Quality Control
Standardized susceptibility test procedures require the use of quality control organisms to control the technical aspects of the test procedures. Standardized fluconazole powder and 25 µg disks should provide the following range of values noted in Table 2. NOTE: Quality control microorganisms are specific strains of organisms with intrinsic biological properties relating to resistance mechanisms and their genetic expression within fungi; the specific strains used for microbiological control are not clinically significant.

Table 2: Acceptable Quality Control Ranges for Fluconazole to be Used in Validation of Susceptibility Test Results  QC Strain Macrodilution
(MIC in µg/mL)
@ 48 hours Microdilution
(MIC in µg/mL)
@ 48 hours Disk Diffusion
(Zone Diameter in mm)
@ 24 hours
*
Quality control ranges have not been established for this strain/antifungal agent combination due to their extensive interlaboratory variation during initial quality control studies. 
Candida parapsilosis ATCC 22019 2.0–8.0 1.0–4.0 22–33
Candida krusei ATCC 6258 16–64 16–128 ---*
Candida albicans ATCC 90028 ---* ---* 28–39
Candida tropicalis ATCC 750 ---* ---* 26–37

Activity In Vivo
Fungistatic activity has also been demonstrated in normal and immunocompromised animal models for systemic and intracranial fungal infections due to Cryptococcus neoformans and for systemic infections due to Candida albicans.

In common with other azole antifungal agents, most fungi show a higher apparent sensitivity to fluconazole in vivo than in vitro. Fluconazole administered orally and/or intravenously was active in a variety of animal models of fungal infection using standard laboratory strains of fungi. Activity has been demonstrated against fungal infections caused by Aspergillus flavus and Aspergillus fumigatus in normal mice. Fluconazole has also been shown to be active in animal models of endemic mycoses, including one model of Blastomyces dermatitidis pulmonary infections in normal mice; one model of Coccidioides immitis intracranial infections in normal mice; and several models of Histoplasma capsulatum pulmonary infection in normal and immunosuppressed mice. The clinical significance of results obtained in these studies is unknown.

Oral fluconazole has been shown to be active in an animal model of vaginal candidiasis.

Concurrent administration of fluconazole and amphotericin B in infected normal and immunosuppressed mice showed the following results: a small additive antifungal effect in systemic infection with C. albicans, no interaction in intracranial infection with Cryptococcus neoformans, and antagonism of the two drugs in systemic infection with A. fumigatus. The clinical significance of results obtained in these studies is unknown.

Drug Resistance
Fluconazole resistance may arise from a modification in the quality or quantity of the target enzyme (lanosterol 14-α-demethylase), reduced access to the drug target, or some combination of these mechanisms.

Point mutations in the gene (ERG11) encoding for the target enzyme lead to an altered target with decreased affinity for azoles. Overexpression of ERG11 results in the production of high concentrations of the target enzyme, creating the need for higher int