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.     

Tracheobronchial aspergillosis in a patient with AIDS treated with aerosolized amphotericin B combined with itraconazole

Summary. The clinical features of a tracheobronchial infection due to Aspergillus flavus in an AIDS patient with a normal neutrophil count is described. Diagnosis was made by culture and microscopic examination of biopsies obtained from bronchial vegetations seen at bronchoscopy. Radiographic examination of the neck revealed the presence of large endoluminal fungal masses. Initially the patient was treated with a combination of itraconazole, flucytosine and aerosolized amphotericin B, then only with itraconazole plus aerosolized amphotericin B. A good therapeutic response was observed.
Zusammenfassung. Das klinische Bild einer tracheobronchialen Infektion, verursacht durch Aspergillus flavus bei einem AIDS-Patienten mit normaler Leukozytenzahl, wird vorgestellt. Die Diagnose wurde mikroskopisch und kulturell aus Biopsiematerial von Bronchialbelägen gestellt. Im Nacken-Röntgenbild waren endoluminale Pilzmassen nachweisbar. Der Patient wurde anfänglich mit einer Kombination von Itraconazol. Flucytosin und Amphotericin B-Aerosol behandelt, später nur mit Itraconazol und Amphotericin B-Aerosol. Der Patient sprach gut auf diese Therapie an.     

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.     

Small-dose itraconazole pulse therapy in the treatment of onychomycosis

Summary. The aim was to evaluate efficacy and tolerance of a short-schedule treatment regimen using a small dose of itraconazole in pulse intermittently. The open study evaluated the pulse therapy consisting of monthly 1-week cycles of oral itraconazole 200 mg daily for 2–3 consecutive months in 42 patients with onychomycosis. After active therapy, patients were evaluated for a maximum period of 1 year. Twelve of 42 patients were considered as being clinically cured, 17 were markedly improved, 11 were improved and two were failures. A mycological examination at the final visit was performed on all patients. Thirty-five were negative and seven were positive. This short treatment was well tolerated, with no adverse reactions, and may offer a new option for treatment of onychomycosis.
Zusammenfassung. Ziel der Studie war, Wirksamkeit und Verträglichkeit einer Niedrigdosis-Itraconazol-Pulstherapie in der Onychomykose-Behandlung zu bewerten. In einer offenen Studie wurden 42 Onychomykose-Patienten mit 200 mg Itraconzol oral täglich über eine Woche pro Monat behandelt; die Behandlung lief über eine Dauer von zwei bis drei Monaten. Die Patienten wurden danach maximal ein Jahr lang beobachtet. Zwölf der 42 Patienten wurden als klinisch geheilt befunden, 17 als deutlich gebessert, 11 als gebessert, und bei 2 Patienten versagte die Therapie. In der mykologischen Untersuchung beim letzten Beobachtungstermin waren 35 Patienten negativ und 7 positiv. Diese Kurzbehandlung war gut verträglich. Die Niedrigdosis-Itraconazol-Pulstherapie könnte daher eine neue Option für die Onychomykose-Behandlung darstellen.     

Candidosis, aspergillosis and zygomycosis in an oncology department

The incidence, aetiology and treatment of fungal infections in a 60-bed department of clinical oncology over 2 years is reported. During the second year, after the moving of the department from an old to a new building with an improved epidemiologic regimen, the incidence decreased rapidly, although the mortality due to systemic disseminated mycosis did not change.     

Disseminated aspergillosis due to Aspergillus flavus in an experimental model: efficacy of azole therapy

The aim of this investigation was to create a reproducible experimental model of disseminated Aspergillus flavus aspergillosis, and to compare the relative therapeutic efficacies of itraconazole and fluconazole in this model. Temporarily immunosuppressed male Wistar rats received intravenous challenge by A. flavus conidia. Treatment was initiated 24 h later with oral itraconazole (1 mg kg-1 BW day-1), oral fluconazole (1 mg kg-1 BW day-1) or excipient only (infected-untreated rats); this was continued for 10 days. At this time, although 100% mortality had occurred among all infected-untreated rats, no mortality was noted among the control-uninfected, infected-itraconazole-treated or infected-fluconazole-treated rats. After killing, essential organs were processed for microbiological and histopathological studies. Aspergillus flavus was recovered in high colony counts from the organs of infected-untreated rats (lungs > liver > brain > kidneys), but in significantly lower colony counts, or not at all, from the organs of itraconazole-treated and fluconazole-treated rats. Histopathological alterations were pronounced in tissues of infected-untreated rats, but less so in treated rats. These data suggest that administration of itraconazole or fluconazole sufficiently early may prevent, or retard, progression of lesions in disseminated aspergillosis.     

Successful treatment of cerebral aspergillosis by stereotactic operation and antifungal therapy

Summary. The following is a case report of a cerebral Aspergillus abscess in a male patient predisposed to this disease on account of many years of alcohol abuse. After timely identification of the pathogenic organism, the patient was cured by stereotactic operation in conjunction with antifungal therapy using amphotericin B and 5-fluorocytosine. The origin and the starting point of the infection remain obscure.
Zusammenfassung. Im folgenden wird ein Fall eines zerebralen Aspergillus -Abszesses bei einem durch langjährigen Alkoholabusus prädisponierten Patienten beschrieben. Er konnte durch stereotaktische Operation und antimykotische Therapie mit Amphotericin B und 5-Fluorcytosin nach rechtzeitigem Erregernachweis geheilt werden. Ursprung und Beginn der Infektion blieben unklar.     

Surveillance of invasive mold infections in lung transplant recipients: effect of antimycotic prophylaxis with itraconazole and voriconazole

Between January 2002 and December 2003 all 157 patients (pts) that underwent lung transplantation (LTx) at our institution were prospectively screened for invasive aspergillosis (IA) during their perioperative hospital stay. Patients were regarded as IA positive, if they met the EORTC criteria for 'probable' or 'proven' IA. Records of pts were screened retrospectively for antimycotic prophylaxis. Eight of the 157 pts developed 'probable' or 'proven' IA (5.1%) within 17 +/- 10 days after LTx. This was associated with a 14-fold increased mortality compared with all pts without aspergillosis (P < 0.01, OR 13.8, CI(95%) 2.5-82). Preoperative colonization with Aspergillus was a significant risk factor for IA (P < 0.001, OR 21.9, CI(95%) 4.9-97). We switched our prophylactic strategies to the primary administration of voriconazole in high risk pts (pre-LTx colonization) starting in December 2002. Six pts (6%) of 101 pts receiving itraconazole for antimycotic prophylaxis beginning at postoperative day (POD) one developed IA, of which three pts showed cerebral aspergillosis. One pt (5%) of 18 pts receiving voriconazole prophylaxis developed IA, while 10 pts showed pretransplant colonization with Aspergillus species. Thirty-eight pts received itraconazole prophylaxis at a later time point (>POD 14). By switching our prophylactic strategy to the use of voriconazole in high risk pts, we have decreased the incidence of IA from 8% (six of 75) in 2002 to 2% (two of 82) in 2003. This study shows a high incidence of IA during the very early postoperative course after LTx of 5%. This is associated with a significantly increased risk for mortality. Voriconazole prophylaxis appears to be superior to itraconazole, especially in high risk pts with pretransplant Aspergillus colonization.     

Antigen detection in invasive aspergillosis and candidosis: the Austrian experience

In order to assess the performance of different methods for the detection of fungal antigens, data of five Austrian hospitals were evaluated. The enzyme immunoassay (EIA) Platelia Aspergillus Antigen (Bio-Rad, USA) was used for the diagnosis of invasive aspergillosis and compared with clinical data. It could be shown that it is more effective to investigate at least two sequential sera than only one sole serum. For several high-risk patients diagnosis could be improved or confirmed by investigating other body fluids such as cerebrospinal fluid or bronchoalveolar lavage fluid in addition to sera. For invasive Candida infections several diagnostic kits detecting antigens are commercially available. The performance of the EIA Platelia Candida Antigen (Bio-Rad, USA), the latexagglutination test Cand-Tec (Ramco, USA) and the detection of (1-3)-Beta-D-Glucan using the test kit Glucatell (CAPE COD, USA) were evaluated. The detection of (1-3)-Beta-D-Glucan by means of Glucatell showed the highest sensitivity as all sera of 15 patients with invasive candidosis showed positive results. The other tests showed positive and negative results independently of the occurrence of an invasive infection. However, the number of tested sera is too small to decide which test is the most appropriate for establishing an early and definite diagnosis. Prospective studies in combination with clinical data are still needed for definite evaluation.     

The epidemiology of pseudallescheriasis complicating transplantation: nosocomial and community-acquired infection

The epidemiology of two cases of pseudallescheriasis in organ transplant patients are described and the disease in that population is reviewed. Disseminated hospital-acquired infection occurred in a liver transplant recipient and was fatal despite therapy with miconazole. A heart transplant recipient developed localized disease following soil contamination of soft tissue trauma which was cured with surgical resection and miconazole therapy. Itraconazole showed in vitro activity against Pseudallescheria boydii and should be evaluated in pseudallescheriasis. P. boydii infections are important complications of transplantation and should be considered in the differential diagnosis of community-acquired as well as nosocomial fungal infections in this population.