Fluconazole might be beneficial for secondary prophylaxis in patients with AIDS

In Vitro Susceptibility

Amphotericin B and other polyenes NCCLS method is yet insufficient in discrimination of amphotericin B-resistant isolates from the susceptible ones, primarily due to the narrow range of MICs that it generates for all test strains. Modifications of this method, such as the use of Antibiotic Medium 3 supplemented to 2% glucose (AM3) instead of the reference RPMI 1640 medium, and use of 24 h incubation instead of the standard 48 h readings, have yielded inconsistent results in various investigators' hands. While efforts to develop a novel relevant methodology for amphotericin B susceptibility testing are in progress, amphotericin B has proven to be fungicidal against Candida strains. Liposomal nystatin appeared active in vitro against some of the isolates with relatively high amphotericin B MICs. Azoles and Allylamines In vitro resistance to azoles is observed in various Candida spp. While Candida krusei is intrinsically resistant to fluconazole, Candida glabrata may be susceptible, dose-dependent susceptible, or resistant. Other species, such as Candida inconspicua and Candida tropicalis may also generate high fluconazole MIC. In systemic infections, fluconazole-resistant Candida albicans isolates are rare but do exist. On the other hand, patients with AIDS receiving fluconazole prophylaxis are particularly under risk to develop infections due to fluconazole-resistant Candida albicans. Genetic mechanisms involved in multidrug resistance of Candida albicans have recently been explore. Multidrug efflux pumps have been shown to be involved in fluconazole resistance in Candida albicans and Candida tropicalis. Mutation in sterol 14-demethylase P450 enzyme may also lead to azole resistance. The most striking feature of itraconazole is its favorable in vitro activity against some of the fluconazole-resistant Candida strains. This property, as well as the availability of its parenteral formulation, now makes itraconazole a good candidate for treatment of systemic Candida infections. However, there is definitely cross-resistance between fluconazole and itraconazole remains relevant for a subset of Candida isolates, such as some Candida glabrata strains. Terbinafine, in combination with fluconazole and itraconazole may also yield enhanced in vitro activity against some azole-resistant Candida albicans strains. Candida lipolytica and Candida pelliculosa, on the other hand, generate high itraconazole MICs in general. The novel triazoles have favorable in vitro activity against most Candida spp. Although voriconazole MICs are relatively high against Candida guilliermondii and Candida krusei, a recent animal study of therapy of C. krusei infections suggested good activity. Posaconazole (SCH56592) MICs in general appear low. Flucytosine While flucytosine is effective but now less commonly used against Candida infections, strains which are primarily resistant to flucytosine or develop resistance during therapy have been identified. Glucan Synthesis Inhibitors (Echinocandins) In vitro data obtained so far against Candida for these novel agents are promising. Agents of this class are active and often appear fungicidal against both fluconazole-resistant and -susceptible isolates. Isolates of Candida parapsilosis consistently have elevated MICs, but the relevance of this is unclear.

In Vivo Efficacy

Amphotericin B, fluconazole, and itraconazole in general show favorable activity in vivo in treatment of Candida infections. Itraconazole alone, as well as itraconazole and flucytosine combination, proved to have good long term therapeutic efficacy in esophageal candidiasis in AIDS patients. Importantly and in general, improvement of unfavorable immune factors constitutes the major issue in successful clinical outcome of Candida infections. Removal of the predisposing medical devices, such as catheters or shunts are frequently required for clinical cure. Nevertheless, failure despite appropriate therapy with the agent that appears active in vitro, such as amphotericin B or fluconazole, may be observed. Ketoconazole is now less commonly used in treatment of Candida infections due to the availability of more efficacious and less toxic azole compounds. The echinocandins in development, caspofungin and FK463 appear promising in treatment of oropharyngeal and esophageal candidiasis. Although use of fluconazole might be beneficial for secondary prophylaxis in patients with AIDS who have recovered from the primary attack of esophageal candidiasis, the potential risk of emergence of fluconazole resistance [or appearance of candidiasis due to fluconazole-resistant species remains. Similarly, fluconazole prophylaxis following bone marrow transplantation has limited activity against some non-albicans Candida spp. and no activity against filamentous fungi