Early prediction of dose-response and PK/PD relationships of antifungals by quantitative measurement of tissue burden using real-time quantitative PCR in an animal model of invasive aspergillosis

S. Seyedmousavi*, W. Melchers, J. Bakkers, P. Verweij, J. Mouton

Author address: 

(Nijmegen, NL)

Abstract: 

Objectives: Experimental models of invasive aspergillosis (IA) have been used to explore pharmacokinetic and pharmacodynamic (PK/PD) properties of antifungal agents. Survival is still considered the most reliable effect measure to determine exposure-response. We here study the feasibility of quantitative PCR (qPCR) to measure fungal load in target tissues for early assessment of antifungals efficacy in an experimental model of IA. Methods: We studied in vivo pharmacokinetics and antifungal efficacy of voriconazole (VCZ) vs. anidulafungin (AFG) in an immunocompetent model of Aspergillus fumigatus (AF) infection (VCZ-susceptible and VCZ-resistant isolates). Groups of 17 mice were randomized for doses regimens of 2.5, 5, 10 and 20 mg/kg/body weight. Therapy was started 24 hour after fungal inoculation for seven consecutive days, once daily intraperitoneally. The therapeutic efficacy was investigated using animal survival at 7 and 14 days postinfection, compared to the decrease in tissues fungal burden at 48 and 72 hour postchallenge, utilizing real-time qPCR targeting the 28s region of AF. Kidneys were collected from three treated and three control mice at each timepoint and also from all surviving mice at the end of the experiment. Results: The mean number of genome copies detected in untreated animals was 3 · 104 in kidneys (n = 3, range = 1 · 103-2 · 105) at days 2 and 3 post infection. There was a mean 2-3 log10 (n = 3, range = 1 · 102-2 · 104) reduction of AF genome copies in infected animals treated with highest dosage of VCZ (100% survival at days 7 and 14). A stronger correlation between 7 days survival and qPCR was observed at day 3 post infection (r2 = 0.90, p = 0.01) compared to day 2 (r2 = 0.84, p = 0.02). Survival due to AFG therapy maximized at 72% and qPCR showed a significantly lower reduction (1-2 log10, p
2012

abstract No: 

P750

Full conference title: 

22nd European Congress of Clinical Microbiology and Infectious Diseases
    • ECCMID 22nd (2012)