Treatment with Itraconazole of Experimental Coccidioidomycosis in the Wistar Rat/Itraconazol-Behandlung der experimentellen Coccidioidomykose an Wistar-Ratten

Summary: The results obtained in a comparative study between ketoconazole and itraconazole in the treatment of the experimental coccidioidomycosis of the Wistar rat are presented. Animals weighing 250 g were inoculated intracardiacally with 200 arthrospores of Coccidioides immitis. Both drugs were administered once a day by gavage 16 mg/kg for itraconazole and 80 mg/kg for ketoconazole. Two therapeutic schedules of 14 days were used. The first one was set up 3 d before the infecting inoculation (earlier treatment) and the second one 7 d after it (later treatment). The control group of animals received only the solvent of both drugs (PEG 200). 98 animals which received the earlier treatment were evaluated. Only 3/30 rats that received itraconazole showed lung granulomas without spherules and the cultures were negative in all cases. From the 31 animals belonging to the ketoconazole group, 15 showed granulomas, 11 showed spherules and in 10 C. immitis developed in cultures. From the 37 rats used as controls, 35 had lung granulomas, 34 of them with spherules, and the cultures were positive in 35 cases. The later starting scheme was used on 30 rats, 8/10 of the animals treated with ketoconazole showed granulomas with spherules and the cultures were positive in 3 rats with 256 C.F.U./g of the lung; 9/10 of the itraconazole treated rats showed pulmonary granulomas with sporangia, with positive cultures in 2 cases and an average of 231 CF.U./g of the lung. The whole population of the control animals showed granulomas with sporangia and positive cultures, with an average of 18.247 C.F.U./g of the lung. All the treated animals exhibited very small sporangia without endospores. It was concluded that itraconazole was better in the treatment of the earlier schedule and showed similar efficacy to ketoconazole in the later schedule with doses 5 times lower. Zusammenfassung: Die Resultate einer Vergleichsstudie zwischen Ketoconazol and Itraconazol in der Behandlung der experimentellen Coccidioidomykose der Wistar-Ratte werden dargestellt. Es wurden Tiere mit einem Gewicht von 250 g verwendet und 200 Arthrosporen von Coccidioides immitis intrakardial inokuliert. Die Verabreichung beider Medikamente erfolgte 1 x/d in einer Dosierung von 16 mg/kg Itraconazol sowie 80 mg/kg Ketoconazol. Es kamen zwei therapeutische Schemata von 14-tägiger Dauer zur Anwendung, das erste begann 3 d vor der Infektion (Frühtherapie), das zweite 7 d danach (Spättherapie). Die Kontroll-gruppe erhielt ausschlißlich das Lösungsmittel beider Medikamente (PEG 200): 98 Versuchstiere mit Frühtherapie wurden ausgewertet. Nur 3/30 Ratten, denen Itraconazol appliziert wurde, zeigten pulmonale Granulome ohne Spherulen, und die Kulturen waren in allen Fällen negativ. Von 31 mit Ketoconazol behandelten Tieren wiesen 15 Granulome, 11 Spherulen auf, und bei 10 wuchs C. Immitis in Kulturen. Von den 37 Ratten der Kontrollgruppe zeigten 35 Lungengranulome, 34 davon mit Spherulen, und in 35 Fällen waren die Kulturen positiv. Die Spättherapie wurde bei 30 Ratten ange-wandt; 8/10 dieser Tiere, behandelt mit Ketoconazol, zeigten Granulome mit Spherulen, und bei drei Ratten waren die Kulturen positiv mit 256 KfE/g Lunge. 9/10 der mit Itraconazol therapierten Ratten wiesen pulmonale Granulome mit Spherulen auf mit positiven Kulturen in zwei Fällen und einem Durchschnitt von 231 KfE/g Lunge. Die gesamte Kontrollgruppe zeigte Granulome mit Spherulen und positive Kulturen mit einem Durchschnitt von 18.247 KfE/g Lunge. Alle behandelten Tiere wiesen sehr kleine Spherulen ohne Endosporen auf, die Kontrollgruppe hingegen reife Spherulen mit Endosporen. Daraus wird geschlossen, daß Itraconazol in der Friihtherapie besser wirkt und in der Spättherapie dem Ketoconazol vergleichbare Wirksamkeit mit einer fünffach niedrigeren Dosis erzielt     

Day-to-day follow-up after a short oral treatment of acute vaginal candidosis with itraconazole

Seventeen patients with acute vaginal candidosis were treated for 2 days with itraconazole (200 mg daily). During 5 days after the start of the treatment, patients were daily screened for the presence of Candida (culture and microscopy) and the presence of signs and symptoms. Four days after treatment, no Candida could be detected in smears of vaginal fluid and cultures from these patients. At that time leucorrhoea, pruritus, vulvitis, and erythema were strongly reduced but had not completely disappeared.     

Pathogenicity of Trichosporon capitatum for normal and irradiated mice and the efficacy of miconazole on experimental systemic trichosporosis in mice

The authors describe the course of experimental trichosporosis in normal and X-irradiated ICR mice after i.v. inoculation with Trichosporon capitatum. The irradiated animals were considerably more sensitive to infection than normal animals. The LD50 challenge dose used was by approximately two orders lower (1 X 10(3) c.f.u. ml-1) in irradiated mice than in control animals. The histopathological examination of the internal organs of the infected mice demonstrated that the greatest tissue damage was associated with the kidneys, liver and spleen. However, the infectious agent was also found in heart, lungs and brain. The degree of impairment of the tissues was dependent on the inoculation dose and on the irradiation status. Miconazole (50 mg kg-1) was administered i.p. immediately after inoculation with Ts. capitatum and resulted in an alteration of infection and prolonged survival time. Miconazole was ineffective when challenge dose were used which produced 100% mortality (1 X 10(6) and 1 X 10(4) c.f.u. ml-1 for normal and irradiated mice, respectively). With the use of these doses also the course of infection was nearly identical both in the miconazole-treated and untreated animals.     

Therapy of invasive aspergillosis with itraconazole: improvement of therapeutic efficacy by early diagnosis

We report on the treatment of invasive aspergillosis with the new triazole antimycotic agent itraconazole. All 11 patients suffered from pulmonary invasive aspergillosis. Two patients also had cerebral aspergillosis; in one of these patients the paranasal sinuses were also invaded. Underlying diseases were acute lymphoblastic leukaemia (n = 3), acute myeloid leukaemia (n = 4); one patient underwent allogeneic bone marrow transplantation before he developed aspergillosis; another was transplanted after successful aspergillosis treatment, liver cirrhosis (n = 1), lung infarction after pulmonary embolism (n = 1), chronic bronchitis after pulmonary tuberculosis (n = 1) and AIDS (n = 1). In five cases initial diagnosis was established by means of mycological methods and clinical signs. In six patients invasive pulmonary aspergillosis was initially diagnosed due to the clinical criteria presented in this paper. Secondary mycological confirmation after onset of therapy was achieved in five out of these six patients. All of the patients initially responded to therapy. One female patient experienced a relapse of aspergillosis and died of cerebral involvement and relapsing leukaemia. Two further patients died due to underlying diseases (pulmonary embolism, relapsing leukaemia). Nine patients (82%) were cured of the mycosis, including the patient with cerebral involvement; two underwent surgical resection of residual pulmonary lesions. Itraconazole is a very effective drug for treatment of invasive aspergillosis. Therapeutic efficacy can be optimized by early diagnosis using clinical criteria and prompt start of treatment.     

Sporotrichosis in the metropolitan area of Cusco, Peru, and in its region

Eight cases of sporotrichosis originating from the metropolitan area of Cusco, Peru, and its region are described, including the circumstances of infection and the isolation of Sporothrix schenckii from the lesions. This finding classifies this particular area with high altitude, low temperature and dry weather as an endemic zone of interest in the epidemiological and ecological study of Andean sporotrichosis. Among the eight cases observed, five were of the fixed cutaneous type and three were lymphocutaneous. Six patients were male and two female. Two paediatric cases were also observed. Therapy with potassium iodide was very satisfactory, whereas poor results were obtained with ketoconazole.     

Systemic treatment of skin candidosis: a randomized comparison of terbinafine and ketoconazole

Terbinafine is an antimycotic drug which has a much higher in vitro activity against dermatophytes than against yeasts. To investigate the clinical relevance of these in vitro data, 118 patients with cutaneous candidosis were enrolled in a randomized, double-blind study and allocated to a 4-week treatment with a daily dose of either 250 mg b.i.d. terbinafine or 200 mg once-daily ketoconazole. At the final assessment, 3 weeks after cessation of therapy, mycological cure rates (negative culture and negative microscopy) were 82% in the terbinafine group and 73% in the ketoconazole group. Effective treatment with negative mycology and no or minimal signs or symptoms could be achieved in 65% of those who received terbinafine and in 57% of those randomized to ketoconazole. Five per cent and 7% of the patients taking terbinafine and ketoconazole, respectively, complained about adverse events, which were usually mild and did not lead to discontinuation of treatment. In one patient in the ketoconazole group, abnormal liver enzymes were noted at the final laboratory assessment. The results of this study indicate that terbinafine 500 mg daily can be an alternative to ketoconazole when systemic treatment of skin candidosis is required.     

Experimental aspergillosis in guinea pigs: influence of itraconazole on fungaemia and invasive fungal growth

Summary. The guinea pig model of experimental aspergillosis was used to evaluate the efficacy of itraconazole 2.5 and 5 mg kg^-1 in preventing the invasive phase of the disease when animals were already loaded with Aspergillus conidia. Evaluations were made by recording the survival rates, culturing fragments of nine organs, examining seven organs by means of histochemistry and immunohistochemistry (mAb EB-Al to Aspergillus galactomannan) and by serological titration of galactomannan. The data indicate that itraconazole is highly effective in preventing true invasive aspergillosis. Serological evaluations of antigenaemia suggest that low titres may only reflect fungaemia, while titres of 1:8 and above are suggestive of invasive disease.
Zusammenfassung. Das Meerschweinchen-Modell der experimentellen Aspergillose wurde eingesetzt, um die Wirkung von 2,5 mg und 5 mg kg^-1 Itraconazol zur Prävention der invasiven Krankheitsphase zu bewerten, wenn die Versuchstiere bereits mit Aspergillus -Konidien beladen sind. Die Bewertung stützt sich auf die Überlebensrate, auf Pilzkulturen aus neun verschiedenen Organen, auf histochemische und immunhistochemische Untersuchungen von sieben Organen mittels MOB EB-Al-Antikörpern gegen Aspergillus -Galactomannan sowie auf die Serotitration dieses Antigens. Die Ergebnisse belegen die hohe Wirksamkeit des Itraconazols in der Prävention der echt invasiven Aspergillose. Antigen-Titrationen im Serum sprechen dafür, daß geringe Titer lediglich das Fungämie-Stadium widerspiegeln, während Antigentiter ≥ 1:8 eine invasive Aspergillose belegen.     

Treatment of chronic disseminated Geotrichum capitatum infection with high cumulative dose of colloidal amphotericin B and itraconazole in a leukaemia patient

Summary. A case of disseminated granulomatous Geotrichum capitatum infection is reported. A young patient with blastic crisis of chronic myelogenous leukaemia developed septicaemia caused by G. capitatum in the post-chemotherapy aplastic phase. Subsequently, disseminated infection of the liver, spleen, pancreas and kidneys was observed. Treatment with high cumulative doses of a lipid formulation of amphotericin B (Amphocil®, 20.2 g in 11 weeks) and maintenance with itraconazole resolved clinical manifestations of G. capitatum granulomatous disseminated disease and controlled reactivation of the infection during the two subsequent courses of cytotoxic chemotherapy.
Zusammenfassung. Es wird über einen Fall von disseminierter, granulomatöser Geotrichum capitatum -Infektion berichtet. Eine junge Patientin mit blastischer Krise bei chronisch-myeloischer Leukämie entwickelte eine Septikämie, verursacht durch G. capitatum in der ablastischen Phase nach zytotoxischer Chemotherapie. Anschließend wurden Disseminierungen in Leber, Milz, Pankreas und Nieren beobachtet. Die Behandlung erfoigte mit hohen Dosen einer Amphotericin B-Lipid-Formulierung, nämlich 20.2 g Amphocil®über 11 Wochen, sowie einer Erhaltungstherapie mit Itraconazol. Diese Behandlung führte zur Heilung der klinischen Manifestationen der Pilzin-fektion und verhinderte die Reaktivierung des Prozesses während zweier nachfolgender Behand-lungsperioden mit zytotoxischer Chemotherapie.     

Combination therapy in a model of pulmonary aspergillosis

The current treatment for pulmonary aspergillosis, amphotericin B, is toxic and not always effective. This study was done to evaluate combinations of amphotericin B with other agents in an animal model of pulmonary aspergillosis. Sprague-Dawley rats were treated with cortisone acetate, infected intratracheally with 10(6) spores of Aspergillus fumigatus, and followed daily for survival. Mortality among controls started on day 2, and it was 80% by day seven, whereas therapy with amphotericin B resulted in survival of all animals. When given alone, ketoconazole, 5-fluorocytosine and rifampin did not improve survival. The combination of ketoconazole with amphotericin B resulted in complete antagonism. When animals received a combination of aerosol amphotericin B prophylaxis two days prior to infection followed by treatments with SCH39304 or itraconazole seven days after infection, survival rates were superior as compared to animals that had received aerosol prophylaxis only. The combinations of either 5-fluorocytosine or rifampin with amphotericin B were not better than amphotericin B alone. While combinations with 5-fluorocytosine or rifampin appear not to offer any advantage over therapy with amphotericin B alone, additional studies to further evaluate the role of azoles in combination therapy are needed.     

The Activity of Ketoconazole and Itraconazole Against Aspergillus fumigatus in Mixed Cultures with Macrophages or Leukocytes/Die Aktivität von Ketoconazol und Itraconazol gegen Aspergillus fumigatus in Mischkulturen mit Makrophagen oder Leukozyten

Summary: Concentrations of ketoconazole of 10⁻⁴ and 10⁻⁵ M and of itraconazole of 10⁻⁵ to 3.10⁻⁷ M strongly suppress the development of Aspergillus fumigatus in Eagle's minimum essential medium. Itraconazole is about 100 times more potent than ketoconazole against the growth of A. fumigatus. Leukocytes are able to delay temporarily the germination and mycelial development. Ketoconazole (10⁻⁵ M or lower) and itraconazole (10⁻⁶ M or lower) do not affect the leukocytes. At these concentrations the compounds show a synergistic effect with leukocytes in delaying outgrowth.
Zusammenfassung: Konzentrationen zwischen 10⁻⁴ und 10⁻⁵ M von Ketoconazol und zwischen 10⁻⁵ und 3.10⁻⁷ M von Itraconazol wirken stark hemmend auf die Entwicklung von Aspergillus fumigatus in Eagle's minimal-essentiellem Medium (EMEM). Itraconazol beeinflußt das Wachstum von A. fumigatus gegenüber Ketoconazol etwa 100 mal stärker. Leukozyten sind imstande, die Sprossung und die Myzelentwicklung vorübergehend zu verzögem. Ketoconazol (10⁻⁵ M oder weniger) und Itraconazol (10⁻⁶ M oder weniger) haben keinerlei Einfluß auf die Leukozyten. Bei diesen Konzentrationen zeigen beide Verbindungen einen synergistischen Effekt mit den Leukozyten hinsichtlich der Verzögerung der Sprossung.     

Candidiasis in cancer patients: Epidemiology, diagnosis, prophylaxis and therapy

New approaches in successful treatment of cancer patients are impaired by increasing incidence of fungal infections with high mortality. Relevant prognostic factors could be identified by numerous trials, such as age, kind and status of disease, intensity of previous chemotherapy, bone marrow transplantation, advanced fungal colonization of gastrointestinal tract. In clinical practice options for prompt and sensitive diagnostics are limited despite of new PCR-techniques. Prophylactic efficiency of polyenes or azoles is proven in high risk patients. Amphotericin B is established for treatment in case of documented or assumed invasive fungal infection. Liposomal preparations are less toxic and at least as effective as conventional amphotericin B in randomized trials.