Pharmacodynamic (PD) of Posaconazole (P) in a Murine Invasive Pulmonary Aspergillosis (IPA) Model Against Wild Type and Cyp51 mutant Isolates

Ref ID: 18687

Author:

A. Lepak, MD – Fellow, K. Marchillo, . – Res Assistant, J. VanHecker, . – Res Assistant, D. R. Andes, MD – Professor;

Author address:

Univ. of Wisconsin, Madison, WI.

Full conference title:

52nd Annual ICAAC

Date: 9 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 pharamcodynamic target of the triazole, posaconazole. 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. Infection was induced by nasal inoculation and aspiration of conidia. P dose ranged from 0.156-160 mg/kg/24h 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. The sigmoid Emax was used to model the exposure response data. We determined the P exposure needed for net stasis (SD) and 1-log kill for wild type and resistant isolates. Results: At the start of therapy mice had 5.59 ± 0.19 log10 C.E./ml. Lung burden increased to 7.11 ± 0.29 log10 C.E./ml in controls. A 3-log reduction was observed for 3 of 4 wild-type strains and 1 of 3 Cyp51 mutants over the dose range. 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 0.79). There were no significant differences in SD or 1-log kill AUCf/MIC endpoint between wild-type and Cyp51 mutants (p=0.21). Conclusions: Similarity in PD target in organisms with and without Cyp51 mutations suggests that drug exposure and MIC are the critical predictor of outcomes. The triazole PD magnitude is surprisingly, markedly lower for invasive aspergillosis than for invasive candidiasis in this murine model. Consideration of human PK and current P regimens would predict effectiveness against Aspergillus isolates with MICs as high as 0.5 and 0.25 mg/L for stasis and 1 log kill endpoints, respectively.

Abstract Number: A-1932

Conference Year: 2012

Link to conference website: NULL

New link: NULL

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