Nationwide Survey of In Vitro Activities of Itraconazole and Voriconazole against Clinical Aspergillus fumigatus Isolates Cultured between 1945 and 1998

Abstract

The isolates in a collection of 170 Aspergillus fumigatus isolates recovered from 114 patients and 21 different medical centers in The Netherlands over a period of 53 years were tested for the presence of resistance to itraconazole and voriconazole according to the guidelines of NCCLS document M38-P and by the E-test. Three isolates were highly resistant to itraconazole, and voriconazole MICs were low for all isolates.Over the past few decades the incidence of invasive fungal infections has increased, especially those caused by Aspergillus species (11, 16). The treatment of choice for infected patients remains amphotericin B, although alternative drugs with activities against Aspergillus species are becoming available for clinical use, including the antifungal azoles itraconazole and voriconazole. Itraconazole is highly active against Aspergillus species but has been used almost exclusively as follow-up therapy in patients with invasive aspergillosis. However, with the availability of a new intravenous formulation of itraconazole and an oral solution, first-line therapy may become an option (1). Voriconazole is active against a wide range of filamentous molds including Aspergillus species. The drug can be administered both intravenously and orally and was found to be superior to amphotericin B as first-line therapy for the treatment of invasive aspergillosis ( Although testing of the susceptibilities of Aspergillus fumigatus isolates to amphotericin B in vitro is problematic, resistance to azoles can be detected (3,5,6). The in vitro resistance of A. fumigatus to itraconazole was confirmed by use of animal experimental models (3, 5). However, the prevalence of resistance to itraconazole and voriconazole among A. fumigatus isolates is unknown. In the present study we investigated the prevalence of resistance among A. fumigatus isolates that had been cultured from patients admitted to hospitals throughout The Netherlands.(This work was presented in part at the 38th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Diego, Calif., 24 to 27 September 1998.) Medical microbiology laboratories in The Netherlands were asked to send A. fumigatus isolates that had been cultured from clinical samples at their hospitals. In addition, the database of the collection of the Centraalbureau voor Schimmelcultures (CBS) was searched for A. fumigatus isolates that had been cultured from clinical specimens from Dutch patients. The isolates were subcultured onto Sabouraud glucose agar plates supplemented with 0.5% chloramphenicol; the plates were incubated at 29°C for 7 days, and the identifications were confirmed. Candida parapsilosis ATCC 22019 and Candida krusei ATCC 6258 were used as quality controls. In addition, an itraconazole-susceptible A. fumigatus isolate (isolate AF71; MIC, 0.25 g/ml) and an itraconazole-resistant A. fumigatus isolate (isolate AF91; MIC, Ͼ64 g/ml) were included in each test (5).Reference-grade lots of itraconazole (Janssen-Cilag, Tilburg, The Netherlands) and voriconazole (Pfizer Centra...

In Vitro Susceptibilities of Clinical Isolates of Candida Species, Cryptococcus neoformans , and Aspergillus Species to Itraconazole: Global Survey of 9,359 Isolates Tested by Clinical and Laboratory Standards Institute Broth Microdilution Methods

“…Certainly a great deal of attention has been paid to the new triazoles (e.g., voriconazole, posaconazole, and ravuconazole), with their potency and improved spectrum of activity, including activity against fluconazole-resistant Candida spp., C. neoformans, and Aspergillus spp. (6,7,12,13,22,24,32,33,37,38). Despite the wellfounded enthusiasm for the new antifungal agents, it is important to continue to assess the activity of the older, more established agents, especially those, such as itraconazole, for which the development of new formulations has overcome some of the major deficiencies (i.e., bioavailability) of the drug when it was first introduced (2-5, 10, 16, 18, 19, 29, 36, 39, 40).…”

“…Despite the wellfounded enthusiasm for the new antifungal agents, it is important to continue to assess the activity of the older, more established agents, especially those, such as itraconazole, for which the development of new formulations has overcome some of the major deficiencies (i.e., bioavailability) of the drug when it was first introduced (2-5, 10, 16, 18, 19, 29, 36, 39, 40). The inherent potency and broad spectrum of itraconazole (1,5,13,16,17,22,24,29,38), coupled with the availability of an intravenous formulation (IVF), suggests that the use of itraconazole as first-line therapy for some of the opportunistic mycoses may well become an option (29).…”

Aspergillus Monitoring Project in a Large Educational Hospital Using Molecular Assay

“…Patients with severe, prolonged, granulocytopenia, especially bone-marrow transplant recipients, are at the highest risk. A. fumigatus and A. flavus are the most frequently isolated species in patients with proven aspergillosis (Verweij et al, 2002). The presence of invasive disease may be inferred by the clinical symptoms and signs, and images obtained by CT scanning etc.…”

“…Recently, some immunological and molecular tests were used for the identification of Aspergillus species causing HAIs (Verweij et al, 2002;Healy et al, 2004). Different molecular methods such as restriction fragment length polymorphism (RFLP) based on amplification of ribosomal RNA have been employed to identify Aspergilli in the level of species (Moody and Tyler, 1990).…”

In Vitro Interactions between Amphotericin B, Itraconazole, and Flucytosine against 21 Clinical Aspergillus Isolates Determined by Two Drug Interaction Models

“…The isolates with the AZN prefix were obtained from the private collection of the Department of Medical Microbiology, University Medical Center Nijmegen, Nijmegen, The Netherlands, and isolate AZG 7 was obtained from the University Hospital Groningen, Groningen, The Netherlands (30). Isolates had been frozen in glycerol broth at Ϫ80°C and were revived by subculturing them on Sabouraud glucose agar tubes supplemented with 0.5% chloramphenicol and incubating them for 5 to 7 days at 35°C.…”