Impact of Candida species on the Isavuconazole (ISA) Pharmacodynamic (PD) Target in an in vivo Neutropenic Murine Model of Invasive Candidiasis (IC)

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

Author address: 

Univ. of Wisconsin, Madison, WI; Univ. of Iowa, Madison, WI

Abstract: 

Background: Isavuconazole (ISA) is a potent and broad-spectrum triazole. PD studies with echinocandins demonstrated species specific differences. The triazole PD target has not been examined for non-albicans Candida. The goal of the current study was to determine the PD magnitude associated with efficacy in treatment of invasive C. albicans (CA), C. tropicalis (CT), and C. glabrata (CG)infection.Methods: 5 clinical CA, 1 CT, and 2 CG isolates were selected based on fitness and varying triazole resistance. MICs were determined using CLSI M27-A3 methods. The neutropenic murine disseminated candidiasis model was used. Serum pharmacokinetics (PK) were determined in mice given 10, 40, 160, and 640 mg/kg of the prodrug (Isavuconazonium sulfate) by oral gavage. ISA treatment regimens included 6 two-fold increasing dose levels (20 to 320 mg/kg) of the prodrug administered q12 h. Animals were treated for either 24 or 96 h, after which animals were sacrificed and kidneys were harvested for fungal burden determination. ISA exposure response data was modeled using a sigmoid Emax model. The ED50 was utilized as the treatment endpoint. Results: MICs varied 32-fold. PK was linear over the dose range and protein binding was 99%. The ISA dose response relationship was well described by the Emax model using the AUC/MIC index to express drug exposure (R2of 0.89). The fAUC/MIC values associated with the ED50 endpoint for CA was near 50 and was lower for the 96h compared to the 24h treatment duration. The mean and median values are similar to those described for other triazoles in this model. However, the AUC/MIC target for the 3 non-albicans strains was markedly lower than for CA (p=0.04) Conclusions: 1] The PD target of ISA against CA strains is similar to other triazoles, including those that are resistant to fluconazole. 2] The PD target for two common nonalbicans species was more than 10-fold lower than for CA. These PD results should be helpful in determination of initial susceptibility breakpoints.
2013

abstract No: 

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Full conference title: 

53rd Interscience Conference on Antimicrobial Agents and Chemotherapy
    • ICAAC, 53rd (2013)