Correlation between Triazole Treatment History and Susceptibility in Clinically Isolated Aspergillus fumigatus

Abstract

b 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 g/ml (0.5 g/ml versus 2 g/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 g/ml (0.25 g/ml versus 0.5 g/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.

Whole-Genome Comparison of Aspergillus fumigatus Strains Serially Isolated from Patients with Aspergillosis

“…This isolate subsequently showed a high ITCZ MIC, revealing its resistance to ITCZ. This is likely to have been caused by the 16-month exposure to azole treatment inside the host, which is consistent with previous reports that showed that resistance mutations were generated during azole treatment (3,5,6).…”

“…In some cases in which the strains are serially isolated from a single patient undergoing azole treatment, the first cultured isolates show azole sensitivity and carry no cyp51A mutations, whereas subsequent isolates are azole resistant and possess cyp51A mutations (3,5,6,13). Although it is not clear whether the host environment itself promotes genetic mutations, azole treatment appears to be a selective factor for cyp51A mutants.…”

“…Consequently, the number of cases for which treatment has failed is increasing (3,4). Recent studies from several research groups show that prolonged azole therapy tends to promote the occurrence of azole-resistant strains (5,6). However, long-term antifungal therapy is indispensable for the treatment of chronic aspergillosis.…”

“…Intensive genotyping studies have shown that clinical isolates recovered from a single patient with aspergilloma sometimes contain different genotypes (6,16,17). In a recent study by Howard et al (18), strains recovered from surgically removed fungal balls that consisted of masses of mycelia and resided in the lungs of aspergilloma patients were used for genetic typing.…”

“…Generally, most mutations causing azole resistance are thought to have been generated during infection in an azole-treated host (3,5,6). In some cases in which the strains are serially isolated from a single patient undergoing azole treatment, the first cultured isolates show azole sensitivity and carry no cyp51A mutations, whereas subsequent isolates are azole resistant and possess cyp51A mutations (3,5,6,13).…”