Evaluation of Bay R 3783 in rodent models of superficial and systemic candidiasis, meningeal cryptococcosis, and pulmonary aspergillosis.

The triazole Bay R 3783 was compared with fluconazole, itraconazole, ketoconazole, and amphotericin B in rodent models of superficial and systemic candidiasis, meningocerebral cryptococcosis, and pulmonary aspergillosis. Overall, Bay R 3783 was comparable or slightly superior to fluconazole and markedly superior to itraconazole and ketoconazole in both survival and short-term organ load experiments in models of candidiasis and cryptococcosis but was less effective than amphotericin B. Of the antifungal agents tested, only Bay R 3783 and itraconazole showed any efficacy in the model of pulmonary aspergillosis.     

Comparison of the efficacies of amphotericin B, fluconazole, and itraconazole against a systemic Candida albicans infection in normal and neutropenic mice.

We compared the efficacies of the new triazole antifungal drugs fluconazole and itraconazole with that of amphotericin B in vitro and in an animal model of systemic candidiasis in normal and neutropenic mice. Antifungal treatment with fluconazole (2.5 to 20 mg/kg orally twice daily), itraconazole (10 to 40 mg/kg orally twice daily), or amphotericin B (0.1 to 4 mg/kg intraperitoneally once daily) was started 1 day after intravenous injection of 10(4) Candida albicans into normal mice or 10(3) C. albicans into neutropenic mice; the drugs were administered for 2 days. In normal mice the efficacy of treatment, which was assessed on the basis of the number of C. albicans cultured from the kidney, was greater for amphotericin B than for the triazoles. Fluconazole was more potent than itraconazole on the basis of equivalent doses, although itraconazole was more potent on the basis of the amount of free drug that was available. In neutropenic mice amphotericin B was less effective than it was in normal mice, whereas the triazoles were equally effective in normal and neutropenic mice. This was not expected, since in vitro data showed that amphotericin B was highly fungicidal, whereas both fluconazole and itraconazole had only a minimal effect on the growth of C. albicans in vitro.     

Comparison of a new triazole, posaconazole, with itraconazole and amphotericin B for treatment of histoplasmosis following pulmonary challenge in immunocompromised mice

A murine model of intratracheally induced histoplasmosis in immunocompromised B6C3F(1) mice was used to evaluate a new triazole antifungal agent, posaconazole. This compound was previously shown to be comparable to amphotericin B and superior to itraconazole for the treatment of histoplasmosis in immunocompetent mice. The current study used mice that were depleted of T lymphocytes by intraperitoneal injection of anti-CD4 and anti-CD8 monoclonal antibodies beginning 2 days before infection and continuing at 5-day intervals until completion of the study. Groups of B6C3F(1) mice that were depleted of CD4 and CD8 T cells were infected with an inoculum of 10(4) Histoplasma capsulatum yeasts. All mice receiving posaconazole at 1 or 0.1 mg/kg of body weight/day, amphotericin B at 2 mg/kg every other day (qod), or itraconazole at 75 mg/kg/day survived to day 29. Only 60% of mice receiving itraconazole at 10 mg/kg/day and none receiving amphotericin B at 0.2 mg/kg qod survived to that date. Fungal burdens were determined at day 14 of infection, 1 day after discontinuation of therapy. Quantitative colony counts and Histoplasma antigen levels in lung and spleen tissues declined following treatment with amphotericin B at 2 mg/kg qod, posaconazole at 5 and 1 mg/kg/day, and itraconazole at 75 mg/kg/day but not in mice treated with amphotericin B at 0.2 mg/kg qod or itraconazole at 10 mg/kg/day. Posaconazole at 0.1 mg/kg/day reduced fungal colony counts and antigen levels in spleens but not in lungs. This study shows posaconazole activity for the treatment of histoplasmosis in immunosuppressed animals.     

SCH 39304 in the treatment of acute or established murine pulmonary blastomycosis.

SCH 39304 was tested for treatment of acute or established murine pulmonary blastomycosis and was compared with ketoconazole and fluconazole in a model of acute infection. Only SCH 39304 at 25 or 50 mg/kg of body weight per day produced 100% survival for 30 days after the 20-day treatment, although only 33% of the mice were cleared of infection. SCH 39304 at 2 mg/kg/day was similar to ketoconazole at 100 mg/kg/day and to fluconazole at 10 mg/kg/day. In a model of established blastomycosis, used to evaluate long-term treatment of very sick or moribund mice, SCH 39304 at 50 mg/kg/day protected against death with a 96% cumulative 8-week survival. SCH 39304 was clearly superior on a milligram-per-kilogram basis in acute blastomycosis, and long-term treatment of more severe blastomycosis was curative.     

Pulmonary mycoses. New concepts and new therapy

The pathogenic and opportunistic fungi that commonly infect the human respiratory system cause diseases such as histoplasmosis, blastomycosis, aspergillosis, and invasive candidiasis. The increase in the incidence and severity of mycotic infections due to more aggressive immunosuppressive therapy and the spread of acquired immunodeficiency syndrome (AIDS) has had an impact on diagnosis and treatment of these conditions. Several therapeutic agents are currently available or undergoing clinical trials in the treatment of the pulmonary mycoses; among the agents with the greatest potential usefulness are the oral imidazoles, ketoconazole, itraconazole, and fluconazole.     

In-vitro antifungal activity of liposomal nystatin in comparison with nystatin, amphotericin B cholesteryl sulphate, liposomal amphotericin B, amphotericin B lipid complex, amphotericin B desoxycholate, fluconazole and itraconazole.

The in-vitro susceptibilities of 120 clinical isolates of yeasts to liposomal nystatin were compared with those to amphotericin B lipid complex (ABLC), liposomal amphotericin B (LAB), amphotericin B cholesteryl sulphate (ABCD), amphotericin B desoxycholate, nystatin, fluconazole and itraconazole. Yeast isolates examined included strains of Candida albicans, Candida parapsilosis, Candida glabrata, Candida krusei, Candida guilliermondii, Candida tropicalis, Candida kefyr, Candida viswanathii, Candida famata, Candida rugosa, Rhodotorula rubra, Trichosporon spp., Cryptococcus laurentii and Cryptococcus neoformans. The mean MICs for all strains examined were: liposomal nystatin 0.96 mg/L; nystatin 0.54 mg/L; ABLC 0.65 mg/L; LAB 1.07 mg/L; ABCD 0.75 mg/L; amphotericin B 0.43 mg/L; fluconazole 5.53 mg/L; and itraconazole 0.33 mg/L. No significant differences were seen between the activity of liposomal nystatin and the polyene drugs or itraconazole, but liposomal nystatin was more active than fluconazole. MICs were lower than the reported blood concentrations following therapeutic doses of this drug, indicating the potential for a therapeutic use of liposomal nystatin in humans. These results indicate good activity in vitro against medically important yeasts, which compares favourably with the activities of other currently available antifungal drugs. Liposomal nystatin may have a role in the treatment of disseminated and systemic mycoses.     

In vitro and in vivo activities of SCH 56592 against Blastomyces dermatitidis.

The new triazole derivative SCH 56592 has been tested in a National Committee for Clinical Laboratory Standards-adapted in vitro susceptibility test, and its activity against 12 isolates of Blastomyces dermatitidis yeast-like forms has been compared with those of amphotericin B, itraconazole, and fluconazole. SCH 56592 was the most active of the four compounds, with an MIC at which 90% of the isolates are inhibited of 0.06 microgram/ml and a minimal fungicidal concentration at which 90% of the isolates are inhibited of 4 micrograms/ml. The results of the treatment of mice infected with B. dermatitidis with three different doses of SCH 56592 (25, 5, or 1 mg/kg of body weight), amphotericin B (1 mg/kg), or itraconazole (150 mg/kg) confirmed the potent activity of SCH 56592. Survival was prolonged at each dose of SCH 56592, and sterilization of the lungs occurred in the high-dose group but not in the groups treated with itraconazole or fluconazole. SCH 56592 is a promising new azole antifungal drug that should be studied in humans with blastomycosis.     

Endemic mycoses: a treatment update

Endemic mycoses remain a major public health problem in several countries and they are becoming increasingly frequent with the spread of HIV infection. Amphotericin B remains the drug of choice during the acute stage of life-threatening endemic mycoses occurring in both immunocompetent and immunocompromised hosts. Ketoconazole is effective in non-AIDS patients with non-life-threatening histoplasmosis, blastomycosis, or paracoccidioidomycosis. Itraconazole is the treatment of choice for non-life-threatening Histoplasma capsulatum or Blastomyces dermatitidis infections occurring in immunocompetent individuals and is the most efficient secondary prophylaxis of histoplasmosis in AIDS patients. Itraconazole is also effective in lymphocutaneous and visceral sporotrichosis, in paracoccidioidomycosis, for Penicillum marneffei infection, and is an alternative to amphotericin B for Histoplasma duboisii infection. Coccidioidomycosis may be effectively treated with prolonged and sometimes life-long itraconazole or fluconazole therapy. Fluconazole has relatively poor efficacy against histoplasmosis, blastomycosis and sporotrichosis. New antifungal agents have been tested in vitro or in animal models and may soon be evaluated in clinical trials.     

In vitro susceptibility of 245 yeast isolates to amphotericin B, 5-fluorocytosine, ketoconazole, fluconazole and itraconazole.

The in vitro activity of amphotericin B, 5-fluorocytosine, ketoconazole, fluconazole and itraconazole was tested against 245 yeast strains isolated from clinical specimens (68 Candida albicans, 74 Candida tropicalis, 43 Candida krusei, 28 Candida glabrata, 19 Candida parapsilosis, 8 Candida lusitaniae and 5 Candida guilliermondii). An agar dilution method was employed to carry out testing. Minimal inhibitory concentrations to restrain 90% of isolate growth (MIC90) ranged from 0.12 to 2 mg/l for amphotericin B and for 5-fluorocytosine, from 0.03 to 8 mg/l for ketoconazole, from 0.05 to 50 mg/l for itraconazole and from 0.1 to > 100 mg/l for fluconazole. Among the azole derivatives, the most active was ketoconazole, followed by itraconazole. Only 1 strain of C. albicans was resistant to amphotericin B (MIC > 4 mg/l). Both C. tropicalis and C. krusei responded poorly to fluconazole and the former to itraconazole as well. The species most susceptible to the antifungal agents tested was C. glabrata and the most resistant were C. tropicalis and C. krusei.     

In vitro and in vivo antifungal activities of ER-30346, a novel oral triazole with a broad antifungal spectrum.

ER-30346 is a novel oral triazole with a broad spectrum of potent activity against a wide range of fungi. ER-30346, with MICs at which 90% of the strains tested are inhibited (MIC90s) ranging from 0.025 to 0.78 microgram/ml, was 4 to 32 times more active than itraconazole, fluconazole, and amphotericin B against Candida albicans, Candida parapsilosis, and Candida glabrata. Against Candida tropicalis, ER-30346, with an MIC90 of 12.5 micrograms/ml, was 2 to > 8 times more active than itraconazole and fluconazole, but was 16 times less active than amphotericin B. ER-30346 (MIC90, 0.78 microgram/ml) was four to eight times more active than fluconazole and amphotericin B and had activity comparable to that of itraconazole against Trichosporon beigelli. The MIC90s of ER-30346 were 0.10 microgram/ml for Cryptococcus neoformans and 0.39 microgram/ml for Aspergillus fumigatus. ER-30346 was 2 to 8 times more active than itraconazole and amphotericin B and 32 to > 256 times more active than fluconazole. ER-30346 also showed good activity against dermatophytes, with MICs ranging from 0.05 to 0.39 microgram/ml, and its activity was comparable to or 2 to 16 times higher than those of itraconazole and amphotericin B and > 32 times higher than that of fluconazole. In vivo activity was evaluated with systemic infections in mice. Against systemic candidiasis and cryptococcosis, ER-30346 was comparable in efficacy to fluconazole and was more effective than itraconazole. Of the drugs tested, ER-30346 was the most effective drug against systemic aspergillosis. We studied the levels of ER-30346 in mouse plasma. The maximum concentration of drug in plasma and the area under the concentration-time curve for ER-30346 showed good linearity over a range of doses from 2 to 40 mg/kg of body weight.     

Comparison of a New Triazole Antifungal Agent, Schering 56592, with Itraconazole and Amphotericin B for Treatment of Histoplasmosis in Immunocompetent Mice

A murine model of intratracheally induced histoplasmosis was used to evaluate a new triazole antifungal agent, Schering (SCH) 56592, for treatment of histoplasmosis. MICs were determined for SCH 56592, amphotericin B, and itraconazole by testing yeast-phase isolates from 20 patients by a macrobroth dilution method. The MICs at which 90% of the isolates are inhibited were for 0.019 μg/ml for SCH 56592, 0.5 μg/ml for amphotericin B, and ≤0.019 μg/ml for itraconazole. Survival studies were done on groups of 10 B6C3F₁ mice with a lethal inoculum of 10⁵. All mice receiving 5, 1, or 0.25 mg of SCH 56592 per kg of body weight per day, 2.5 mg of amphotericin B per kg every other day (qod), or 75 mg of itraconazole per kg per day survived to day 29. Only 44% of mice receiving 5 mg of itraconazole/kg/day survived to day 29. Fungal burden studies done in similar groups of mice with a sublethal inoculum of 10⁴ showed a reduction in CFUs and Histoplasma antigen levels in lung and spleen tissue in animals treated with 2 mg of amphotericin B/kg qod, 1 mg of SCH 56592/kg/day, and 75 mg of itraconazole/kg/day, but not in those treated with lower doses of the study drugs (0.2 mg of amphotericin B/kg qod, 0.1 mg of SCH 56592/kg/day, or 10 mg of itraconazole/kg/day). Serum drug concentrations were measured 3 and 24 h after the last dose in mice (groups of five to seven mice), each treated for 7 days with SCH 56592 (10 and 1 mg/kg/day) and itraconazole (75 and 10 mg/kg/day). Mean levels measured by bioassay were as follows: SCH 56592, 10 mg/kg/day (2.15 μg/ml at 3 h and 0.35 μg/ml at 24 h); SCH 56592, 1 mg/kg/day (0.54 μg/ml at 3 h and none detected at 24 h); itraconazole, 75 mg/kg/day (22.53 μg/ml at 3 h and none detected at 24 h); itraconazole, 10 mg/kg/day (1.33 μg/ml at 3 h and none detected at 24 h). Confirmatory results were obtained by high-pressure liquid chromatography assay. These studies show SCH 56592 to be a promising candidate for studies of treatment of histoplasmosis in humans.     

Response to antifungal therapy by human immunodeficiency virus-infected patients with disseminated Penicillium marneffei infections and in vitro susceptibilities of isolates from clinical specimens.

Eighty-six patients with laboratory evidence of human immunodeficiency virus infection presented to Chiang Mai University Hospital in Chiang Mai, Thailand, between 1 June 1990 and 30 June 1992 with systemic infection caused by the dimorphic fungus Penicillium marneffei. Thirty isolates of P. marneffei from clinical specimens from these patients were tested for their in vitro susceptibilities to amphotericin B, 5-fluorocytosine, miconazole, ketoconazole, itraconazole, and fluconazole. P. marneffei was highly susceptible to miconazole, itraconazole, ketoconazole, and 5-fluorocytosine. Amphotericin B showed intermediate antifungal activity, while fluconazole was the least active; some strains of the fungus were resistant to fluconazole. The clinical and microbiological responses correlated with the overall patterns of in vitro susceptibility to the azoles, whereas results with amphotericin B were more difficult to assess. Antibiotic failures of initial therapy occurred in 8 of 35 (22.8%) patients treated with amphotericin B, 3 of 12 (25%) patients treated with itraconazole, and 7 of 11 (63.6%) patients treated with fluconazole. Itraconazole or ketoconazole should be considered to be the drug of first choice in the treatment of mild to moderately severe P. marneffei infection. Parenteral therapy with amphotericin B may be required for seriously ill patients. Since at least 12 patients who responded to initial therapy relapsed within 6 months regardless of initial antifungal therapy, maintenance oral therapy with itraconazole or ketoconazole may be necessary.     

Treatment of murine pulmonary blastomycosis with SCH 39304, a new triazole antifungal agent.

SCH 39304, a broad-spectrum azole derivative, was evaluated in an experimental mouse model of blastomycosis pneumonia. Five days after being inoculated with Blastomyces dermatitidis, infected mice were treated with either oral SCH 39304, fluconazole, or intraperitoneal amphotericin B. A dose response protective effect was observed with SCH 39304 at 5 to 100 mg/kg of body weight per day, with 5 mg of SCH 39304 per kg per day providing activity similar to that of 100 mg of fluconazole per kg per day. Colony counts of yeasts in the lungs of mice sacrificed while on therapy with SCH 39304 were consistently below those of controls, and several lungs were sterile. We conclude that SCH 39304 is effective in murine blastomycosis treatment and deserves to be evaluated in the treatment of human blastomycosis.     

Efficacy of ravuconazole in treatment of systemic murine histoplasmosis

Ravuconazole (RCZ) was evaluated for efficacy in comparison to fluconazole (FCZ) and itraconazole (ITZ) in murine models of disseminated histoplasmosis. All regimens tested prolonged survival (P < 0.05 to 0.0001). At equivalent doses of 50 mg/kg of body weight, RCZ and ITZ were equally effective and RCZ was more effective than FCZ (P = 0.02). Clearance of fungal burden from the livers and spleens of mice showed RCZ and ITZ at doses of 50 mg/kg to be efficacious but not curative. These data indicate that RCZ should be studied further.     

Histoplasmosis: update 1998

Histoplasmosis is an important cause of morbidity and death in HIV-infected patients. Significant developments concerning the diagnosis, treatment, follow-up, and prophylaxis of histoplasmosis are discussed. Itraconazole is highly effective at both inducing and maintaining remission in mild to moderate cases of disseminated histoplasmosis. In cases of moderate to severe disease, amphotericin B remains the therapy of choice. A table presents comparative results of treating mild to moderate disseminated histoplasmosis with the drugs itraconazole versus fluconazole. Currently, no resistance of Histoplasmosis capsulatum to itraconazole has emerged from prolonged therapy. Maintenance therapy for life is recommended for patients with CD4 counts less than 100; however, feasibility studies are evaluating the possibility of its discontinuance. While no prophylaxis recommendations currently exist, patients with CD4 counts less than 100 who are exposed to histoplasmosis are recommended to begin oral itraconazole (200 mg daily).     

In vitro susceptibility of Cryptococcus neoformans isolates to five antifungal drugs using a colorimetric system and the reference microbroth method

Minimum inhibitory concentrations (MICs) of amphotericin B, 5-flucytosine, fluconazole, itraconazole and ketoconazole were determined against 42 clinical isolates of Cryptococcus neoformans var. neoformans using the Alamar YeastOne colorimetric method and the NCCLS reference microdilution method. No strains with resistance to amphotericin B, itraconazole or ketoconazole were detected with either method. Using the reference method, the MICs of fluconazole were >/= 64 mg/L, whereas using the colorimetric method all MICs were >/=16 mg/L. The MIC values of 5-flucytosine were also higher using the reference method (8-16 mg/L for 32% of isolates) compared with the colorimetric method. The percentage of agreement between the methods, using a difference of two dilutions, was 70.7% for itraconazole, 73.2% for amphotericin B, 80% for fluconazole, 88% for 5-flucytosine and 95% for ketoconazole. Overall, we conclude that for fluconazole and 5-flucytosine, in a low but not insignificant number of isolates, results with the two methods are discordant, some isolates being found sensitive with the colorimetric test, but resistant with the reference method.     

Antifungal susceptibility of Cryptococcus neoformans and Cryptococcus gattii isolates from decayed wood of trunk hollows of Ficus religiosa and Syzygium cumini trees in north-western India

BACKGROUND: We present antifungal susceptibility data on environmental isolates of Cryptococcus neoformans (serotype A, n=117) and Cryptococcus gattii (serotype B, n=65) cultured from decayed wood of trunk hollows of Ficus religiosa and Syzygium cumini trees. METHODS: Susceptibilities to amphotericin B, fluconazole, ketoconazole, itraconazole and voriconazole were determined by using Etest. The MICs were read after 48 h as per the guidelines provided by the manufacturer. RESULTS: The MIC90s and susceptibility ranges for C. neoformans isolates were as follows: 0.094 (0.004-0.25) mg/L for amphotericin B, 4 (0.032-12) mg/L for fluconazole, 0.094 (0.004-0.75) mg/L for itraconazole, 0.064 (0.002-0.19) mg/L for ketoconazole, and 0.047 (0.006-0.125) mg/L for voriconazole, whereas for C. gattii isolates these were 0.125 (0.023-0.5) mg/L for amphotericin B, 8 (0.032-16) mg/L for fluconazole, 0.75 (0.006-2) mg/L for itraconazole, 0.125 (0.003-0.19) mg/L for ketoconazole, and 0.094 (0.004-0.125) mg/L for voriconazole. A comparison of the geometric means of MICs (mg/L) revealed that C. gattii was less susceptible than C. neoformans to amphotericin B (0.075 versus 0.051, P=0.0003), fluconazole (2.912 versus 2.316, P=0.003), itraconazole (0.198 versus 0.0344, P<0.0001), ketoconazole (0.072 versus 0.037, P<0.0001), and voriconazole (0.045 versus 0.023, P<0.0001). CONCLUSIONS: The antifungal susceptibility data obtained in this study indicate that the occurrence of primary resistance among environmental isolates of C. neoformans serotype A and C. gattii serotype B is rare, and serotype B isolates are less susceptible than serotype A isolates.     

Efficacy of nikkomycin Z against experimental pulmonary blastomycosis.

Nikkomycin Z is a chitin synthetase inhibitor. In vitro, nikkomycin Z had good activity against Blastomyces dermatitidis, with an MIC of 0.78 microg/ml and a minimal fungicidal concentration of 3.1 microg/ml. The efficacies of various treatment durations (3, 5, or 10 days) and doses (200, 400, or 1,000 mg/kg of body weight) of nikkomycin Z given twice daily were compared with those of itraconazole at 200 mg/kg given twice daily and amphotericin B at 6.25 mg/kg in a murine model of pulmonary blastomycosis. All treatments prolonged survival compared with untreated controls (P < 0.05 to 0.01); 100% survival was achieved with 5 or 10 days of any nikkomycin Z dose or with amphotericin B. Amphotericin B and nikkomycin Z, but not itraconazole, reduced infection compared with controls. Amphotericin B and the 10-day regimens of all nikkomycin Z doses were equivalent and superior to itraconazole or nikkomycin Z for < or = 5 days at any dose (P < 0.05 to 0.01). Increased duration and/or dosage improved the efficacy of nikkomycin Z, with 10 days of each dose curing 50 to 90% of the animals. Only a 1,000-mg/kg/day dose of nikkomycin Z was curative when treatment lasted less than 10 days. In contrast, itraconazole cured no mice, while amphotericin B cured all mice. Based on the total amount of drug given, amphotericin B was estimated to be 32 times as active as nikkomycin Z and nikkomycin Z was estimated to be 3 times as active as itraconazole. Overall, nikkomycin Z given orally was well tolerated, had good activity against blastomycosis, and could result in biological cure, thus producing results equivalent to those of parenteral amphotericin B.     

Activities of the triazole SCH 51048 against Coccidioides immitis in vitro and in vivo.

The activity of the novel triazole SCH 51048 was tested against Coccidioides immitis. SCH 51048 inhibited C. immitis in vitro; MICs for 13 isolates ranged from < or = 0.39 to 0.78 micrograms/ml, and minimum fungicidal concentrations ranged from < or = 0.39 to 1.6 micrograms/ml. In vivo, no mice treated with SCH 51048 at 2 to 50 mg/kg of body weight or 100 mg of fluconazole or itraconazole per kg died of systemic coccidioidomycosis, whereas 60 to 100% of the control mice died. SCH 51048 given at 25 or 50 mg/kg was curative, whereas fluconazole or itraconazole given at 100 mg/kg was not curative. Pharmacokinetic studies showed peak levels in serum of > 14 micrograms/ml, with an estimated half-life of > 12 h. SCH 51048 was 5- to 50-fold or more superior to fluconazole or itraconazole.     

Intravenous itraconazole.

OBJECTIVE: To review the pharmacology, mycology, chemistry, pharmacokinetics, efficacy, safety, tolerability, dosage, administration, and economic issues of intravenous itraconazole. DATA SOURCES: A MEDLINE search from 1978 to June 2000 of the English-language literature and an extensive review of meeting abstracts was conducted. Due to the paucity of published information concerning the pharmacokinetics, efficacy, and safety of the intravenous formulation of intravenous itraconazole, additional information was obtained from the manufacturer. DATA EXTRACTION: Data from in vitro and preclinical studies, as well as Phase II and III clinical trials, were included. DATA SYNTHESIS: The triazole antifungal agent itraconazole is available in a cyclodextrin-based intravenous formulation. Intravenous itraconazole is indicated for the treatment of pulmonary and extrapulmonary blastomycosis; histoplasmosis, including chronic cavitary pulmonary disease and disseminated, nonmeningeal histoplasmosis; and pulmonary and extrapulmonary aspergillosis in patients who are intolerant of or who are refractory to amphotericin B. This formulation provides quicker and more consistent therapeutic concentrations than the oral formulations. Clinical data comparing the efficacy of intravenous itraconazole with that of amphotericin B are lacking. CONCLUSIONS: Intravenous itraconazole offers a less toxic alternative for patients with pulmonary and extrapulmonary blastomycosis, histoplasmosis, and aspergillosis who cannot receive oral medications or who are intolerant of or refractory to amphotericin B.