Lack of Cross‐Hepatotoxicity between Fluconazole and Voriconazole

Sir—A recent letter to the editor from Potoski and Brown [1] addressed the issue of voriconazole hepatotoxicity. These authors nicely summarized the available data regarding the incidence of abnormal liver function test (LFT) results during voriconazole treatment. They also cited data suggesting the incidence of hepatotoxocity during voriconazole treatment is greater than that seen during fluconazole treatment for esophageal candidiasis. However, to our knowledge, no data are currently available addressing the issue of fluconazole and voriconazole cross-hepatotoxicity (Helen Boucher, personal communication). In this regard, we recently cared for a patient with coccidioidal meningitis who developed hepatotoxicity related to fluconazole but subsequently tolerated voriconazole therapy. The patient was a 32-year-old Hispanic man with a history of type I diabetes mellitus who presented with headache and nuchal rigidity; a cavitary lesion was revealed by a chest radiograph, and analysis of CSF samples obtained by lumbar puncture revealed a lymphocytic pleocytosis. The patient began to receive empirical treatment with fluconazole, 1200 mg iv per day, for possible fungal meningitis, and also an oral regimen of isoniazid 300 mg q.d., rifampin 600 mg q.d., pyrazinamide 1500 mg q.d., and ethambutol 1200 mg q.d., for possible tuberculous meningitis. On the first day of azole treatment, the patient's LFT results were normal, including a total bilirubin level of 0.6 mg/dL, an alkaline phosphatase level of 45 mU/mL, an apartate aminotransferase (AST) level of 13 mU/mL, and an alanine aminotransferase (ALT) level of 20 mU/mL (figure 1). The patient's serum C. immitis complement-fixation titer was subsequently determined to be positive, at 1 : 8, and Coccidioides immitis grew from a CSF sample, confirming the diagnosis of coccidioidal meningitis. Consequently, all antituberculous therapy was discontinued on day 7 of fluconazole therapy. The only other medications the patient received during this time were insulin and acyclovir, and acyclovir therapy was also stopped on day 7 of fluconazole treatment. Changes in transaminases levels following initiation of azole therapy. Flu, fluconazole; Vori, voriconazole (400 mg iv q12h for 2 doses, then 300 mg iv q12h); AmB, amphotericin B deoxycholate (0.7 mg/kg iv q.d.); ABLC, amphotericin B lipid complex (10 mg/kg iv q.d.). An increase in the patient's transaminase levels was first noted on day 13 of azole therapy, and the transaminase levels continued to increase until day 17 of azole treatment, at which time the fluconazole dosage was lowered to 400 mg iv per day, resulting in a temporary decrease in transaminase levels (figure 1). However, within several days, the transaminase levels rose again, peaking on day 22 of azole therapy at an ALT concentration of 967 mU/mL and an AST concentration of 378 mU/mL. Although the total bilirubin level remained normal, the alkaline phosphatase level also increased to 132 mU/mL on that same day. Other medications the patient received during this time included fluoxetine, fludrocortisone, prednisone, famotidine, several doses of intracisternal amphotericin B deoxycholate, and intravenous amphotericin B deoxycholate, the last of which was administered at a dosage of 0.7 mg/kg per day from days 17 to 20 of fluconazole treatment. On the basis of the extreme elevation of the transaminase levels, fluconazole therapy was stopped after 22 days of treatment, and voriconazole therapy was initiated at a dosage of 400 mg iv q12h, for 2 doses, and continued at a dosage of 300 mg iv q12h (figure 1). Both the ALT and AST levels steadily decreased following initiation of voriconazole treatment, and the alkaline phosphatase level normalized. No other medications were discontinued from the drug regimen during this time; several medications were added, including levetiracetam for seizure prophylaxis and, on day 2 of voriconazole therapy (day 24 of azole therapy), amphotericin B lipid complex at a dosage of 10 mg/kg per day iv. After 8 days of voriconazole treatment (30 days of azole therapy), the AST level had decreased to 43 mU/mL and the ALT level had decreased to 164 mU/mL. Voriconazole therapy was therefore stopped, and the patient was rechallenged with fluconazole therapy at a dosage of 400 mg iv q.d. (figure 1). The patient's transaminase levels immediately rose again over the next 2 days, to an AST level of 72 mU/mL and an ALT level of 209 mU/mL. Because of this increase, on day 32 of azole therapy, treatment with fluconazole was again stopped and voriconazole therapy was reinitiated at a dosage of 300 mg iv q12h (figure 1). Within 2 days, the AST level had normalized and the ALT level had decreased to 143 mU/mL. No other medications were added to or removed from the regimen from days 30 to 34 of azole therapy. The patient was never hypotensive during the hospitalization. Unfortunately, the patient developed obstructive hydrocephalus while receiving therapy and subsequently suffered multiple bilateral cerebral infarcts involving the frontal, parietal, and occipital lobes, as well as the brainstem. He died on day 35 of azole therapy. Although fluconazole-induced hepatotoxicity is rare (incidence, < 5%), it is well described [2]. The timing of the decreases in this patient's transaminase levels correlated exactly with a decrease in the dosage of fluconazole and cessation of fluconazole administration, whereas rechallenge with fluconazole led to a recurrent increase in his transaminase levels. The only other potentially hepatotoxic agents to which the patient was exposed were isoniazid, rifampin, and pyrazinamide. However, he received these drugs during only the initial 6 days of therapy, and treatment with them was stopped 1 week before the rise in transaminase levels was first noted and 3 weeks before the transaminase levels peaked. Although acetaminophen (650 mg q.d. for 4 days) was administered as premedication foramphotericin B dioxycholate therapy (on days 17 to 20 of fluconazole therapy), it is unlikely that such a small dosage could mediate severe hepatotoxicity. Thus, on the basis of the timing of fluconazole administration and the lack of exposure to other hepatotoxic drugs, we think that fluconazole therapy was the likely etiology of this patient's elevated transaminase levels. In both instances when voriconazole was substituted for fluconazole, the transaminase levels steadily decreased towards normal. Our experience with this patient therefore provides evidence that fluconazole and voriconazole are not necessarily cross-hepatotoxic, and suggests that voriconazole may be cautiously substituted for fluconazole in the treatment of patients with fluconazole-induced hepatotoxicity who require azole therapy for mycotic infections.