title: Interaction of azoles with rifampin, phenytoin, and carbamazepine: in vitro and clinical observations.
abstract: Twelve patients receiving therapy with an azole agent (ketoconazole, itraconazole, and/or fluconazole) for systemic mycoses experienced drug interactions with rifampin, phenytoin, and/or carbamazepine resulting in substantial decreases in azole concentrations in serum. All four patients receiving azoles and concurrent phenytoin and/or carbamazepine failed to respond to treatment or suffered a relapse of their fungal infection. Four of five patients with cryptococcosis who received itraconazole and rifampin responded despite decreases in their serum itraconazole concentrations; synergy between itraconazole and rifampin was documented by in vitro analysis of inhibition and of killing of Cryptococcus neoformans isolates from all patients receiving this combination. In contrast, two patients with coccidioidomycosis failed to respond to itraconazole/rifampin. Moreover, two patients with cryptococcosis suffered a relapse or persistence of seborrheic dermatitis while receiving itraconazole/rifampin. The latter combination showed synergy in vitro in the inhibition of the mycelial phase of Coccidioides immitis and, to a lesser extent, of the pathogenic spherule phase of this fungus; synergy in the killing of C. immitis was not noted, nor was synergy seen against Malassezia furfur, the purported etiologic agent of seborrheic dermatitis. These findings illustrate several drug interactions that may affect clinical outcome and that must be considered in the management of antifungal therapy.
authors.affiliation: Department of Medicine, Santa Clara Valley Medical Center, San Jose, California 95128.
authors.forename: R M
authors.initials: RM
authors.lastname: Tucker
authors.forename: D W
authors.initials: DW
authors.lastname: Denning
authors.forename: L H
authors.initials: LH
authors.lastname: Hanson
authors.forename: M G
authors.initials: MG
authors.lastname: Rinaldi
authors.forename: J R
authors.initials: JR
authors.lastname: Graybill
authors.forename: P K
authors.initials: PK
authors.lastname: Sharkey
authors.forename: D
authors.initials: D
authors.lastname: Pappagianis
authors.forename: D A
authors.initials: DA
authors.lastname: Stevens
mesh_terms: D000328:Adult; D000368:Aged; D000935:Antifungal Agents / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D001393:Azoles / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D002220:Carbamazepine / Q000494:pharmacology* / Q000627:therapeutic use; D003045:Coccidioides / Q000187:drug effects; D003455:Cryptococcus neoformans / Q000187:drug effects; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D005260:Female; D015725:Fluconazole / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D017964:Itraconazole; D007654:Ketoconazole / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D008290:Malassezia / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D009181:Mycoses / Q000188:drug therapy; D010672:Phenytoin / Q000494:pharmacology* / Q000627:therapeutic use; D012293:Rifampin / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000935:Antifungal Agents; D001393:Azoles; D017964:Itraconazole; D002220:Carbamazepine; D010672:Phenytoin; D015725:Fluconazole; D007654:Ketoconazole; D012293:Rifampin