- Fluconazole is a synthetic bis-triazole compound, where triazole is one of the classes of antifungal.
- It is basically used for the treatment of fungal infections, including yeast infections of the mouth, throat, oesophagus, abdomen, lungs, blood, vagina and other organs.
- It can be found in both tablet and suspension form as well as intravenous infusion.
Mechanism of action of Fluconazole:
- Fluconazole works like other azoles and is a potent inhibitor of ergosterol biosynthesis through its action on the cytochrome P-450- dependent enzyme, lanosterol 14
-demethylase.
- Ergosterol the principal sterol in the membrane of susceptible fungal cells
- Depletion of ergosterol, and accumulation of methylated sterols leads to disruptions in membrane structure and function.
Spectrum of action:
- Fluconazole is most active against Candida species, Cryptococcus neoformans and C . immitis.
- It has more limited activity against Blastomyces dermatitidis, Histoplasma capsulatum and Sporothrix schenckii, and is used as a second-line agent in infections with these fungi.
- Fluconazole is active against the dermatophytes (Trichophyton, Microsporum and Epidermophyton species), but appears to be ineffective against most other moulds, including Aspergillus species and Zygomycetes.
- Even if it is active against many Candida species, C . krusei is intrinsically resistant to fluconazole.
- Isolates of Candida glabrata are also less sensitive, and as many as 10% of bloodstream isolates of this species are resistant.
Acquired Fluconazole resistance:
- The resistance is seen in Candida albicans or C. tropicalis during short-term fluconazole treatment in patients with mucosal or deep- seated forms of candidosis.
- In AIDS patients, resistant strains of C. albicans have appeared following repeated courses of low-dose fluconazole treatment for oral or oesophageal infection.
- Many ofthese fluconazole-resistant C. albicans strains are seen to be cross-resistant to other azoles.
- This is an unusual problem at present.
- There are a few reports ofresistant strains of Cryptococcus neoformans from AIDS patients with relapsed infection following long-term maintenance treatment with fluconazole.
- Several molecular mechanisms of azole drug resistance in C. albicans have now been elucidated.
- These include overexpression of a number of efflux pump genes, including the ABC transporter genes, CDRl and CDR2, and the major facilitator gene, MDRl.
- Over- expression of these pumps leads to reduced drug accumulation in the cells of resistant strains.
- The second resistance mechanism is point mutations in the ERG11 gene that encodes the target enzyme, lanosterol 14
-demethylase.
- These mutations result in structural alteration of the enzyme and this leads to decreased binding to azole antifungals.
- The third resistance mechanism is overexpression of the ERG11 gene.
- This leads to overproduction of the target enzyme.
- In addition, evidence is accumulating that changes in other enzymes involved in ergosterol biosynthesis, such as C5(6)sterol desaturase, can also contribute to azole resistance.
Pharmacokinetics of fluconazole:
- Oral administration of fluconazole leads to rapid and almost complete absorption of the drug.
- Identical serum concentrations are achieved after oral and parenteral administration indicating that first-pass metabolism of the drug does not occur.
- Blood concentrations increase in proportion to dosage over a wide range of dose levels.
- Two hours after a single 50-mg oral dose, serum concentrations in the region of 1.0 mg/L can be anticipated, but after repeated dosing this increases to about 2.0-3.0 mg/ L.
- The absorption is not affected by administration of the drug with food.
- Oral or parenteral administration of fluconazole results in rapid and widespread distribution of the drug.
- Unlike other azole antifungals, the protein binding of fluconazole is low (about 12%)resulting in high levels of circulating unbound drug.
- In most tissues and fluids, levels of the drug usually exceed 50% ofthe simultaneous blood concentration.
- Unlike other azole antifungals, fluconazole is not extensively metabolized in man. More than 90% of a given dose is eliminated in the urine: about 80% as unchanged drug and 10% as inactive metabolites.
- The drug is cleared through glomerular filtration, but significant tubular reabsorption occurs.
- Fluconazole has a serum half-life of about 30 h (range 20-50 h), but this is prolonged in renal failure, necessitating adjustment of the dosage regimen in patients with glomerular filtration rates below 50ml/min.
- In children the volume of distribution and clearance rates are increased, and the half-life is considerably shorter (15-25 h).
- In infants fluconazole has a prolonged half-life of 55-90 h.
- Fluconazole is removed during haemodialysis and, to a lesser extent, during peritoneal dialysis.
- A3-h haemodialysis session will decrease the blood concentration by about 50%.
Therapeutic use of Fluconzole:
- Fluconazole is available in oral and parenteral forms: as tablets, oral suspension and an intravenous infusion.
- The drug is supplied for parenteral administration at a concentration of 2.0mg/ml in 0.9% sodium chloride solution.
- Dosing recommendations are identical for all dosage forms
- Fluconazole can be used to treat mucosal and cutaneous forms of candidosis.
- It is also effective in various forms of dermatophytosis and pityriasis versicolor.
- It is an effective drug for treatment of deep forms of Candida albicans, C. tropicalis and C. parapsilosis infection in patients who are stable (individuals who do not have an unexplained fever, are improving, and are not hypotensive).
- Opinion is divided as to whether fluconazole should be used in patients with C. glabrata infection, but it should not be used in those with C. krusei infection.
- Fluconazole has proved to be an effective prophylactic treatment against candidosis in haematopoietic stem cell transplant (HSCT)recipients.
- However, it is ineffective in aspergillosis and mucormycosis.
- Fluconazole is a useful drug in acute cryptococcal meningitis, however it should not be used as first-line treatment in persons with AIDS unless there are particular reasons for withholding amphotericin B.
- However, it is more effective and better tolerated than amphotericin B as maintenance treatment to prevent relapse of cryptococcosis in patients with AIDS.
- Fluconazole is the drug of choice for patients with coccidioidal meningitis. However, it must be continued for life to prevent relapse.
Mode of administration:
- As absorption following oral administration is good, this is the preferred method of administration.
- If the patient cannot take the drug by mouth, the intravenous solution can be used.
- This should be infused at a maximum rate of 200 mg/h.
- Vaginal candidosis can be treated with a single 150- mg oral dose of fluconazole. Oropharyngeal candidosis should be treated with 200 mg on the first day followed by 100mg/day for 2 weeks.
- Oesophageal candidosis should be treated with 200 mg on the first day followed by 100mg/day for at least 3 weeks; treatment should be continued for at least 2 weeks following resolution of symptoms.
- The recommended dose for adult patients with cryptococcosis or deep forms of candidosis is 6mg/kg per day (400mg/day in a 70-kg patient).
- However, some clinicians have used higher dosages in life-threatening infections.
- The duration of treatment will differ from patient to patient, depending upon the nature and extent of the infection and the underlying illness.
- At least 6-8 weeks is usually required for successful treatment of cryptococcosis in human immunodeficiency virus (HIV)-negative persons.
- The recommended dose for children is 3mg/kg for oropharyngeal and oesophageal candidosis, and 6mgkg for cryptococcosis or deep forms of candidosis.
- Because of its more rapid clearance in children, fluconazole should be administered at 12-h intervals for the treatment of life-threatening infections
- Long term maintenance treatment with fluconazole to prevent relapse in AIDS patients with cryptococcosis should be administered at a dosage of 200mg/day.
- To reduce the risk of invasive candidosis in neutropenic HSCT recipients, prophylactic treatment with fluconazole should be given at a dosage of400 mg/day.
- Patients with renal impairment should be given the normal dose for the first 48h of treatment.
- Thereafter, in persons with a creatinine clearance of 21-40 ml/min, the dosage interval should be doubled to 48h or the dose halved.
- Persons with a clearance of 10-20 ml/min require a 72-h interval between doses.
- Patients receiving regular haemodialysis require the usual dose after each dialysis session.
Side effects of Fluconazole
- The commonest side-effects are gastrointestinal in origin, such as nausea and abdominal discomfort, but these seldom necessitate discontinuation of treatment in patients receiving up to 400 mg/day.
- Transient asymptomatic elevations of serum transaminase levels are quite common in AIDS patients treated with the drug, and treatment should be discontinued in patients who have test findings indicative of progressive or persistent hepatic dysfunction.
- There have been rare cases of serious hepatic reactions during fluconazole treatment, including hepatitis, cholestasis, and fulminant hepatic failure.
- Occasional fatal hepatic reactions have occurred, particularly in patients with serious underlying medical conditions such as AIDS or malignancies.
- Fatal exfoliative skin rashes (Stevens-Johnson syndrome) have been reported in patients with AIDS or cancer, but the causal relationship with fluconazole is unclear because of the concomitant administration of other drugs.
- It is advisable to discontinue fluconazole in a patient with a superficial fungal infection who develops a skin rash.
- Patients with deep-seated fungal infection who develop rashes should be monitored and the drug discontinued if the lesions progress.
- Unlike ketoconazole, fluconazole, when given in recommended doses, does not inhibit human adrenal or testicular steroid metabolism.