Fluconazole microbiology

Fluconazole

DIFLUCAN® FDA Package Insert
Description
Clinical Pharmacology
Microbiology
Indications and Usage
Contraindications
Warnings and Precautions
Adverse Reactions
Drug Interactions
Overdosage
Clinical Studies
Dosage and Administration
How Supplied
Labels and Packages

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:  Ahmed Zaghw, M.D. [2]

## Microbiology

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### Mechanism of Action

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Fluconazole is a highly selective inhibitor of fungal cytochrome P450 dependent enzyme lanosterol 14-α-demethylase. This enzyme functions to convert lanosterol to ergosterol. The subsequent loss of normal sterols correlates with the accumulation of 14-α-methyl sterols in fungi and may be responsible for the fungistatic activity of fluconazole. Mammalian cell demethylation is much less sensitive to fluconazole inhibition.

### Drug Resistance

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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 intracellular drug concentrations to inhibit all of the enzyme molecules in the cell.

The second major mechanism of drug resistance involves active efflux of fluconazole out of the cell through the activation of two types of multidrug efflux transporters; the major facilitators (encoded by MDR genes) and those of the ATP-binding cassette superfamily (encoded by CDR genes). Upregulation of the MDR gene leads to fluconazole resistance, whereas, upregulation of CDR genes may lead to resistance to multiple azoles.

Resistance in Candida glabrata usually includes upregulation of CDR genes resulting in resistance to multiple azoles. For an isolate where the MIC is categorized as Intermediate (16 to 32 µg/mL), the highest fluconazole dose is recommended.

Candida krusei should be considered to be resistant to fluconazole. Resistance in C. krusei appears to be mediated by reduced sensitivity of the target enzyme to inhibition by the agent.

There have been reports of cases of superinfection with Candida species other than C. albicans, which are often inherently not susceptible to DIFLUCAN (e.g., Candida krusei). Such cases may require alternative antifungal therapy.

### Activity In Vitro and In Clinical Infections

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Fluconazole has been shown to be active against most strains of the following microorganisms both in vitro and in clinical infections.

* Candida albicans
* Candida glabrata (Many strains are intermediately susceptible)1
* Candida parapsilosis
* Candida tropicalis
* Cryptococcus neoformans

The following in vitro data are available, but their clinical significance is unknown.

Fluconazole exhibits in vitro minimum inhibitory concentrations (MIC values) of 8 µg/mL or less against most (≥90%) strains of the following microorganisms, however, the safety and effectiveness of fluconazole in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled trials.

* Candida dubliniensis
* Candida guilliermondii
* Candida kefyr
* Candida lusitaniae
* Candida krusei should be considered to be resistant to fluconazole. Resistance in C. krusei appears to be mediated by reduced sensitivity of the target enzyme to inhibition by the agent.

There have been reports of cases of superinfection with Candida species other than C. albicans, which are often inherently not susceptible to DIFLUCAN (e.g., Candida krusei). Such cases may require alternative antifungal therapy.

* In a majority of the studies, fluconazole MIC90 values against C. glabrata were above the susceptible breakpoint (≥16 µg/mL). Resistance in Candida glabrata usually includes upregulation of CDR genes resulting in resistance to multiple azoles. For an isolate where the MIC is categorized as intermediate (16 to 32 µg/mL, see Table 1), the highest dose is recommended (see DOSAGE AND ADMINISTRATION). For resistant isolates, alternative therapy is recommended.

### Susceptibility Testing Methods

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Cryptococcus neoformans and filamentous fungi

No interpretive criteria have been established for Cryptococcus neoformans and filamentous fungi.

Candida species

* Broth Dilution Techniques

Quantitative methods are used to determine antifungal minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility ofCandida spp. to antifungal agents. MICs should be determined using a standardized procedure. Standardized procedures are based on a dilution method (broth)1 with standardized inoculum concentrations of fluconazole powder. The MIC values should be interpreted according to the criteria provided in Table 1.

* Diffusion Techniques

Qualitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of Candida spp. to an antifungal agent. One such standardized procedure2 requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 25 µg of fluconazole to test the susceptibility of yeasts to fluconazole. Disk diffusion interpretive criteria are also provided in Table 1.

### Quality Control

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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.

[1]

## References

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1. ↑ "DIFLUCAN (FLUCONAZOLE) TABLET DIFLUCAN (FLUCONAZOLE) POWDER, FOR SUSPENSION DIFLUCAN (FLUCONAZOLE) SOLUTION [ROERIG]".

Adapted from the FDA Package Insert.