Kieren A. Marr, MD

Candida is recognized as the fourth most common cause of bloodstreaminfection in the United States, with a high attributable mortalityrate. While Candida albicans remains the most common pathogen, nonalbicansCandida species, including Candida glabrata and Candidakrusei, with greater resistance to triazoles are being increasingly isolated.These epidemiologic changes are attributable to a combinationof factors, such as the use of fluconazole prophylaxis, changes in patientdemographics and underlying diseases, and use of therapeuticstrategies that may pose unique risks. Of particular concern is the increasedprevalence of species that are resistant to the azole antifungals.Candida glabrata, for example, is often resistant to fluconazole,and its ability to become cross-resistant to newer azole antifungals is arecent concern. Increasing evidence underscores the need to carefullyevaluate antifungal treatment options, according to both host and therapeuticrisks for drug resistance.

Combination therapy with amphotericin B and flucytosine is consideredto be the treatment of choice for cryptococcal infections. However,for other infections and combinations of antifungal infections,the data are less clear-cut. The concurrent use of amphotericin B withan azole has elicited controversy, given the potential of antimicrobialantagonism. The results of one recent candidemia study suggest thatthe potential antagonism may not be an issue; the combination of amphotericinB and fluconazole provided more effective clearance of Candidafrom the bloodstream than did fluconazole used alone. Several invitro and animal studies have shown antagonism between the azolesand amphotericin B for aspergillosis. However, introduction of the newclass of agents that target β-glucan synthase (echinocandins) has invigoratedthe prospects of combination therapy. The echinocandins andpolyenes are not antagonistic, and there is evidence that theechinocandins may provide additive to synergistic activity in combinationwith triazoles. For patients whose aspergillosis is progressing despitemonotherapy, the addition of a second agent, such as anechinocandin, may be reasonable.

Efforts at preventing and treating fungal infection in hematopoietic stem cell transplant (HSCT) recipients must take into account the types of infections likely to be encountered during the different risk periods in hosts with different underlying risks. Given the emergence of molds as prevalent pathogens and the long duration of risk in allogeneic HSCT recipients, optimal antifungal prophylaxis would consist of treatment that can be given over a prolonged period and that would provide both anti-Candida and anti-Aspergillus activity. Optimal empiric therapy would consist of a broad-spectrum agent in the absence of more sensitive and specific methods for microbial diagnosis. Fluconazole (Diflucan) is currently the standard prophylactic agent for candidiasis, although mold-active agents and alternative strategies for polyene administration are being investigated. The gold standard for empiric therapy is currently a polyene antifungal, yet an increased appreciation for amphotericin B-resistant yeasts and molds, and less toxic mold-active alternatives, might lead to the use of other compounds in the future. The recent development of multiple alternatives emphasizes our need to establish treatment algorithms that consider both the likely pathogens and potential toxicities. [ONCOLOGY 15(Suppl 9):15-19, 2001]

Among the serious complications associated with bone marrow transplantation are invasive fungal infections caused by organisms such as Candida and Aspergillus species and end-organ disease caused by