RESUMO
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.
Assuntos
Aspergillus fumigatus/efeitos dos fármacos , Aspergillus fumigatus/genética , Sistema Enzimático do Citocromo P-450/genética , Farmacorresistência Fúngica/efeitos dos fármacos , Proteínas Fúngicas/genética , Aspergilose Pulmonar/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Antifúngicos/administração & dosagem , Antifúngicos/efeitos adversos , Aspergillus fumigatus/enzimologia , Aspergillus fumigatus/isolamento & purificação , Sistema Enzimático do Citocromo P-450/metabolismo , Farmacorresistência Fúngica/genética , Feminino , Proteínas Fúngicas/metabolismo , Humanos , Itraconazol/administração & dosagem , Itraconazol/efeitos adversos , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Mutação , Aspergilose Pulmonar/microbiologia , Fatores de Tempo , Triazóis/administração & dosagem , Triazóis/efeitos adversosRESUMO
There has been no literature which reports a case of interstitial lung disease associated with sorafenib. However, a recent post-marketing survey in Japan revealed that interstitial pneumonia occurred in 4 among approximately 2 000 Japanese patients treated with sorafenib. In this article, we describe a Japanese patient with severe interstitial pneumonia probably caused by sorafenib treatment for metastatic renal cell carcinoma. Oncologists supervising future clinical trials for lung cancer should be alert to the fact that sorafenib can potentially induce serious interstitial lung disease, although this might depend on racial differences.