Aspergillus species have emerged as an important cause of life-threatening infections in immunocompromised patients. This expanding population is composed of patients with prolonged neutropenia, advanced HIV infection, and inherited immunodeficiency and patients who have undergone allogeneic hematopoietic stem cell transplantation (HSCT) and/or lung transplantation. This document constitutes the guidelines of the Infectious Diseases Society of America for treatment of aspergillosis and replaces the practice guidelines for Aspergillus published in 2000 [1]. The objective of these guidelines is to summarize the current evidence for treatment of different forms of aspergillosis. The quality of evidence for treatment is scored according to a standard system used in other Infectious Diseases Society of America guidelines. This document reviews guidelines for management of the 3 major forms of aspergillosis: invasive aspergillosis, chronic (and saprophytic) forms of aspergillosis, and allergic forms of aspergillosis. Given the public health importance of invasive aspergillosis, emphasis is placed on the diagnosis, treatment, and prevention of the different forms of invasive aspergillosis, including invasive pulmonary aspergillosis, sinus aspergillosis, disseminated aspergillosis, and several types of single-organ invasive aspergillosis. There are few randomized trials on the treatment of invasive aspergillosis. The largest randomized controlled trial demonstrates that voriconazole is superior to deoxycholate amphotericin B (D-AMB) as primary treatment for invasive aspergillosis. Voriconazole is recommended for the primary treatment of invasive aspergillosis in most patients (A-I). Although invasive pulmonary aspergillosis accounts for the preponderance of cases treated with voriconazole, voriconazole has been used in enough cases of extrapulmonary and disseminated infection to allow one to infer that voriconazole is effective in these cases. A randomized trial comparing 2 doses of liposomal amphotericin B (L-AMB) showed similar efficacy in both arms, suggesting that liposomal therapy could be considered as alternative primary therapy in some patients (A-I). For salvage therapy, agents include lipid formulations of amphotericin (LFAB; A-II), posaconazole (B-II), itraconazole (B-II), caspofungin (B-II), or micafungin (B-II). Salvage therapy for invasive aspergillosis poses important challenges with significant gaps in knowledge. In patients whose aspergillosis is refractory to voriconazole, a paucity of data exist to guide management. Therapeutic options include a change of class using an amphotericin B (AMB) formulation or an echinocandin, such as caspofungin (B-II); further use of azoles should take into account host factors and pharmacokinetic considerations. Refractory infection may respond to a change to another drug class (B-II) or to a combination of agents (B-II). The role of combination therapy in the treatment of invasive aspergillosis as primary or salvage therapy is uncertain and warrants a prospective, controlled clinical trial. Assessment of patients with refractory aspergillosis may be difficult. In evaluating such patients, the diagnosis of invasive aspergillosis should be established if it was previously uncertain and should be confirmed if it was previously known. The drug dosage should be considered. Management options include a change to intravenous (IV) therapy, therapeutic monitoring of drug levels, change of drug class, and/or combination therapy. Antifungal prophylaxis with posaconazole can be recommended in the subgroup of HSCT recipients with graft-versus-host disease (GVHD) who are at high risk for invasive aspergillosis and in neutropenic patients with acute myelogenous leukemia or myelodysplastic syndrome who are at high risk for invasive aspergillosis (A-I). Management of breakthrough invasive aspergillosis in the context of mould-active azole prophylaxis is not defined by clinical trial data. The approach to such patients should be individualized on the basis of clinical criteria, including host immunosuppression, underlying disease, and site of infection, as well as consideration of antifungal dosing, therapeutic monitoring of drug levels, a switch to IV therapy, and/or a switch to another drug class (B-III). Certain conditions of invasive aspergillosis warrant consideration for surgical resection of the infected focus. These include but are not limited to pulmonary lesions contiguous with the heart or great vessels, invasion of the chest wall, osteomyelitis, pericardial infection, and endocarditis (B-III). Restoration of impaired host defenses is critical for improved outcome of invasive aspergillosis (A-III). Recovery from neutropenia in a persistently neutropenic host or reduction of corticosteroids in a patient receiving high-dose glucocorticosteroids is paramount for improved outcome in invasive aspergillosis. A special consideration is made concerning recommendations for therapy of aspergillosis in uncommon sites, such as osteomyelitis and endocarditis. There are very limited data on these infections, and most involve D-AMB as primary therapy simply because of its long-standing availability. Based on the strength of the randomized study, the panel recommends voriconazole for primary treatment of these very uncommon manifestations of invasive aspergillosis (B-III). Management of the chronic or saprophytic forms of aspergillosis varies depending on the condition. Single pulmonary aspergillomas may be best managed by surgical resection (B-III), whereas chronic cavitary and chronic necrotizing pulmonary aspergillosis require long-term medical therapy (B-III). The management of allergic forms of aspergillosis involves a combination of medical and anti-inflammatory therapy. For example, management of allergic bronchopulmonary aspergillosis (ABPA) involves the administration of itraconazole and corticosteroids (A-I). © 2008 by the Infectious Diseases Society of America. All rights reserved.

/pdf/treatment-of-aspergillosis-clinical-practice-guidelines-of-22h30ces3m.pdf

Treatment of Aspergillosis: Clinical Practice Guidelines of the Infectious Diseases Society of America

Aspergillus fumigatus is one of the most ubiquitous of the airborne saprophytic fungi. Humans and animals constantly inhale numerous conidia of this fungus. The conidia are normally eliminated in the immunocompetent host by innate immune mechanisms, and aspergilloma and allergic bronchopulmonary aspergillosis, uncommon clinical syndromes, are the only infections observed in such hosts. Thus, A. fumigatus was considered for years to be a weak pathogen. With increases in the number of immunosuppressed patients, however, there has been a dramatic increase in severe and usually fatal invasive aspergillosis, now the most common mold infection worldwide. In this review, the focus is on the biology of A. fumigatus and the diseases it causes. Included are discussions of (i) genomic and molecular characterization of the organism, (ii) clinical and laboratory methods available for the diagnosis of aspergillosis in immunocompetent and immunocompromised hosts, (iii) identification of host and fungal factors that play a role in the establishment of the fungus in vivo, and (iv) problems associated with antifungal therapy.

Aspergillus fumigatus and Aspergillosis

SUMMARY Aspergillus fumigatus is one of the most ubiquitous of the airborne saprophytic fungi. Humans and animals constantly inhale numerous conidia of this fungus. The conidia are normally eliminated in the immunocompetent host by innate immune mechanisms, and aspergilloma and allergic bronchopulmonary aspergillosis, uncommon clinical syndromes, are the only infections observed in such hosts. Thus, A. fumigatus was considered for years to be a weak pathogen. With increases in the number of immunosuppressed patients, however, there has been a dramatic increase in severe and usually fatal invasive aspergillosis, now the most common mold infection worldwide. In this review, the focus is on the biology of A. fumigatus and the diseases it causes. Included are discussions of (i) genomic and molecular characterization of the organism, (ii) clinical and laboratory methods available for the diagnosis of aspergillosis in immunocompetent and immunocompromised hosts, (iii) identification of host and fungal factors that play a role in the establishment of the fungus in vivo, and (iv) problems associated with antifungal therapy.

Aspergillus fumigatus and aspergillosis.

Major developments in research into the azole class of antifungal agents during the 1990s have provided expanded options for the treatment of many opportunistic and endemic fungal infections. Fluconazole and itraconazole have proved to be safer than both amphotericin B and ketoconazole. Despite these advances, serious fungal infections remain difficult to treat, and resistance to the available drugs is emerging. This review describes present and future uses of the currently available azole antifungal agents in the treatment of systemic and superficial fungal infections and provides a brief overview of the current status of in vitro susceptibility testing and the growing problem of clinical resistance to the azoles. Use of the currently available azoles in combination with other antifungal agents with different mechanisms of action is likely to provide enhanced efficacy. Detailed information on some of the second-generation triazoles being developed to provide extended coverage of opportunistic, endemic, and emerging fungal pathogens, as well as those in which resistance to older agents is becoming problematic, is provided.

Current and Emerging Azole Antifungal Agents

Echinocandin antifungal drugs

https://www.amjmed.com/article/0002-9343(94)90023-X/pdf

NIAID mycoses study group multicenter trial of oral itraconazole therapy for invasive aspergillosis

Erratum: NIAID mycoses study group multicenter trial of oral itraconazole therapy for invasive aspergillosis (American Journal of Medicine (August 1994) 97 (135-144))

The therapeutic efficacy of itraconazole solubilized in either the commonly used vehicle, polyethylene-glycol-200 (PEG) or hydroxypropyl beta-cyclodextrin was compared in a murine model of disseminated cryptococcosis. Itraconazole at doses of up to 120 mg/kg/day solubilized in PEG were found not to be effective. However, itraconazole at doses > or = 30 mg/kg/day solubilized in hydroxypropyl-beta-cyclodextrin markedly prolonged survival and a relationship between dose and survival was seen.

John S. Hostetler

Papers

NIAID mycoses study group multicenter trial of oral itraconazole therapy for invasive aspergillosis

Erratum: NIAID mycoses study group multicenter trial of oral itraconazole therapy for invasive aspergillosis (American Journal of Medicine (August 1994) 97 (135-144))

Effect of hydroxypropyl-β-cyclodextrin on efficacy of oral itraconazole in disseminated murine cryptococcosis