European experience with itraconazole in systemic mycoses

doi:10.1016/0190-9622(90)70260-O

Journal of the American Academy of Dermatology

Volume 23, Issue 3, Part 2, September 1990, Pages 587-593

https://doi.org/10.1016/0190-9622(90)70260-O Get rights and content

Since January 1985 more than 100 patients with deep fungal infections have been treated with itraconazole (200 to 400 mg/day) in Northern Italy. Evaluation of the drug efficacy and tolerance was possible in one patient with sporotrichosis, in 34 with aspergillosis, and in 36 with cryptococcosis (mainly patients positive for human immunodeficiency virus). Response to itraconazole alone was obtained in the case of sporotrichosis and in 24 of 34 patients with different forms of aspergillosis (of the 18 patients with invasive pulmonary aspergillosis,15 were cured). Patients with cryptococcosis received itraconazole for active infection and/or for prevention of relapse. Active infection was treated successfully with itraconazole alone in 9 of 12 patients and with itraconazole plus flucytosine in 8 of 10 patients. Of the 31 patients who received itraconazole maintenance therapy for up to 27 months, 4 (l3%) had relapses; 14 (45%) did not have relapses, and decline of serum antigen was detected in 12 of them; and 13 (42%) were completely cured (serum antigen titer dropped to zero). With the exception of hypokalemia in one patient, itraconazole was well tolerated even in patients who received the drug for several months or years.

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Synergysm of voriconazole or itraconazole with other antifungal agents against species of Fusarium
2013, Revista Iberoamericana de Micologia
Citation Excerpt :
The combinations of FCY + ITZ or KTZ or posaconazole in animal models have resulted in improvements in survival12,27 and tissue clearance31 in cases of cryptococal meningitis. In addition, in a clinical case series of systemic mycosis the outcomes with ITZ + FCY were comparable or better than those for ITZ alone.32 The azole damages the fungal cell membrane, enabling increased uptake of flucytosine.
Infections caused by Fusarium are difficult to treat because these fungi show in vitro and in vivo resistance to practically all the antifungal agents available, which explains the high mortality rates. An attempt to overcome fungal resistance is the combination of antifungal agents, especially those with different mechanisms of action.
Evaluate the in vitro interactions of combinations of voriconazole or itraconazole with other antifungal agents against 32 isolates of Fusarium spp.: Fusarium chlamydosporum, Fusarium oxysporum, Fusarium proliferatum and Fusarium solani.
Drug interactions were assessed by a checkerboard microdilution method that also included the determination of the MIC of each drug alone according to CLSI (Clinical and Laboratory Standards Institute) document M38-A2, 2008.
The best combinations were voriconazole + terbinafine which showed synergism against 84% of Fusarium strains. Other synergistic combinations were voriconazole + itraconazole (50%), voriconazole + fluconazole (50%), voriconazole + miconazole (38%), voriconazole + flucytosine (22%) and voriconazole + ketoconazole (25%). The synergisms observed with itraconazole combinations were itraconazole + terbinafine (25%) and itraconazole + flucytosine (9.37%). The antagonisms observed were: voriconazole + fluconazole (3%) and itraconazole + flucytosine (12.5%).
The synergism showed by voriconazole + terbinafine was remarkable. To better elucidate the potential usefulness of our findings, new in vivo and in vitro studies deserve be performed.
Las micosis causadas por Fusarium son difíciles de tratar porque tanto in vivo como in vitro estos hongos muestran resistencia a casi todos los fármacos antimicóticos disponibles, lo que explica las altas tasas de mortalidad. Una tentativa de resolver la resistencia fúngica es combinar los fármacos antifúngicos, en especial los preparados con mecanismos de acción diferentes.
Valorar las interacciones in vitro de la combinación de voriconazol o itraconazol con otros fármacos antimicóticos frente a 32 aislamientos de Fusarium spp: Fusarium chlamydosporum, Fusarium oxysporum, Fusarium proliferatum y Fusarium solani.
Las interacciones farmacológicas se valoraron con el método de microdilución en tablero de ajedrez, que también incluyó la determinación de la concentración inhibitoria mínima de cada fármaco por separado de acuerdo con el documento M38-A2, 2008, del Clinical and Laboratory Standards Institute.
Las mejores combinaciones fueron voriconazol + terbinafina que mostró sinergia frente al 84% de los aislamientos de Fusarium. Otras combinaciones sinérgicas fueron: voriconazol + itraconazol (50%), voriconazol + fluconazol (50%), voriconazol + miconazol (38%), voriconazol + flucitosina (22%) y voriconazol + ketoconazol (25%). Las sinergias observadas con las combinaciones de itraconazol fueron itraconazol + terbinafina (25%), e itraconazol + flucitosina (9,37%). Los antagonismos observados fueron voriconazol + fluconazol (3%) e itraconazol + flucitosina (12,5%).
La sinergia observada con voriconazol + terbinafina fue extraordinaria. Para dilucidar mejor la utilidad potencial de los hallazgos del presente estudio, han de realizarse nuevos estudios tanto in vivo como in vitro.
Antifimgal agents. part ii. the azoles
1999, Mayo Clinic Proceedings
Before 1978, amphotericin Band flucytosine were the only drugs available for the treatment of systemic fungal infections. The imidazoles, miconazole and ketoconazole, were introduced during the next 3 years. Intravenously administered miconazole served a limited therapeutic role and is no longer available. Orally administered ketoconazole, an inexpensive, effective, and convenient option for treating mucosal candidiasis, was widely used for a decade because it was the only available oral therapy for systemic fungal infections. During the 1990s, use of ketoconazole diminished because of the release of the triazoles fluconazole and itraconazole. Fluconazole is less toxic and has several pharmacologic advantages over ketoconazole, including penetration into the cerebrospinal fluid. In addition, it has superior efficacy against systemic candidiasis, cryptococcosis, and coccidioidomycosis. Despite a myriad of drug interactions and less favorable pharmacologic and toxicity profiles in comparison with fluconazole, itraconazole has become a valuable addition to the antifungal armamentarium. It has excellent activity against sporotrichosis and seems promising in the treatment of aspergillosis. Itraconazole has replaced ketoconazole as the therapy of choice for nonmeningeal, non-life-threatening cases of histoplasmosis, blastomycosis, and paracoccidioidomycosis and is effective in patients with cryptococcosis and coccidioidomycosis, including those with meningitis. Further investigation into the development of new antifungal agents is ongoing.
Endemic pulmonary mycoses
1998, Seminars in Pediatric Infectious Diseases
Fungal infections are seen with increasing frequency in the pediatric age group. Aspergillus fumigatus, Coccidioides immitis, Cryptococcus neoformans, Blastomyces dermatitidis, and Histoplasma capsulatum all have a spectrum of illness ranging from asymptomatic exposure to significant pulmonary and disseminated disease. Coccidiomycosis, blastomycosis, and histoplasmosis are seen in well-described endemic regions. Diagnosis can be made by the identification of the causative organism. New serological and chemical methods may provide a more rapid and complete diagnosis. Amphotericin B has been the mainstay of treatment, but oral azole antifungal agents now provide a less toxic altermative in some cases and allow for treatment of less severe pulmonary mycotic infections.
Pulmonary aspergillosis and invasive disease in AIDS: Review of 342 cases
1998, Chest
Aspergillosis is an infrequent but commonly fatal infection among HIV-infected individuals. We review 342 cases of pulmonary Aspergillus infection that have been reported among HIV-infected patients, with a focus on invasive disease. Invasive pulmonary aspergillosis usually occurs among patients with <50 CD4 cells/mm³. Major predisposing conditions include neutropenia and steroid treatment. Fever, cough, and dyspnea are each present in >60% of the cases. BAL is often suggestive, but biopsy specimens are necessary for definite diagnosis. Amphotericin B is the mainstay of treatment and mortality is >80%. Avoiding neutropenia and judicious use of steroids may be helpful in prevention. Aggressive diagnostic approach, early initiation of treatment, adequate dosing of antifungals, and close follow-up may improve the currently dismal prognosis.
Clinical Pharmacology of Systemic Antifungal Agents:A Comprehensive Review of Agents in Clinical Use, Current Investigational Compounds, and Putative Targets for Antifungal Drug Development
1998, Advances in Pharmacology
Use of Azoles for Systemic Antifungal Therapy
1997, Advances in Pharmacology
The azole antifungal agents have expanded the armamentarium of agents useful in the treatment of systemic fungal infections. Clotrimazole, an early imidazole antifungal, proved was found to rapidly induce its own metabolism after oral or intravenous administration. Its use is now confined to topical therapy. Miconazole is toxic and its availability is only as an intravenous formulation. Ketoconazole, the first oral imidazole, has proved useful for a wide variety of fungal infections. This chapter focuses on the use of these four azole agents that have proved beneficial in treating systemic fungal infections. The imidazole compounds contain a five member azole ring with two nitrogen atoms. The triazoles have a third nitrogen atom added. The triazole ring increases tissue penetration, prolongs half-life, and enhances efficacy of the azoles while decreasing the toxicity when compared with imidazole antifungal agents. Azoles inhibit the biosynthesis of ergosterol, a component of fungal cell membranes, via inhibition of the cytochromes P450-dependent enzyme lanosterol14-α-demethylase.Lanosterol14-α-demethylase is necessary for the conversion of lanosterol to ergosterol. Depletion of ergosterol in the fungal cell membrane results in altered membrane fluidity, thereby reducing the activity of membrane-associated enzymes. This leads to increased permeability and subsequent inhibition of cell growth and replication. The binding efficiency of azole antifungal agents to cytochromes P450 differs, resulting in differences in antifungal activity, toxicity of the agents, and the drug interactions with other cytochrome P45O-metabolized drugs. The chapter details the antifungal activity of the azoles, their pharmacology, clinical use, side effects, and administration. Drug interactions with azole antifungals are of two categories—decreases in azole bioavailability because of chelation or secondary to increases in gastric pH; and interactions with other cytochrome P45O-metabolized drugs. Drug interactions in the second category may result in increases or decreases in the azole antifungal, in the interacting drug, or in both drugs.

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: Supported in part by grants from Ministero della Sanita, Instituto Superiore di Sanita, Roma. Secondo Progetto di Ricerche sull'AIDS 1989. Contratto di Ricerco N. 4203 25.

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European experience with itraconazole in systemic mycoses

Itraconazole, a new triazole that is orally active in aspergillosis

Antimicrob Agents Chemother

Experience with itraconazole in deep mycoses in Northern Italy

Mykosen