Pharmacy and Therapeutics - January 2008 - (Page 43) DRUG FORECAST action with the bacterial cell wall contributes to dalbavancin’s pharmaco kinetic and pharmacodynamic properties, specifically its extended half-life. follows primarily nonrenal clearance.17 Therefore, dose adjustments in patients with renal disease do not seem to be necessary. Data are limited in terms of hepatic impairment and dose adjustments. In one trial, Pope and Roecker noted no differences in the terminal half-life between patients with mild, moderate, and severe liver disease and participants with normal hepatic function.21 methicillin-susceptible coagulase-negative streptococci (MSCNS), methicillinresistant CNS (MRSCNS), and vancomycin-intermediate CNS (VICNS).24–34 Dalbavancin has in vitro activity against streptococci that are both susceptible and resistant to erythromycin and penicillin.26,28,29,31,34 In tests of vancomycin-susceptible and vancomycin-resistant enterococci (VRE) in vitro, dalbavancin displayed activity against susceptible and resistant strains that possessed vanB and vanC genes but not vanA phenotypes of VRE.21 Goldstein BP, et al.24 PHARMACOKINETICS Leighton et al. evaluated multiple daily doses of dalbavancin, ranging from a loading dose of 300 to 1,000 mg, followed by 30 to 100 mg, administered via a 30minute intravenous (IV) infusion.15 The peak concentration (C max) and areaunder-the-curve (AUC0–24 hours) concentration increased proportionally and linearly in relation to the dose. The half-life ranged from 185 to 213 hours, supporting once-weekly administration. In the single-dose part of this trial, the volume of distribution (Vd) ranged from 7 to 13 liters. In another study of human volunteers, Dorr et al. reported similar pharmacokinetic parameters.16 The average terminal elimination half-life of dalbavancin was 170 ± 18.6 hours (seven days), and the Vd was 9.7 ± 2 liters. Studies have shown that dalbavancin is highly protein-bound to albumin (93%), in contrast to vancomycin (30%–55%) and linezolid (31%).17–19 In addition, dalbavancin achieved up to 60% penetration into the blister fluid following a 1,000-mg single IV dose in human healthy volunteers, suggesting good tissue penetration.17 Dalbavancin does not seem to undergo hepatic biotransformation with the cytochrome CYP 450 enzyme system.20 Approximately 40% of the drug is excreted unchanged in the urine, indicating that it PHARMACODYNAMICS Dalbavancin’s concentration in the macrophages is predictive of its intracellular penetration. In mouse models of thigh infection, large, infrequent doses were more ef ficacious than multiple doses.21 Dalbavancin demonstrated concentration-dependent killing because the ratio of Cmax to minimum inhibitory concentration (MIC90) and the AUC:MIC ratio were more predictive of bactericidal activity rather than the time above the MIC.17,21 Other analyses revealed similar results of concentration-dependent eradication by dalbavancin; in contrast, vancomycin causes time-dependent, concentration-independent killing.22,23 ANTIMICROBIAL ACTIVITY IN VITRO Gram-Positive Organisms Dalbavancin is active against methicillinsusceptible S. aureus (MSSA), MRSA, vancomy cin-intermediate S. aureus (VISA), vancomycin-resistant S. aureus (VRSA), and linezolid-resistant S. aureus.24–27 In vitro, dalbavancin also inhibits Goldstein and colleagues tested the bactericidal activity of dalbavancin in vitro against S. aureus (MSSA, MRSA, VISA), S. pyogenes, E. faecalis, and E. faecium isolates from various hospitals in the U.S. In every case, dalbavancin had lower MICs and minimum bactericidal concentrations (MBCs) than vanco mycin and teicoplanin (Table 1). The potential for the development of staphylococci resistance was tested by direct selection and serial passages of microorganisms through various concentrations of dalbavancin, including 0.5x, 1x, 2x, 4x, and 8x the initial broth microdilution MIC. After retesting isolates that were grown on drug-free media for three days, the investigators found that MICs were equal to or within one doubling dilution of the original MICs. This suggests that both tests failed to produce mutants with decreased susceptibility to dalbavancin. Table 1 Minimum Inhibitory Concentration (MIC) and Minimal Bacterial Concentration (MBC) of Dalbavancin,Vancomycin, and Teicoplanin Dalbavancin Isolate MIC (mcg/mL) MBC (mcg/mL) 0.06–1 0.06–0.5 2 0.03–0.25 0.008–0.25 0.008 4–8 2 Vancomycin MIC MBC (mcg/mL) (mcg/mL) 1 1–2 1 1 8 8 1–4 2–>32 0.5 0.5–>2 0.5 0.5 0.25 16 32 0.06–0.5 0.03 >32 16–>32 MSSA 0.06 MRSA 0.06 VISA 1 MRCNS 0.03–0.12 Streptococcus pyogenes (erythromycin-susceptible) 0.008 S. pyogenes (erythromycin-resistant) 0.008 Enterococcus faecalis (vancomycin-susceptible) 0.03–0.06 0.015–0.03 E. faecium (vancomycin-susceptible) MRSA = methicillin-resistant S. aureus; MSSA = methicillin-susceptible S. aureus; VISA = vancomycin-intermediate S. aureus; MRCNS = methicillin-resistant coagulase-negative staphylococci. Vol. 33 No. 1 • January 2008 • P&T® 43
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