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Astellas Pharma Inc.

Focus on Fungal Infections Newsletter
Focus on Fungal Infections Newsletter

Focus on Invasive Aspergillosis


Dr. Patterson from the University of Texas Health Science Center at San Antonio reviewed the difficulties in diagnosing and treating refractory invasive aspergillosis (IA).

Dr. Patterson began by presenting data showing the increase in mortality from Aspergillus infections since the 1980s. This increase is reported in a recent review by Lin and colleagues,1 who reviewed 1,941 patients from 50 studies. The overall mortality rate was 58% in patients with IA. In BMT patients, however, mortality was greater than 90%, a result of severe immunosuppression and underlying disease according to Dr. Patterson. These data suggest that dramatic changes are needed in the approach to treating IA, especially in severely immunocompromised patients.

Dr. Patterson stressed that one of the reasons IA is so difficult to manage is that diagnosis still remains extremely difficult to establish. He emphasized the importance of CT scans in identifying hallmark clinical signs and symptoms of pulmonary IA. CT scans potentially improve the ability to diagnose these infections, and earlier diagnosis may improve outcomes. A study by Caillot and colleagues reported that the early use of CT scans led to improved outcomes in febrile neutropenic patients with IA.2 Another study by Yeghen and colleagues found that patients who underwent surgical lung resection of suspected lesions had improved responses compared to patients who had a diagnosis established by a positive respiratory sample.3 In addition, non-culture based methods such as serial galactomannan and polymerase chain reaction (PCR) screening may be useful in establishing earlier diagnosis and may result in improved outcomes. None of these methods are approved for clinical use in the United States.

Dr. Patterson then reviewed the antifungal agents currently used to treat IA. The efficacy of amphotericin B deoxycholate is hampered by toxicity; response rates are about 30%. New options are available with the lipid formulations of amphotericin B, the extended spectrum triazoles, and the echinocandins, a new class of antifungals. Specifically, Dr. Patterson pointed out that higher doses of the lipid formulations of amphotericin B may be efficacious in high-risk patients with documented refractory IA. Recent clinical data suggest that very high doses of liposomal amphotericin B (7.5 to 15 mg/kg/day) were well tolerated and provided effective therapy for IA and other filamentous fungal infections in a highly immunosuppressed patient population.4

Dr. Patterson mentioned that the newer triazoles such as voriconazole may have a role in treating patients with IA, and presented results of a study that showed encouraging response rates in patients with advanced disease treated with voriconazole as primary therapy.5 The Global Comparative Aspergillosis Study, which compared voriconazole to amphotericin B deoxycholate followed by other licensed antifungal therapies (OLAT), found that responses in allogeneic BMT recipients treated with voriconazole were about 30%,6 a substantial improvement compared with earlier outcomes. An interesting point in this study raised by Dr. Patterson was that patients who received OLAT following amphotericin B therapy did not fare very well, suggesting that the standard approach of initiating antifungal therapy with amphotericin B deoxycholate and switching patients to OLAT produces suboptimal outcomes.

Dr. Patterson also explored the potential role of the echinocandins in treating IA, and presented results of a study that reported a response rate of 41% in 56 patients treated with caspofungin.7 The potential role of these agents in combination therapy with amphotericin B and the azoles is currently being studied in animal models, and ongoing-clinical studies are aimed at establishing the optimal dose of these preparations.


References:

1. Lin S, et al. Aspergillosis case fatality rate: systematic review of the literature. Clin Infect Dis 2001;32:358–66.

2. Caillot D, et al. Improved management of invasive pulmonary aspergillosis in neutropenic patients using early thoracic computed tomographic scan and surgery. J Clin Oncol 1997;15:139–147.

3. Yeghen T, et al. Management of invasive pulmonary aspergillosis in hematology patients: a review of 87 consecutive cases at a single institution. Clin Infect Dis 2000;31:859–68.

4. Walsh TJ, et al. Safety, tolerance, and pharmacokinetics of high-dose liposomal amphotericin B (AmBisome) in patients with Aspergillus species and other filamentous fungi: Maximum tolerated dose study. Antimicrob Agents Chemother 2001;45:3487–96.

5. Denning DW, et al. Efficacy and safety of voriconazole in the treatment of acute invasive aspergillosis. Clin Infect Dis 2002;34:563–71.

6. Herbrecht R, et al. Open, randomised comparison of voriconazole (VRC) and amphotericin B (AmB) followed by other licensed antifungal therapy (OLAT) for primary therapy of invasive aspergillosis (IA). Proceedings of the 41st ICAAC 2001;[abstract J-680].

7. Maertens J, et al. Efficacy of caspofungin as salvage therapy in invasive aspergillosis as compared to standard therapy in a historical cohort ECCMID 2001;[abstract O-248].


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