Correlation between triazole treatment history and susceptibility in clinically isolated Aspergillus fumigatus

Abstract

This is the first report of a detailed relationship between triazole treatment history and triazole MICs for 154 Aspergillus fumigatus clinical isolates. The duration of itraconazole dosage increased as the itraconazole MIC increased, and a positive correlation was observed (r = 0.5700, P < 0.0001). The number of itraconazole-naïve isolates dramatically decreased as the itraconazole MIC increased, particularly for MICs exceeding 2 μg/ml (0.5 μg/ml versus 2 μg/ml, P = 0.03). We also examined the relationship between cumulative itraconazole usage and the MICs of other azoles. A positive correlation existed between itraconazole dosage period and posaconazole MIC (r = 0.5237, P < 0.0001). The number of itraconazole-naïve isolates also decreased as the posaconazole MIC increased, particularly for MICs exceeding 0.5 μg/ml (0.25 μg/ml versus 0.5 μg/ml, P = 0.004). Conversely, the correlation coefficient obtained from the scattergram of itraconazole usage and voriconazole MICs was small (r = -0.2627, P = 0.001). Susceptibility to three triazole agents did not change as the duration of voriconazole exposure changed. In addition, we carried out detailed analysis, including microsatellite genotyping, for isolates obtained from patients infected with azole-resistant A. fumigatus. We confirmed the presence of acquired resistance to itraconazole and posaconazole due to a G54 substitution in the cyp51A gene for a patient with chronic pulmonary aspergillosis after oral itraconazole therapy. We should consider the possible appearance of azole-resistant A. fumigatus if itraconazole is used for extended periods.

Fig 1

Relationship between itraconazole MICs and the history of itraconazole usage for 154 A. fumigatus clinical isolates. (A) The itraconazole dosage duration increased as the itraconazole MIC increased, and a positive correlation was observed between the itraconazole dosage duration and the itraconazole MIC (r = 0.5700, P < 0.0001). (B) The number of itraconazole-naïve isolates dramatically decreased as the itraconazole MIC increased, particularly for itraconazole MICs exceeding 2 μg/ml (0.5 μg/ml versus 2 μg/ml, P = 0.03). *, P < 0.05 (Fisher's exact test).

Fig 2

Relationship between the MICs of other triazoles and the history of itraconazole usage for the 154 A. fumigatus clinical isolates. (A) A positive correlation was observed between the itraconazole dosage period and the posaconazole MIC (r = 0.5237, P < 0.0001). (B) The number of itraconazole-naïve isolates decreased as the posaconazole MIC increased, particularly for posaconazole MICs exceeding 0.5 μg/ml (0.25 μg/ml versus 0.5 μg/ml, P = 0.004). (C) The correlation coefficient obtained from the scattergram of itraconazole usage and voriconazole MICs was small (r = −0.2627, P = 0.001). (D) No significant difference was observed in the percentages of itraconazole-naïve isolates and the individual MICs of voriconazole. *, P < 0.05 (Fisher's exact test).

Fig 3

We examined the relationship between itraconazole MICs and the time from the end of itraconazole therapy to A. fumigatus isolation. Of the 154 isolates, 42 had been exposed to itraconazole before isolation. These isolates were analyzed for the relationship; however, the relationship could not be confirmed by the scatter plot (r = −0.1302, P = 0.4110).