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

Ref ID: 17734

Author:

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

Author address:

(Nijmegen, NL)

Full conference title:

22nd European Congress of Clinical Microbiology and Infectious Diseases

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 < 0.05). The relationship between reduction in tissue burden at day 3 postinfection and 7 days survival were similar for VCZ-susceptible and VCZ-resistant isolates with highest dosage of VCZ (r2 = 0.90 vs. R2 = 0.95, p < 0.05).

Abstract Number: P750

Conference Poster: y

Conference Year: 2012

Link to conference website: NULL

New link: NULL

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