Fluconazole (Page 3 of 8)

Microbiology

Mechanism of Action
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.

Resistance

A potential for development of resistance to fluconazole is well known. Fungal isolates exhibiting reduced susceptibility to other azoles may also show reduced susceptibility to fluconazole. The frequency of drug resistance development for the various fungi for which this drug is indicated is not known.


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 minimum inhibitory concentration (MIC) is categorized as Intermediate (16 to 32 mcg/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 fluconazole (e.g., Candida krusei). Such cases may require alternative antifungal therapy.
Antimicrobial Activity
Fluconazole has been shown to be active against most isolates of the following microorganisms both in vitro and in clinical infections.
Candida albicans
Candida glabrata (Many isolates are intermediately susceptible)*
Candida parapsilosis
Candida tropicalis
Cryptococcus neoformans
*In a majority of the studies, fluconazole MIC 90 values against C. glabrata were above the susceptible breakpoint (≥16 mcg/mL). Resistance in Candida glabrata usually includes upregulation of CDR genes resulting in resistance to multiple azoles. For an isolate where the MIC is between 16 to 32 mcg/mL, (see Table 1), the highest dose is recommended. (See DOSAGE AND ADMINISTRATION. ) For resistant isolates, alternative therapy is recommended.
The following in vitro data are available, but their clinical significance is unknown. At least 90% of the following fungi exhibit an in vitro MIC less than or equal to the susceptible breakpoint for fluconazole against isolates of similar genus or organism group. However, the effectiveness of fluconazole in treating clinical infections due to these fungi has not been established in adequate and well-controlled clinical 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 fluconazole (e.g., Candida krusei). Such cases may require alternative antifungal therapy.

Susceptibility Testing

For specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for this drug, please see: https://www.fda.gov/STIC.

INDICATIONS AND USAGE

Fluconazole tablets USP are indicated for the treatment of:

  1. Vaginal candidiasis (vaginal yeast infections due to Candida).
  2. Oropharyngeal and esophageal candidiasis. In open noncomparative studies of relatively small numbers of patients, fluconazole tablets USP were also effective for the treatment of Candida urinary tract infections, peritonitis, and systemic Candida infections including candidemia, disseminated candidiasis, and pneumonia.
  3. Cryptococcal meningitis. Before prescribing fluconazole tablets USP for AIDS patients with cryptococcal meningitis , please see CLINICAL STUDIES section. Studies comparing fluconazole tablets USP to amphotericin B in non-HIV infected patients have not been conducted.

Prophylaxis: Fluconazole tablets USP are also indicated to decrease the incidence of candidiasis in patients undergoing bone marrow transplantation who receive cytotoxic chemotherapy and/or radiation therapy.
Specimens for fungal culture and other relevant laboratory studies (serology, histopathology) should be obtained prior to therapy to isolate and identify causative organisms. Therapy may be instituted before the results of the cultures and other laboratory studies are known; however, once these results become available, anti-infective therapy should be adjusted accordingly.

CLINICAL STUDIES

Cryptococcal meningitis: In a multicenter study comparing fluconazole (200 mg/day) to amphotericin B (0.3 mg/kg/day) for treatment of cryptococcal meningitis in patients with AIDS, a multivariate analysis revealed three pretreatment factors that predicted death during the course of therapy: abnormal mental status, cerebrospinal fluid cryptococcal antigen titer greater than 1:1024, and cerebrospinal fluid white blood cell count of less than 20 cells/mm 3. Mortality among high risk patients was 33% and 40% for amphotericin B and fluconazole patients, respectively (p=0.58), with overall deaths 14% (9 of 63 subjects) and 18% (24 of 131 subjects) for the 2 arms of the study (p=0.48). Optimal doses and regimens for patients with acute cryptococcal meningitis and at high risk for treatment failure remain to be determined. (Saag, et al. N Engl J Med 1992; 326:83-9.)
Vaginal candidiasis: Two adequate and well-controlled studies were conducted in the U.S. using the 150 mg tablet. In both, the results of the fluconazole regimen were comparable to the control regimen (clotrimazole or miconazole intravaginally for 7 days) both clinically and statistically at the one month post-treatment evaluation. The therapeutic cure rate, defined as a complete resolution of signs and symptoms of vaginal candidiasis (clinical cure), along with a negative KOH examination and negative culture for Candida (microbiologic eradication), was 55% in both the fluconazole group and the vaginal products group.

Fluconazole PO 150 mg tablet Vaginal Product qhs x 7 days
Enrolled 448 422
Evaluable at Late Follow-up 347 (77%) 327 (77%)
Clinical cure 239/347 (69%) 235/327 (72%)
Mycologic eradication 213/347 (61%) 196/327 (60%)
Therapeutic cure 190/347 (55%) 179/327 (55%)

Approximately three-fourths of the enrolled patients had acute vaginitis (<4 episodes/12 months) and achieved 80% clinical cure, 67% mycologic eradication, and 59% therapeutic cure when treated with a 150 mg fluconazole tablet administered orally. These rates were comparable to control products. The remaining one-fourth of enrolled patients had recurrent vaginitis (≥4 episodes/12 months) and achieved 57% clinical cure, 47% mycologic eradication, and 40% therapeutic cure. The numbers are too small to make meaningful clinical or statistical comparisons with vaginal products in the treatment of patients with recurrent vaginitis. Substantially more gastrointestinal events were reported in the fluconazole group compared to the vaginal product group. Most of the events were mild to moderate. Because fluconazole was given as a single dose, no discontinuations occurred.

Parameter Fluconazole PO Vaginal Products
Evaluable patients 448 422
With any adverse event 141 (31%) 112 (27%)
Nervous System 90 (20%) 69 (16%)
Gastrointestinal 73 (16%) 18 (4%)
With drug-related event 117 (26%) 67 (16%)
Nervous System 61 (14%) 29 (7%)
Headache 58 (13%) 28 (7%)
Gastrointestinal 68 (15%) 13 (3%)
Abdominal pain 25 (6%) 7 (2%)
Nausea 30 (7%) 3 (1%)
Diarrhea 12 (3%) 2 (<1%)
Application site event 0 (0%) 19 (5%)
Taste Perversion 6 (1%) 0 (0%)

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