Early onset hepatotoxicity associated with low dose fluconazole therapy in a critically ill patient

Abstract

Hepatotoxicity associated with fluconazole is less implicated than other antifungals although cases of fatalities were reported. We describe a 34-year-old kidney impaired male with Marfan syndrome manifested with acute elevated liver enzymes due to fluconazole therapy intravenous (IV) 200 mg stat followed by IV 100 mg daily. His baseline alanine aminotransferase (ALT) was 38 U/L, total bilirubin was 36 µmol/L and prothrombin time was 19.7 seconds. Marked elevation of ALT level (214 U/L), total bilirubin (54 µmol/L) and prothrombin time (37 seconds) were noticed starting from day 4 of fluconazole therapy. The patient subsequently developed nausea and vomiting and the ALT and total bilirubin level further rose to 2394 U/L and 94 µmol/L on day 6.  Discontinuation of fluconazole without re-challenged on day 8 resulted in sharp decreased in prothrombin time from 65.3 seconds to 31.9 seconds and normalization of liver enzymes in 2 weeks time. In conclusion, low dose fluconazole may induce early onset of hepatotoxicity in critically ill patient with kidney failure. Prompt discontinuation of fluconazole therapy is needed to prevent further deterioration in liver function.

Keywords

• Hepatotoxicity
• fluconazole
• antifungal agent
• adverse effect

References

1. Charlier C, Hart E, Lefort A, et al. Fluconazole for the management of invasive candidiasis: where do we stand after 15 years? J Antimicrob Chemother 2006; 57: 384-410.
2. Wang JL, Chang CH, Young-Xu Y, Chan KA. Systematic review and meta-analysis of the tolerability and hepatotoxicity of antifungals in empirical and definitive therapy for invasive fungal infection. Antimicrob Agents Chemother 2010; 54: 2409-2419.
3. Chiou CC, Walsh TJ, Groll AH. Clinical pharmacology of antifungal agents in pediatric patients. Expert Opin Pharmacother 2007; 8: 246524
4. Scott LJ, Simpson D. Voriconazole : a review of its use in the management of invasive fungal infections. Drugs 2007; 67: 269-298.
5. Ally R, Schürmann D, Kreisel W, et al. A randomized, double-blind, double-dummy, multicenter trial of voriconazole and fluconazole in the treatment of esophageal candidiasis in immunocompromised patients. Clin Infect Dis 2001; 33: 1447-1454.
6. Monastirli A, Pasmatzi E, Vryzaki E, Georgiou S, Tsambaos D. Fluconazole-induced Stevens-Johnson syndrome in a HIV-negative patient. Acta Derm Venereol 2008; 88: 521-522.
7. Heikkilä H, Timonen K, Stubb S. Fixed drug eruption due to fluconazole. J Am Acad Dermatol 2000; 42: 883-8
8. Neuhaus G, Pavic N, Pletscher M. Anaphylactic reaction after oral fluconazole. BMJ 1991; 302: 1341.

9. Jacobson MA, Hanks DK, Ferrell LD. Fatal acute hepatic necrosis due to fluconazole. Am J Med 1994; 96: 188-190.
10. Franklin IM, Elias E, Hirsch C. Fluconazole-induced jaundice. Lancet 1990; 336: 565.
11. Wells C, Lever AM. Dose-dependent fluconazole hepatotoxicity proven on biopsy and rechallenge. J Infect 1992; 24: 111-112.
12. Muńoz P, Moreno S, Berenguer J, Bernaldo de Quirós JC, Bouza E. Fluconazole-related hepatotoxicity in patients with acquired immunodeficiency syndrome. Arch Intern Med 1991; 151: 1020-1021.
13. Bronstein JA, Gros P, Hernandez E, Larroque P, Molinié C. Fatal acute hepatic necrosis due to dosedependent fluconazole hepatotoxicity. Clin Infect Dis 1997; 25: 1266-1267.
14. Girois SB, Chapuis F, Decullier E, Revol BG. Adverse effects of antifungal therapies in invasive fungal infections: review and meta-analysis. Eur J Clin Microbiol Infect Dis 2006; 25: 138-149.
15. García Rodríguez LA, Duque A, Castellsague J, Pérez-Gutthann S, Stricker BH. A cohort study on the risk of acute liver injury among users of ketoconazole and other antifungal drugs. Br J Clin Pharmacol 1999; 48: 847-852.
16. Bonkovsky HL, Jones DP, Russo MW, Shedlofsky SI. Drug-Induced Liver Injury. In: Boyer TD, Manns MP, Sanyal AJ, (eds). Zakim and Boyer's Hepatology (6 th ed). Saint Louis: W.B. Saunders, 2012, pp 417-461.
17. Guillaume MP, De Prez C, Cogan E. Subacute mitochondrial liver disease in a patient with AIDS: possible relationship to prolonged fluconazole administration. Am J Gastroenterol 1996; 91: 1651
18. Somchit N, Hassim SM, Samsudin SH. Itraconazole and fluconazole-induced toxicity in rat hepatocytes: a comparativein vitro study. Hum Exp Toxicol 2002; 21: 43-48.
19. Rodriguez RJ, Acosta D. Metabolism of ketoconazole and deacetylated ketoconazole by rat hepatic microsomes and flavin-containing monooxygenases. Drug Metab Dispos 1997; 25: 772-777.
20. Rodriguez RJ, Acosta Jr D. N-Deacetyl ketoconazoleinduced hepatotoxicity in a primary culture system of rat hepatocytes. Toxicology 1997; 117: 123-131.
21. Crerar-Gilbert A, Boots R, Fraenkel D, MacDonald GA. Survival following fulminant hepatic failure from fluconazole induced hepatitis. Anaesth Intensive Care 1999; 27: 650-652.
22. Trujillo MA, Galgiani JN, Sampliner RE. Evaluation of hepatic injury arising during fluconazole therapy. Arch Intern Med 1994; 154: 102-104.
23. Sunny AL, Bennett LP. Pulmonary and hepatic toxicity due to nitrofurantoin and fluconazole treatment. Ann Pharmacother 2004; 38: 612-616.
24. Thai KE, Sinclair RD. Spironolactone-induced hepatitis. Australas J Dermatol 2001; 42:180-182.
25. Schumaker AL, Okulicz JF. Meropenem-induced vanishing bile duct syndrome. Pharmacotherapy 2010; 30: 9
26. Lee TH, Vega KJ, El Khoury JG. Ranitidine induced hepatitis. J Gastrointestin Liver Dis 2010; 19: 3373
27. Hiratzka LF, Bakris GL, Beckman JA, et al. 2010 ACCF/AHA/AATS/ACR/ASA/SCA/SCAI/SIR/STS/S VM guidelines for the diagnosis and management of patients with Thoracic Aortic Disease: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, American Association for
28. Thoracic Surgery, American College of Radiology, American Stroke Association, Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, Society of Interventional Radiology, Society of Thoracic Surgeons, and Society for Vascular Medicine. Circulation 2010; 121: 266-369.