Itraconazole and therapy of fungal infections.
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Animals↗
Biomedical subjects
J Van Cutsem
Publications and source records attributed to J Van Cutsem.
Onychomycosis caused by Microsporum canis: treatment with itraconazole.
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Adult↗
Deferoxamine augments growth and pathogenicity of Rhizopus, while hydroxypyridinone chelators have no effect.
Deferoxamine (DFO), when used in dialysis patients, is a well recognized risk factor for the development of mucormycosis caused by Rhizopus. This study compares, both in vivo and in vitro, the effects produced on Rhizopus by DFO and by two chelators of the hydroxypyridinone class, L1 and CP94. Experimental systemic mucormycosis was induced in the guinea pig by an i.v. injection of two different strains of Rhizopus: R. microsporus and R. arrhizus. Concomitant i.p. administration of DFO for four days shortened animal survival (P < 0.05), whereas concomitant administration of either L1 or CP94 did not. In vitro radioiron uptake by R. microsporus was 100-fold higher from the 55ferric complex of DFO than of L1 or CP94. In vitro fungal growth was stimulated sevenfold by the ferric complex of DFO (P < 0.0001) but not significantly by the ferric complex of either L1 or CP94. These results indicate that the ferric complex of DFO but not that of L1 or CP94 specifically stimulates both the iron uptake and the growth of Rhizopus. They suggest that the risk of developing mucormycosis should be minimal with L1 or CP94, as opposed to DFO.
Animals↗
Antifungal drug susceptibility testing.
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Antifungal Agents↗
Itraconazole versus griseofulvin in the treatment of tinea capitis: a double-blind randomized study in children.
BACKGROUND: Tinea capitis is a fungal infection in which topical therapy is often unsuccessful. Griseofulvin has been considered to be a first-line therapy. Other antifungal agents are the azole derivatives. Among these, itraconazole was compared with griseofulvin in children in a double-blind study. PATIENTS AND METHODS: Thirty-four children and one adult with clinical signs and symptoms of tinea capitis and with positive culture and microscopy for dermatophytes have been included in a double-blind comparison between itraconazole, 100 mg daily, and ultramicronized griseofulvin, 500 mg daily. Both drugs were given for 6 consecutive weeks. The final evaluation was made 8 weeks after the end of treatment to allow the hairs to regrow. Seventeen itraconazole- and 15 griseofulvin-treated patients received the complete 6-week treatment course. Fifteen of these 17 itraconazole patients and 14 of the 15 griseofulvin patients had infections caused by Microsporum canis. Fifteen of 17 patients were cured by itraconazole (88%) and 15 of 17 patients by griseofulvin (88%). One of the patients who discontinued griseofulvin therapy after 4 weeks was clinically and mycologically cured. Two of the original 17 griseofulvin patients discontinued therapy because of vomiting. None of the itraconazole-treated children experienced side effects. CONCLUSIONS: Itraconazole is the first azole derivate that matches griseofulvin for the treatment of tinea capitis in children. The drug also appears to be better tolerated than griseofulvin.
Child↗
Mucormycosis during deferoxamine therapy is a siderophore-mediated infection. In vitro and in vivo animal studies.
This study investigates the pathophysiology of mucormycosis caused by Rhizopus, which has been reported in 46 dialysis patients, while treated with deferoxamine (DFO). This drug aggravates mucormycosis, which we experimentally induced in guinea pigs and which lead to a shortened animal survival (P < or = 0.01). The drug's effect on Rhizopus is not mediated through the polymorphonuclear cells. Fe.DFO, the iron chelate of DFO, abolishes the fungistatic effect of serum on Rhizopus and increases the in vitro growth of the fungus (P < or = 0.0001). This effect is present at Fe.DFO concentrations > or = 0.01 microM, at which fungal uptake of radioiron from 55Fe.DFO is observed. A 1,000-fold higher concentration of iron citrate is required to achieve a similar rate of radioiron uptake and of in vitro growth stimulation as observed with Fe.DFO. These in vitro effects of Fe.DFO (1 microM) in serum on radioiron uptake and on growth stimulation are more striking for Rhizopus than for Aspergillus fumigatus and are practically absent for Candida albicans. For these three fungal species, the rates of radioiron uptake from 55Fe.DFO and of growth stimulation in the presence of Fe.DFO in serum are directly related (r = 0.886). These results underscore the major role of Fe.DFO in the pathogenesis of DFO-related mucormycosis. Pharmacokinetic changes in uremia lead to a prolonged accumulation of Fe.DFO after DFO administration, which helps explain the increased sensitivity of dialysis patients to DFO-related mucormycosis.
Animals↗
Posttreatment itraconazole levels in the nail. New implications for treatment in onychomycosis.
BACKGROUND: A problem in the treatment of onychomycosis is the lengthy duration of therapy. The pharmacokinetics of itraconazole suggest a potential for briefer treatment. OBJECTIVE: This study was designed to investigate itraconazole nail kinetics in 39 patients with onychomycosis in relation to their therapeutic outcome. METHODS: All patients received itraconazole for 3 months at a dose of 100 or 200 mg daily. Itraconazole levels of distal nail clippings were determined during a 6-month posttherapy period. RESULTS: Therapeutic itraconazole concentrations were found in the nail plates of fingernails and toenails for up to 6 months after treatment. Cure of the toenails was observed in 79% of the patients treated with the 200 mg dosage and in 26% of those treated with 100 mg at 6 months after therapy. CONCLUSION: The data suggest that the drug reaches the nail via incorporation into the matrix and by diffusion from the nail bed and is eliminated with regrowth of the nail after discontinuation of treatment.
Antifungal Agents↗
Immunomodulation and antifungal therapy of experimental invasive candidosis, histoplasmosis and aspergillosis: recent advances and concepts.
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Animals↗
Immunohistochemical identification of Penicillium marneffei by monoclonal antibody.
We present an experimental study on the immunohistochemical identification of Penicillium marneffei in paraffin-embedded, formalin-fixed tissue. The monoclonal antibody EB-A1 detects a specific galactomannan that appears to have at least one epitope identical in P. marneffei and Aspergillus sp. This immunohistochemical approach could be useful in the diagnosis of a rare diseae, penicilliosis marneffei, which proves to be difficult to identify by conventional microscopy.
Animals↗
Itraconazole in the treatment of chromoblastomycosis due to Fonsecaea pedrosoi.
The efficacy and tolerability of itraconazole in chromoblastomycosis due to Fonsecaea pedrosoi were evaluated in a non-comparative open clinical trial in 19 Brazilian patients with histopathologically and mycologically proven active chromoblastomycosis. Patients were classified in terms of severity and received itraconazole at the dosage of 200 to 400 mg per day until previously described criteria of cure have been reached. Clinical, mycologic, histopathologic, and laboratory evaluations were performed before, during, and after therapy. The plasma levels of itraconazole and the in vitro susceptibility of the isolates were determined in 15 cases. Clinical and biologic cure were achieved by eight patients (42%) having mild to moderate disease, after a mean duration of therapy of 7.2 months (3.2-29.6 months). Sterile scarred lesions were observed in a post-therapy follow-up lasting on average 9.6 months that was carried out in this subgroup. Clinical cure alone occurred after a mean period of 25.1 months of treatment (16-30.5 months) in seven patients (36%) with moderate to severe disease. Finally, clinical improvement was obtained in four patients (21%) with severe lesions after a mean treatment time of 17.6 months (10.7-22.5 months). All patients responded favorably to itraconazole therapy. No significant side effects nor biochemical alteration during this trial were important enough to interrupt the treatment. Our results support those of previous trials, suggesting that itraconazole is an effective compound against chromoblastomycosis due to Fonsecaea pedrosoi.
Adult↗
In vitro antifungal spectrum of itraconazole and treatment of systemic mycoses with old and new antimycotic agents.
Itraconazole is a lipophilic triazole with potent in vitro activity. It is also effective after topical, oral and parenteral administration. The antifungal activity of itraconazole has been evaluated against more than 6,500 different strains, belonging to more than 260 fungal species, using the serial decimal dilution test in fluid broth medium (brain-heart infusion broth). Candida spp., Torulopsis spp., Cryptococcus neoformans, Pityrosporum spp. (Dixon broth), various other yeasts, dermatophytes, Aspergillus spp., Penicillium spp., Sporothrix schenckii, dimorphic fungi (mycelium phase and yeast phase), Phaeohyphomycetes, Entomophthorales and various Hyalohyphomycetes are sensitive. Most strains of Fusarium and Zygomycetes are poorly sensitive. Itraconazole was administered orally and parenterally in normal and immunocompromised guinea-pigs infected with C. albicans, Cr. neoformans, Histoplasma duboisii, S. schenckii, P. marneffei and A. fumigatus. It was effective in terms of both survival of the animals and elimination of the fungi from the various tissues. Itraconazole was superior to fluconazole in candidosis, cryptococcosis, sporotrichosis and aspergillosis, and to amphotericin B and to flucytosine in candidosis, cryptococcosis and aspergillosis. No comparative studies have yet been undertaken for other deep mycoses. The results of combination therapy with itraconazole and fluconazole in cryptococcosis were indifferent; with flucytosine or amphotericin B, additive or synergistic effects were seen in systemic candidosis, cryptococcosis and aspergillosis. No drug-related side-effects were observed after oral or parenteral administration of itraconazole.
Amphotericin B↗
Phase II trial: an evaluation of oral saperconazole in acute vaginal candidosis: a comparison of three dosage schedules.
In an open, randomized phase II comparative study, 256 patients with acute vaginal candidosis (less than two episodes of vaginal candidosis in the 6 months preceding study entry) were treated with saperconazole according to one of the following treatment schedules: 2 x 100 mg o.d. for 1 day (87 patients), 2 x 100 mg b.i.d. for 1 day (83 patients), or 2 x 100 mg o.d. for 2 days (86 patients). A total of 236 patients were included in the efficacy analysis. Diagnosis of vaginal candidosis was made at the start by a direct microscopic examination of a vaginal smear and was confirmed by culture. The majority of isolated yeasts were Candida albicans (97.6%). All three dose regimens resulted in clinical cure rates of over 75%, and these were maintained for at least 1 month after the end of treatment. There was a difference in mycological cure rates between the three dose schedules (71, 85 and 92%) 1 week after the end of therapy. In view of the clinical and mycological results both 1 week and 1 month after the end of treatment, it can be concluded that a total dose of 400 mg of saperconazole given in a single day is the optimum treatment schedule. All treatment regimens were well tolerated (adverse experiences occurred in 1.6% of the patients) and the results 1 month after termination of therapy suggest a low relapse rate.
Acute Disease↗
Imaging of systemic Candida albicans infections with a radioiodinated monoclonal antibody: experimental study in the guinea pig.
Guinea pigs intravenously infected with Candida albicans were scanned to evaluate the use of radioiodinated monoclonal antibodies (MAb) to fungal antigens for detecting tissue infection sites. A total of 18 infected and 8 uninfected animals were used. MAb and F(ab')2 fragments directed against cell wall glycoproteins of C. albicans were labeled with 131I. Another MAb directed against a Schistosoma mansoni glycoprotein was labeled with 125I and used as a nonspecific control. Radiolabeled MAbs were injected at a dose of 12.5 micrograms (500 kBq) per animal. Images were acquired 24 h later. Animals were then killed and the dissected organs were separately gamma-counted. The number of C. albicans colony forming units (cfu) per gram was determined in each organ. A clear relationship was found between the anatomic distributions of C. albicans and 131I. The biodistribution of 131I radioactivity associated with anti-Candida MAb was greater in infected animals than in healthy animals and increased with the number of cfu per g in each organ. The distribution was highly specific in animals with Candida endophthalmitis, a pathognomic feature of organ involvement during hematogenous dissemination. In contrast, the distribution of 125I radioactivity associated with the nonspecific MAb was similar in healthy and infected animals. In infected animals, it was totally independent of the intensity of fungal infection.
Animals↗
The in vitro activity of terconazole against yeasts: its topical long-acting therapeutic efficacy in experimental vaginal candidiasis in rats.
The activity of the broad-spectrum triazole antifungal terconazole was evaluated in vitro by the serial decimal dilution technique in broth media. The best correlation between in vitro and in vivo activity was found in brain-heart infusion broth and Eagle's minimum essential medium. All strains of Candida albicans, C. tropicalis, C. krusei, C. parapsilosis, C. guilliermondii, C. glabrata, and Trichosporon beigelii tested were susceptible. Terconazole blocked the morphogenetic transformation from the yeast into the filamentous form at concentrations of 0.008 to 0.05 microgram/ml. In experimental candidiasis in castrated rats with estrogen-induced permanent pseudoestrus, topical treatment with terconazole was superior to miconazole, clotrimazole, econazole, butoconazole, tioconazole, sulconazole, bifonazole, valconazole, fenticonazole, nystatin, and amphotericin B in the various schedules used. A 3-day once-daily intravaginal application of terconazole 0.8% was usually sufficient to provide a functional therapeutic period of 7 days because of prolonged high biologically active antifungal levels in the vagina. No side effects were observed at any concentration of terconazole.
Administration, Topical↗
Ketoconazole 2% emulsion in the treatment of seborrheic dermatitis.
Fifty patients (42 men, 8 women) with seborrheic dermatitis were included in the trial. Ketoconazole 2% emulsion or the same emulsion without active drug was applied b.i.d. for 4 weeks. Two patients dropped out in the ketoconazole group and nine in the placebo group. Pityrosporum ovale was cultured from all patients at the start and from six out of 23 in the ketoconazole group versus nine out of 16 in the placebo group at week 4. The overall assessment showed a significantly better response to treatment for the ketoconazole emulsion (72%) than for the placebo (32%).
Dermatitis, Seborrheic↗
[In-vitro and in-vivo activity of itraconazole].
Itraconazole is a lipophilic triazole with potent in vitro activity. It is also highly efficacious after topical, oral and parenteral administration. The antifungal activity of itraconazole has been evaluated against more than 6500 different strains, belonging to more than 260 fungal species using the serial decimal dilution test in fluid media (BHI broth). Candida, Torulopsis, Cryptococcus, Pityrosporum (Dixon broth), various other yeasts, dermatophytes, Aspergillus, Penicillium, Sporothrix, dimorphic fungi (MP and YP), Phaeohyphomycetes, Entomophthorales and various Hyalohyphomycetes are sensitive. Most strains of Fusarium and Zygomycetes are poorly sensitive. Itraconazole was administered orally and parenterally in normal and in immunocompromised guinea-pigs, infected with C. albicans, Cr. neoformans, H. duboisii, Sp. schenckii, P. marneffei and A. fumigatus. It was efficacious both in survival of the animals and in eliminating the fungi from the various tissues. Itraconazole was superior to fluconazole in candidosis, cryptococcosis, sporotrichosis and aspergillosis, to amphotericin B and to flucytosine in candidosis, cryptococcosis and aspergillosis. No comparative studies were done up to now for the other deep mycoses. The results of combination therapy of itraconazole with fluconazole in cryptococcosis were indifferent, with 5-flucytosine or amphotericin B, additive or synergistic in systemic candidosis, cryptococcosis and aspergillosis. No drug-related side-effects were observed after oral or parenteral administration of itraconazole.
Animals↗
The antiinflammatory effects of ketoconazole. A comparative study with hydrocortisone acetate in a model using living and killed Staphylococcus aureus on the skin of guinea-pigs.
Several reports have demonstrated the efficacy of topical ketoconazole in dermatologic conditions that are not exclusively related to fungi. Some basic pharmacologic studies have indicated effects of ketoconazole on cholesterol production in keratinocytes, on the 5-lipoxygenase enzyme, and on the metabolism of all-trans-retinoic acid in the skin. These observations have led to the hypothesis that topically applied ketoconazole may possess antiinflammatory properties. This hypothesis was tested in an animal model in which living and killed Staphylococcus aureus applied to the backs of guinea pigs resulted in inflammation with erythema and hyperkeratosis. Ketoconazole 0.5% or 2% was applied topically once daily in an ointment base, either as monotherapy or in combination with hydrocortisone acetate 1%. In addition, untreated, excipient-treated, and hydrocortisone acetate-treated animals were included in the study design. All groups consisted of 10 animals that were observed and scored daily up to 3 days after the experimental therapy was stopped. In the animal model involving killed bacteria (i.e., no infection), topical ketoconazole had antiinflammatory activity comparable to that of hydrocortisone acetate. The activity of ketoconazole on the skin of animals infected with living bacteria (i.e., active bacterial infection) was superior to that of steroid therapy, which suggests some antibacterial effect of topically applied ketoconazole. The combination therapy was highly active under both conditions. These results suggest that, apart from the known antimycotic effects of ketoconazole, this molecule might also have effects against gram-positive bacteria at the high concentrations obtained after local application.(ABSTRACT TRUNCATED AT 250 WORDS)
Administration, Cutaneous↗
The in vitro antifungal activity of ketoconazole, zinc pyrithione, and selenium sulfide against Pityrosporum and their efficacy as a shampoo in the treatment of experimental pityrosporosis in guinea pigs.
The fungistatic and fungicidal activity of ketoconazole, zinc pyrithione, and selenium sulfide against Pityrosporum, a yeast thought to play a pathogenic role in seborrheic dermatitis and dandruff, was assessed in Dixon broth for Pityrosporum ovale and Sabouraud broth for Pityrosporum pachydermatis. Ketoconazole inhibited growth at concentrations ranging from 0.001 to 1 micrograms/ml. For zinc pyrithione and selenium sulfide higher concentrations were needed. In a guinea pig model the efficacy of treatment with four shampoos (Nizoral [Jansen], EDS Zinc [Schering], Zinkan [Lederle], and Selsun [Abbott]) was compared. The animals were inoculated for 7 consecutive days on intact skin. The lesions were scored for erythema, folliculitis, and hyperkeratosis 24 hours after the last inoculation and after treatment. Final evaluations were made 13 days after infection (10 days after last shampoo application). Treatment with undiluted and diluted (1:10) shampoos showed consistently superior clinical and mycologic results for Nizoral shampoo. None of the shampoos produced side effects.
Animals↗