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Fluconazole

An Update of its Antimicrobial Activity, Pharmacokinetic Properties, and Therapeutic Use in Vaginal Candidiasis

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Summary

Synopsis

Fluconazole is a bis-triazole antifungal drug which has a pharmacokinetic profile characterised by its high water solubility, low affinity for plasma proteins, and metabolic stability. After a single 150mg oral dose, therapeutic concentrations in vaginal secretions are rapidly achieved and are sustained for a duration sufficient to produce high clinical and mycological responses in nonimmuno-compromised patients with vaginal candidiasis (candidosis). At this dosage, clinical and mycological responses have compared favourably with responses achieved after multiple dose regimens of other oral and intravaginal antifungal agents. Clinical efficacy rates have ranged between 92 and 99% at short term evaluation (5 days post-treatment). At 80 to 100 days post-treatment clinical efficacy rates of 91% have been reported.

In addition, limited data indicate that fluconazole is more effective than placebo as prophylactic treatment of frequently recurring vaginal candidiasis.

Single oral doses of fluconazole 150mg are well tolerated. Most frequently observed adverse events are gastrointestinal symptoms, which are generally mild and transient in nature.

Thus, fluconazole is a valuable alternative to established systemic and intravaginal azole antifungal drugs which are used to treat vaginal candidiasis. Moreover, in view of its favourable patient acceptability and compliance profile compared with alternative treatments, single-dose oral fluconazole should be considered as a first-line therapeutic choice for the treatment of women with vaginal candidiasis.

Pharmacodynamic Properties

When conventional standard culture media are used for in vitro susceptibility testing of fluconazole, minimum inhibitory concentrations that are achieved do not reflect the clinical efficacy of the drug. However, recent advances in fluconazole susceptibility testing of Candida species (with broth dilution methods) have improved the reproducibility of in vitro testing and yield results more accurately reflecting therapeutic response. Most species of Candida are susceptible to fluconazole with minimum inhibitory concentrations for 90% of isolates (MIC90) ranging from 0.25 to 6.4 mg/L for C. albicans. MIC90 values of ≤ 2.0 mg/L for C. tropicalis have been reported in the majority of studies.

Fluconazole, a highly specific inhibitor of the fungal enzyme lanosterol 14α-demethylase, prevents conversion of fungal cell lanosterol to the membrane lipid ergosterol. As a result, fungal cell membrane permeability increases and cell growth and replication are inhibited. In contrast to ketoconazole, fluconazole is highly selective for fungal cytochrome P450 enzymes and does not appear to inhibit cytochrome P450 enzyme pathways in mammalian organs when administered as a single oral 150mg dose. Compared with other azoles such as itraconazole, clotrimazole, econazole and ketoconazole, fluconazole was the weakest inhibitor of evaluated cytochrome P450-mediated drug oxidative pathways in human hepatic microsomes in vitro. In addition, data suggest that fluconazole administered as a single oral 150mg dose does not adversely affect the biosynthesis of endogenous steroids in humans.

Pharmacokinetic Properties

After oral administration, fluconazole is widely distributed as free drug in body fluids and tissues. Maximum plasma concentrations of fluconazole, ranging between 2.44 and 3.58 mg/L (2 hours after administration of a 150mg oral dose) have been reported in patients with vaginal candidiasis (candidosis). Concentrations of fluconazole in vaginal secretions are very similar to plasma concentrations following oral administration. Maximum concentrations of fluconazole in vaginal secretions are reached approximately 8 hours after oral administration and are sustained at this level for at least 24 hours post-treatment. Fluconazole has a low affinity for plasma proteins, and slight alterations in plasma concentrations are unlikely to alter the pharmacological or therapeutic effects of fluconazole.

The mean plasma elimination half-life of fluconazole following a single oral dose has ranged from 30.2 to 37.3 hours in healthy volunteers and patients with vaginal candidiasis.

Therapeutic Efficacy

Clinical efficacy rates, evaluated in terms of resolution and improvement of signs and symptoms of vaginal candidiasis, have ranged between 92 and 99% at short term assessment (5 days) and 91% at long term assessment (80 to 100 days).

In the small number of published studies that have compared fluconazole with oral itraconazole and ketoconazole, fluconazole administered as a single oral 150mg dose achieved similar clinical and mycological cure rates to itraconazole 200mg twice daily for 1 or 2 days and ketoconazole 400mg/day for 5 days at short and long term assessments.

Single doses of oral fluconazole have been compared with intravaginal clotrimazole, miconazole, econazole and terconazole in several studies involving a total of more than 1800 women with vaginal candidiasis. In most studies, similar rates of clinical and mycological responses were achieved after either fluconazole or the comparator agent at short and long term evaluation. However, results of some studies should be interpreted with caution as they involved only small patient numbers. A large multicentre study has demonstrated that fluconazole is equally effective in patients with or without factors predisposing them to vaginal candidiasis. Few published data are available on the efficacy of single oral doses of fluconazole as a prophylactic treatment of women who experience recurrent episodes of vaginal candidiasis. However, these limited data indicate that fluconazole, administered as a single oral 150mg dose every 28 days, is more effective than placebo in reducing the incidence of recurrent episodes of vaginal candidiasis.

Although an association between rectal colonisation by Candida species and the incidence of recurrent episodes of vaginal candidiasis is unproven, several noncomparative and comparative studies have shown that rectal carriage of Candida is reduced by single oral 150mg doses of fluconazole and that there may be an association between mycological rectal and vaginal cure.

Tolerability

Fluconazole, administered as a single oral 150mg dose, is generally well tolerated, with gastrointestinal symptoms including abdominal pain, diarrhoea and nausea the most common reported adverse effects associated with the drug. Skin rashes and headache/migraine have also been reported. Mild and transient asymptomatic elevations of hepatic enzymes have been reported in patients receiving fluconazole. Serious hepatic reactions are rare; however, patients with abnormal liver function tests should be monitored for the development of serious hepatic injury.

Although oral fluconazole is associated with a higher incidence of adverse effects than antifungal azoles administered intravaginally, the tolerability profile of fluconazole appears to be equivalent to that of oral ketoconazole.

Dosage and Administration

Fluconazole administered as a single oral 150mg dose is recommended for treating acute or recurrent vaginal candidiasis. Dosage modification is not required in patients with renal impairment, or in elderly patients. The efficacy and tolerability of single oral doses of fluconazole in patients under 18 years of age with vaginal candidiasis have not been established.

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Various sections of the manuscript reviewed by: M.P. Arévalo, Facultad de Medicina, Universidad de la Laguna, Tenerife, Canary Islands, Spain; I.W. Fong, Division of Infectious Diseases and HIV Clinic, St Michael’s Hospital, Toronto, Ontario, Canada; R.J. Hay, St John’s Institute of Dermatology, Guy’s Hospital, London, England; K.G. Naber, Department of Urology, Elisabeth Hospital, Straubing, Germany; M.A. Pfaller, Department of Pathology, Medical Microbiology Division, The University of Iowa Hospitals and Clinics, Iowa City, Iowa, USA; M.F. Price, Special Infectious Disease Laboratory, Infectious Disease Section, St Luke’s Episcopal Hospital, Houston, Texas, USA; J.D. Sobel, Department of Medicine — Division of Infectious Diseases, Wayne State University School of Medicine, Detroit, Michigan, USA; A.M. Sugar, Section of Infectious Diseases, Boston University Medical Center Hospital, Boston, Massachusetts, USA; H. Timonen, The Deaconess Hospital, Helsinki, Finland; J.M. Tobin, Department of GU Medicine, St Mary’s Hospital, Portsmouth, England; A.M. van Heusden, Department of Obstetrics and Gynaecology, Academic Hospital ‘Dijkzigt’ Rotterdam, Rotterdam, The Netherlands.

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Perry, C.M., Whittington, R. & McTavish, D. Fluconazole. Drugs 49, 984–1006 (1995). https://doi.org/10.2165/00003495-199549060-00009

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