TY - JOUR
AU - Summers, Kelly, M.
AB - Abstract Purpose. The activity, pharmacokinetics, pharmacodynamics, efficacy, safety, and formulary considerations of dalbavancin are reviewed. Summary. Dalbavancin is a novel second-generation lipoglycopeptide antimicrobial with unique pharmacokinetics and excellent activity against resistant gram-positive pathogens, including methicillin-resistant Staphylococcus aureus. Available only in i.v. form, it exhibits excellent tissue penetration, particularly in the skin, and a long half-life that allows once-weekly administration. Clinically relevant drug interactions involving dalbavancin have not been identified. While sharing a similar mechanism of action and spectrum of activity with other glycopeptides, dalbavancin has demonstrated in vitro and in vivo bactericidal potency superior to that of vancomycin, teicoplanin, and other commonly used antimicrobials. Clinical trials indicate that dalbavancin is efficacious for skin and soft-tissue infections and catheter-related bloodstream infections. Dalbavancin appears to be noninferior to linezolid and superior to vancomycin. Adverse events are mild to moderate and include pyrexia, headache, and nausea. Conclusion. Dalbavancin has enhanced activity against gram-positive bacteria and unique pharmacokinetics compared with existing drugs in its class. It appears to be safe and efficacious for use against common infections, including complicated skin infections and catheter-related bloodstream infections. Antibiotics, Bacterial infections, Dalbavancin, Dosage schedules, Drug interactions, Drugs, body distribution, Half-life, Injections, Mechanism of action, Pharmacokinetics, Sustained action medications, Toxicity Antimicrobial resistance is an escalating concern worldwide. Staphylococcus aureus, a leading cause of community-acquired and nosocomial infections, is an aggressive pathogen that has evolved a number of resistance mechanisms.1 Clinically isolated strains of coagulase-negative staphylococci (CoNS), streptococci, and enterococci are frequently resistant to many currently available antibiotics.2,–4 Methicillin and other semisynthetic penicillins were the antimicrobial treatments of choice for gram-positive infections until a sharp rise in methicillin-resistant S. aureus (MRSA) isolates was discovered during the 1980s.1 Between 1975 and 1991, the prevalence of MRSA isolates increased from 2.1% to 35%.5 Since then, glycopeptides, including vancomycin and teicoplanin (available only in Europe), have become mainstays in the treatment of MRSA and other resistant gram-positive infections. However, a strain of vancomycin-intermediate S. aureus (VISA) was first reported in 1997, and vancomycin-resistant S. aureus (VRSA) has emerged more recently.6,7 Agents such as linezolid, quinupristin–dalfopristin, and daptomycin have been developed to overcome glycopeptide resistance, although resistance to these agents has been detected as well.8,–12 The emergence of these multidrug-resistant pathogens has had significant impacts on morbidity, mortality, and cost, leading to a demand for more effective agents. Dalbavancin (Zeven, Pfizer), a novel lipoglycopeptide antibiotic in the same antimicrobial class as teicoplanin and vancomycin, is under review by the Food and Drug Administration (FDA) for the treatment of resistant gram-positive infections. In December 2007, FDA issued an approvable letter for dalbavancin for the treatment of complicated skin and skin-structure infections (SSSIs).13 With its unique pharmacokinetic profile, its potent antimicrobial activity in vitro, and its established clinical efficacy and safety, dalbavancin appears promising. This article reviews the activity, pharmacokinetics, pharmacodynamics, efficacy, safety, and formulary considerations of dalbavancin. Chemistry and pharmacology Dalbavancin (BI-397, MDL 63,397) is a semisynthetic lipoglycopeptide derived from A40926, a naturally occurring glycopeptide produced by actinomycete Nonomuraea species.14,A40926 is similar in structure and activity to teicoplanin but has several functional-group modifications yielding decreased activity against CoNS and an extended elimination half-life. The three-step derivation procedure used to synthesize dalbavancin from A40926 includes esterification of the N-acylaminoglucuronic acid, amidation of the peptide–carboxyl group, and saponification of the sugar methyl ester. Chemical modifications were intended to improve antimicrobial potency and further alter the pharmacokinetics of the molecule while preserving the d-alanyl-d-alanine binding site required for antimicrobial activity.15 Glycopeptide antibiotics exert their antimicrobial effect through inhibition of bacterial cell-wall synthesis (Figure 1). The large, rigid glycopeptide molecules impart their selective toxicity against microbes by binding to terminal d-alanyl-d-alanine residues unique to bacterial cell-wall precursors.15,–18 Hydrogen bonding and hydrophobic interactions initiate a stable complex between the glycopeptide and the peptidoglycan precursors, causing sterical disruption of the formation of the nascent peptidoglycan backbone chains.15,17,18 Transglycosylation and transpeptidation of the bacterial cell wall are inhibited, which ultimately leads to bacterial growth inhibition.15,–18 Dalbavancin is characterized as a second-generation glycopeptide, or lipoglycopeptide, because of its long, lipophilic side chain on the heptapeptide backbone.15 It has been proposed that the lipid group serves as a membrane anchor, allowing for enhanced binding and improved antibacterial efficacy.15,16 In vitro antimicrobial activity Dalbavancin has demonstrated excellent in vitro activity against a broad spectrum of anaerobes and gram-positive organisms, including staphylococci, streptococci, enterococci, and corynebacteria.19,–21 Dalbavancin sustains its activity against microbes resistant to penicillin, methicillin (or oxacillin), linezolid, and vancomycin, with the exception of vancomycin-resistant enterococci (VRE) of the vanA phenotype.19,–22 The glycopeptide resistance of vanA enterococci occurs as a result of a mutated bacterial gene sequence leading to the synthesis of a cell-wall precursor terminating in d-alanyl-d-lactate rather than d-alanyl-d-alanine. The resulting altered precursor exhibits reduced hydrogen bonding, which produces a lower affinity for glycopeptides. This specific mechanism of resistance is a classwide effect for glycopeptides, including dalbavancin.23 In addition, because expression of the vanA gene is the same mechanism by which VRSA has developed, it is presumable that dalbavancin would have reduced potency against these strains as well.23 Notwithstanding these two exceptions, dalbavancin has consistently demonstrated bactericidal potency superior to that of the available comparator glycopeptides vancomycin and teicoplanin.19,–22 Data from the trials discussed below are consistent with the findings of multiple other in vitro susceptibility studies (Table 1).24,–26 Comparative activity Streit et al.19 evaluated the comparative in vitro activities of dalbavancin and 20 other antibacterial agents against 6336 clinically obtained gram-positive isolates collected in North America, South America, and Europe by using the reference minimum inhibitory concentration (MIC) methods described by the Clinical and Laboratory Standards Institute. Organisms tested included S. aureus, CoNS, Streptococcus pneumoniae, enterococci, β-hemolytic streptococci, viridans-group streptococci, Streptococcus bovis, and other gram-positive organisms. Overall, dalbavancin MICs ranged from ≤0.015 to >32 μg/mL; however, >99% of MICs were ≤1 μg/mL. S. aureus and CoNS isolates were highly susceptible to dalbavancin, with an MIC for 90% of strains (MIC90) of 0.06 μg/mL for both, including strains that were resistant to oxacillin, linezolid, teicoplanin, and quinupristin–dalfopristin. Dalbavancin consistently demonstrated excellent antimicrobial potency, with vancomycin being the only other agent active against all oxacillin-resistant S. aureus strains (MIC90, 0.5 μg/mL). Dalbavancin was the most active agent against vancomycin-susceptible Enterococcus faecalis, with an MIC90 of 0.06 μg/mL. The MIC90 of linezolid was 2 μg/mL. Against VRE isolates suspected to be of the vanB phenotype, dalbavancin had an MIC90 of ≤0.12 μg/mL. However, it had markedly decreased activity against VRE strains displaying vanA phenotypes, resulting in an MIC90 of 32 μg/mL. Similarly, the MIC90 of dalbavancin for vancomycin-resistant Enterococcus faecium was 32 μg/mL, whereas vancomycin-susceptible strains were susceptible to dalbavancin (MIC90, 0.12 μg/mL). Dalbavancin was highly active against penicillin-susceptible and -nonsusceptible S. pneumoniae (MIC90, 0.03 μg/mL) and viridans streptococci (0.03 μg/mL). Potent activity was also demonstrated against Corynebacterium, Bacillus, and Listeria species. Overall, the in vitro activity of dalbavancin was consistently equal or superior to that of vancomycin, teicoplanin, quinupristin–dalfopristin, and linezolid against a wide variety of bacterial isolates. Jones et al.21 reported the results of a similar surveillance study to determine the activity of dalbavancin and 10 comparator agents against 7765 gram-positive isolates from medical centers in Europe and North America. VRE isolates were tested for genotype confirmation, and the presence of glycopeptide resistance genes vanA, vanB, vanC1, and vanC2–3 was assessed. The dalbavancin MIC50/90 was 0.03/0.06 μg/mL for S. aureus and CoNS of all origins, including oxacillin-resistant strains. Dalbavancin was 16 to 32 times more active than vancomycin against all staphylococcal isolates (vancomycin MIC90, 1 or 2 μg/mL) (n = 4648). The MIC90 of dalbavancin against streptococci ranged from 0.016 to 0.03 μg/mL, which was again superior to that of vancomycin by a 16- to 32-fold margin (MIC90, 0.5 to ≤1 μg/mL). Resistance and intermediate susceptibility to penicillin in the tested strains did not affect dalbavancin’s MIC. The susceptibility of enterococci varied in relation to both the vancomycin resistance phenotype and the geographic origin. Demographically, the incidence of (and thus concerns regarding) nosocomial infection due to VRE is much greater in the United States than in Europe, where most VRE strains have been isolated from farm animals, meat, and the environment rather than from humans.27 Consistent with this observation, Jones et al.21 found that resistance rates of enterococci to vancomycin were significantly lower in Europe than in North America. Dalbavancin MIC90 values were 0.12 μg/mL for European isolates and 16 μg/mL for North American isolates. This was the most significant distribution variance observed. Despite the variability, dalbavancin again displayed 16- to 32-fold greater activity than vancomycin against susceptible strains. Vancomycin-resistant strains with the vanA phenotype had generally higher MICs (MIC50/90, ≥8/≥8 μg/mL). Bacillus, Corynebacterium, Listeria, and Micrococcus species were inhibited at dalbavancin concentrations of ≤0.25 μg/mL. Table 1. Minimum Inhibitory Concentration for 90% of Isolates (MIC90) of Dalbavancin and Other Antimicrobials MIC90(μg/mL) Organism and Reference No. Isolates Dalbavancin Vancomycin Teicoplanin Linezolid Quinupristin–Dalfopristin Daptomycin Levofloxacin aNot available. bIncludes S. epidermidis isolates only. cNOS = not otherwise specified. dIncludes isolates collected from North America only. eIncludes anaerobic gram-positive cocci, including Peptostreptococcus anaerobius, Peptoniphilus harei, Peptostreptococcus vaginalis, Micromonas species, and Anaerococcus tetradius. Staphylococcus aureus     Methicillin susceptible         19 1815 0.06 1 1 2 0.5 . . .a 0.5         24 10 0.13 1 4 . . . . . . . . . . . .         25 43 0.06 1 1 4 0.5 0.5 . . .         20 43 0.125 0.5 . . . 4 . . . 0.5 0.25     Methicillin resistant         19 1177 0.06 2 2 2 1 . . . >4         24 23 0.25 4 8 . . . . . . . . . . . .         25 29 0.06 1 1 4 0.5 0.5 . . .         20 60 0.125 1 . . . 4 0.5 0.5 >8 Coagulase-negative staphylococci     Methicillin susceptible         19 157 0.06 2 4 1 0.25 . . . 4         24b 13 0.25 1 8 . . . . . . . . . . . .         25 38 0.06 2 8 2 0.5 0.5 . . .     Methicillin resistant         19 617 0.06 2 4 1 0.5 . . . >4         24b 12 0.25 4 16 . . . . . . . . . . . .         25 36 0.06 2 16 2 0.5 0.5 . . . Streptococcus pneumoniae     Penicillin susceptible         19 996 0.03 0.5 . . . 1 0.5 . . . 1         24 12 0.06 0.5 0.06 . . . . . . . . . . . .     Penicillin resistant         19 400 0.03 0.5 . . . 1 0.5 . . . 1     Penicillin NOSc         26 208 0.016 0.5 ≤2 1 ≤0.5 . . . 2         21d . . . 0.016 0.5 ≤2 1 ≤0.5 . . . 2 Viridans streptococci     Penicillin susceptible         19 104 0.03 1 . . . 1 1 . . . 2     Penicillin resistant         19 30 0.03 0.5 . . . 1 1 . . . 2     Penicillin NOS         26 13 0.016 1 ≤2 1 0.5 . . . 4         21d 66 0.03 1 ≤2 1 1 . . . 2     Beta-haemolytic streptococci         19 234 0.06 0.5 . . . 1 0.5 . . . 1         26 53 0.06 0.5 ≤2 1 0.5 . . . 0.5         21d 175 0.03 0.5 ≤2 1 0.5 . . . 1 Enterococcus faecalis     Vancomycin susceptible         19 586 0.06 . . . 0.5 2 >8 . . . >4     Vancomycin resistant         19 20 32 . . . >16 2 >8 . . . >4 Enterococcus faecium     Vancomycin susceptible         19 77 0.12 . . . 0.5 2 2 . . . >4     Vancomycin resistant         19 51 32 . . . >16 2 1 . . . >4 Anaerobes     Clostridium species         20 20 2 1 . . . 8 . . . . . . >8 Other     20e 0.125 0.5 . . . . . . 1 . . . 1 >8 MIC90(μg/mL) Organism and Reference No. Isolates Dalbavancin Vancomycin Teicoplanin Linezolid Quinupristin–Dalfopristin Daptomycin Levofloxacin aNot available. bIncludes S. epidermidis isolates only. cNOS = not otherwise specified. dIncludes isolates collected from North America only. eIncludes anaerobic gram-positive cocci, including Peptostreptococcus anaerobius, Peptoniphilus harei, Peptostreptococcus vaginalis, Micromonas species, and Anaerococcus tetradius. Staphylococcus aureus     Methicillin susceptible         19 1815 0.06 1 1 2 0.5 . . .a 0.5         24 10 0.13 1 4 . . . . . . . . . . . .         25 43 0.06 1 1 4 0.5 0.5 . . .         20 43 0.125 0.5 . . . 4 . . . 0.5 0.25     Methicillin resistant         19 1177 0.06 2 2 2 1 . . . >4         24 23 0.25 4 8 . . . . . . . . . . . .         25 29 0.06 1 1 4 0.5 0.5 . . .         20 60 0.125 1 . . . 4 0.5 0.5 >8 Coagulase-negative staphylococci     Methicillin susceptible         19 157 0.06 2 4 1 0.25 . . . 4         24b 13 0.25 1 8 . . . . . . . . . . . .         25 38 0.06 2 8 2 0.5 0.5 . . .     Methicillin resistant         19 617 0.06 2 4 1 0.5 . . . >4         24b 12 0.25 4 16 . . . . . . . . . . . .         25 36 0.06 2 16 2 0.5 0.5 . . . Streptococcus pneumoniae     Penicillin susceptible         19 996 0.03 0.5 . . . 1 0.5 . . . 1         24 12 0.06 0.5 0.06 . . . . . . . . . . . .     Penicillin resistant         19 400 0.03 0.5 . . . 1 0.5 . . . 1     Penicillin NOSc         26 208 0.016 0.5 ≤2 1 ≤0.5 . . . 2         21d . . . 0.016 0.5 ≤2 1 ≤0.5 . . . 2 Viridans streptococci     Penicillin susceptible         19 104 0.03 1 . . . 1 1 . . . 2     Penicillin resistant         19 30 0.03 0.5 . . . 1 1 . . . 2     Penicillin NOS         26 13 0.016 1 ≤2 1 0.5 . . . 4         21d 66 0.03 1 ≤2 1 1 . . . 2     Beta-haemolytic streptococci         19 234 0.06 0.5 . . . 1 0.5 . . . 1         26 53 0.06 0.5 ≤2 1 0.5 . . . 0.5         21d 175 0.03 0.5 ≤2 1 0.5 . . . 1 Enterococcus faecalis     Vancomycin susceptible         19 586 0.06 . . . 0.5 2 >8 . . . >4     Vancomycin resistant         19 20 32 . . . >16 2 >8 . . . >4 Enterococcus faecium     Vancomycin susceptible         19 77 0.12 . . . 0.5 2 2 . . . >4     Vancomycin resistant         19 51 32 . . . >16 2 1 . . . >4 Anaerobes     Clostridium species         20 20 2 1 . . . 8 . . . . . . >8 Other     20e 0.125 0.5 . . . . . . 1 . . . 1 >8 Open in new tab Table 1. Minimum Inhibitory Concentration for 90% of Isolates (MIC90) of Dalbavancin and Other Antimicrobials MIC90(μg/mL) Organism and Reference No. Isolates Dalbavancin Vancomycin Teicoplanin Linezolid Quinupristin–Dalfopristin Daptomycin Levofloxacin aNot available. bIncludes S. epidermidis isolates only. cNOS = not otherwise specified. dIncludes isolates collected from North America only. eIncludes anaerobic gram-positive cocci, including Peptostreptococcus anaerobius, Peptoniphilus harei, Peptostreptococcus vaginalis, Micromonas species, and Anaerococcus tetradius. Staphylococcus aureus     Methicillin susceptible         19 1815 0.06 1 1 2 0.5 . . .a 0.5         24 10 0.13 1 4 . . . . . . . . . . . .         25 43 0.06 1 1 4 0.5 0.5 . . .         20 43 0.125 0.5 . . . 4 . . . 0.5 0.25     Methicillin resistant         19 1177 0.06 2 2 2 1 . . . >4         24 23 0.25 4 8 . . . . . . . . . . . .         25 29 0.06 1 1 4 0.5 0.5 . . .         20 60 0.125 1 . . . 4 0.5 0.5 >8 Coagulase-negative staphylococci     Methicillin susceptible         19 157 0.06 2 4 1 0.25 . . . 4         24b 13 0.25 1 8 . . . . . . . . . . . .         25 38 0.06 2 8 2 0.5 0.5 . . .     Methicillin resistant         19 617 0.06 2 4 1 0.5 . . . >4         24b 12 0.25 4 16 . . . . . . . . . . . .         25 36 0.06 2 16 2 0.5 0.5 . . . Streptococcus pneumoniae     Penicillin susceptible         19 996 0.03 0.5 . . . 1 0.5 . . . 1         24 12 0.06 0.5 0.06 . . . . . . . . . . . .     Penicillin resistant         19 400 0.03 0.5 . . . 1 0.5 . . . 1     Penicillin NOSc         26 208 0.016 0.5 ≤2 1 ≤0.5 . . . 2         21d . . . 0.016 0.5 ≤2 1 ≤0.5 . . . 2 Viridans streptococci     Penicillin susceptible         19 104 0.03 1 . . . 1 1 . . . 2     Penicillin resistant         19 30 0.03 0.5 . . . 1 1 . . . 2     Penicillin NOS         26 13 0.016 1 ≤2 1 0.5 . . . 4         21d 66 0.03 1 ≤2 1 1 . . . 2     Beta-haemolytic streptococci         19 234 0.06 0.5 . . . 1 0.5 . . . 1         26 53 0.06 0.5 ≤2 1 0.5 . . . 0.5         21d 175 0.03 0.5 ≤2 1 0.5 . . . 1 Enterococcus faecalis     Vancomycin susceptible         19 586 0.06 . . . 0.5 2 >8 . . . >4     Vancomycin resistant         19 20 32 . . . >16 2 >8 . . . >4 Enterococcus faecium     Vancomycin susceptible         19 77 0.12 . . . 0.5 2 2 . . . >4     Vancomycin resistant         19 51 32 . . . >16 2 1 . . . >4 Anaerobes     Clostridium species         20 20 2 1 . . . 8 . . . . . . >8 Other     20e 0.125 0.5 . . . . . . 1 . . . 1 >8 MIC90(μg/mL) Organism and Reference No. Isolates Dalbavancin Vancomycin Teicoplanin Linezolid Quinupristin–Dalfopristin Daptomycin Levofloxacin aNot available. bIncludes S. epidermidis isolates only. cNOS = not otherwise specified. dIncludes isolates collected from North America only. eIncludes anaerobic gram-positive cocci, including Peptostreptococcus anaerobius, Peptoniphilus harei, Peptostreptococcus vaginalis, Micromonas species, and Anaerococcus tetradius. Staphylococcus aureus     Methicillin susceptible         19 1815 0.06 1 1 2 0.5 . . .a 0.5         24 10 0.13 1 4 . . . . . . . . . . . .         25 43 0.06 1 1 4 0.5 0.5 . . .         20 43 0.125 0.5 . . . 4 . . . 0.5 0.25     Methicillin resistant         19 1177 0.06 2 2 2 1 . . . >4         24 23 0.25 4 8 . . . . . . . . . . . .         25 29 0.06 1 1 4 0.5 0.5 . . .         20 60 0.125 1 . . . 4 0.5 0.5 >8 Coagulase-negative staphylococci     Methicillin susceptible         19 157 0.06 2 4 1 0.25 . . . 4         24b 13 0.25 1 8 . . . . . . . . . . . .         25 38 0.06 2 8 2 0.5 0.5 . . .     Methicillin resistant         19 617 0.06 2 4 1 0.5 . . . >4         24b 12 0.25 4 16 . . . . . . . . . . . .         25 36 0.06 2 16 2 0.5 0.5 . . . Streptococcus pneumoniae     Penicillin susceptible         19 996 0.03 0.5 . . . 1 0.5 . . . 1         24 12 0.06 0.5 0.06 . . . . . . . . . . . .     Penicillin resistant         19 400 0.03 0.5 . . . 1 0.5 . . . 1     Penicillin NOSc         26 208 0.016 0.5 ≤2 1 ≤0.5 . . . 2         21d . . . 0.016 0.5 ≤2 1 ≤0.5 . . . 2 Viridans streptococci     Penicillin susceptible         19 104 0.03 1 . . . 1 1 . . . 2     Penicillin resistant         19 30 0.03 0.5 . . . 1 1 . . . 2     Penicillin NOS         26 13 0.016 1 ≤2 1 0.5 . . . 4         21d 66 0.03 1 ≤2 1 1 . . . 2     Beta-haemolytic streptococci         19 234 0.06 0.5 . . . 1 0.5 . . . 1         26 53 0.06 0.5 ≤2 1 0.5 . . . 0.5         21d 175 0.03 0.5 ≤2 1 0.5 . . . 1 Enterococcus faecalis     Vancomycin susceptible         19 586 0.06 . . . 0.5 2 >8 . . . >4     Vancomycin resistant         19 20 32 . . . >16 2 >8 . . . >4 Enterococcus faecium     Vancomycin susceptible         19 77 0.12 . . . 0.5 2 2 . . . >4     Vancomycin resistant         19 51 32 . . . >16 2 1 . . . >4 Anaerobes     Clostridium species         20 20 2 1 . . . 8 . . . . . . >8 Other     20e 0.125 0.5 . . . . . . 1 . . . 1 >8 Open in new tab Figure 1. Open in new tabDownload slide Mechanism of action of dalbavancin. The top panel represents normal cell-wall synthesis in a gram-positive microbe. Peptidoglycan strands are produced from lipid II by transglycosylase, and the resulting strands are then cross-linked by transpeptidase. The bottom panel illustrates dalbavancin binding in a stable complex to the d-alanyl-d-alanine portion of cell-wall precursors. It is postulated that the long, lipophilic side chain of dalbavancin acts as a membrane anchor and enhances target binding. Upon binding, dalbavancin inhibits both transglycosylation and transpeptidation steps, thereby inhibiting the essential processes of peptidoglycan polymerization and cross-linkage. Illustration by Taina Litwak, CMI; adapted from Am J Health-Syst Pharm. 2007 ; 64 : 2337 . Figure 1. Open in new tabDownload slide Mechanism of action of dalbavancin. The top panel represents normal cell-wall synthesis in a gram-positive microbe. Peptidoglycan strands are produced from lipid II by transglycosylase, and the resulting strands are then cross-linked by transpeptidase. The bottom panel illustrates dalbavancin binding in a stable complex to the d-alanyl-d-alanine portion of cell-wall precursors. It is postulated that the long, lipophilic side chain of dalbavancin acts as a membrane anchor and enhances target binding. Upon binding, dalbavancin inhibits both transglycosylation and transpeptidation steps, thereby inhibiting the essential processes of peptidoglycan polymerization and cross-linkage. Illustration by Taina Litwak, CMI; adapted from Am J Health-Syst Pharm. 2007 ; 64 : 2337 . Activity in combination with other antimicrobials Johnson et al.28 further explored the in vitro activity of dalbavancin against staphylococci, streptococci, and enterococci, including oxacillin- and vancomycin-resistant strains, by testing its efficacy and interaction with each of nine drugs representative of various antimicrobial classes. Dalbavancin 0.016–8 μg/mL was used in combination with the following: clindamycin 0.008–16 μg/mL, daptomycin 0.016–16 μg/mL, gentamicin 0.03–64 μg/mL, levofloxacin 0.06–64 μg/mL, linezolid 0.06–64 μg/mL, oxacillin 0.004–64 μg/mL, quinupristin–dalfopristin 0.06–64 μg/mL, rifampin 0.008–8 μg/mL, and vancomycin 0.06–8 μg/mL. Interactions were classified as (1) antagonism (fourfold or greater increase in the MICs of both agents), (2) synergy (fourfold or greater decrease in the MICs of both agents), (3) partial synergy (fourfold or greater decrease in the MIC of one agent and twofold reduction in the MIC of the other), (4) additive (twofold decrease in the MICs of both tested agents), (5) indifference (no decrease in the MIC of either agent or twofold decrease or increase in the MIC of one agent), or (6) indeterminate (results inconsistent with the described categories or results beyond the tested dilution ranges). The most commonly observed interactions were partial synergy (34.4%), indifference (33.3%), and additive effects (22.2%).28 Synergy was observed in 5.6% of interactions, and 4.4% were found to be indeterminate. No interactions were antagonistic. The greatest number of interactions were detected with the dalbavancin and oxacillin combination, which demonstrated synergy against all strains of oxacillin-resistant staphylococci and one strain with intermediate vancomycin resistance, the most resistant isolate tested. In addition, partial synergy between dalbavancin and oxacillin was detected against three other isolates. No other combinations demonstrated synergy. The dalbavancin–gentamicin and dalbavancin–vancomycin combinations were equally effective, yielding partial synergy or an additive effect against nine strains. Dalbavancin–linezolid was the least active combination, demonstrating indifferent activity against 8 of 10 isolates. Unless contravened by investigations in vivo, these results support a potential future role for dalbavancin as an add-on therapy for difficult-to-treat gram-positive infections. Pharmacokinetics The unique pharmacokinetic characteristics of dalbavancin help distinguish it from its comparators vancomycin and teicoplanin. Early experiments in rodents demonstrated dalbavancin’s high and prolonged plasma concentrations and wide tissue distribution following single i.v. doses.24,29 These properties introduced the potential for extended dosage intervals. Studies in healthy volunteers and in subjects with renal and hepatic impairment have further characterized the drug’s pharmacokinetics. Single doses of 140–1120 mg and loading doses of 300–1000 mg followed by daily maintenance doses of 30–100 mg for six days have been assessed. In addition, clinical trials have evaluated a 1000-mg dose followed by a 500-mg dose one week later. Absorption and distribution Dalbavancin, like other glycopeptides, is poorly absorbed after oral administration and is available for i.v. administration only. The maximum plasma concentration (Cmax) is achieved following the end of an infusion and increases in proportion to the dose.30,31 The immediate rise in concentration is followed by a rapid, log-linear decline over 12 hours during the distribution phase. Thus, dalbavancin exhibits dose-dependent, linear pharmacokinetics best described by a two-compartment model with first-order elimination.31 It displays reversible protein binding approximating 93% and a volume of distribution at steady state (V) ranging from 9.75 to 15.5 L.30,31 Steady-state concentrations are typically achieved within two to three days following administration, and blister fluid concentrations have correlated well with plasma drug levels, with the ratio of concentrations ranging from 0.84 to 1.11.30 In a Phase II trial in patients with SSSIs, plasma concentrations of >20 mg/L were maintained for 20 days in patients who received 1000 mg followed by 500 mg one week later.32 Metabolism and excretion Dalbavancin does not appear to be a substrate for, an inhibitor of, or an inducer of the hepatic cytochrome P-450 (CYP) isoenzyme system.31 The terminal elimination half-life (t½) has been reported to be in the range of 149–198 hours (mean, 181 hours), exceeding the t½ of vancomycin (4–6 hours) and teicoplanin (90–157 hours).30,33,34 Dalbavancin’s high but reversible protein-binding capacity helps explain its long serum t½ and provides the rationale for the weekly dosage strategy implemented in clinical trials. Dalbavancin is eliminated both renally and nonrenally (vancomycin and teicoplanin are cleared exclusively by the kidneys).33,34 Approximately one third of a dose (range, 25–45%) is excreted unchanged in the urine.30 Overall, while both Cmax and area under the plasma concentration–time curve (AUC) increased proportionately with the dose, t½, clearance (CL), and V remained unchanged with respect to the dose in healthy volunteers.30 In a comparison between male and female subjects, t½, V, and CL were similar between the sexes after correction for body weight.30 Variability in pharmacokinetics A population pharmacokinetic model was developed to determine the impact of interpatient variability in demographics and concomitant medication use on dalbavancin’s pharmacokinetics.31 Simulations were performed with human blood samples from Phase II and III trial participants. The demographic variables tested were age, body weight, sex, race, body surface area (BSA), baseline creatinine clearance (CLcr), and baseline serum albumin level. Medications examined included CYP isoenzyme substrates, inhibitors, and inducers and other drugs commonly prescribed for the studied population. Interpatient variability was <34% for all variables except intercompartmental CL. Initial graphic evaluation and modeling analysis indicated that CLcr, body weight, and BSA might be related to dalbavancin CL, with weight and BSA accounting for similar variability. The other demographic and concomitant medication covariates did not appear to influence dalbavancin’s pharmacokinetics and were not included in the final model. Covariate testing of CLcr and BSA demonstrated significant linear relationships between those variables and dalbavancin CL, as well as between BSA and central V. Several Monte Carlo simulations were conducted with ranges of BSA and CLcr values to assess their impact on the originally derived population pharmacokinetics. While both increases in BSA and decreases in CLcr significantly decreased the overall CL of dalbavancin, its Cmax and CL profiles closely overlapped those of patients with normal BSA and CLcr. Dosage adjustment for renal impairment Dosage adjustment is not necessary in patients with mild-to-moderate hepatic impairment, mild-to-moderate renal impairment, or end-stage renal disease requiring dialysis.35,–37 Dalbavancin concentrations and exposure were increased in subjects with severe renal impairment (CLcr, <30 mL/min) but not receiving hemodialysis, suggesting the need for a modest dosage adjustment in this subpopulation.36 However, specific recommendations regarding dosage modifications for patients with severe renal impairment or for any other special populations are not yet available. Pharmacodynamics Bowker et al.38 studied dalbavancin’s pharmacodynamics by using an in vitro pharmacokinetic system.The experiment was modeled after previously established pharmacokinetic values in humans, specifically 93% protein binding and a 240-hour elimination t½. Four strains of S. aureus (106 CFU/mL), including an oxacillin-susceptible strain, two oxacillin-resistant strains, and a strain with intermediate resistance to vancomycin, were exposed to sequentially decreasing concentrations of dalbavancin over 240 hours. Simulated peak concentrations ranged from 0.6 to 21 mg/L in order to model the estimated free drug concentration of 21 mg/L following a 1-g dose, as previously described in the literature.36 Viable bacteria counts were performed at 12 hours, 24 hours, and every 24 hours thereafter, with a limit of detection of 2 × 102 CFU/mL. Dalbavancin concentrations were determined by bioassay with a limit of detection of 1 mg/mL. Dalbavancin was bactericidal, with MICs of 0.14, 0.12, 0.08, and 0.8 mg/L for oxacillin-susceptible S. aureus, oxacillin-resistant S. aureus (strains 7023 and 30902), and VISA strains, respectively. Concentrations of 0.6 mg/L did not produce sustained bacterial killing; regrowth was evident by 72 hours. The most rapid killing was seen with initial concentrations of 15 and 21 mg/L; oxacillin-susceptible and -resistant S. aureus strains were undetectable by 48–96 hours and remained so to 240 hours. VISA strains were undetectable by 144 and 96 hours for initial concentrations of 15 and 21 mg/L, respectively. The three vancomycin-susceptible strains displayed non-concentration-dependent killing in the range of 3–21 mg/L, and the intermediate strains displayed similar effects (in the range of 15–21 mg/L). The authors noted that this relationship differed from the findings of a previous analysis with a rat granuloma pouch model in which killing was concentration dependent for up to 50 hours.39 A good correlation (r2 = 0.81–0.83) between AUC for 0–24 hours divided by MIC (AUC24/MIC) and antibacterial effect was observed. The AUC24/MIC range for a bacteriostatic effect was 36–100, and for a −2 log drop in bacterial count was 214–331. Although they did not attempt predictions for the effect in humans, the authors suggested that a free drug target based on AUC24/MIC values of 200–300 would seem most appropriate for moderate-to-severe infections. Efficacy in animals Dalbavancin’s in vivo activity was first tested in comparison with vancomycin and teicoplanin in rodent models of infection.24 In the treatment of mice with acute MRSA-associated septicemia or S. pneumoniae infection, dalbavancin and teicoplanin had similar potency and were more efficacious than vancomycin. Against Staphylococcus epidermidis, dalbavancin was more active than teicoplanin and vancomycin, whereas dalbavancin was inferior to teicoplanin against vancomycin-susceptible E. faecalis. In immunocompetent or neutropenic rats with induced pneumococcal infections, a single 10-mg/kg dose of dalbavancin reduced bacterial counts to undetectable levels for both penicillin-susceptible and penicillin-resistant strains. In a rat endocarditis model, dalbavancin was as effective as vancomycin against S. aureus and S. epidermidis, with less frequent administration.24 These models provided the foundation for in vivo studies in humans. Efficacy in humans To date, two Phase II trials and one Phase III trial have been published for review. Seltzer et al. study The safety and efficacy of one- and two-dose regimens of dalbavancin in the treatment of gram-positive skin and soft-tissue infections (SSTIs) were examined in a randomized, controlled, multicenter, open-label, Phase II, proof-of-concept trial.32 Eligible SSTIs were specified as infections that involved deep soft tissue or required significant surgical intervention, such as a major abscess, an infected ulcer, a major burn, or deep and extensive cellulitis. In addition, eligible subjects were required to display at least two SSTI symptoms, which include drainage, erythema, fluctuance, heat, tenderness to palpation, and swelling. Patients were excluded if they had a CLcr of less than 50 mL/min, recent antibiotic treatment for their SSTI, self-limited infection, SSTI with compromised vascularity, documented osteomyelitis, or a history of hypersensitivity to glycopeptides. Sixty-two men and women received one dose of i.v. dalbavancin (a single 1100-mg dose) (n = 20), a two-dose sequence of i.v. dalbavancin (a 1000-mg dose on day 1 followed by a 500-mg dose on day 8) (n = 21), or a standard-of-care comparator therapy regimen predetermined by the investigator (n = 21). Comparator regimens included ceftriaxone, cefazolin, piperacillin–tazobactam, clindamycin, vancomycin, linezolid, and cephalexin given singly or in some combination. The primary efficacy endpoint was clinical cure, improvement, or failure based on clinical and microbiological examination at the follow-up visit 10–12 days after the end of treatment. Gram-positive isolates, predominately staphylococci and streptococci, were identified in 41 patients (66%) and included 13 MRSA strains. Most patients had deep or complicated infections (>90%), and a majority required surgical intervention (~70%) prior to randomization. A greater clinical response was observed in the two-dose dalbavancin group than in the other treatment groups across all populations analyzed. In the clinically evaluable population, clinical success rates were 94.1% for two-dose dalbavancin, 61.5% for one-dose dalbavancin, and 76.2% for comparator regimens. The respective microbiological success rates followed a similar pattern: 92%, 58%, and 71%. Specifically, MRSA eradication rates were 80%, 50%, and 50% for two-dose dalbavancin, one-dose dalbavancin, and comparator regimens, respectively. This trial provided the first evidence of dalbavancin’s efficacy in the treatment of adults with SSTIs and provided proof-of-concept for the efficacy of the two-dose regimen. Study limitations included a relatively small population, variable visit schedules and treatment durations, and inconsistent timing of efficacy assessments. Raad et al. study In another Phase II, open-label, randomized, controlled, multicenter study, Raad et al.40 compared the safety and efficacy of dalbavancin in the treatment of catheter-related bloodstream infections with vancomycin, the current standard of care. Seventy-five adult patients with definite or probable gram-positive bacteremia of intravascular-access-catheter origin were randomized to receive either i.v. dalbavancin (a 1000-mg loading dose on day 1 followed by a 500-mg dose on day 8) (n = 33) or i.v. vancomycin (1000 mg [as the hydrochloride salt] twice daily for 14 days) (n = 34). The primary outcome measure was overall efficacy at the test-of-cure (TOC) visit (18–24 days after the end of treatment), as determined from clinical and microbiological responses based on physical examination and blood culture results. Secondary outcomes included independent clinical and microbiological responses at the end of therapy (within two days after the end of treatment) and at the TOC visit. Sixty-seven subjects were included in the analysis, with a subset of 51 classified as the microbiologically confirmed intention-to-treat (micro-ITT) population. At baseline, the evaluated groups were similar, except that antibiotic- or antiseptic-coated catheters were more common in the vancomycin group. Baseline microbiology indicated an even distribution of CoNS (26 isolates), S. aureus (23 isolates), and E. faecalis (5 isolates) among treatment groups, although more MRSA isolates were encountered in the vancomycin group. In the micro-ITT population, the primary outcome was significantly more frequent in the dalbavancin group (87.0%) (95% confidence interval [CI], 73.2–100%) than in the vancomycin group (50.0%) (95% CI, 31.5–68.5%). The same outcome was achieved regardless of the classification of catheter-related infection, baseline catheter status, or strategy of catheter management. Secondary endpoints of clinical and microbiological response rates in the micro-ITT population at TOC visits were also more frequent among subjects treated with dalbavancin than with vancomycin (87% versus 50% and 95.7% versus 78.6%, respectively (no CI or p values were reported). A key finding was the superiority of dalbavancin to vancomycin, which may be in accordance with documented observations of limited vancomycin efficacy against staphylococci embedded in biofilm (embedding occurs in catheter-related infections). The authors suggested that these results may introduce a defined therapeutic role for dalbavancin, particularly in patients with catheter-related bloodstream infections in whom the catheter has not been removed. The need for additional efficacious antimicrobials is underscored by the observation that catheter-related infections are the most common reported cause of nosocomial sepsis.40 Jauregui et al. study A Phase III, randomized, double-blind, multicenter, noninferiority study compared the safety and efficacy of dalbavancin with those of linezolid for treating complicated SSSIs.41 SSSIs qualifying as complicated in this study were similar to the SSTIs treated in the study by Seltzer et al.32 and included major abscesses and burns, extensive or ulcerating cellulitis, and wound infections that involved deep soft tissue or required significant surgical intervention. Men with suspected or confirmed SSSIs due to gram-positive pathogens and having at least two predefined local signs or symptoms of a complicated SSSI were randomly assigned in a 2:1 fashion to receive either dalbavancin 1000 mg i.v. followed by 500 mg i.v. one week later (n = 571) or linezolid 600 mg i.v. (or i.v. followed by p.o.) every 12 hours for 14 days (n = 283). At least 24 hours of i.v. therapy was required prior to oral conversion. The most common types of infection in both treatment groups were major abscesses (32%) and cellulitis (28%). No data were presented regarding the need for abscess drainage in either group. Efficacy was defined by clinical examination and by microbiological evaluation showing eradication of gram-positive pathogens. Patients were assessed at baseline, on the day of i.v.-to-oral conversion, within 3 days of treatment completion, and 12–16 days after treatment completion (the TOC visit). The primary endpoint was clinical success at the TOC visit. Baseline cultures identified at least one gram-positive pathogen for 550 of the 660 patients who were clinically evaluable at the TOC visit. S. aureus was the predominant pathogen, including 278 MRSA isolates. The primary endpoint was achieved in 88.9% of patients receiving dalbavancin and in 91.2% of patients receiving linezolid. Microbiological success at the TOC visit was also comparable between treatment groups, with overall eradication rates of 87.5% and 89.5% and MRSA eradication rates of 91% and 89% for dalbavancin and linezolid, respectively. All results met the authors’ defined statistical criteria for noninferiority. In a follow-up telephone interview designed to examine the durability of responses, a 0.6% relapse rate was reported for both groups. The nature and severity of adverse events were similar between groups. Overall, this study demonstrated that dalbavancin was well tolerated and noninferior to linezolid for SSSI treatment. Major strengths of this trial were the double-blind design, the use of a patient population representative of the broad range of complicated SSSIs, and prudent matching of treatment groups for demographics and the site, type, and cause of infection. Comparative efficacy The efficacy of dalbavancin has been compared with that of other antimicrobials labeled for the infections for which dalbavancin has been studied. As reported previously by Raad et al.,40 in patients with catheter-related bloodstream infections, of which 19.2% were documented as involving MRSA, dalbavancin was associated with a clinical success rate of 87%, versus 50% for vancomycin. In a randomized, open-label study by Stevens et al.42 assessing clinical cure rates for linezolid and vancomycin in hospitalized patients with any type of presumed or documented MRSA infection, recorded cure rates in the subset of 65 patients with bacteremia (micro-ITT population) were 56.5% for linezolid and 50% for vancomycin. With respect to complicated skin infections, dalbavancin demonstrated a clinical success rate of 94% in the open-label study by Seltzer et al.,32 versus 76% for various comparator regimens, and a rate of 88.9% in the Phase III study by Jauregui et al.,41 versus 91.2% for linezolid. Two multicenter Phase III studies evaluating tigecycline for complicated SSSIs found cure rates of 86.5% at the TOC visit in clinically evaluable patients.43 Daptomycin demonstrated a clinical success rate of 83.4% in a large Phase III study of complicated SSSIs,44 while quinupristin– dalfopristin led to a clinical success rate of 68.2% in another group with complicated SSTIs.45 For skin infections specifically caused by MRSA, dalbavancin has shown an efficacy rate of 91%, compared with 89% for linezolid,41 78.1% for tigecycline,43 75% for daptomycin,44 77.8% for quinupristin–dalfopristin,45 and 73.3% for vancomycin.42 Thus, although statistical analysis is lacking, it would appear that, for catheter-related bloodstream infections by MRSA, dalbavancin may be superior to vancomycin and linezolid. For complicated skin infections caused by any pathogen, these reported success rates likewise suggest that dalbavancin may be comparable to linezolid, tigecycline, and daptomycin, while being potentially superior to quinupristin–dalfopristin. It is notable that, with the exception of linezolid, the clinical success rates achieved in dalbavancin-treated patients have exceeded rates achieved with commonly used agents specifically reserved for MRSA eradication. Adverse events Clinical trials indicate that dalbavancin is well tolerated by patients.30,32,40,41 Most adverse drug events (ADEs) have been mild to moderate in severity. There have been no reported deaths related to therapy. In a Phase I dose-escalation trial, healthy adult volunteers (n = 39) were exposed to single and multiple doses of dalbavancin (140–1120 mg).30 Multiple-dose regimens consisted of six daily doses following one loading dose given in a 10:1 ratio, ranging from 300:30 to 1000:100 mg. Dalbavancin was well tolerated at all doses. Sixty-seven percent of subjects reported at least one treatment-emergent ADE; however, most ADEs were mild, and none met the criteria for dose-limiting toxicity. No serious ADEs or dose-limiting toxicities were reported. The most common ADEs were pyrexia (50%), headache (25%), and nausea (6%). The placebo group had a 38% frequency of pyrexia and a 31% rate of headache. One subject receiving dalbavancin 350 mg experienced mild, transient, asymptomatic elevations in alanine and aspartate aminotransferases, while another subject receiving dalbavancin had transient hyperglycemia (dose not reported). A placebo recipient also had mild hyperglycemia. There were no clinically significant changes from baseline in laboratory test results, vital signs, physical examination findings, or electrocardiograms. No audiologic changes were observed. Overall, there was no difference in the frequency of ADEs between the dalbavancin and placebo groups. In the two Phase II and one Phase III published trials, dalbavancin was consistently well tolerated, with ADE rates similar to those of the standard comparator therapies.32,40,41 The dalbavancin regimen used in all the trials was a single 1000-mg dose followed by a single 500-mg dose one week later. In 33 patients with catheter-related bloodstream infections receiving multiple-dose dalbavancin, the most common ADEs were oral candidiasis (12.1%), diarrhea (21.2%), constipation (18.2%), and pyrexia (18.2%).40 Laboratory changes were generally mild and included anemia (18.2%) and hypokalemia (18.2%). No serious ADEs were attributed to treatment in the dalbavancin group. The most common ADEs in the vancomycin group were oral candidiasis, loose stools, skin and vaginal fungal infections, acute renal failure, and renal impairment. Among 62 patients with SSTIs, drug-related ADEs were reported in 11 (55%) who received a single 1100-mg dose of dalbavancin, 10 (48%) who received multiple doses of dalbavancin, and 12 (57%) who received comparator regimens.32 No clinically significant laboratory abnormalities were found in any group, and there were no instances of drug discontinuation or withdrawal of a patient from a study because of ADEs. Similar results were seen in a Phase III study of patients with SSSIs who received either a multiple-dose regimen of dalbavancin or a 14-day regimen of linezolid.41 ADEs were reported by 56% of patients in the dalbavancin group and 61% of patients in the linezolid group. ADEs considered probably or possibly related to the study medications occurred in 25.4% of patients receiving dalbavancin and 32.2% of patients receiving linezolid. The mean duration of ADEs was similar between groups; however, the median duration was one day shorter in the dalbavancin group. The types of ADEs were similar, with the most common being nausea (3.2%, dalbavancin; 5.3%, linezolid) and diarrhea (2.5%, dalbavancin; 5.7%, linezolid). Of particular interest was the lower rate of thrombocytopenia for dalbavancin (0.2%, versus 2.5% for linezolid). The only serious ADE considered to be probably or possibly related to dalbavancin was mild leukemia, in a single patient, that resolved spontaneously. Dalbavancin has been tested for its effect on the intestinal flora in healthy subjects.46 Twelve men and women 18–40 years of age received a single 1-g dose of i.v. dalbavancin administered as a 30-minute infusion. Plasma and fecal samples were collected for 60 days. Dalbavancin was found to have some impact on aerobic microflora. There were increased numbers of enterococci and Escherichia coli in individual patients, although no overall changes in colonization were observed. No significant alterations in numbers of anaerobic microflora (lactobacilli, clostridia, and bacteroids) were found. The authors concluded that dalbavancin has no major ecological effect on the human intestinal microflora. Although the data are limited, no significant drug interactions involving dalbavancin have been reported. A population pharmacokinetic model based on Phase II and Phase III trial data was analyzed to evaluate several potential drug interactions.31 There was no evidence that dalbavancin is an inducer, inhibitor, or substrate of CYP isoenzymes. A group of medications with frequent (>7%) concomitant use with dalbavancin were also analyzed for interactions, including acetaminophen, aztreonam, fentanyl, metronidazole, furosemide, proton-pump inhibitors, midazolam, and simvastatin. No interactions were found. Dosage and administration Because of the poor absorption of glycopeptides from the gastrointestinal tract, dalbavancin is available only in an i.v. formulation. Although the oral bioavailability of dalbavancin has not yet been quantified, it can be presumed to be negligible, as the similarly structured vancomycin’s oral bioavailability is less than 5%.47 The maximum cumulative dose tested in healthy human volunteers was 1600 mg.30 No dose-limiting toxicities have been observed, and all doses tested have been well tolerated.30 Several single- and multiple-dose regimens have been studied. The long t½ allows for weekly administration. The most effective dosage in clinical trials was a single 1000-mg dose followed by a 500-mg dose one week later.32,40,41 The pharmacokinetic and preclinical pharmacodynamic data used to develop the once-weekly regimen have been summarized by Dorr et al.48 Dosage adjustment is not necessary in patients with hepatic impairment or mild-to-moderate renal impairment or in patients receiving hemodialysis; however, patients with severe renal impairment (and not receiving dialysis) may require a modest dosage reduction.35,–37 Formulary considerations Dalbavancin remains under review by FDA for the treatment of resistant infections by gram-positive organisms. A new drug application was filed in December 2004, and FDA issued an approvable letter in 2007.13 Dalbavancin is expected to serve as an alternative to currently existing therapies for infections by gram-positive organisms, including many resistant strains. The expected indication for use is treatment of complicated SSSIs due to gram-positive organisms.13,32,41 Additional potential indications include treatment of catheter-related bloodstream infections, for which dalbavancin already has shown efficacy in a clinical trial.40 Other potential indications include treatment of other serious gram-positive infections, such as endocarditis, osteomyelitis, pneumonia, and diabetic foot ulcers, although further supportive clinical data are needed. No information on the cost of dalbavancin is available. As a branded drug under patent by its parent pharmaceutical company, dalbavancin is expected to cost more than older drugs now available generically, such as vancomycin, yet to be priced competitively with existing agents with comparable indications that are still under patent, such as linezolid, quinupristin–dalfopristin, daptomycin, and tigecycline. At this writing, pharmacy acquisition costs are $52.53 for a 600-mg pre-mixed i.v. bag of linezolid, $156.57 for a 500-mg vial of quinupristin–dalfopristin, $214.90 for a 500-mg vial of daptomycin, and $63.20 for a 50-mg vial of tigecycline.49 Given the potential variations in the duration of treatment for different infections, in patient weight, in the cost of home infusion services, and in the number of i.v. doses needed before switching to oral antibiotics, comparing the potential costs of full treatment courses of dalbavancin and its competitor agents is beyond the scope of this article. When considering the pharmacoeconomics of dalbavancin use and its once-weekly, two-dose regimen, pharmacists should bear in mind that the potential advantages of convenience, improved adherence, and decreased consumption of hospital resources for i.v. treatment may help offset dalbavancin’s potentially high acquisition cost and provide other benefits over currently available treatments. Conclusion Dalbavancin is a lipoglycopeptide with enhanced activity against gram-positive bacteria and unique pharmacokinetics compared with existing drugs in its class. Studies have shown dalbavancin to be safe and efficacious for use against commonly encountered infections, including complicated skin infections and catheter-related bloodstream infections. References 1 Smith TL, Pearson ML, Wilox KR et al. Emergence of vancomycin resistance in Staphylococcus aureus. N Engl J Med . 1999 ; 340 : 493 –501. Crossref Search ADS PubMed 2 Archer GL, Climo MW. Antimicrobial susceptibility of coagulase-negative staphylococci. Antimicrob Agents Chemother . 2004 ; 38 : 2231 –7. 3 Applebaum PC. Antimicrobial resistance in Streptococcus pneumoniae: an overview. Clin Infect Dis . 1992 ; 15 : 77 –83. Crossref Search ADS PubMed 4 Morris JG, Shay DK, Hebden JN et al. Enterococci resistant to multiple antimicrobial agents, including vancomycin: establishment of endemicity in a university medical center. Ann Intern Med . 1995 ; 123 : 250 –9. Crossref Search ADS PubMed 5 Panlilio AL, Culver DH, Gaynes RP et al. Methicillin-resistant Staphylococcus aureus in U.S. hospitals. Infect Control Hosp Epidemiol . 1992 ; 13 : 582 –6. Crossref Search ADS PubMed 6 Hiramatsu K, Hanaki H, Ino T et al. Methicillin-resistant Staphylococcus aureus clinical strain with reduced vancomycin susceptibility. J Antimicrob Chemother . 1997 ; 40 : 135 –46. Crossref Search ADS PubMed 7 Anstead GM, Owens AD. Recent advances in the treatment of infections due to resistant Staphylococcus aureus. Curr Opin Infect Dis . 2004 ; 17 : 549 –55. Crossref Search ADS PubMed 8 Potoski BA, Adams J, Clarke L et al. Epidemiological profile of linezolid-resistant coagulase-negative staphylococci. Clin Infect Dis . 2006 ; 43 : 165 –71. Crossref Search ADS PubMed 9 Bonora MG, Solbiati M, Zorzi SE et al. Emergence of linezolid resistance in the vancomycin-resistant Enterococcus faecium multilocus sequence typing C1 epidemic lineage. J Clin Microbiol . 2006 ; 44 : 1153 –5. Crossref Search ADS PubMed 10 Cuevas O, Cercenado E, Vindel A et al. Evolution of the antimicrobial resistance of Staphylococcus spp. in Spain: five nationwide prevalence studies, 1986–2002. Antimicrob Agents Chemother . 2004 ; 48 : 4240 –5. Crossref Search ADS PubMed 11 Anastasiou DM, Thorne GM, Luperchio SA et al. In vitro activity of daptomycin against clinical isolates with reduced susceptibilities to linezolid and quinupristin/dalfopristin. Int J Antimicrob Agents . 2006 ; 28 : 385 –8. Crossref Search ADS PubMed 12 Hayden MK, Rezai K, Hayes RA et al. Development of daptomycin resistance in vivo in methicillin-resistant Staphylococcus aureus. J Clin Microbiol . 2005 ; 43 : 5285 –7. Crossref Search ADS PubMed 13 Pfizer Inc. Pfizer receives approvable letter from FDA for dalbavancin. http://mediaroom.pfizer.com/portal/site/pfizer/index.jsp?ndmViewId=news_view&newsId=20071221005672&newsLang=en (accessed 2008 Jan 29). 14 Sosio M, Stinchi S, Beltrametti F et al. The gene cluster for the biosynthesis of the glycopeptide antibiotic A40926 by Nonomuraea species. Chem Biol . 2003 ; 10 : 541 –9. Crossref Search ADS PubMed 15 Malabarba A, Goldstein BP. Origin, structure, and activity in vitro and in vivo of dalbavancin. J Antimicrob Chemother. 2005 ; 55 (suppl S2): ii15 –20. Crossref Search ADS PubMed 16 Beauregard DA, Williams DH, Gwynn MN et al. Dimerization and membrane anchors in extracellular targeting of vancomycin group antibiotics. Antimicrob Agents Chemother . 1995 ; 39 : 781 –5. Crossref Search ADS PubMed 17 Nagarajan R. Minireview: antibacterial activities and modes of action of vancomycin and related glycopeptides. Antimicrob Agents Chemother . 1991 ; 35 : 605 –9. Crossref Search ADS PubMed 18 Allen NE, LeTourneau DL, Hobbs JN et al. Hexapeptide derivatives of glycopeptide antibiotics: tools for mechanism of action studies. Antimicrob Agents Chemother . 2002 ; 46 : 2344 –8. Crossref Search ADS PubMed 19 Streit JM, Fritsche TR, Sader HS et al. Worldwide assessment of dalbavancin activity and spectrum against over 6,000 clinical isolates. Diagn Microbiol Infect Dis . 2004 ; 48 : 137 –43. Crossref Search ADS PubMed 20 Goldstein EJ, Citron DM, Warren YA et al. In vitro activities of dalbavancin and 12 other agents against 329 aerobic and anaerobic gram-positive isolates recovered from diabetic foot infections. Antimicrob Agents Chemother . 2006 ; 50 : 2875 –9. Crossref Search ADS PubMed 21 Jones RN, Fritsche TR, Sader HS et al. Antimicrobial spectrum and potency of dalbavancin tested against clinical isolates from Europe and North America (2003): initial results from an international surveillance protocol. J Chemother . 2005 ; 17 : 593 –600. Crossref Search ADS PubMed 22 Streit JM, Sader HS, Fritsche TR et al. Dalbavancin activity against selected populations of antimicrobial-resistant gram-positive pathogens. Diagn Microbiol Infect Dis . 2005 ; 53 : 307 –10. Crossref Search ADS PubMed 23 Pace JL, Yang G. Glycopeptides: update on an old successful antibiotic class. Biochem Pharmacol . 2006 ; 71 : 968 –80. Crossref Search ADS PubMed 24 Candiani G, Abbondi M, Borgonovi M et al. In-vitro and in-vivo antibacterial activity of BI 397, a new semisynthetic glycopeptide antibiotic. J Antimicrob Chemother . 1999 ; 44 : 179 –92. Crossref Search ADS PubMed 25 Lin G, Credito K, Ednie LM. Antistaphylococcal activity of dalbavancin, an experimental glycopeptide. Antimicrob Agents Chemother . 2005 ; 49 : 770 –2. Crossref Search ADS PubMed 26 Gales AC, Sader HS, Jones RN. Antimicrobial activity of dalbavancin tested against gram-positive clinical isolates from Latin America medical centres. Clin Microbiol Infect . 2005 ; 11 : 95 –100. Crossref Search ADS PubMed 27 Goosens H, Jabes D, Rossi R et al. European survey of vancomycin-resistant enterococci in at-risk hospital wards and in vitro susceptibility testing of ramoplanin against these isolates. J Antimicrob Chemother. 2003 ; 51 (suppl S3): iii5 –12. Crossref Search ADS PubMed 28 Johnson DM, Fritsche TR, Sader HS et al. Evaluation of dalbavancin in combination with nine antimicrobial agents to detect enhanced or antagonistic interactions. Int J Antimicrob Agents . 2006 ; 27 : 557 –60. Crossref Search ADS PubMed 29 Cavaleri M, Riva S, Valagussa A et al. Pharmacokinetics and excretion of dalbavancin in the rat. J Antimicrob Chemother. 2005 ; 55 (suppl S2): ii31 –5. Crossref Search ADS PubMed 30 Leighton A, Gottlieb AB, Dorr MB et al. Tolerability, pharmacokinetics, and serum bactericidal activity of intravenous dalbavancin in healthy volunteers. Antimicrob Agents Chemother . 2003 ; 48 : 940 –5. 31 Buckwalter M, Dowell AD. Population pharmacokinetic analysis of dalbavancin, a novel lipoglycopeptide. J Clin Pharmacol . 2005 ; 45 : 1279 –87. Crossref Search ADS PubMed 32 Seltzer E, Dorr MB, Goldstein BP et al. Once-weekly dalbavancin versus standard-of-care antimicrobial regimens for treatment of skin and soft-tissue infections. Clin Infect Dis . 2003 ; 37 : 1298 –303. Crossref Search ADS PubMed 33 Micromedex Healthcare Series. DRUGDEX evaluations: Vancomycin. www.thomsonhc.com.proxy-hs.researchport.umd.edu/hcs/librarian (accessed 2007 Mar 3). 34 Micromedex Healthcare Series. DRUGDEX evaluations: Teicoplanin. www.thomsonhc.com.proxy-hs.researchport.umd.edu/hcs/librarian (accessed 2007 Mar 3). 35 Dowell J, Seltzer E, Stogniew M et al. Dalbavancin (DAL) pharmacokinetics (PK) in subjects with mild or moderate hepatic impairment (HI). In: Proceedings of the 44th International Conference on Antimicrobial Agents and Chemotherapy. Washington, DC: American Society of Microbiology; 2004 :4. Abstract. 36 Dowell JA, Seltzer E, Krause R et al. The safety and pharmacokinetics of dalbavancin in subjects with renal impairment or end-stage renal disease. Clin Microbiol Infect. 2005 ; 11 (suppl 2): 272 . Abstract. 37 Dowell JA, Seltzer E, Stogniew M et al. Dalbavancin dosage adjustments not required for patients with mild renal impairment. Clin Microbiol Infect. 2003 ; 9 (suppl 1): 291 . Abstract. 38 Bowker KE, Noel AR, MacGowan AP. Pharmacodynamics of dalbavancin studied in an in vitro pharmacokinetics system. J Antimicrob Chemother . 2006 ; 58 : 802 –5. Crossref Search ADS PubMed 39 Jabes D, Candiani G, Romano G et al. Efficacy of dalbavancin against methicillin-resistant Staphylococcus aureus in the rat granuloma pouch model. Antimicrob Agents Chemother . 2004 ; 48 : 1118 –23. Crossref Search ADS PubMed 40 Raad I, Darouiche R, Vazquez J et al. Efficacy and safety of weekly dalbavancin therapy for catheter-related bloodstream infection caused by gram-positive pathogens. Clin Infect Dis . 2005 ; 40 : 374 –80. Crossref Search ADS PubMed 41 Jauregui LE, Babazadeh S, Seltzer E et al. Randomized, double-blind comparison of once-weekly dalbavancin versus twice-daily linezolid therapy for the treatment of complicated skin and skin structure infections. Clin Infect Dis . 2005 ; 41 : 1407 –15. Crossref Search ADS PubMed 42 Stevens DL, Herr D, Lampiris H et al. Linezolid versus vancomycin for the treatment of methicillin resistant Staphylococcus aureus infections. Clin Infect Dis . 2002 ; 34 : 1481 –90. Crossref Search ADS PubMed 43 Ellis-Grosse EJ, Babinchak T, Dartois N et al. The efficacy and safety of tigecycline in the treatment of skin and skin structure infections: results of 2 double-blind phase 3 comparisons with vancomycin-aztreonam. Clin Infect Dis . 2005 ; 41 : S341 –53. Crossref Search ADS PubMed 44 Arbeit RD, Maki D, Tally FP et al. The safety and efficacy of daptomycin for the treatment of complicated skin-structure infections. Clin Infect Dis . 2004 ; 38 : 1673 –81. Crossref Search ADS PubMed 45 Nichols RL, Graham DR, Barrierre SL et al. Treatment of hospitalized patients with complicated gram-positive skin and skin structure infections: two randomized, multicentre studies of quinupristin/dalfopristin versus cefazolin, oxacillin, or vancomycin. J Antimicrob Chemother . 1999 ; 44 : 263 –73. Crossref Search ADS PubMed 46 Nord CE, Rasmanis G, Wahlund E. Effect of dalbavancin on the normal intestinal microflora. J Antimicrob Chemother . 2006 ; 58 : 627 –31. Crossref Search ADS PubMed 47 Lexi-Comp Online. American Hospital Formulary Service drug information: vancomycin. http://online.lexi.com/crlsql/servlet/crlonline (accessed 2007 Mar 31). 48 Dorr MB, Jabes D, Cavaleri M et al. Human pharmacokinetics and rationale for once-weekly dosing of dalbavancin, a semi-synthetic glycopeptide. J Antimicrob Chemother. 2005 ; 55 (suppl S2): ii25 –30. Crossref Search ADS PubMed 49 McKesson Supply Management Online. https://supply.mckesson.com/portal/site/smoportal/template.LOGIN (accessed 2007 Aug 29). Copyright © 2008, American Society of Health-System Pharmacists, Inc. All rights reserved.
TI - Dalbavancin: A new lipoglycopeptide antibiotic
JF - American Journal of Health-System Pharmacy
DO - 10.2146/ajhp070255
DA - 2008-04-01
UR - https://www.deepdyve.com/lp/oxford-university-press/dalbavancin-a-new-lipoglycopeptide-antibiotic-6cEWUogbOI
SP - 599
VL - 65
IS - 7
DP - DeepDyve
ER -