New Antifungal Drugs for Pulmonary Mycoses

chronic necrotizing pulmonary aspergillosis cerebrospinal fluid progressive disseminated histoplasmosis Amphotericin B has been the standard therapy for most serious fungal infections since the 1950s. However, amphotericin B use is frequently limited by adverse effects such as fever, rigors, hypotension, and nephrotoxicity.1Gallis HA Drew RH Pickard WW. Amphotericin B: 30 years of clinical experience.Rev Infect Dis. 1990; 12: 308-329Crossref PubMed Scopus (927) Google Scholar With the increasing numbers of immunocompromised patients due to cytotoxic chemotherapy, organ transplantation, and AIDS, the number of invasive fungal diseases due to the endemic mycoses, histoplasmosis, and coccidioidomycosis, as well as to the opportunistic fungi, Cryptococcus, Aspergillus, and unusual pathogens, has increased markedly. The need for new antifungal drugs that are well tolerated, orally administered, and have a broad spectrum of activity has resulted in the development of the new azole antifungal agents, fluconazole and itraconazole. The nephrotoxicity of amphotericin B has been reduced in the novel formulations of liposomal amphotericin B, amphotericin B colloidal dispersion, and amphotericin B lipid complex, but improved clinical outcomes have not yet been convincingly demonstrated. These new antifungal agents offer alternative therapy to amphotericin B for many invasive fungal diseases, and in some instances have become the preferred agents for the treatment of disseminated fungal infection.ANTIFUNGAL AGENTSThe azole antifungal agents are comprised of the imidazole and triazole groups. These agents are structurally similar with a five-numbered azole ring containing either two or three nitrogens (Fig 1). The imidazoles, miconazole and ketoconazole, have been available for many years but have a narrower spectrum of activity, more adverse effects, and a shorter half-life than the newer triazole agents, fluconazole and itraconazole.All azole drugs have the same mechanism of action, ie, interfering with ergosterol synthesis in the cell membrane of yeasts and fungi by binding to the cytochrome P-450 mediated enzyme, 14 alphademethy-lase. This results in the accumulation of 14-methylated ergosterol precursors that destabilize the cell membrane leading to inhibition of cell growth and ultimately to cell death.2Vanden Bossche H. Itraconazole: a selective inhibitor of the cytochrome p-450 dependent ergosterol biosynthesis.in: Fromtling RA Recent trends in the discovery, development, and evaluation of antifungal agents. JR Prous Science Publishers, Barcelona, Spain1987: 207-221Google Scholar The first oral azole drug, keta-conazole, has been useful for the treatment of various forms of candidiasis, nonmeningeal histoplasmosis, blastomycosis, paracoccidioidomycosis, and nonmeningeal coccidioidomycosis. Activity against non-albicans species of Candida, Cryptococcus, aspergillosis, and extracutaneous sporotrichosis is poor or nonexistent. Ketoconazole has been associated with a number of troublesome adverse effects, including anorexia and GI intolerance, hepatitis, depression of testosterone and adrenocorticotropic hormone-stimulated cortisol response, gynecomastia, impotence, and rash, limiting its use.3Lewis JH Zimmerman HJ Benson GD et al.Hepatic injury associated with ketoconazole therapy: analysis of 33 cases.Gastroenterology. 1984; 86: 503-513Abstract Full Text PDF PubMed Scopus (326) Google Scholar, 4National Institute of Allergy and Infectious Diseases Mycoses Study GroupTreatment of blastomycosis and histoplasmosis with ketoconazole: results of a prospective randomized clinical trial.Ann Intern Med. 1985; 103: 861-872Crossref PubMed Google Scholar, 5Sugar AM Alsip SG Galgiani JN et al.Pharmacology and toxicity of high-dose ketoconazole.Antimicrob Agents Chemother. 1987; 31: 1874-1878Crossref PubMed Scopus (106) Google Scholar, 6Pont A Williams PL Loose DS et al.Ketoconazole inhibits adrenal steroid synthesis [abstract].Clin Res. 1982; 30: 520AGoogle Scholar, 7Pont A Williams PL Loose DS et al.Ketoconazole blocks adrenal steroid synthesis.Ann Intern Med. 1982; 97: 370-372Crossref PubMed Scopus (355) Google Scholar The absorption of ketoconazole requires an acidic environment, and is limited by the use of H2-receptor-blocking agents such as cimetidine, ranitidine, or famotidine.8Van der Meer JWM Keuning JJ Scheijgrond HW et al.The influence of gastric acidity on the bio-availability of ketoconazole [letter].J Antimicrob Chemother. 1980; 6: 552-554Crossref PubMed Scopus (126) Google Scholar, 9Lake-Bakaar G Tom W Lake Bakaar D et al.Gastropathy and ketoconazole malabsorption in the acquired immunodeficiency syndrome (AIDS).Ann Intern Med. 1988; 109: 471-473Crossref PubMed Scopus (161) Google ScholarA number of drug interactions occur with ketoconazole. Drugs such as rifampin and phenytoin, which increase hepatic P450-dependent enzymes, increase the metabolism of ketoconazole reducing plasma levels of the drug.10Brass C Galgiani JN Blaschke TF et al.Disposition of ketoconazole, an oral antifungal in humans.Antimicrob Agents Chemother. 1982; 21: 151-158Crossref PubMed Scopus (139) Google Scholar Ketoconazole can inhibit the metabolism of cyclosporine, prolonging its half-life and increasing the risk of nephrotoxicity.11White DJG Blatchford NR Cauwenbergh G. Cyclosporine and ketoconazole.Transplantation. 1984; 37: 214-215Crossref PubMed Scopus (44) Google Scholar, 12Daaneshmend TK. Ketoconazole-cyclosporin interaction.Lancet. 1982; 2: 1342-1344Abstract Scopus (35) Google Scholar The concomitant administration of ketoconazole with terfenadine or cisapride inhibits cytochrome P450 3A4 metabolism resulting in high levels of unmetabolized terfenadine or high cisapride blood levels, which may prolong the QT interval resulting in serious cardiac arrhythmias.13Honig PK Wortham DC Samani K et al.Terfenadine-ketoconazole interaction.JAMA. 1993; 269: 1513-1518Crossref PubMed Scopus (684) Google Scholar, 14Monahan BP Ferguson CL Killeavy ES et al.Torsades de pointes occurring in association with terfenadine use.JAMA. 1990; 266: 2788-2790Crossref Scopus (597) Google ScholarThe newer triazoles, fluconazole and itraconazole, have improved therapeutic and safety profiles when compared with ketoconazole15Sugar AM. Fluconazole and itraconazole: current status.Curr Clin Topics Infect Dis. 1993; 13: 74-98PubMed Google Scholar, 16Zuckennan JM Tunkel AR. Itraconazole: a new triazole antifungal agent.Infect Control Hosp Epidemiol. 1994; 15: 397-410Crossref PubMed Google Scholar (Table 1). Fluconazole is highly water soluble, is minimally protein bound, and is distributed throughout the body water.15Sugar AM. Fluconazole and itraconazole: current status.Curr Clin Topics Infect Dis. 1993; 13: 74-98PubMed Google Scholar, 17Grant SM Clissold SP. Fluconazole: a review of its pharmaco-dynamic and pharmacokinetic properties, and therapeutic potential in superficial and systemic mycoses.Drugs. 1990; 39: 877-916Crossref PubMed Scopus (406) Google Scholar Itraconazole like ketoconazole is almost totally insoluble in water, highly lipophilic, and highly protein bound.15Sugar AM. Fluconazole and itraconazole: current status.Curr Clin Topics Infect Dis. 1993; 13: 74-98PubMed Google Scholar, 16Zuckennan JM Tunkel AR. Itraconazole: a new triazole antifungal agent.Infect Control Hosp Epidemiol. 1994; 15: 397-410Crossref PubMed Google Scholar, 17Grant SM Clissold SP. Fluconazole: a review of its pharmaco-dynamic and pharmacokinetic properties, and therapeutic potential in superficial and systemic mycoses.Drugs. 1990; 39: 877-916Crossref PubMed Scopus (406) Google Scholar Therefore, itraconazole plasma levels are low and negligible amounts of itraconazole are found in cerebrospinal fluid (CSF), but high concentrations of the drug are found in most tissues, especially skin, nails, adipose tissue, endometrium, and cervical and vaginal tissues.18Cleary JD Taylor JW Chapman SW. Itraconazole in antifungal therapy.Ann Pharmacother. 1992; 26: 502-509Crossref PubMed Scopus (45) Google ScholarIn contrast to ketoconazole and itraconazole, high concentrations of fluconazole are achieved in the CSF and urine.19Brammer KW Coakley AJ Jezequel SG et al.The disposition and metabolism of 4C fluconazole in humans.Drug Metab Dispos Biol Fate Chem. 1991; 19: 764-767PubMed Google Scholar, 20Tucker RM Williams PL Arathoon EG et al.Pharmacokinetics of fluconazole in cerebrospinal fluid and serum in human coccidioidal meningitis.Antimicrob Agents Chemother. 1988; 32: 369-373Crossref PubMed Scopus (137) Google Scholar Fluconazole penetrates well into peritoneal fluid and has been used successfully to treat fungal peritonitis.21Blum RA D'Andres DT Florentino BM et al.Increased gastric pH and the bioavailability of fluconazole and ketoconazole.Ann Intern Med. 1991; 114: 755-757Crossref PubMed Scopus (140) Google Scholar While the oral absorption of both ketoconazole and itraconazole is decreased by antacids or H2-blockers, gastric acid is not required for the absorption of fluconazole.22Levine J Bernard DB Idelson BA et al.Fungal peritonitis complicating continuous ambulatory peritoneal dialysis: successful treatment with fluconazole, a new orally active antifungal agent.Am J Med. 1989; 86: 825-827Abstract Full Text PDF PubMed Scopus (67) Google Scholar The presence of food and gastric acid increases the bioavailability of itraconazole.23Bodey GP. Azole antifungal cream.Clin Infect Dis. 1992; 14: S161-69Crossref PubMed Google Scholar Fluconazole is primarily excreted renally, while itraconazole undergoes extensive hepatic metabolism and at least one metabolite, hydroxyitraconazole, has in vitro antifungal activity.24Van Cauteren H Heykants J De Coster R et al.Itraconazole pharmacologic studies in animals and humans.Rev Infect Dis. 1987; 9: S43-46Crossref PubMed Google Scholar, 25Heykants J Van Peer AA Van de Velde P et al.The clinical pharmacokinetics of itraconazole: an overview.Mycoses. 1989; 32: 67-87Crossref PubMed Scopus (345) Google Scholar Therefore, fluconazole dosing must be adjusted in patients with renal failure, while no dose adjustment of itraconazole is necessary in patients receiving dialysis or patients with renal insufficiency.26Boelaert J Schurgers M Matthys E et al.Itraconazole pharmacokinetics in patients with renal dysfunction.Antimicrob Agents Chemother. 1988; 32: 1595-1597Crossref PubMed Scopus (67) Google ScholarThe serum half-life of both fluconazole and itraconazole is approximately 24 h, so both drugs can be administered once daily. An IV form of fluconazole can be used in patients unable to take oral medications.Less frequent adverse effects have been reported for both fluconazole and itraconazole than ketoconazole. GI complaints, including nausea, vomiting, diarrhea, and abdominal complaints, occur in less than 10% of patients.7Pont A Williams PL Loose DS et al.Ketoconazole blocks adrenal steroid synthesis.Ann Intern Med. 1982; 97: 370-372Crossref PubMed Scopus (355) Google Scholar, 27Tucker RM Haq Y Denning DW et al.Adverse events associated with itraconazole in 189 patients on chronic therapy.J Antimicrob Chemother. 1990; 26: 561-566Crossref PubMed Scopus (165) Google Scholar Other less common adverse reactions reported include rash, headache, fatigue, edema, hypokalemia, and abnormal results of liver function tests. Abnormal results of liver function tests occurred in 7% of patients receiving long-term itraconazole therapy but were reversible on discontinuing treatment with the drug.27Tucker RM Haq Y Denning DW et al.Adverse events associated with itraconazole in 189 patients on chronic therapy.J Antimicrob Chemother. 1990; 26: 561-566Crossref PubMed Scopus (165) Google Scholar Mild transient elevations of liver function test values have been reported in patients taking fluconazole, but severe hepatotoxicity is extremely rare.7Pont A Williams PL Loose DS et al.Ketoconazole blocks adrenal steroid synthesis.Ann Intern Med. 1982; 97: 370-372Crossref PubMed Scopus (355) Google Scholar Drug interactions with both fluconazole and itraconazole are similar to those occurring with ketoconazole. Like ketoconazole, the coadministration of terfenadene, astemizole, or cisapride with itraconazole and possibly fluconazole, can result in prolongation of the QT interval and life-threatening cardiac arrhythmias and should be avoided.28Crane JK Hue-Teh S. Syncope and cardiac arrhythmia due to an interaction between itraconazole and terfenadine.Am J Med. 1993; 95: 445-446Abstract Full Text PDF PubMed Scopus (71) Google Scholar Rifampin, phenytoin, phenobarbital, and carbamazapine administration can enhance hepatic metabolism of itraconazole leading to treatment failures.29Tucker RM Denning DW Hanson LH et al.Interaction of azoles with rifampin, phenytoin, and carbamazepine: in vitro and clinical observations.Clin Infect Dis. 1992; 14: 165-174Crossref PubMed Scopus (165) Google Scholar Administration of fluconazole with phenytoin may result in toxic serum phenytoin levels.17Grant SM Clissold SP. Fluconazole: a review of its pharmaco-dynamic and pharmacokinetic properties, and therapeutic potential in superficial and systemic mycoses.Drugs. 1990; 39: 877-916Crossref PubMed Scopus (406) Google Scholar Both fluconazole and itraconazole may enhance the anticoagulant effect of warfarin and the hypoglycemic effect of oral hypoglycemic agents.30ItraconazoleMed Lett Drug Ther. 1993; 35: 7-9PubMed Google Scholar, 31Kauffman CA Bagnasco FA. Digoxin toxicity associated with itraconazole therapy.Clin Infect Dis. 1992; 15: 886-887Crossref PubMed Scopus (26) Google Scholar The administration of itraconazole to patients receiving digoxin may increase serum digoxin concentrations leading to toxic levels.31Kauffman CA Bagnasco FA. Digoxin toxicity associated with itraconazole therapy.Clin Infect Dis. 1992; 15: 886-887Crossref PubMed Scopus (26) Google Scholar, 32Rex J. Itraconazole-digoxin interaction.Ann Intern Med. 1992; 116: 525Crossref PubMed Scopus (35) Google Scholar Like ketoconazole, coadministration of cyclosporine with itraconazole and possibly fluconazole can result in increased concentrations of serum cyclosporine leading to nephrotoxicity.33Kramer MR Marshall SE Denning DW et al.Cyclosporine and itraconazole interaction in heart and lung transplantation recipients.Ann Intern Med. 1990; 113: 327-329Crossref PubMed Scopus (129) Google Scholar Cyclosporine doses should be reduced by 50% when concurrent itraconazole is administered, and serum cyclosporine levels should be monitored.33Kramer MR Marshall SE Denning DW et al.Cyclosporine and itraconazole interaction in heart and lung transplantation recipients.Ann Intern Med. 1990; 113: 327-329Crossref PubMed Scopus (129) Google ScholarSPECTRUM OF ACTIVITYThe triazoles, fluconazole and itraconazole, have broad spectrum in vitro antifungal activity against most fungal pathogens15Sugar AM. Fluconazole and itraconazole: current status.Curr Clin Topics Infect Dis. 1993; 13: 74-98PubMed Google Scholar, 16Zuckennan JM Tunkel AR. Itraconazole: a new triazole antifungal agent.Infect Control Hosp Epidemiol. 1994; 15: 397-410Crossref PubMed Google Scholar, 34Bodey GP. Azole antifungal agents.Clin Infect Dis. 1992; 14: S161-69Crossref PubMed Scopus (204) Google Scholar (Table 2). Itraconazole is the first azole drug with activity against Aspergillus species. In vitro studies show itraconazole compares favorably to amphotericin (with minimum inhibitory concentration ≤1 μgAnL) against Aspergillus fumigatus.35Dupont B Drouhet E. Early experience with itraconazole in vitro and in patients: pharmacokinetic studies and clinical results.Rev Infect Dis. 1987; 9: S71-6Crossref PubMed Google Scholar, 36Van Cutsem J Van Gerven F Janssen PAJ. Activity of orally, topically, and parenterally administered itraconazole in the treatment of superficial and deep mycoses: animal models.Rev Infect Dis. 1987; 9: S15-32Crossref PubMed Google Scholar Itraconazole also has excellent activity against Sporothrix schenckii, Blastomyces dermatitidis, Paracoccidioides brasiliensis, and Histoplasma capsulatum.36Van Cutsem J Van Gerven F Janssen PAJ. Activity of orally, topically, and parenterally administered itraconazole in the treatment of superficial and deep mycoses: animal models.Rev Infect Dis. 1987; 9: S15-32Crossref PubMed Google Scholar, 37Espinel-Ingroff A Shadomy S Gebhart RI. In vitro studies with R51,211 (itraconazole).Antimicrob Agents Chemother. 1984; 26: 5-9Crossref PubMed Scopus (116) Google Scholar Fluconazole has excellent activity against Candida albicans, Cryptococcus neoformans, and Coccidioides immitis; however, some non-albicans species such as Candida krusei, and Candida glabrata are resistant.38Galgiani JN Catanzaro A Cloud GA et al.Fluconazole therapy for coccidioidal meningitis.Ann Intern Med. 1993; 119: 28-35Crossref PubMed Scopus (190) Google Scholar, 39Wingard JR Merz WG Rinaldi MG et al.Increase in Candida krusei infection among patients with bone marrow transplantation and neutropenia treated prophylactically with fluconazole.N Engl J Med. 1991; 325: 1274-1277Crossref PubMed Scopus (885) Google Scholar Ketoconazole, fluconazole, and itraconazole are not active against the agents of mucormycoses.PULMONARY MYCOSESFungal pneumonia occurs in both immunocompetent and immunocompromised hosts. The major pulmonary fungal diseases seen in the United States are the endemic mycoses, histoplasmosis, coccidioidomycosis, and blastomycoses, and the opportunistic pathogens Cryptococcus, Candida, Aspergillus, and the agents of Mucormycoses. Paracoccidioidomycosis is a common cause of pulmonary fungal disease in Central and South America. Unusual fungi such as Pseudall-escheria boydii, Penicillium marneffei, and the pulmonary phaeohyphomycosis may cause lung infection in the immunocompromised host. S schenckii is an endemic fungi that occasionally causes pulmonary sporotrichosis in normal or immunosuppressed persons. Amphotericin B has been the treatment of choice for most serious systemic fungal disease. The new azole drugs, fluconazole and itraconazole, are effective alternatives to amphotericin B for the treatment of many fungal lung infections (Table 3).Table 3Therapy of the Pulmonary Fungal MycosesPulmonary SyndromeTherapy of ChoiceAspergillosis Allergic bronchopulmonary aspergillosisCorticosteroids, itraconazole AspergillomaSurgical resection, itraconazole Chronic necrotizing pulmonary aspergillosisItraconazole oramphotericin B Invasive aspergillosisAmphotericin BBlastomycosis Acute pulmonary diseaseItraconazole Chronic pulmonary diseaseItraconazole oramphotericin BCoccidioidomycosis Acute pulmonary diseaseKetoconazole oritraconazole Chronic pulmonary diseaseItraconazole orketoconazole oramphotericin B Pulmonary cryptococcosisFluconazole oramphotericin BHistoplasmosis Acute pulmonary histoplasmosisNo therapy oritraconazole Chronic pulmonary histoplasmosisItraconazole orketoconazole oramphotericin B Disseminated histoplasmosisAmphotericin B Maintenance therapy for AIDS patientsItraconazole oramphotericin BParacoccidioidomycosis Mild pulmonary diseaseItraconazole Severe pulmonary diseaseAmphotericin B ±sulfadiazidine oritraconazoleSporotrichosis Mild pulmonary diseaseItraconazole Severe pulmonary diseaseAmphotericin B Open table in a new tab AspergillosisAspergillus, a ubiquitous mold and an important pathogen in immunosuppressed patients and patients with preexisting lung disease, is responsible for four types of pulmonary disease, allergic bronchopulmonary aspergillosis, aspergilloma, chronic necrotizing pulmonary aspergillosis (CNPA), and invasive aspergillosis. Allergic bronchopulmonary aspergillosis characterized by eosinophilia, fleeting pulmonary infiltrates, a positive immediate type skin test response to Aspergillus, elevated serum IgE, and anti-Aspergillus IgG titers is usually treated with corticosteroids, not antifungal therapy.40Young RC Bennett JE Vogel CL et al.Aspergillosis: the spectrum of the disease in 98 patients.Medicine. 1970; 49: 147-173Crossref PubMed Scopus (821) Google Scholar, 41Mroueh S Spock A. Allergic bronchopulmonary aspergillosis in patients with cystic fibrosis.Chest. 1994; 105: 32-36Abstract Full Text Full Text PDF PubMed Scopus (127) Google Scholar However, itraconazole has been used to treat a few patients with improvement of pulmonary function.42Denning DW Van Wye JE Lewiston NJ et al.Adjunctive therapy of allergic bronchopulmonary aspergillosis with itraconazole.Chest. 1991; 100: 813-819Abstract Full Text Full Text PDF PubMed Scopus (188) Google ScholarPatients with aspergilloma have preexisting lung disease such as sarcoidosis, tuberculosis, or bronchiectasis and high serum IgG antibody titers to Aspergillus. Treatment of an aspergilloma is usually conservative management unless massive hemoptysis develops requiring surgical excision. Patients who have inoperable conditions have been treated with transthoracic intracavitary instillation of amphotericin B with questionable benefit.43Jackson M Flower CDR Shneerson JM. Aspergillomas with intracavitary instillation of amphotericin B through an indwelling catheter.Thorax. 1993; 48: 928-930Crossref PubMed Scopus (37) Google Scholar, 44Giron JM Poey CG Fajadet PP et al.Inoperable pulmonary aspergilloma: percutaneous CT-guided injection with glycerin and amphotericin B paste in 15 cases.Radiology. 1993; 188: 825-827Crossref PubMed Scopus (45) Google Scholar, 45Lee KS Kim HT Kim YH et al.Treatment of hemoptysis in patients with cavitary aspergilloma of the lung: value of percutaneous instillation of amphotericin B.Am J Radiol. 1993; 161: 727-731Google Scholar Itraconazole has been used with some success for the treatment of aspergilloma.46Viviani MA Tortorano AM Pagano A et al.European experience with itraconazole in systemic mycoses.J Am Acad Dermatol. 1990; 23: 587-593Abstract Full Text PDF PubMed Google Scholar, 47Dupont B. Itraconazole therapy in aspergillosis: study in 49 patients.J Am Acad Dermatol. 1990; 23: 607-614Abstract Full Text PDF PubMed Scopus (173) Google Scholar, 48Phillips P Fetchick R Weisman I et al.Tolerance to and efficacy of itraconazole in treatment of systemic mycoses: results.Rev Infect Dis. 1987; 9: PubMed Google Scholar In one of 14 patients treated with itraconazole, patients were and patients improved while or conditions B. Itraconazole therapy in aspergillosis: study in 49 patients.J Am Acad Dermatol. 1990; 23: 607-614Abstract Full Text PDF PubMed Scopus (173) Google Scholar In two of patients with the patients of improvement therapy with itraconazole MA Tortorano AM Pagano A et al.European experience with itraconazole in systemic mycoses.J Am Acad Dermatol. 1990; 23: 587-593Abstract Full Text PDF PubMed Google Scholar, 48Phillips P Fetchick R Weisman I et al.Tolerance to and efficacy of itraconazole in treatment of systemic mycoses: results.Rev Infect Dis. 1987; 9: PubMed Google Scholar Itraconazole has also been used to treat or MA Tortorano AM Pagano A et al.European experience with itraconazole in systemic mycoses.J Am Acad Dermatol. 1990; 23: 587-593Abstract Full Text PDF PubMed Google Scholar, 47Dupont B. Itraconazole therapy in aspergillosis: study in 49 patients.J Am Acad Dermatol. 1990; 23: 607-614Abstract Full Text PDF PubMed Scopus (173) Google Scholar, Chronic necrotizing pulmonary aspergillosis: itraconazole Clin Full Text Full Text PDF PubMed Scopus Google Scholar patients in one were and MA Tortorano AM Pagano A et al.European experience with itraconazole in systemic mycoses.J Am Acad Dermatol. 1990; 23: 587-593Abstract Full Text PDF PubMed Google Scholar, 47Dupont B. Itraconazole therapy in aspergillosis: study in 49 patients.J Am Acad Dermatol. 1990; 23: 607-614Abstract Full Text PDF PubMed Scopus (173) Google Scholar patients with were successfully with however, at or at Chronic necrotizing pulmonary aspergillosis: itraconazole Clin Full Text Full Text PDF PubMed Scopus Google ScholarThe therapy of choice for invasive aspergillosis in especially amphotericin B. However, itraconazole has been used with success in of patients with invasive disease. a of of patients treated with to itraconazole were of the MA Tortorano AM Pagano A et al.European experience with itraconazole in systemic mycoses.J Am Acad Dermatol. 1990; 23: 587-593Abstract Full Text PDF PubMed Google Scholar, 47Dupont B. Itraconazole therapy in aspergillosis: study in 49 patients.J Am Acad Dermatol. 1990; 23: 607-614Abstract Full Text PDF PubMed Scopus (173) Google Scholar, DW RM Hanson LH et al.Treatment of invasive aspergillosis with J Med. 1989; 86: Full Text PDF PubMed Scopus Google is a systemic disease most the skin, and by the B The endemic in the United States include the and especially the the and an in the and the pulmonary blastomycosis is a characterized by such as fever, and at first by a that usually of may be are not and the usually or Van et of pulmonary Clin 1991; Full Text Full Text PDF PubMed Scopus Google Scholar are of of most patients with pulmonary disease an progressive chronic pneumonia characterized by fever, and most that may DW RM Hanson LH et al.Treatment of invasive aspergillosis with J Med. 1989; 86: Full Text PDF PubMed Scopus Google Scholar, Van et of pulmonary Clin 1991; Full Text Full Text PDF PubMed Scopus Google Scholar, GA a of Google Scholar, GA et of pulmonary Engl J Med. PubMed Scopus (44) Google Scholar of chronic pulmonary disease include disease, and JH et pulmonary 1994; Scopus Google Scholar, et and the Dis. 1982; Google B the drug of choice for forms of blastomycosis in the immunosuppressed and for patients with disease or life-threatening MG GD et in immunocompromised patients.Medicine. 1993; PubMed Scopus Google Scholar, P G. therapy of major fungal diseases of the Clin 1991; Google Scholar Itraconazole is an effective alternative therapy for both and chronic pulmonary disease in the immunocompetent but should be in patients with or at doses of to for approximately effective in of patients with nonmeningeal Cloud et al.Itraconazole therapy for blastomycosis and J Med. 1992; Full Text PDF PubMed Scopus Google pneumonia not occur in normal or hosts. lung occurs as of a disseminated invasive that may occur in patients receiving major surgical or in Candida pneumonia associated invasive disease not have been reported in the and are not more to pneumonia than are to Aspergillus The of Candida or is common in patients receiving or as well as in and Therefore, the of Candida a with a in a normal or with pulmonary is not of Candida pneumonia and should not be used as the for therapy