798. Pharmacodynamic (PD) Activity of Dalbavancin against VISA Staphylococcus aureus (SA) isolates in the Neutropenic Murine Thigh Infection Model
Session: Poster Abstract Session: Antimicrobial Agents: PK/PD Studies
Friday, October 9, 2015
Room: Poster Hall
Posters
  • Dalbavancin ICAAC POSTER.pdf (136.1 kB)
  • Background: Dalbavancin is a novel lipoglycopeptide with activity against SA, including beta-lactam resistant isolates, and is currently approved for use in acute bacterial skin and skin structure infections.  Previous studies examined the PD target against a group of SA isolates with a relatively low and narrow MIC range.  The aim of this study was to examine the PD targets for a group of isolates with dalbavancin MICs above that observed in typical wild-type populations. Methods: 7 clinical isolates of SA, including 5 vancomycin-intermediate isolates, were selected for in vivo study.  MICs were determined using CLSI methods.  A neutropenic murine thigh infection model was utilized for all treatment studies.  Treatment outcome was measured by determining organism burden in the thigh (CFU) at the end of each experiment (144 h).  Dosing was by intra-peritoneal (IP) route for all studies.  Serum pharmacokinetics were determined after IP administration of 2.5, 10, 40, 80, and 160 mg/kg by LC/MS-MS.  Treatment studies were performed using 2-fold increasing doses from 2.5-160 mg/kg/12 h.  The PK/PD index AUC/MIC was examined using the Hill sigmoid Emax exposure-response model.  The PK/PD target AUC/MIC was determined for net stasis, 1-log kill, and 2-log kill.  Results: MICs to dalbavancin were 0.12-0.5 mg/L.  IP administration resulted in linear PK over the dose range.  The drug exposure-response model was well described by the PD index AUC/MIC (R2=0.86).  A 1-log and 2-log kill was achieved against 6 and 7 of the isolates.  The mean 24 h total dose and PD target free drug AUC/MIC for net stasis, 1-log kill and 2-log kill for all isolates are listed in the table below.

    Endpoint

    24 h dose (mg/kg)

    24 h free drug AUC/MIC

    Net Stasis

    14.4

    27.1

    1-log kill

    29.9

    53.3

    2-log kill

    61.1

    111.1

    Conclusion: Dalbavancin PD stasis and killing targets were achieved against this group of glycopeptide-resistant SA isolates at dose levels that correspond to clinically achievable exposures.  Translation of  this data suggests the current human dosing regimen could achieve a 1-log kill for SA strains with dalbavancin MICs of ≤1 mg/L.  Modification of clinical breakpoints should be considered based on this PD study and additional clinical data.

    Alexander Lepak, MD, Medicine, University of Wisconsin, Madison, WI and David Andes, MD, FIDSA, University of Wisconsin, Madison, WI

    Disclosures:

    A. Lepak, None

    D. Andes, None

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