Pharmacodynamics (PD) of Isavuconazole (Isav) in a Murine Invasive Pulmonary Aspergillosis (IPA) Model Against Wildtype (WT) and Cyp51 mutants

Ref ID: 19288

Author:

A. Lepak, K. Marchillo, J. Van Hecker, D. R. Andes

Author address:

Univ. of Wisconsin, Madison, WI

Full conference title:

53rd Interscience Conference on Antimicrobial Agents and Chemotherapy

Date: 10 September 2014

Abstract:

Background: Aspergillus active azoles are first line therapy for IPA. However, azole resistance is increasing and threatens treatment utility. The goal of the current study was to identify the PD target of the novel triazole, Isav. Methods: A neutropenic and corticosteroid treated murine model of IPA was utilized. A. fumigatus strains consisted of 4 wild-type and 6 Cyp51 mutants. MICs were determined by CLSI M38 methods. Pulmonary infection was induced by nasal inoculation and aspiration of conidial suspension. Isav dose ranged from 40-640 mg/kg/12h given by oral gavage. Study duration was 7 days. Drug efficacy was determined by qPCR of lung homogenates and standardized to conidial equivalents (C.E.). Dose and associated AUC/MIC were used to estimate drug exposure using both total and unbound concentrations. The sigmoid Emax model was used to evaluate the exposure response data. We determined the Isav exposure needed for net stasis (SD) and 1-log kill for each strain. Results: MICs varied from 0.125-8 mg/L. At the start of therapy mice had 4.9 ± 0.33 log10 C.E./ml. Lung burden increased to 6.82 ± 0.51 log10 C.E./ml in controls. A killing endpoint was observed for all of the strains with MICs of 8804;1.0 mg/L. Therapy was ineffective for strains with MICs of 2, 4, or 8 mg/L. The SD, 1-log kill dose, and associated AUCf/MIC are shown below. The exposure-response relationship
between AUCf/MIC and fungal burden was strong (R2 0.75).
There were no significant differences in AUCf/MIC endpoint
between wild-type and Cyp51 mutants (p=0.18). Conclusions: Similarity of the PD target in organisms with
and without Cyp51 mutations suggests that drug exposure
and MIC are the critical predictors of outcomes. The Isav
PD magnitude was 10-fold lower for invasive aspergillosis
than for invasive candidiasis in this murine model. Efficacy
in this model was observed against strains with MICs as
high as 1 mg/L which encompasses >90% of clinical
isolates.

Abstract Number: NULL

Conference Year: 2013

Link to conference website: NULL

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