New drugs, trials lead to updated IDSA aspergillosis treatment guidelines

February 2008

The Infectious Diseases Society of America has released new clinical practice guidelines for the treatment of aspergillosis. The new guidelines incorporate new thinking and data from research conducted over the last several years.

“Since the previous aspergillosis guidelines were published in 2000, there have been extensive developments in new drugs that target aspergillosis and in the publication of new clinical trial data that help guide management of invasive aspergillosis,” Thomas F. Patterson, MD, told Infectious Disease News. Patterson co-authored the guidelines, published in Clinical Infectious Diseases.

The guidelines indicated that Aspergillus species are an important cause of life-threatening infections among immunocompromised patients; this population, including individuals with advanced HIV infection, inherited immunodeficiency and prolonged neutropenia, is growing.

Drug therapy

“A key message of these guidelines is the importance of early, effective antifungal therapy in this disease — getting it right the first time,” said Patterson, a professor of medicine in the section of infectious diseases at the University of Texas Health Science Center at San Antonio.

Although few randomized, controlled trials have been performed with drugs aimed at treating invasive aspergillosis, results from one large study found that voriconazole (Vfend, Pfizer) is superior to deoxycholate amphotericin B as a primary treatment. The evidence is strongest for the drug’s use in patients with invasive pulmonary aspergillosis, but according to the guidelines, there is sufficient evidence to use voriconazole in cases of extrapulmonary and disseminated infection as well.

The trial data found that after 12 weeks of therapy, a successful outcome was achieved in 53% of patients in the voriconazole arm vs. 32% of patients in the deoxycholate amphotericin B arm. The survival rate at 12 weeks was 71% among patients treated with voriconazole and 58% among those treated with deoxycholate amphotericin B. There were also fewer severe drug-related adverse events in the voriconazole group.

“The efficacy of voriconazole was further demonstrated in pediatric and adult patients receiving voriconazole for treatment of invasive aspergillosis who were refractory to or intolerant of conventional antifungal therapy,” the guideline authors wrote. “The overall response rate was 43% for pediatric patients and 48% for adult patients.”

Alternatives

The researchers of another randomized trial testing liposomal amphotericin B found similarly effective results with two different doses, indicating that this can be used as an alternative primary therapy in some patients. Data on salvage therapy, however, are lacking.

“In patients whose aspergillosis is refractory to voriconazole, a paucity of data exist to guide management,” the guideline authors wrote. Options include a change of class to an amphotericin B or an echinocandin such as caspofungin (Cancidas, Merck). Combination therapy as both primary and salvage treatment for invasive aspergillosis may be useful, but currently there are no data on the topic. The guideline authors wrote that this area “warrants a prospective, controlled clinical trial.”

Another important area is that of antifungal prophylaxis among high-risk patients. Patients considered to be at high risk include hematopoietic stem cell transplantation recipients with graft-versus-host disease as well as neutropenic patients with acute myelogenous leukemia or myelodysplastic syndrome. Patterson said that posaconazole (Noxafil, Schering-Plough) “is the preferred agent for prophylaxis in high-risk patients.”

In some specific conditions, surgical resection of the infected focus can be warranted with invasive aspergillosis. These conditions include pulmonary lesions contiguous with the heart or great vessels, invasion of the chest wall, osteomyelitis, pericardial infection and endocarditis. “Restoration of impaired host defenses is critical for improved outcome of invasive aspergillosis,” the guideline authors wrote. “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.”

Other guidelines

Although the IDSA panel gave special consideration to aspergillosis in uncommon sites, such as osteomyelitis and endocarditis, the data on therapy for these infections are limited. Because of the strength of the randomized trial of voriconazole, however, the guidelines recommend the use of this drug as primary therapy for these “very uncommon manifestations of invasive aspergillosis.”

Managing chronic or saprophytic aspergillosis should vary based on the specific condition. For example, single pulmonary aspergillomas can be managed with surgical resection, whereas management of chronic cavitary and chronic necrotizing pulmonary aspergillosis involves long-term medical therapy. Finally, the management of allergic forms of aspergillosis involves the combination of antiinflammatory therapy with standard medical therapy, usually with the azole class of drugs.

Patterson said that although progress has been made, there is a need for more research. “More clinical data are urgently needed to guide the use of combination therapy and for optimizing salvage regimens,” he said. “Additionally, improved tools for early diagnosis are a major focus of ongoing research.”

Dr. Patterson has received grant support from Merck, Pfizer and Schering-Plough, and has also served on their speaker’s bureaus.

For more information:

• Walsh TJ, Anaissie EJ, Denning DW, et al. Treatment of aspergillosis: clinical practice guidelines of the Infectious Diseases Society of America. Clin Infect Dis. 2008;46:327-360.