 g/ml by microdilution. For all strains, MICs of vancomycin, linezolid, ranbezolid, oritavancin, daptomycin, and quinupristin-dalfopristin were <4.0 g/ml. Dalbavancin was bactericidal at four times the MIC against all six strains tested.Emergence of staphylococci that are intermediate and resistant to methicillin and quinolone and recently to vancomycin, as well as the propensity of these organisms to cause serious systemic infections in immunocompromised hosts, necessitates other therapeutic modalities (2,3,10,11,15,18,21,25). During 2002, two clinical strains of vancomycin-resistant Staphylococcus aureus (VRSA) carrying van(A), one from Detroit, Mich., and one from our hospital, were isolated (3). Most methicillin-resistant staphylococci are also resistant to available quinolones, such as ciprofloxacin, levofloxacin, gatifloxacin, and moxifloxacin (2,10,15,18,21). Thus, these last compounds may not be safely used in empirical therapy for patients with methicillin-resistant staphylococcal infections.Dalbavancin is an experimental glycopeptide with a long half-life (4) with excellent activity against gram-positive aerobic and anaerobic bacteria (1,4,8,13,24). This study examined the susceptibilities of 146 staphylococci to dalbavancin compared to susceptibilities to vancomycin, teicoplanin, linezolid, ranbezolid, oritavancin, daptomycin, and quinupristin-dalfopristin by MIC and time-kill analysis. Although dalbavancin activity by MIC is well known, little has thus far been published on its kill kinetics against staphylococci.Twenty-nine methicillin-resistant and 43 methicillin-susceptible S. aureus strains as well as 36 methicillin-resistant and 38 methicillin-susceptible coagulase-negative staphylococci were studied by microdilution, and six strains (three S. aureus strains and three coagulase-negative staphylococci: two methicillin resistant strains and one methicillin-susceptible strain in each group) were subjected to time-kill analysis. Sources of drugs were as follows: dalbavancin, Vicuron Pharmaceuticals, King of Prussia, Pa.; vancomycin, Sigma, Inc., St. Louis, Mo.; oritavancin (as LY 333328), Eli Lilly & Co., Indianapolis, Ind.; teicoplanin and quinupristin-dalfopristin, Aventis Pharma, Romainville, France; linezolid, Pfizer, Inc., Groton, Conn.; ranbezolid, Ranbaxy Laboratories, New Delhi, India; and daptomycin, Cubist Pharmaceuticals, Lexington, Mass. Microdilutions were performed as recommended by NCCLS (17) using commercially prepared trays (TREK, Inc., Westlake, Ohio) with dehydrated dalbavancin and all other drugs in the frozen state. MICs of vancomycin were read after a full 24-h incubation. Calcium was added to daptomycin wells, as recommended by NCCLS (17).For time kills, tubes containing 5 ml of cation-adjusted Mueller-Hinton broth (BBL) with doubling antibiotic concentrations...

Comparison of Dalbavancin MIC Values Determined by Etest (AB BIODISK) and Reference Dilution Methods Using Gram-Positive Organisms

“…The mechanism of bactericidal activity is similar to that of other glycopeptides, via interference with bacterial cell wall biosynthesis through binding to the terminal D-alanyl-D-alanine of nascent peptidoglycan chains. Dalbavancin has demonstrated potent activity against clinically relevant aerobic and anaerobic gram-positive organisms, including oxacillin (methicillin)-resistant staphylococci, penicillin-resistant Streptococcus pneumoniae, and certain vancomycin-resistant enterococci (vanB phenotypes), and has proven efficacy in clinical trials with skin and soft-tissue infections (3,4,8,13,14).…”

“…The mechanism of bactericidal activity is similar to that of other glycopeptides, via interference with bacterial cell wall biosynthesis through binding to the terminal D-alanyl-D-alanine of nascent peptidoglycan chains. Dalbavancin has demonstrated potent activity against clinically relevant aerobic and anaerobic gram-positive organisms, including oxacillin (methicillin)-resistant staphylococci, penicillin-resistant Streptococcus pneumoniae, and certain vancomycin-resistant enterococci (vanB phenotypes), and has proven efficacy in clinical trials with skin and soft-tissue infections (3,4,8,13,14).The Clinical and Laboratory Standards Institute (CLSI; formerly the National Committee for Clinical Laboratory Standards [NCCLS]) reference broth microdilution MIC testing methodology and quality control (QC) guidelines for dalbavancin have been reported on previously, and the use of dryform broth microdilution panels for routine laboratory testing has also been validated (1, 2, 5, 6, 10). Importantly, the incorporation of the surfactant polysorbate-80 into dalbavancincontaining wells in reference frozen-form panels has been found to be critical for accuracy and reproducibility of MIC results (2, 5, 7).…”

Factors Influencing Broth Microdilution Antimicrobial Susceptibility Test Results for Dalbavancin, a New Glycopeptide Agent

“…Dalbavancin is a new semisynthetic glycopeptide antimicrobial agent with potent activity against gram-positive bacterial species including Staphylococcus aureus (both methicillin-susceptible S. aureus [MSSA] and methicillin-resistant S. aureus [MRSA]), Streptococcus pneumoniae (penicillin susceptible and resistant), beta-hemolytic streptococci, and vancomycinsusceptible enterococci (7)(8)(9)(10)(11)(12). Some strains of vancomycinresistant enterococci (vanA strains) display elevated MICs for dalbavancin, whereas the agent retains activity against strains expressing the vanB or vanC resistance patterns (12).…”

Dalbavancin in the treatment of complicated skin and soft-tissue infections: a review

“…Although no susceptibility breakpoints have been established, dalbavancin appears to demonstrate excellent activity against staphylococci. MICs for MSSA, MRSA, and Coagulase negative Staphylococcus (CoNS) range from 0.06 to 0.5 µg/mL in most reports (Candiani et al 1999;Woodford 2003;Flamm et al 2004;Streit et al 2004;Jones et al 2005;Lin et al 2005;Goldstein et al 2006b). Dalbavancin displays generally lower MICs against staphylococci when compared to other agents (Candiani et al 1999;Malabarba and Ciabatti 2001;Woodford 2003;Streit et al 2004;Lin et al 2005).…”