Does Long-Term Itraconazole Prophylaxis Result in In Vitro Azole Resistance in Mucosal Candida albicans Isolates from Persons with Advanced Human Immunodeficiency Virus Infection?

Abstract

The effects of prolonged itraconazole exposure on the susceptibility of Candida albicans isolates to itraconazole and fluconazole have not been well characterized. A recent placebo-controlled study of long-term itraconazole antifungal prophylaxis in persons with advanced human immunodeficiency virus infection afforded the opportunity to address this question. Mucosal Candida sp. isolates were obtained from subjects who developed oropharyngeal or esophageal candidiasis, and in vitro susceptibilities of the last isolate obtained at removal from the study as a prophylaxis failure were compared in itraconazole and placebo recipients. More subjects in the placebo group (74 of 146 [51%]) than in the itraconazole group (51 of 149 [34%]) developed mucosal candidiasis (P ‫؍‬ 0.004). A total of 112 isolates were recovered from 56 of the 74 (76%) subjects with mucosal candidiasis assigned to the placebo group, compared to 97 isolates from 45 of the 51 (88%) subjects in the itraconazole group. C. albicans accounted for 98% of isolates in the placebo group and 89% of isolates in the itraconazole group. The itraconazole MIC at which 50% of the isolates tested were inhibited (MIC 50 ) for last-episode isolates from the itraconazole group was 0.125 g/ml compared to 0.015 g/ml for the placebo group subjects, P ‫؍‬ 0.0001. The MIC 50 of fluconazole for the last isolates from the itraconazole group was 1.5 g/ml compared to 0.5 g/ml for the placebo subjects (P ‫؍‬ 0.005). A lower proportion of isolates recovered from subjects on itraconazole therapy were classified as susceptible to itraconazole (63%) compared to isolates from the placebo group (96%) (P ‫؍‬ 0.001). Similarly, a lower proportion of C. albicans isolates from subjects on itraconazole therapy were susceptible to fluconazole (78%) compared to isolates from the placebo group (96%) (P ‫؍‬ 0.01). Also, the proportion of isolates that were not fully susceptible to itraconazole or fluconazole was greater in patients assigned to the itraconazole group than the placebo group (itraconazole susceptibility, 37 and 4%, respectively (P ‫؍‬ 0.001); fluconazole susceptibility, 23 and 4%, respectively (P ‫؍‬ 0.01). In conclusion, long-term itraconazole prophylaxis in patients with AIDS is associated with reduction in susceptibility to itraconazole and cross-resistance to fluconazole.

Voriconazole and fluconazole susceptibility of Candida isolates

“…At steady state, peak and trough Unlike Candida spp. isolated in the first years of clinical use of FLC, this study investigated the in-vitro susceptibility of isolates collected in recent years, reflecting a more clinically relevant situation with regards to azole resistance and therapeutic options [2,[23][24][25]. The increasing rate of invasive infection caused by Candida isolates that are not susceptible to FLC is a major concern for clinicians [7,24,26,27].…”

Identificação microbiológica e sensibilidade in vitro de Candida isoladas da cavidade oral de indivíduos HIV positivos

“…O uso de itraconazol profilático em pacientes com AIDS foi associado à redução da susceptibilidade ao fluconazol para espécies isoladas de Caindida albicans em episódios de candidíase oral recorrente 7 . Apesar dos mais de 50 anos de uso dos polienos, a resistência a anfotericina B é rara, porém, neste estudo dois dos 57 isolados testados demonstraram CIM>2µg/ml para a anfotericina B, caracterizando resistência.…”

Randomized, Double-Blind, Multicenter Study of Caspofungin versus Amphotericin B for Treatment of Oropharyngeal and Esophageal Candidiases

“…Amphotericin B deoxycholate has been the standard recourse for patients infected with Candida sp. unresponsive to azole therapy (5,10,24,36). The use of conventional amphotericin B preparations is complicated by its significant toxicity.…”