Efficacy of azoles against various clinical Aspergillus fumigatus isolates with cyp51A mutations

E.M. Mavridou1, R.J. Brüggemann1, W.J.G. Melchers1, J.W. Mouton2, P.E. Verweij1

Author address: 

1Radboud University Nijmegen Medical Center, NIJMEGEN, The Netherlands 2Canisius Wilhelmina Hospital, NIJMEGEN, The Netherlands


Introduction: Azole resistance in Aspergillus fumigatus (Af) has been associated with substitutions in the cyp51A gene. These substitutions cause different susceptibility profiles and it is unclear if the in vitro activity corresponds with in vivo efficacy. We investigated the correlation between in vitro activity of posaconazole (POS) and voriconazole (VCZ) against clinical Af isolates with L98H, G54W, and M220I substitutions and in vivo survival. Methods: In vitro activity of VCZ and POS was determined based on the CLSI M-38A method. A total of 36 groups (n=11/group) of CD-1 mice, were randomized into 8 groups for the 4 different Af isolates and were infected i.v. Oral therapy with VCZ at 80, 40, and 10 mg/kg and with POS at 128, 64, 16 and 4 mg/kg once daily was begun 24 hours post challenge for 14 days. Control groups received saline orally. Mortality data was analyzed by the long rank test. Survival was determined on day 14. Additional 48 groups (n=3/group) have been used to determine the pharmacokinetics (PK). PK index was determined in infected animals by collecting plasma at day 2 of treatment through the orbital vein at 8 different time points. Results were analyzed by survival curve analysis and plotting PD indices against survival and fitting the Hill equation with variable slope (HEVS) using Prism 5.0. Results: The MICs of POS were: 0.031 mg/L (WT), 0.5 mg/L (M220I and L98H) and >16 mg/L (G54W). For POS the AUC was strongly correlated with dose in a linear fashion from 1 to 16 mg/kg (r2 = 0.99). However, higher dosages of 64 mg/kg resulted in a slightly less linear relation (r2= 0.92). Survival curves indicated that exposure responses were obtained for all 4 strains, with increasing exposure needed to obtain the same result if the MIC was higher. Survival best correlated with AUC/MIC ratio; an AUC/MIC - survival plot of all four strains indicated a clear sigmoid exposure-response. The HEVS fitted the data well with a R2 of 0.93. The ED50 was 321 (95% CI 222.1 - 573.8). The AUC - dose correlation of POS is linear for dosages up to 16 mg/kg. In case of VCZ the MICs were: 0.25 mg/L (WT, M220I), 0.125 mg/L (G54W) and 2 mg/L (L98H).VCZ treatment improved survival of the L98H M220I and G54W groups compared to controls (p

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Full conference title: 

4th Trends in Medical Mycology
    • TIMM 4th (2012)