Exposure-response relationship after prophylaxis with posaconazole in a rat model of invasive pulmonary aspergillosis

Ref ID: 19194

Author:

E. Cendejas-Bueno, A. Forastiero, J. Gavaldá, C. Orbegozo, E. Mellado, Y. Meije, I. Ruiz, A. Gomez-Lopez

Author address:

Majadahonda, Barcelona, ES

Full conference title:

23rd European Congress of Clinical Microbiology and
Infectious Diseases

Date: 27 April 2014

Abstract:

Background: Analyses of drug exposure and response play an important role in antifungal management, providing evidence of effectiveness. In the context of prophylactic use of posaconazole (PSC) (recommended use) scant number of data has contributed to controversial information.
Objectives: The aim of this study was to evaluate the efficacy of PSC as prophylaxis in a steroid-immunosuppressed murine model of invasive pulmonary aspergillosis.
Methods: For this purpose two different strains of Aspergillus fumigatus, differing on PSC susceptibility (CM-237, MICPOS= 0.06mg/L; CM-2266 MICPOS=>8 mg/L) were included. Cortisone immunosuppressed female Wistar rats were administered a prophylactic regimen of PSC (24 mg/kg) by oral gavage, 2 days prior to infection (via tracheotomy, size 2×106 conidia/animal) and was subsequently administered at -1, 0, 1, 2, 3 and 4 days postchallenge (seven doses). Groups of three animals were sacrificed at prefixed time points (2, 6, 8, 24 hs after the 4th dose and 2, 6 and 8 hs after the 7th dose) and posaconazole serum concentration was quantified by HPLC-UV. Response was evaluated by direct measurement of fungal burden in lungs (Real Time-PCR) and indirectly by galactomannan (GM) index in serum (Platelia Aspergillusâ„¢).
Results: PSC exposure, expressed as AUC0-80hs and calculated between the 4th and 7th doses remained similar regardless of the infecting strain (266 vs 269 h.mg/L). Slightly higher serum concentrations were observed after the 7th dose of PSC (PSC average 4th dose, 3.66 mg/L¸ PSC avg 7th dose, 3.99 mg/L). However, PSC response showed great differences between strains. Fungal burden and GM index increased significantly from 5.80 to 20.0 pgDNA/gr of tissue and 0.47 to 6.97 respectively in treated rats infected with less susceptible strain (CM-2266) during the observed period (4th-7th dose). Fungal burden and GM index decreased or remained constant in treated rats infected with the susceptible strain (from 1.70 to 0.45 pg/gr of tissue and 0.51 to 0.34 respectively).
Conclusions: 1) This model provided a valuable strategy by which PSC exposure-response relationships may be evaluated. 2) PSC was more effective as prophylaxis against Aspergillus infection caused by azole susceptible strains. 3) Further studies are needed to better define whether infections with an azole-resistant strains could still be prevented with PSC.

Abstract Number: P1085

Conference Year: 2013

Link to conference website: http://registration.akm.ch/einsicht.php?XNABSTRACT_ID=164550&XNSPRACHE_ID=2&XNKONGRESS_ID=180&XNMASK

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