IN-VITRO INTERACTION BETWEEN AMPHOTERICIN-B AND AZOLES IN CANDIDA-ALBICANS

The use of azole prophylaxis as a measure to prevent invasive fungal i nfections in high-risk patients is increasing and is now the standard of care in many institutions, Previous studies disagree on whether pre exposure of Candida albicans to azoles affects their subsequent suscep tibility to amphotericin B (AmB), The present in vitro study indicates that azole exposure generates a subpopulation of cells that are not a ffected by subsequent exposure to AmB. These cells that are phenotypic ally resistant to AmB are not stably resistant, but for short periods of exposure, they can tolerate up to 100-fold the level of AmB tolerat ed by most cells not exposed to azole, The percentage of cells that co nvert to phenotypic resistance to AmB varies with the concentration an d the azole, Itraconazole is more effective than fluconazole in genera ting cells that are phenotypically resistant to AmB and that tolerate an otherwise lethal transient exposure to AmB, Until cells that are no t exposed to fluconazole are simultaneously challenged with AmB, they are not protected to a significant extent from killing by AmB, Cells t hat are challenged with continuous exposure to AmB also acquire phenot ypic resistane to AmB at increased frequencies by azole preexposure, b ut this requires that the azole be continuously present during incubat ion with AmB, In addition, Candida cells taken from mature colonies th at are not actively growing are not susceptible to the short-term kill ing effects of AmB without azole preexposure. The adaptive responses o f C. albicans to AmB and potentially other antifungal agents that may result from prior exposure to azoles in vitro or potentially in microe nvironments in vivo that induce physiological changes may have major c linical implications.