High-dose itraconazole in the treatment of severe mycoses

Abstract

Eight patients with systemic mycoses and with prior treatment failures were treated with itraconazole (600 mg/day) for a mean duration of 5.5 months. All six patients without AIDS experienced improvement or stabilization of their fungal infections while receiving high-dose itraconazole, although two patients later experienced treatment failures, one by relapse and one by progression, on lower doses. Treatment failures also occurred in the two patients with AIDS and cryptococcal meningitis. The failures were associated with low serum itraconazole concentrations (<2.5 ,ug/ml) in both patients. All other patients had mean trough levels in serum above 5 ,ug/ml. One patient who was improving on 600 mg/day developed a progressive infection after reduction of the dose to 400 mg/day. Side effects included reversible adrenal insufficiency in one patient; severe hypokalemia, mild diastolic hypertension, and rhabdomyolysis in one patient; mild hypokalemia and hypertension in four other patients; and breast tenderness in one patient. The mean decrease in serum potassium during treatment was statistically significant (P = 0.05). Selected patients with severe systemic mycoses may benefit from prolonged high-dose itraconazole treatment. However, 600 mg/day may be approaching the upper limits of acceptable dosing for long-term treatment.

Iatrogenic adrenal insufficiency as a side-effect of combined treatment of itraconazole and budesonide

“…Some authors have suggested the possibility of drug-induced Conn9s syndrome during itraconazole treatment due to the presence of hypokalemia, oedema and hypertension [25,[44][45][46]. In the present study normal plasma-renin levels indicate that no involvement of mineralocorticoid secretion was present in any of the patients.…”

“…However, suppression of gonadal steroids was not observed in any patient in the present study. Itraconazole has been reported to have a greater sensitivity for 11b-hydroxylase and a relative sparing of the C17-20 lyase enzyme activity (and androgen activity) [25,26,34], which may explain the finding of adrenal but no gonadal suppression.…”

“…Thus, Cushing9s syndrome in this patient may be explained by an increased systemic concentration of budesonide due to inhibition of CYP3A4, and in turn, suppression of pituitary ACTH production leading to adrenal insufficiency. In addition, steroidogenesis in the adrenals may be suppressed by itraconazole [25].…”

“…dexamethasone and methylprednisolone [17]. Although other azole compounds (itraconazole, fluconazole and miconazole) have a higher affinity to the fungal than the human enzyme system and are assumed to induce less side-effects [26,27,31], these drugs may also compromise the adrenal function when given in high doses and over long periods of time [25].…”

Efficacy of intravenous itraconazole against experimental pulmonary aspergillosis

“…It is possible, however, that the immunosuppression and the rapid rate of injection of the drug contributed to the apparent toxicity. Sharkey et al reported that toxicity is common with clinical doses of more than 400 mg of oral itraconazole per day (23).…”