1948. Comparative In vivo Pharmacokinetics/Pharmacodynamics of Telavancin and Vancomycin in the Neutropenic Murine Thigh Infection Model Against Staphylococcus aureus
Session: Poster Abstract Session: Antimicrobial Pharmacokinetics and Pharmacodynamics
Saturday, October 29, 2016
Room: Poster Hall
Posters
  • Lepak(Andes) telavancin neutropenic thigh model ID Week poster Final.pdf (139.2 kB)
  • Background: Telavancin (TLV) is a lipoglycopeptide with potent activity against S. aureus (SA), including beta-lactam resistant isolates. The aim of this study was to examine the PD targets of TLV against SA in the neutropenic murine thigh model and compare those targets to vancomycin (VAN).

    Methods: Four clinical isolates of SA (1 MSSA, 2 MRSA, 1 MRSA/VISA) were used. MICs were determined using current CLSI methods. The neutropenic murine thigh infection model was used for all treatment studies. Treatment outcome was determined by organism burden in the thigh (CFU) at the end of each experiment (24 h). Dosing was by subcutaneous (SC) route. Plasma PK of TLV and VAN were determined after administration of 1.25, 5, 20, and 80 mg/kg. Drug exposure-response studies were performed with each isolate for both drugs. Five total doses were studied (range 1.25 to 320 mg/kg/24) and were fractionated into 6-hourly dosing regimens. The PD index 24 h AUC/MIC was used for all analyses. The correlation between treatment efficacy and AUC/MIC was determined by nonlinear least-squares multivariate regression using the Hill equation. The AUC/MIC exposure associated with net stasis and 1-log kill (when achieved) were determined.

    Results: MICs to TLV were 0.06-0.25 mg/L and to VAN 1-4 mg/L. SC administration resulted in linear PK over the dose range for both drugs. Stasis endpoints were achieved against all strains for both drugs; however, a 1-log kill was achieved in 3 of 4 strains for TLV but only against a single strain for VAN. The drug exposure-response model was well described by the PD index AUC/MIC (TLV R2=0.85, VAN R2=0.86). The mean 24 h total dose and PD target free drug AUC/MIC for net stasis and 1-log kill for all isolates are listed in the table.

    Drug

    Endpoint

    24 h dose (mg/kg)

    24 h fAUC/MIC

    TLV

    Stasis

    39

    83

    TLV

    1-log kill

    74

    215

    VAN

    Stasis

    192

    97

    VAN

    1-log kill

    NA*

    NA*

    *not achieved

    Conclusion: TLV exhibits dose-dependent in vivo activity against SA in the neutropenic murine thigh model. AUC/MIC was a robust predictor of treatment efficacy. Static and killing endpoints were numerically lower for TLV compared to VAN and were achieved at relatively modest AUC/MIC targets. The current dosing regimen of TLV would be expected to meet or exceed 1-log kill AUC/MIC exposures identified in this study.

    Alexander J. Lepak, M.D.1, Miao Zhao, MS1, Karen Marchillo, MLT2, Jamie Vanhecker, CVT2, Jennifer I. Smart, PhD3, Jon Bruss, MD, MSPH, MBA3 and David R. Andes, M.D., FIDSA4, (1)Medicine, University of Wisconsin, Madison, WI, (2)University of Wisconsin and VA Hospital, Madison, WI, (3)Theravance Biopharma US, Inc., South San Francisco, CA, (4)University of Wisconsin School of Medicine and Public Health, Madison, WI

    Disclosures:

    A. J. Lepak, None

    M. Zhao, None

    K. Marchillo, None

    J. Vanhecker, None

    J. I. Smart, Theravance: Employee , Salary

    J. Bruss, Theravance: Employee , Salary

    D. R. Andes, Theravance: Grant Investigator , Research grant

    Findings in the abstracts are embargoed until 12:01 a.m. CDT, Wednesday Oct. 26th with the exception of research findings presented at the IDWeek press conferences.