Oral and parenteral therapy with saperconazole (R 66905) of invasive aspergillosis in normal and immunocompromised animals

Cutsem, J. Van; Gerven, F. Van; Janßen, Paul

doi:10.1128/aac.33.12.2063

Cited by 44 publications

(25 citation statements)

References 15 publications

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“…On the other hand, pigeons inoculated with A. fumigatus spores intravenously showed similar results as the models for Group 1, HBSS in right thoracic air sac; Group 2, HBSS in right lung; Group 3, dexamethasone; Group 4, A. fumigatus in right thoracic air sac; Group 5, A. fumigatus in right lung; Group 6, A. fumigatus in right thoracic air sac after dexamethasone injections; Group 7, A. fumigatus in right lung after dexamethasone injections; Group 8, A. fumigatus in trachea after dexamethasone injections. acute aspergillosis in this study (Van Cutsem et al, 1989;Elmubarak & Fadlelmula, 1991). Discrepancy with literature can be caused by species-dependent susceptibility for A. fumigatus infections and/or variability of pathogenicity of the A. fumigatus isolates used in the different studies (Peden & Rhoades, 1992).…”

Section: Discussionmentioning

confidence: 99%

“…The more acute model may allow the detection of strain-dependent differences of virulence. Although experimental infections with A. fumigatus have been carried out in quails, starlings, pigeons, turkeys and chickens using different inoculation routes (intravenously, intratracheally, in the abdominal/thoracic air sac, intrapulmonary and using aerosol), there is an absolute necessity to compare these routes in one bird species in order to select the appropriate model (Chute & O'Meara, 1958;Wright et al, 1960;Richard et al, 1973Richard et al, , 1981Richard & Thurston, 1983;Dyar et al, 1984;Van Cutsem et al, 1989;Julian & Goryo, 1990;Elmubarak & Fadlelmula, 1991;Peden & Rhoades, 1992;Perelman, 1993;Kunkle & Rimler, 1996;Kunkle et al, 1999;Atasever & Gü mü ssoy, 2004;Gü mü ssoy et al, 2004;Femenia et al, 2007). It was therefore the aim of this study to select an acute and a chronic aspergillosis model in pigeons.…”

Section: Introductionmentioning

confidence: 99%

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ModellingAspergillus fumigatusinfections in racing pigeons (Columba livia domestica)

et al. 2008

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In vivo modelling of aspergillosis in birds allows the evaluation of control measures and the study of hostÁ pathogen interactions. In this study the impact of the use of different inoculation routes and immunosuppression on the course of an infection with Aspergillus fumigatus in racing pigeons (Columba livia domestica) was examined. A. fumigatus conidia were inoculated in the thoracic air sac, lung or trachea in immunocompetent or immunosuppressed pigeon squabs. Immunosuppression was induced by three dexamethasone injections before inoculation. Mortality in the A. fumigatus-inoculated groups varied between 1/4 and 4/4. The highest and more acute mortality was seen in immunocompetent pigeons inoculated in the thoracic air sac and in pigeons inoculated in the thoracic air sac or lung after immunosuppression. Pigeons inoculated in the lung or inoculated intratracheally after immunosuppression developed an aspergillosis infection with a slower course of disease and more prominent clinical symptoms. Using microsatellite length polymorphism, it was confirmed that all mycoses were caused by the inoculated strain except for one isolate in a dexamethasone-treated pigeon. In conclusion, inoculation in the lung is selected as the preferred model for chronic aspergillosis in pigeons, and inoculation in the thoracic air sac as the preferred model for acute aspergillosis. The use of immunosuppressed birds seems to be contra-indicated due to the risk of opportunistic infections.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

ModellingAspergillus fumigatusinfections in racing pigeons (Columba livia domestica)

et al. 2008

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“…There are a number of drugs that interfere with the absorption of itraconazole, among which are agents such as antacids that are also commonly used in neutropenic patients (32,90). In one study on prophylactic itraconazole in 72 neutropenic patients, suspected or proven fungal infections, including IPA, occurred significantly more often in patients with inadequate serum itraconazole levels (<250 ng/ml) (10 (7,35,86,97 (40).…”

Section: Systemic Prophylaxis With Azole Antifungal Agentsmentioning

confidence: 99%

Strategies in prevention of invasive pulmonary aspergillosis in immunosuppressed or neutropenic patients

Beyer

Schwartz

Heinemann

et al. 1994

Antimicrob Agents Chemother

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Aspergillus species are increasingly recognized as major fungal pathogens in severely immunosuppressed or neutropenic patients (8,9,20,22,51,62,71,81,82,103,107, 112). As organ transplantations and aggressive antineoplastic chemotherapy regimens are becoming more frequent, increasing numbers of patients will be susceptible to an Aspergillus infection. Moreover, patients with AIDS probably have a higher incidence ofAspergillus infections than immunocompetent individuals (21). In the immunosuppressed or neutropenic host, invasive pulmonary aspergillosis (IPA), characterized by hyphal invasion and destruction of pulmonary tissue, is the most common manifestation of an Aspergillus infection, although local infections also occur in the sinuses, the skin, or intravenous catheters (1,8,9,20,82,89,101). Dissemination from these initial ports of entry to other organs can be a secondary event in about 20% or more of the cases (1,8,9,20,22,82,101). Aspergillus fumigatus, A. flavus, A. niger, and A. terreus strains were the most frequently observed strains in cases of documented infection (105).Aspergilli are respiratory pathogens, and pulmonary infections are usually acquired through the inhalation ofAspergillus conidia, which are universally present in unfiltered air (9,73,81,103). With a diameter of about 2.5 to 3.5 ,um, these conidia are able to reach small airways and the alveolar space, where the impaired host defense mechanisms allow hyphal germination of the aspergilli and subsequent tissue invasion (9,44,83,103,105). Some patients, however, may have Aspergillus colonization of the nasal sinuses and endogenous spread to the lungs, causing IPA (9, 89, 101). In these latter cases, the exact pathomechanisms of IPA manifestation and the way in which it disseminates from the sinuses to the lungs are less clear.The true incidence of IPA in susceptible patients is not known. In two relatively recent autopsy series, IPA was documented in about 10% of patients with hematological malignancies (8,20). In many cases the condition was not suspected clinically (20). Clinical reports show that the incidence of IPA differs greatly worldwide, at different treatment centers and even within the same institution, ranging from as low as 0% to 25% or more (8,9,28,62,82,88,103 (9,62,73,88). Spore counts in the hospital environment depend on the location and type of building and the type of air filtration used at the time the samples were taken. Without air filtration, spore counts of 5.0/m3 probably do not differ from outdoor samples, whereas by using high-efficiency particulate air (HEPA) filtration, concentrations of spores as low as 0.009/m3 can be achieved (73,88). Aspergillus infections occur more frequently when the spore counts are high. Numerous reports describe microepidemics of IPA coinciding with construction activity or with defective ventilation systems, and variable counts of 2.3 to 5.9 spores per m3 have been measured at these locations (9,72,73,81,88,103). A patient's susceptibility to anAspey*llus infection is determined ...

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“…Saperconazole has been shown to have activity in a guinea pig model and in a murine model of aspergillosis (8,18), but its limited activity in another murine model (15) could be related to the low levels in serum achieved with orally administered drug in that model. Absorption of related triazole compounds, such as ketoconazole and itraconazole, has been reported to be erratic in some immunosuppressed hosts (5,6), so that adequate delivery of drug via oral administration is likely essential for successful therapy.…”

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confidence: 99%

Saperconazole therapy in a rabbit model of invasive aspergillosis

Patterson

George

Miniter

et al. 1992

Antimicrob Agents Chemother

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The efficacy of orally and intravenously administered saperconazole against Aspergillus fumigatus was assessed in an immunosuppressed temporarily leukopenic rabbit model of invasive aspergillosis and compared with that of amphotericin B. Oral saperconazole at dosages of 5, 10, and 15 mg/kg of body weight per day improved survival compared with that of controls. In addition, saperconazole at 10 and 15 mg/kg/day reduced the tissue burden and reduced levels of circulating antigen, which correlated with increasing dosages of saperconazole. Intravenous saperconazole produced levels in serum more than 10-fold that of oral therapy. Intravenous saperconazole not only improved survival and reduced antigen levels but also significantly eradicated A. fumigatus from tissues compared with those of controls and was as effective as amphotericin B in these studies. Saperconazole was effective in the treatment of experimental invasive aspergillosis and demonstrates the potential of the newer azoles in therapy for invasive aspergillosis.

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Oral and parenteral therapy with saperconazole (R 66905) of invasive aspergillosis in normal and immunocompromised animals

Cited by 44 publications

References 15 publications

ModellingAspergillus fumigatusinfections in racing pigeons (Columba livia domestica)

ModellingAspergillus fumigatusinfections in racing pigeons (Columba livia domestica)

Strategies in prevention of invasive pulmonary aspergillosis in immunosuppressed or neutropenic patients

Saperconazole therapy in a rabbit model of invasive aspergillosis

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