Consequences of Fluconazole Drug-Drug Interactions

DONGHUI T. YU, MD, MPH,MA; JOSH F. PETERSON, MD,TN; DIANE SEGER, RPh,MA; WILLIAM C. GERTH,DAVID W. BATES, MD,

Author address: 

Brigham and Women’s Hosp., Harvard Med. Sch., WellesleyUniv. Med. Ctr., Nashville,

Abstract: 

Background: Fluconazole is indicated and widely used for the treatment of systemic fungal infections. Studies have shown that fluconazole interacts with many drugs, resulting in pharmacokinetic changes of either fluconazole or the interacting drugs. However, little is known regarding the consequences of fluconazole interactions in routine clinical practice. Methods: Using a hospital clinical information system, we identified a cohort of 3,953 hospitalized patients treated for systemic fungal infections with an oral or intravenous fluconazole between 7/97 and 6/01 in a single tertiary care hospital. We then identified a sub-cohort of 711 patients concomitantly prescribed a second drug known to have a major drug-drug interaction (DDI) with fluconazole and performed a chart review on a random sample of 100 of these patients. The list of fluconazole-interacting medications and the severity level of interaction were derived using the DRUGDEX® System and Drug Interaction Facts. We assessed the frequency of adverse drug events (ADEs) associated with DDIs involving fluconazole. Results: Of 100 patients with major DDIs, 47 were on a surgical service, and 56 were in an intermediate ward or ICU setting when fluconazole therapy was initiated; 37 had the documentation of fungus in blood or urine as the indication for fluconazole use; 71 experienced multiple incidents of DDIs. Among 240 incidents of DDIs in these 100 patients, 107 were of major severity, 107 were moderate, 26 were minor. In this group, only one potential ADE was found, caused by a fluconazole-warfarin interaction resulting in an increased INR, although no active bleeding occurred. Conclusions: Fluconazole-drug interactions with potential major severity were common, occurring in 18% of hospitalized patients on systemic fluconazoleview of the recent availability of new drugs such as voriconazole (VRC) and caspofungin (CAS) for the treatment of IA, testing of the in vitro susceptibility of a Aspergillus spp might have important implications for the choice of antifungal treatment. Methods: We measured (in triplicate) the in vitro susceptibility (MICs, MEC [CAS], MFCs) of 112 Aspergillus clinical isolates (44 A. fumigatus, 29 A. terreus, 21 A. flavus, 18 A. niger) to amphotericin B (AMB), itraconazole (ITZ), VRC and CAS. We also assessed whether there are differences in susceptibility of Aspergillus isolates recovered from patients with definite/probable IA (n78) versus isolates recovered from patients with colonization by Aspergillus spp (n34) (EORTC/MSG criteria). Results: VRC exhibited enhanced in vitro fungicidal activity against Aspergillus spp compared to AMB and ITZ (P 0.001). The CAS MEC values were also low. A. terreus was less susceptible to all antifungals. VRC and CAS were the most active drugs against A. terreus. No differences in isolate susceptibility were observed between definite/probable IA cases vs. colonization. Conclusions: VRC and CAS have better in vitro activity against Aspergillus spp than that of the established agents AMB and ITZ. In contrast to CAS, VRC has fungicidal activity against Aspergillus spp, including A. terreus. In vitro susceptibility does not differentiate colonizing vs. invasive Aspergillus isolates.
2003

abstract No: 

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Full conference title: 

41st Annual Meeting Infectious Diseases Society of America
    • Infectious Diseases Society of America 41st