Download Daptomycin I. ANTIBIOTIC CLASS: Lipopeptide II. STRUCTURE

Daptomycin I.
ANTIBIOTIC CLASS: Lipopeptide II.
STRUCTURE & CHEMISTRY: Daptomycin consists of a 13-­‐member amino acid peptide linked to a 10-­‐carbon lipophilic tail. It has a molecular mass of 1620.67 (comparisons – vancomycin 1485.71; penicillin 334.39). The core of the molecule is anionic but, on forming complexes with Ca++, the net charge becomes positive. J Antimicrob Chemother 2005; 55:283-­‐8. III.
SPECTRUM OF ACTIVITY: Gram positive organisms, including VRE and MRSA. IV.
MECHANISM OF ACTION: The net positive charge of the molecule resulting from complexation with Ca++ allows electrostatic interaction with negatively charged (at least in part to negatively charged phospholipids, bacterial cell membranes. This results in disruption of cell membrane function with K+ efflux and membrane depolarization, secondary inhibition of DNA and protein synthesis, and rapid cell death. V.
MECHANISM OF RESISTANCE: A. Enterococcus: • In vitro1: increased surface charge & cell wall thickness, decreased daptomycin-­‐induced depolarization • In vitro2: ◦ ΔEF0631 – putative cardiolipin synthase • In vivo3: ◦ ΔliaF – predicted member of 3 component regulatory system involved in stress-­‐sensing response of cell envelope to antibiotics ◦ ΔgdpD – encodes glycerophosphoryl diester phosphodiesterase • In vivo4: ◦ Small colony variants 1. Steed et al. AAC 2011; 55:4748-­‐54. 2. Palmer et al. AAC 2011; 55:3345-­‐56. 3. Arias et al. NEJM 2011; 365:892-­‐900. 4. Wellinghausen et al. JCM 2009; 47:2802-­‐11. B. Staphylococcus aureus: • Mutations in phospholipid synthesis genes, including mprF, cardiolipin synthase (cls2) and CDP-­‐diacylglycerol-­‐glycerol-­‐3-­‐phosphate 3-­‐phosphatidyltransferase (pgsA) genes. Increase in membrane lysyl phosphatidylglycerol and in cell wall thickness.1 1. PLoS 2012; 7(1):e28316. VI.
PHARMACOKINETICS A. Distribution • Protein binding, primarily albumin: 90% to 93% • Protein binding, renal impairment: 83.5% to 87.6% • Vd: 0.1 L/kg [9] • Vd, endocarditis and bacteremia: 0.21 L/kg • Vd, renal impairment: 0.12 to 0.20 L/kg B. Excretion •
•
•
•
•
•
•
VII.
Renal clearance: 0.05 to 0.1 mL/min/kg Renal: 78% Fecal: 5.7% Dialyzable: Yes (hemodialysis), 15% over 4 hr; Yes (peritoneal), 11% over 4 hr Total body clearance: 8.3 to 9.1 mL/hr/kg Total body clearance, renal impairment: 5.9 to 9.9 mL/hr/kg Total body clearance, hemodialysis and continuous ambulatory peritoneal dialysis: 3.7 mL/hr/kg C. Elimination Half Life • 7.7 to 8.3 hr • Severe renal impairment (CrCl less than 30 mL/min), 27.83 hr • Hemodialysis and continuous ambulatory peritoneal dialysis, 19.4 to 45.5 hr PHARMACODYNAMICS: Daptomycin is rapidly bactericidal with concentration-­‐dependent killing (AUC0-­‐24)/MIC and Cmax/MIC. In a neutropenic mouse model, the peak/MIC ratios required for a bacteriostatic effect ranged from 12 to 36 for S. pneumoniae, 59 to 94 for S. aureus, and 0.14 to 0.25 for E. faecium. The AUC/MIC ratios needed for a bacteriostatic effect ranged from 75 to 237 for S. pneumoniae, 388 to 537 for S. aureus, and 0.94 to 1.67 for E. faecium1. Its post-­‐antibiotic effect lasts 4.8 to 10.8 hours. Daptomycin’s antibacterial activity is inhibited by interaction with pulmonary surfactant and is not effective in the treatment of pneumonia (although it is effective in the treatment of hematogenous pneumonia in murine models). Antimicrob Agents Chemother 2004; 48:63-­‐8. VIII.
IX.
INDICATIONS: A. FDA-­‐approved indications: • Bacteremia associated with intravascular line • Bacteremia due to Staphylococcus aureus, Including right-­‐sided endocarditis • Infection of skin AND/OR subcutaneous tissue, Complicated APPROVED USES AT STANFORD: A. ID consult STRONGLY RECOMMENDED (but not required) for the following indications: 1. Complicated skin and skin structure infections or bacteremia due vancomycin resistant gram-­‐
positive organisms WHEN OTHER ANTIBIOTICS NOT ACTIVE. 2. Treatment of MRSA endocarditis or MRSA bacteremia with suspected endocarditis with vancomycin MIC >1.5 mcg/ml; treatment of persistent MRSA bacteremia despite vancomycin therapy B. ID consult required for all other indications X.
XI.
SIGNFICANT ADVERSE EFFECTS: • Myopathy • eosinophilic pneumonia INTERACTIONS: • No PK interactions reported, but coadministration of HMG-­‐CoA reductase inhibitors (statins) may increase the risk of myopathy. XII.
MONITORING: Weekly CPK XIII.
DOSING: INDICATION CRCL >30 Skin and/or Skin Structure Infection (Complicated) Bacteremia, right-­‐sided native valve endocarditis (MRSA or MSSA) Unlabeled dosing for resistant organisms/severe infection DOSING CRCL <30 HEMODIALYSIS 4 mg/kg q24h 4 mg/kg q48h 4 mg/kg q48h 6 mg/kg q24h 6 mg/kg q48h 6 mg/kg q48h 8–12 mg/kg q24h 8–12 mg/kg q48h 8 – 12 mg/kg q48h XIV.
COST: Antibiotic Adult Daptomycin Vancomycin Linezolid Linezolid Telavancin Clindamycin Clindamycin Ceftaroline 8 mg/kg IV QD 15-­‐20 mg/kg IV Q8-­‐12 600 mg IV Q12 600 mg PO Q12h 10 mg/kg IV QD 600 mg IV Q8 600 mg PO Q12 600 mg IV Q12H Drug Acquisition (cost of therapy per day in 70 kg patient) 570.52 15.38 to 23.07 217.68 189.36 181.43 (not available) 38.31 25.54 82.96 CVVHD 4–6 mg/kg Q24H or 8 mg/kg Q48H -­‐