Mycoses

Tóm tắt: Itraconazole (R 51211) là nguyên mẫu của một nhóm thuốc chống nấm triazole có tính chất ưa mỡ cao. Tính chất này quyết định phần lớn dược động học của itraconazole và làm nó khác biệt so với thuốc chống nấm triazole ưa nước fluconazole.

Dược động học của itraconazole ở người được đặc trưng bởi sự hấp thu qua đường uống tốt, phân bố rộng khắp trong mô với nồng độ mô cao gấp nhiều lần trong huyết tương, thời gian bán hủy bài tiết tương đối dài khoảng một ngày và sự chuyển hóa thành một số lượng lớn các chất chuyển hóa. Một trong số đó, hydroxy-itraconazole, có hoạt động chống nấm và giải thích tại sao mức nồng độ chống nấm trong huyết tương, khi đo bằng phương pháp sinh học, cao gấp khoảng ba lần so với mức nồng độ itraconazole đo bằng phương pháp HPLC đặc hiệu.

Các nghiên cứu phân bố đã chỉ ra rằng các mức độ hoạt động điều trị của itraconazole được duy trì lâu hơn nhiều trong một số mô nhiễm bệnh so với trong huyết tương. Ví dụ, mức độ hoạt động tồn tại trong bốn ngày ở biểu mô âm đạo sau khi điều trị một ngày và trong ba tuần ở lớp bì của da sau khi ngừng điều trị. Khác với fluconazole, itraconazole không can thiệp vào các enzym chuyển hóa thuốc ở động vật có vú, giảm thiểu nguy cơ tương tác với các thuốc được dùng đồng thời. Những tính chất dược động học này có thể góp phần vào hiệu quả và an toàn cao của itraconazole đối với bệnh nhân mắc các nhiễm trùng do nấm khác nhau. Các dạng bào chế mới đang được khám phá để mở rộng phạm vi ứng dụng của itraconazole cho liệu pháp tiêm tĩnh mạch và đường uống ở bệnh nhân mắc chứng kém hấp thu.

Invasive aspergillosis is rare in immunocompetent people but contributes to significant morbidity and mortality in immunosuppressed patients. The majority (approximately 80%) of invasive Aspergillus infections is caused by Aspergillus fumigatus. The second most frequent (approximately 15–20%) pathogenic species is Aspergillus flavus and to a lesser extent, Aspergillus niger and Aspergillus terreus. Aspergillus flavus has emerged as a predominant pathogen in patients with fungal sinusitis and fungal keratitis in several institutions worldwide. To date, there has not been any publication exclusively reviewing the topic of A. flavus in the literature. This article reviews the microbiology, toxigenicity and epidemiology of A. flavus as well as describes the clinical characteristics, diagnosis and management of infections caused by this organism.

Summary: Seventy‐two patients with haematological malignancies were treated prophylactically with itraconazole during remission induction therapy.

The incidence of proven fungal infections was 18 %, of which 12.5 % were fatal. Aspergillus, Tomlopsis and Candida proved to be major invasive pathogens. Plasma levels of itraconazole were monitored for all patients.

The occurrence of fungal infection is significantly greater in the group where no therapeutic plasma levels were obtained during at least two weeks.

There is a clear need to obtain quick information on itraconazole plasma levels in order to adapt dosage during prophylactic treatment in immunocompromised patients.

The influence of itraconazole on liver function tests could not be separated from concomitant cytostatic or antibiotic treatment. No jaundice directly related to itraconazole could be found.

During itraconazole prophylaxis a shift from classic pathogens such as Aspergillus and Candida, to Fusarium, Torulopsis and Mucor, may be seen.

Summary:A total of 137 patients with aspergillosis or aspergilloma has been treated with 50 to 400 mg itraconazole daily during 11 to 780 days.

The global assessments »markedly improved« and »cured« were given to 60% of the treatments in invasive aspergillosis (n = 35) and reached 66% in chronic necrotising pulmonary aspergillosis (n = 44). These response rates are sufficiently high regarding the limited number of antifungal agents useful in aspergillosis. Sixty‐two percent of the chronic pulmonary aspergilloma cases (n = 42) showed symptomatic improvement and the radiological picture had improved in 30%. In one patient, the fungus ball disappeared during long‐term treatment. The results in five allergic bronchopulmonary aspergillosis (ABPA) patients indicate a possible role for itraconazole as complementary treatment to corticosteroids. All seven patients with cutaneous aspergillosis were mycologically and clinically cured after a maximum of 158 days of treatment. Two out of three biopsy proven cases of bone aspergillosis responded to itraconazole therapy. These long‐term treatments with itraconazole were well tolerated. The reported side effects were merely of gastro‐intestinal origin and there was no effect on the most important biochemical and haematological parameters.

Itraconazole appears to be a valuable new tool in the treatment of aspergillosis.

Zusammenfassung:Eine Gesamtzahl von 137 Aspergillose‐ und Aspergillom‐Patienten wurde mit 50–400 mg Itraconazol täglich über Perioden zwischen 11 und 780 Tagen behandelt.

Das Globalurteil »wesentlich gebessert« oder »geheilt« erhielten 60% der Behandelten mit invasiver Aspergillose (n = 35) und 66% der Patienten mit chronisch nekrotisierender Lungenaspergillose (n = 44). Diese Ansprechquoten sind recht hoch, wenn man die beschränkte Anzahl der bei Aspergillose wirksamen Antimykotika berücksichtigt. Bei 62% der Fälle mit chronischem Lungenaspergillom (n = 42) wurde eine symptomatische Besserung erzielt, bei 30% besserte sich das radiologische Bild. Bei einem Patienten verschwand der Fungusball während Langzeitbehandlung. Die Ergebnisse von 5 Patienten mit allergischer bronchopulmonaler Aspergilose (ABPA) deuten auf die mögliche Rolle von Itraconazol bei einer Kombinationsbehandlung mit Kortikosteroiden. Alle 7 Patienten mit kutaner Aspergillose waren nach einer maximalen Behandlungsdauer von 158 Tagen mykologisch und klinisch geheilt. Zwei von 3 bioptisch nachgewiesenen Fällen mit Knochenaspergillose sprachen auf Itraconazol‐Behandlung an. Die Langzeitbehandlung mit Itraconazol war gut verträglich. Die angegebenen Nebenwirkungen waren meist gastrointestinalen Ursprunges, die wesentlichsten biochemischen und hämatologischen Parameter blieben unbeeinflußt. Damit erweist sich Itraconazol als ein wertvolles neues Medikament bei der Behandlung der Aspergillose.

Triazole and imidazole antifungal agents inhibit metabolism of vincristine, leading to excess vinca alkaloid exposure and severe neurotoxicity. Recent reports of debilitating interactions between vincristine and itraconazole, as well as posaconazole, voriconazole and ketoconazole underscore the need to improve medical awareness of this adverse combination. We, therefore, undertook a comprehensive analysis of reports of adverse drug interactions (ADIs) with the combination of vincristine and azole antifungal agents, established a new classification, and provided a detailed summary of these toxicities. In patients who had sufficient data for analysis, 47 individuals were identified who had an ADI with the combination of vincristine and antifungal azoles. Median age was 8 years (1.3–68 years) with 33(70%) having a diagnosis of acute lymphoblastic leukaemia. Median time to ADI with vincristine was 9.5 days with itraconazole, 13.5 days posaconazole and 30 days voriconazole. The median number of vincristine doses preceding the ADI was 2 doses with itraconazole, 3 doses posaconazole and 2 doses voriconazole. The most common severe ADIs included gastrointestinal toxicity, peripheral neuropathy, hyponatremia/SIADH, autonomic neuropathy and seizures. Recovery from these ADIs occurred in 80.6% of patients. We recommend using alternative antifungal agents if possible in patients receiving vincristine to avoid this serious and potentially life‐threatening drug interaction.

In the present report we reviewed a total of 2397 cases of dermatophytosis from superficial cutaneous lesions between the years 1978 and 1990. The cases included were from the Department of Dermatology at the University Hospital located in the city of Monterrey, México. A total of 726 tinea pedis, 613 tinea unguium, 441 tinea capitis, 395 tinea corporis and 222 tinea cruris cases were observed. The most commonly isolated dermatophyte species was Trichophyton rubrum (45%), followed by Trichophyton mentagrophytes (23.7%), Trichophyton tonsurans (21%), Microsporum canis (7.1%) and Epidermophyton floccosum (2.5%). Less frequently we isolated Microsporum audouinii, Microsporum gypseum, Trichophyton violaceum and Trichophyton verrucosum. Most of the cases were observed in the warmest months of the year (from March to September), and were equally distributed in both genders, except for tinea cruris which was more prevalent in men (3.5 : 1 ratio).

Pseudomembranous and obstructive Aspergillus tracheobronchitis (PMATB/OATB) are still considered to be refractory to therapy and to have a fatal outcome. To evaluate the optimal diagnostic strategy and to describe factors affecting the outcome of PMATB and OATB. Retrospective analysis of four new cases of PMATB and OATB combined with 16 previously reported cases over a 10‐year period (1995–2004). Among the four new cases reported and the 16 published cases, four patients survived their infection. The mortality rate was significantly higher in the group of ventilated patients [94% (15 of 16 patients)] than in the group of non‐ventilated patients [25% (1 of 4 patients), P < 0.05, Fisher's exact test]. In all 20 patients, diagnosis was established by bronchoscopy. Culture examination of mucous plugs was positive in 8 of 10, culture of the tracheobronchial aspirate was positive in 8 of 12, and bronchoalveolar lavage was diagnostic in 7 of 13 patients. All bronchoscopic techniques were complementary in improving the yield of bronchoscopy. However, microscopy of mucous plugs and/or necrotic material was the best diagnostic modality [positive in 94% (17 of 18 patients)]. Prognosis of PMATB and OATB remains poor. Microscopy of respiratory specimens is the most sensitive tool to confirm the diagnosis. The characteristic appearance of the disease makes it possible to start antifungal therapy immediately.

Summary: Forty consecutive patients suffering from mycotic keratitis (19 due to Fusarium solani and other Fusarium spp., 15 due to Aspergillus flavus and Aspergillus fumigatus and six cases due to other fungi) were treated with itraconazole, a triazole derivative. The compound was administered orally once daily in a dose of 200 mg for a median duration of treatment of 17 days. Progressive corneal ulceration stopped and there was complete resolution of all lesions and eradication of the infecting fungus from the lesions in 22 patients. In five patients, the infecting fungi were eradicated from the lesions but ultimately surgery had to be performed due to incomplete resolution of the lesions. In the remaining 13 patients, progressive corneal ulceration continued and the infecting fungi (F. solani and other Fusarium spp. in nine patients, A. fumigatus in two patients, A. flavus in one and Cladosporium spp. in one patient) were not eradicated from the lesion. Excellent or moderate responsiveness to therapy was observed more frequently in cases of keratitis due to Aspergillus than in cases of keratitis due to Fusarium. There was no evidence of serious adverse reactions in any of the patients.

Zusammenfassung: Vierzig Patienten mit mykotischer Keratitis (19 verursacht durch Fusarium solani und andere Fusarium‐Arten, 15 durch Aspergillus flavus und A. fumigatus und 6 durch andere Pilze) wurden mit dem Triazol‐Derivat Itraconazol behandelt. Das Mittel wurde einmal täglich in einer Dosis von 200 mg bei einer mittleren Behandlungsdauer von 17 d gegeben. Bei 22 Patienten kam die progrediente Hornhautulzeration zum Still‐stand, es kam zur vollständigen Ausheilung aller Läsionen und zur Eliminierung des Pilzes. Bei 5 Patienten konnte der Pilz eliminiert werden, jedoch mußte wegen der nur unvollständigen Abheilung der Läsionen chirurgisch nachbehandelt werden. Bei den restlichen 13 Patienten schritt die Hornhautulzeration weiter fort und der Erreger (F. solani und andere Fusarium‐Arten bei 9 Patienten, A. fumigatus bei 2 und A. flavus und Cladosporium spec. in je einem Patienten) konnten nicht aus den Läsionen eliminiert werden. Hervorragendes und mäßiges Ansprechen auf die Therapie wurde Öfter bei Aspergillus‐bedingter als bei Fusarium‐bedingter Keratitis beobachtet. Ernsthafte Nebenwirkungen wurden bei keinem der Patienten gesehen.

Summary. Eighteen adult white male patients with cutaneous sporotrichosis were treated with itraconazole following different daily dose schemes. Cure was obtained in all cases after periods of 15–75 days (median 44 days) with total doses between 3.1 and 14.8 g (median 8.4 g). No serious side effects were observed and no relapses occurred in the follow‐up period of between 1 and 26 months (median 14.7). These results show that itraconazole represents a safe and effective drug for the treatment of sporotrichosis. Comparison with other studies leads us to consider a daily dose of 200 mg as the most appropriate. A concomitant warming of the affected limbs should be recommended.

Zusammenfassung. Achtzehn männliche Erwachsene weißer Hautfarbe mit kutaner Sporotrichose wurden nach unterschiedlichen Dosierungsschemata mit Itraconazol behandelt. Eine Heilung wurde in allen Fällen nach einer Behandlungsdauer zwischen 15 und 75 d (Mittel 44 d) mit Gesamtdosen von 3.1 bis 14.8 g (Mittel 8.4 g) erzielt. Bedeutsame Nebenwirkungen wurden nicht beobachtet. In der Nachbeobachtungszeit, die mit einem Mittel von 14.7 Monaten zwischen einem und 26 Monaten lag, traten keine Rück‐fälle auf. Die Ergebnisse belegen, daß Itraconazol ein sicher wirksames Medikament für die Behandlung der Sporotrichose darstellt. Unter Einbeziehung der Ergebnisse anderer Studien erscheint uns eine tägliche Itraconazol‐Dosis von 200 mg als am günstigsten. Eine gleichzeitige Erwärmung der befallenen Gliedmaßen wird empfohlen.