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Fluconazole in 2015



Dr Atul K Patel
Infectious Diseases Clinic
Vedanta Institute of Medical Sciences
Ahmedabad, India

Candidemia is associated with very high morbidity and about 40% mortality. In a recent study from India, candidemia was associated with 44.7% mortality in non-neutropenic patients in the ICU.1 The introduction of fluconazole revolutionized the therapy of Candida infections in the 1990s by offering a well-tolerated alternative to amphotericin B, which has significant associated toxicity. Fluconazole is widely used in India. Despite recommendations of echinocandin use in ICU patients, 64% of patients in ICU were treated with fluconazole and 6.2% of Candida isolates were resistant to fluconazole.1

Fluconazole remains an attractive option for treatment of candidiasis because of its excellent oral bioavailability, safety and clinical efficacy. Echinocandins have reported good efficacy and safety in critically ill patients with candidemia. Clinicians practicing in resource-limited settings are still using older antifungal agents such as fluconazole and amphotericin B deoxycholate for candidemia despite the availability of echinocandins in those countries. This article will discuss important pharmacological parameters of fluconazole that can help clinicians get maximum benefits out of fluconazole use.

Spectrum of activity

Fluconazole is active against Candida species, including C. albicans, C. tropicalis, C. parapsilosis, C. lusitaniae and C. glabrata (up to 30-40% are resistant to azoles), as well as Cryptococcus neoformans, Histoplasma capsulatum, Coccidioides immitis.

Pharmacokinetic parameters

After oral administration, fluconazole is rapidly and fully absorbed (bioavailability >90%), with a time to maximum absorption of 0.5-1.5 h after intake of medication.

Pharmacokinetic parameters of fluconazole

 

AUC, area under the plasma drug concentration-time curve

Fluconazole total clearance significantly increases when used in renal failure patients receiving continuous venovenous hemofiltration (CVVH) or continuous venovenous hemodialysis (CVVHD), requiring higher doses to achieve therapeutic drug levels and optimal antifungal activity.2,3

Data on fluconazole pharmacokinetics in adult patients on extracorporeal membrane oxygenation (ECMO) is not available. However, in infants on ECMO, similar clearance but higher volume of distribution are seen, thus, higher doses may be needed for treatment.4

Dosage recommendations

A loading dose of 12 mg/kg followed by 6 mg/kg/day in patients with normal renal function is recommended. Loading dose is required to reach steady state level within 24 hours.

Fluconazole is relatively well tolerated with daily dosage up to 2 g/day. Dose/isolate minimum inhibitory concentration (MIC) ratio of >100 is associated with better outcomes in patients with candidemia.5

Suggested dosages in patients with renal impairment

 

CVVH, continuous venovenous hemofiltration; CVVHD, continuous venovenous hemodialysis; CVVHDF, continuous venovenous hemodiafiltration

Fluconazole therapeutic drug monitoring

Unlike voriconazole and posaconazole, routine fluconazole therapeutic drug monitoring (TDM) is not required due to linear pharmacokinetics and predictable drug levels. In patients receiving renal replacement therapy, TDM will help clinicians adjust fluconazole dosage for better clinical outcome.2,3

Clinically relevant drug-drug interactions in critically ill patients

Fluconazole inhibits the CYP3A4 isoenzyme responsible for the metabolism of a wide range of drugs (Table). It is also a strong noncompetitive or mixed-type inhibitor of CYP2C9 and CYP2C19.

Table. Important drug-drug interactions with fluconazole in ICU patients
Drug Interaction mechanism Effect(s) of interaction Recommendation
Glimepiride6 Inhibition of CYP2C9 Glimepiride AUC increased by >100% and Cmax increased by <100% Monitor for glimepiride toxicity and adjust dose if necessary
Midazolam7-10 Inhibition of CYP3A4 Midazolam AUC increased by >100% and Cmax increased by <100% Monitor for toxicity of midazolam and adjust dose if necessary
Omeprazole11 Inhibition of CYP2C19 and CYP3A4 Omeprazole AUC increased by >100% and Cmax increased by <100% Monitor for toxicity of omeprazole and adjust dose if necessary; upon initiation of therapy, start with low dose of omeprazole
Phenytoin12 Inhibition of CYP2C9 Phenytoin AUC increased by <100% Monitor for toxicity of phenytoin and adjust dose if necessary; perform TDM of phenytoin
Fentanyl13 Inhibition of CYP3A4 Fentanyl AUC increased by <100% Monitor for toxicity of fentanyl
Warfarin14 Inhibition of CYP3A4 and CYP2C9 Warfarin AUC increased by <100% Monitor for toxicity of warfarin
AUC, area under the plasma drug concentration-time curve; Cmax, maximum concentration; TDM, therapeutic drug monitoring

Important toxicities associated with fluconazole

enerally fluconazole is well tolerated even at a higher dosage of 1.2 to 2 mg/day. Occasionally, reversible alopecia and transaminitis are observed. Fatal hepatotoxicity, hypokalemia and central nervous system side effects such as headache and dizziness are rare.

Summary

Fluconazole is a valuable treatment option for patients with invasive candidiasis. Careful attention to drug-drug interactions and dose adjustment, according to MIC of isolates and renal replacement treatment status of patients, will help clinicians achieve better clinical outcomes in patients with candidemia.

References:

  1. Chakrabarti A, et al. Intensive Care Med 2015;41:285-295.
  2. Muhl E, et al. Eur J Clin Pharmacol 2000;56:671-678.
  3. Pittrow L, Penk A. Mycoses 1999;42:17-19.
  4. Watt KM, et al. Pediatr Infect Dis J 2012;31:1042-1047.
  5. Clancy CJ, et al. Antimicrob Agents Chemother 2005;49:3171-3177.
  6. Niemi M, et al. Clin Pharmacol Ther 2001;69:194-200.
  7. Ahonen J, et al. Eur J Clin Pharmacol 1997;51:415-419.
  8. Ahonen J, et al. Acta Anaesthesiol Scand 1999;43:509-514.
  9. Olkkola KT, et al. Anesth Analg 1996;82:511-516.
  10. Vanakoski J, et al. Int J Clin Pharmacol Ther 1995;33:518-523.
  11. Kang BC, et al. Biopharm Drug Dispos 2002;23:77-81.
  12. Blum RA, et al. Clin Pharmacol Ther 1991;49:420-425.
  13. Saari TI, et al. Eur J Clin Pharmacol 2008;64:25-30.
  14. Black DJ, et al. Drug Metab Dispos 1996;24:422-428.

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