Efficacy of ravuconazole in treatment of mucosal candidosis in SCID mice.

A model of orogastric candidosis in SCID mice, which mimics disease seen in AIDS patients, was used to evaluate ravuconazole in comparison with fluconazole for treatment. Mice were infected orally with Candida albicans and received either no treatment or oral treatment once daily for 12 days with 1, 5, or 25 mg of ravuconazole per kg of body weight per day, 5 or 25 mg of fluconazole per kg per day, or diluent (10% dimethyl sulfoxide in 0.5% carboxymethyl cellulose). The numbers of C. albicans CFU in the esophagus, stomach, small intestine, and cecum on day 25 in mice given no treatment and diluent were equivalent. Both doses of fluconazole significantly reduced numbers of CFU in all four tissues but were equivalent to each other. Ravuconazole showed dose-responsive improvement of clearance of CFU. Ravuconazole at 25 mg/kg was superior in reduction of numbers of CFU in all tissues to controls or 25 mg of fluconazole per kg and to other regimens in at least three tissues. Fluconazole at 25 mg/kg cured no infection in any tissue, whereas 25 mg of ravuconazole/kg cleared infection in all tissues from 50% of mice. Ravuconazole has good efficacy and the potential to cure mucosal candidosis in the absence of a functional immune response.

Comparative efficacies of terbinafine and fluconazole in treatment of experimental coccidioidal meningitis in a rabbit model.

A rabbit model of coccidioidal meningitis was used to compare the therapeutic efficacies of terbinafine (TBF) and fluconazole (FCZ). Hydrocortisone acetate-treated New Zealand White male rabbits were infected intracisternally with either 2.2 x 10(4) or 6.4 x 10(4) Coccidioides immitis arthroconidia. Oral treatment with polyethylene glycol 200 (PEG) twice daily (n = 8), TBF twice daily (n = 9; 200 mg/kg of body weight/day), or FCZ once daily (n = 8; 80 mg/kg/day) began on day 5 and continued for 21 days. Mean survival times were 20, 24, and 32 days for rabbits treated with PEG, TBF, and FCZ, respectively. All of the FCZ-treated animals (100%; P = 0.003), 56% of the TBF-treated animals (P = 0.4), and 25% of the PEG-treated animals survived the length of the study. Both FCZ and TBF were effective at reducing the incidence of paresis. Only FCZ was effective at reducing most neurological and systemic signs. FCZ treatments resulted in lower cerebrospinal fluid (CSF) protein concentrations and leukocyte counts and faster clearing of CSF fungal cultures compared with those for PEG-treated controls, but TBF treatments had no significant effect on these parameters. Neither drug affected CSF glucose levels. Mean serum TBF levels by bioassay were within the range of 3.5 to 6.2 microgram/ml at 1, 2, and 4 h postdosing and 0.35 to 7.0 microgram/ml at 14 h postdosing. No TBF was detected in CSF. Mean FCZ levels (24 to 25.5 h postdosing) by bioassay were 16.4 to 19.2 and 13.5 to 19.2 microgram/ml in serum and CSF, respectively. The reduction in the numbers of CFU in the spinal cord and brain was over 100-fold (P = 0.0005) in FCZ-treated animals and 2-fold (P

Activity of the triazole SCH 56592 against disseminated murine coccidioidomycosis.

SCH 56592 (SCH) is a new triazole antifungal with a broad spectrum of activity. In vitro susceptibility testing against five strains of Coccidioides immitis revealed MICs from 0.39 to 3.13 microg/ml and minimal fungicidal concentrations from 1.56 to 3.13 microg/ml. A murine model of systemic coccidioidomycosis was established in female CD-1 mice. Groups received either no treatment or oral therapy with fluconazole at 10 or 100 mg/kg of body weight; itraconazole at 10 or 100 mg/kg; SCH at 0.5, 2, 10, or 25 mg/kg; or its methylcellulose diluent alone. Therapy began 2 days postinfection and continued once daily for 19 days. Surviving mice were euthanized 49 days postinfection, and infectious burdens were determined by culture. All drugs were superior to no-treatment or diluent-treatment controls (P < 0.001) in prolonging survival but were not significantly different from one another. Itraconazole at 100 mg/kg was superior to fluconazole in reduction of CFU in the spleen, liver, and lung (P < 0.01 to 0.001). SCH at 0.5 mg/kg was superior to either fluconazole or itraconazole at 10 mg/kg in reduction of CFU in all three organs (P < 0.05 to 0.001). SCH at 2 mg/kg was not significantly different from itraconazole at 100 mg/kg in all three organs. SCH at 10 and 25 mg/kg was superior to either dose of fluconazole or itraconazole in all three organs (P < 0.05 to 0.001). In terms of reduction of CFU, SCH was > or = 200-fold as potent as fluconazole and > or = 50-fold as potent as itraconazole. There was a clear dose-responsive relationship for SCH in each of the organs. It is noteworthy that SCH effected cures (no detectable C. immitis in any organ) in 1 of 9, 6 of 10, or 9 of 9 surviving mice in animals given 2, 10, or 25 mg/kg, respectively. Neither fluconazole nor itraconazole cured any survivor. SCH has potent, fungicidal activity in vivo against C. immitis. It should be considered for clinical trials in patients with coccidioidomycosis.

Effect of granulocyte colony-stimulating factor on the candidacidal activity of polymorphonuclear neutrophils and their collaboration with fluconazole.

The effect of granulocyte colony-stimulating factor (GCSF) treatment of polymorphonuclear neutrophils (PMN) in vitro was studied with respect to their candidacidal activity. The candidacidal activity of PMN was found to be significantly increased when they were pretreated with GCSF. Fluconazole (1 microg/ml) was found to be highly fungistatic (90%) for Candida albicans Sh27 and collaborated with PMN for significantly increased killing. Collaborative killing by PMN significantly increased when they were treated with GCSF before and after fungal exposure. The enhancing activities of GCSF required optimization of the GCSF dose and were thus inoculum and strain dependent.

Itraconazole resistance in Aspergillus fumigatus.

Invasive aspergillosis is an increasingly frequent opportunistic infection in immunocompromised patients. Only two agents, amphotericin B and itraconazole, are licensed for therapy. Itraconazole acts through inhibition of a P-450 enzyme undertaking sterol 14alpha demethylation. In vitro resistance in Aspergillus fumigatus to itraconazole correlated with in vivo outcome has not been previously described. For three isolates (AF72, AF90, and AF91) of A. fumigatus from two patients with invasive aspergillosis itraconazole MICs were elevated. A neutropenic murine model was used to establish the validity of the MICs. The isolates were typed by random amplification of polymorphic DNA. Analysis of sterols, inhibition of cell-free sterol biosynthesis from [14C] mevalonate, quantitation of P-450 content, and [3H]itraconazole concentration in mycelial pellets were used to determine the mechanisms of resistance. The MICs for the three resistant isolates were >16 microg/ml. In vitro resistance was confirmed in vivo for all three isolates. Molecular typing showed the isolates from the two patients to be genetically distinct. Compared to the susceptible isolate from patient 1, AF72 had a reduced ergosterol content, greater quantities of sterol intermediates, a similar susceptibility to itraconazole in cell-free ergosterol biosynthesis, and a reduced intracellular [3H]itraconazole concentration. In contrast, AF91 and AF92 had slightly higher ergosterol and lower intermediate sterol concentrations, fivefold increased resistance in cell-free systems to the effect of itraconazole on sterol 14alpha demethylation, and intracellular [3H] itraconazole concentrations found in susceptible isolates. Resistance to itraconazole in A. fumigatus is detectable in vitro and is present in wild-type isolates, and at least two mechanisms of resistance are responsible.

Treatment of Mycobacterium avium complex infection: do the results of in vitro susceptibility tests predict therapeutic outcome in humans?

The ability of various in vitro methods of antibiotic susceptibility testing to predict therapeutic outcome in patients infected with Mycobacterium avium complex (MAC) was evaluated. Pretreatment bloodstream MAC isolates from 38 patients with AIDS, previously treated in a randomized fashion with either ethambutol, rifampin, or clofazimine, were tested by three conventional methods using broth or agar, as well as by cocultivation with macrophages. The results obtained with each method were compared with the quantitatively determined bacteriologic response to the administration of the single agent in humans. None of the conventional in vitro susceptibility methods was predictive of therapeutic outcome, while the results of cocultivation with macrophages were of moderate predictive value. The positive predictive value of a response in humans based on a response in macrophages (defined by > or = to 1.0 log reduction in baseline colony counts after 5 days of treatment) was 74%. The negative predictive value was 82%.

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.

Therapeutic efficacy of a liposomal formulation of amphotericin B (AmBisome) against murine blastomycosis.

The efficacy of a liposomal amphotericin B preparation (AmBisome) and a deoxycholate suspension (Fungizone) were compared in a pulmonary model of murine blastomycosis. Male, four-week-old CD-1 mice were infected intranasally with 19,400 or 27,450 cfu of viable Blastomyces dermatitidis yeasts and intravenous therapy begun 4 days later. Groups of ten mice were given various dosages of Fungizone or AmBisome or were untreated. All treatments were given 3 times per week for 2 weeks. Deaths were recorded over 49 days and the number of viable yeasts in the lungs of survivors quantitated by viable counting. Therapy with 1.0 mg/kg/dose of Fungizone or 1.0, 3.0, 5.0, 7.5 or 20.0 mg/kg/dose of AmBisome were equivalent and prolonged survival over controls and lower dosages of each drug. No acute or chronic toxicities were observed with any regimen. Quantitation of residual numbers of yeasts in the lung showed that 70-100% of mice given 7.5 mg/kg or greater of AmBisome were free of infection and were superior to other regimens. At equivalent 1.0 mg/kg dosages Fungizone was superior to AmBisome. Although AmBisome was three-fold less active than Fungizone on a dosage basis, higher curative doses could be given that were not toxic. These data indicate that AmBisome should be further tested in other models and in clinical trials.

Activities of the triazole D0870 in vitro and against murine blastomycosis.

The novel triazole D0870 was tested for in vitro activity, as well as in vivo in a murine model of pulmonary blastomycosis. In vitro, D0870 had inhibitory and fungicidal activity against Blastomyces dermatitidis (MIC = 0.048 microgram/ml; minimal fungicidal concentration = 0.097 microgram/ml). In vivo, D0870 was approximately 100-fold more active than fluconazole on the basis of milligrams per kilogram of body weight given once daily (QD) against blastomycosis. D0870 doses of both 1 or 10 mg/kg given QD and 10 or 100 mg/kg given every other day prolonged survival (P < 0.001) over fluconazole (100 mg/kg given QD). A D0870 dosage of 1 mg/kg QD was equivalent to fluconazole given at 100 mg/kg in reduction of lung burdens of B. dermatitidis, and D0870 administered at 10 mg/kg QD and 10 or 100 mg/kg every other day caused greater reduction (P < 0.001). However, D0870 at 100 mg/kg given QD was lethally toxic, whereas fluconazole at 100 mg/kg was not. These results indicate that D0870 is an effective therapy for murine blastomycosis and should be further tested.

Efficacies of amphotericin B lipid complex (ABLC) and conventional amphotericin B against murine coccidioidomycosis.

The comparative activities of two preparations of amphotericin B against Coccidioides immitis were investigated. These preparations were a deoxycholate suspension (conventional amphotericin B) and a lipid-based formulation, amphotericin B lipid complex (ABLC). In-vitro susceptibility testing demonstrated that the MICs of ABLC were < or = 0.25 mg/L and of conventional amphotericin B were 0.5 mg/L for C. immitis. However, conventional amphotericin B was at least four-fold more fungicidal, with a minimum fungicidal concentration of 4.0 vs > 16 mg/L for ABLC. The therapeutic efficacies were tested in murine models of acute systemic coccidioidomycosis. Female CD-1 mice were infected iv with C. immitis arthroconidia to establish high (> 50%) or low (< 50%) mortality models. Therapy with conventional amphotericin B or ABLC was given three times per week for two weeks starting three days post-infection. Controls received no therapy or drug-free diluent only. Survival was tallied up to 49 days post-infection and the fungal cfu counts in spleen, liver, and lungs of all survivors were determined. In the low mortality study all treated mice survived and all therapy regimens reduced infection in all organs. All mice given ABLC 6.6 or 13.2 mg/kg/dose and 80% given ABLC 16.5 mg/kg/dose, as well as 90% given conventional amphotericin B 0.66 mg/kg/dose were free of infection; all controls remained infected. In two high mortality studies, all mice given ABLC 0.66-20 mg/kg/dose or conventional amphotericin B 0.22 or 0.66 mg/kg/dose survived compared with 0-20% of controls. Thirty per cent of uninfected mice given ABLC 20 mg/kg/dose and 40% given conventional amphotericin B 2.0 mg/kg/dose died due to drug toxicity. Mice given ABLC or conventional amphotericin B had lower residual cfu counts of C. immitis in all organs than did controls. Sixty to one hundred per cent of mice given ABLC regimens > or = 6.6 mg/kg/dose were cured, whereas all controls and 50-60% of mice receiving the highest non-toxic conventional amphotericin B regimen (0.66 mg/kg/dose) remained infected. At equal non-toxic amphotericin B doses, conventional amphotericin B was more effective than ABLC in reducing cfu in infected organs.(ABSTRACT TRUNCATED AT 400 WORDS)

Nutrient intake of urban and rural elderly receiving home-delivered meals.

We evaluated nutrient intake (as measured by a 3-day food record) and nondietary factors that may influence nutrient intake in urban (n = 48) and rural (n = 47) elderly clients in the Title III C home-delivered meal program. Mean nutrient intake did not differ significantly between the two populations; each population met or exceeded 100% of the Recommended Dietary Allowances (RDA) for all nutrients other than energy, vitamin B-6, calcium, magnesium, and zinc. However, 70% of the individuals within each population had intakes below 66% of the RDA for three or more nutrients and were thus classified as having poor diets. Factors such as the need for assistance with shopping and cooking, living situation, vitamin/mineral supplementation, prescription drugs, and dentition did not significantly predict nutritional intake in either the urban or the rural cohorts. However, 50% to 70% of both the rural and the urban homebound elderly needed assistance with cooking and shopping for food. The rural elderly relied on family members for help with shopping and cooking to a greater extent than did their urban counterparts. We conclude that nutrient intake of the homebound elderly is not affected by geographic location. However, both rural and urban clients are at risk for developing nutrient deficiencies.

US experience with itraconazole in Aspergillus, Cryptococcus and Histoplasma infections in the immunocompromised host.

Itraconazole has emerged as an important new oral agent in the treatment of systemic fungal infections. This paper summarizes the data available on its use in aspergillosis, cryptococcosis and histoplasmosis, compiled in the United States with particular attention to the immunocompromised host. Data have been accrued in open-label studies including 57 patients with cryptococcal disease where the overall response rate among patients with meningitis was 86%, and in 28 patients (8 with acquired immune deficiency syndrome (AIDS) or human immunodeficiency virus (HIV) infection) with invasive aspergillosis where the overall response rates were 80% in patients without AIDS and 86% in patients with AIDS. Data are summarized on 6 patients with allergic bronchopulmonary aspergillosis, 5 of whom demonstrated marked improvement on therapy, and 12 patients with histoplasmosis including 8 with AIDS, 11 of whom responded and 1 recrudesced on therapy. In summary, itraconazole showed activity in human studies of aspergillosis, cryptococcosis and histoplasmosis with minimal toxicity. Itraconazole offers a new oral alternative to conventional amphotericin B therapy in these infections. Comparative studies are needed to clarify its role.

Efficacy of cilofungin alone and in combination with amphotericin B in a murine model of disseminated aspergillosis.

Cilofungin, amphotericin B, and a combination of the two drugs were compared in a model of aspergillosis in immunocompetent mice in three experiments. Cilofungin was equivalent to amphotericin B in preventing death and eradicating cerebral aspergillosis, but it did not sterilize the kidneys. This is the first demonstration of the in vivo activity of cilofungin against any fungus other than Candida albicans. The mortality with combination therapy was higher than those with amphotericin B alone (P = 0.003) and cilofungin alone (P = 0.054), as was weight loss after infection, indicating antagonism between cilofungin and amphotericin B in this model. The mechanisms of action and antagonism remain to be explained.

Synergy between cilofungin and amphotericin B in a murine model of candidiasis.

The efficacies of cilofungin and amphotericin B separately and together in mice with disseminated candidiasis were studied. Male CD-1 mice (age, 5 weeks) were infected intravenously with 3 X 10(5) CFU of Candida albicans. At 4 days postinfection, intraperitoneal therapy was initiated and was continued for 14 days. Therapy groups included those given cilofungin at 6.25 or 62.5 mg/kg/day (given twice daily), amphotericin B at 0.625 mg/kg/day (given once daily), cilofungin at 6.25 mg/kg/day plus amphotericin B, and cilofungin at 62.5 mg/kg/day plus amphotericin B. Mice were observed through 30 days postinfection. All infected untreated mice died of infection between days 6 and 18. Eighty-five percent of mice receiving cilofungin at 6.25 mg/kg/day died between days 13 and 30. All other mice survived. Quantitative determination of the number of CFU of C. albicans in the spleens and kidneys of all survivors revealed that mice that had received both drugs had lower residual burdens of C. albicans. All mice treated with cilofungin at 62.5 mg/kg/day plus amphotericin B had sterile spleens, whereas 42 to 58% of mice given cilofungin or amphotericin B monotherapy had sterile spleens. All kidneys were infected in mice which had received cilofungin at 62.5 mg/kg/day or amphotericin B. Neither organ was infected in 17% of each group receiving combination therapy with cilofungin and amphotericin B. The number of CFU in the kidneys of mice treated with cilofungin at 62.5 mg/kg/day plus amphotericin B was lower than those cultured from mice treated with cilofungin at 62.5 mg/kg/day (P less than 0.001, Mann-Whitney) or amhotericin B (P less than 0.05). Modest synergy was noted in inhibition of the C. albicans isolate in vitro. Pharmacokinetic studies showed elevated levels of cilofungin but not amphotericin B in sera of mice treated with combined therapy compared with those in mice given monotherapy. No overt toxicity was evident with any regimen. The mechanism of increased efficacy may be altered cilofungin distribution, excretion, or metabolism; antifungal synergy; or both. These results indicate that concurrent cilofungin-amphotericin B therapy has synergistic or additive efficacy in vivo.

Itraconazole treatment of phaeohyphomycosis.

Nineteen patients with phaeohyphomycosis were treated with itraconazole. Of these, 17 were assessable for clinical outcome. Of these, two had received no prior therapy, five had failed amphotericin B therapy, four had failed ketoconazole or miconazole therapy, and five had failed both amphotericin B and azole therapy. One patient had received only prior surgical intervention. Fungi of seven different genera caused disease of the skin in nine patients, soft tissue in nine, sinuses in eight, bone in five, joints in two, and lungs in two. Itraconazole was given in dosages ranging from 50 to 600 mg/day for 1 to 48 months. Clinical improvement or remission occurred in nine patients. Two patients have had stabilization of disease. Six patients failed treatment, one had a relapse after initially successful treatment. Itraconazole appears to be highly effective in some patients with phaeohyphomycosis, including patients refractory to other antifungal agents.

Itraconazole therapy for nonmeningeal coccidioidomycosis: clinical and laboratory observations.

Itraconazole, a new oral triazole antifungal agent, was administered in 75 courses to patients with chronic coccidioidomycosis at dosages of 50 to 400 mg/day for a median duration of 10 months. Assessment of efficacy was made with a standardized scoring system. Responses were seen in 42 of 58 assessable courses (72%). Nonresponse occurred exclusively in patients who had failed previous therapy and was most common in pulmonary disease. Toxicity was minimal at the doses studied. Pharmacokinetic analysis of itraconazole in serum at steady state showed negligible circadian variation; differences in serum concentrations among patients were large. Clinical isolates of Coccidioides immitis showed uniform in vitro susceptibility to itraconazole. Itraconazole shows impressive activity in this series of patients with refractory coccidioidomycosis. Further evaluation of itraconazole in this and in other systemic mycoses is in order.

Itraconazole in opportunistic mycoses: cryptococcosis and aspergillosis.

Striking results were obtained with oral itraconazole therapy in two opportunistic mycoses. Of 28 patients with cryptococcal meningitis, 18 achieved complete responses, including 16 of 24 patients with acquired immunodeficiency syndrome. Other manifestations of cryptococcosis were similarly responsive. In aspergillosis 12 of 15 patients responded, including 8 of 10 immunocompromised hosts. These patients included those with invasive pulmonary disease (4/5), skeletal disease (2/2), pleural disease (1/2), and pericardial, sinus, mastoid, hepatosplenic, or nail disease (1/1). These results with itraconazole compare favorably to conventional (parenteral) therapy, and toxicity was minimal. This suggests that comparative trials are now in order.

Efficacy of short courses of oral novobiocin-rifampin in eradicating carrier state of methicillin-resistant Staphylococcus aureus and in vitro killing studies of clinical isolates.

Methicillin-resistant Staphylococcus aureus (MRSA) is an important nosocomial infection problem. Colonization appears to be more common than invasive disease is. Eradication of colonization or the carrier state could limit the spread of MRSA, thus reducing the potential for mortality and morbidity in other patients. The detection of patients with MRSA infection in a rehabilitation ward led to a study of the combination of novobiocin-rifampin in vivo and in vitro. We found that 300 mg of rifampin plus 500 mg of novobiocin orally twice daily for 5 days, in 18 courses of treatment given to 12 patients, resulted in the clearing of MRSA in 79% of the evaluable courses and 81% of the evaluable sites. A second course cleared MRSA from one of the patients with a treatment failure. Side effects were not noted. All 18 pretherapy isolates were susceptible to either drug in vitro, but 1 of 2 posttherapy isolates was rifampin resistant. Timed-kill studies demonstrated that the rate of killing was the same with either drug alone or both drugs together. Pretherapy isolates from treatment successes or failure were killed at the same rate by the drug combination. However, with the rifampin-resistant isolate killing ceased after 48 h. Results of this study suggest that previously untreated patients are likely to have isolates that are susceptible to the combination of drugs and that the combination is commonly effective in eradicating MRSA carriage. Since the regimen is orally administered, and thus convenient, in conjunction with other measures it has the promise of reducing the spread of MRSA in hospitals.

Comparative effects of cilofungin and amphotericin B on experimental murine candidiasis.

The effectiveness of cilofungin (LY121019, referred to hereafter as LY), a lipopeptide, was studied in a murine candidiasis model. CD-1 mice (5 weeks old) were injected intravenously with 3 x 10(5) Candida albicans yeast cells. Intraperitoneal LY or amphotericin B (AmB) therapy was begun 4 days after infection and was continued daily for 2 weeks. LY and AmB were compared at 62.5, 6.25, and 0.625 mg/kg per day, with the LY dose split into two treatments per day. Mice were observed for 30 days postinfection, and survivors were necropsied. AmB at 62.5 mg/kg per day was lethal in the absence of infection. Cumulative mortality for infected controls was 94% (17 of 18). Survival of mice treated with the control diluent for LY was the same as survival with no treatment. Survival after 0.625 mg of LY per kg per day was the same as that of the controls, and 6.25 or 62.5 mg of LY per kg per day was significantly superior. AmB treatment at 0.625 or 6.25 mg/kg per day was protective and superior to the same LY doses. Atrophied kidneys were common in AmB-treated mice, and mice treated with 6.25 mg of AmB per kg per day appeared ill during therapy. The number of CFU recovered from kidneys and spleens of surviving mice reflected the same relationships between drugs and doses as those described for mortality. C. albicans was not cleared from the kidneys of mice in any group, and only in the 6.25-mg/kg-per-day AmB treatment group was not detectable C. albicans found in the spleens. These data indicate that LY or AmB suppresses candida infection but neither is curative in this model.

Treatment of invasive aspergillosis with itraconazole.

PURPOSE: Invasive aspergillosis in the immunocompromised host is one of the most difficult therapeutic problems. Itraconazole, a new oral triazole, is inhibitory as well as fungicidal against Aspergillus species in vitro. It is active against Aspergillus infections in animal models. We present our experience with itraconazole therapy of 21 patients with aspergillosis. PATIENTS AND METHODS: Eighteen of the 21 patients received 400 mg of itraconazole orally per day; the other three received 100 to 200 mg daily. Serum concentrations of itraconazole were measured and susceptibility testing was performed according to previously described methods. RESULTS: Of 15 evaluable patients, responses were produced in 12. Four of five with invasive pulmonary disease, two of two with skeletal disease, one of two with pleural disease, one of one with pericardial, sinus, mastoid, or hepatosplenic aspergillosis, and one of one with onychomycosis responded. One patient with carotid artery disease did not show a response, although results of cultures were negative at autopsy. One responder with joint disease had a possible relapse three months after completing 12 months of therapy. Ten of these patients were immunocompromised (including four with neutropenia and two renal transplant recipients) and eight of these responded. Side effects with itraconazole, in contrast to previously available therapy, were rare. CONCLUSION: This experience suggests itraconazole may be an important advance in the therapy of aspergillosis.