To date, only two comparative randomized controlled clinical trials have evaluated antifungal therapies for the treatment of diagnosis-proven IA and only one study was sufficiently powered to measure differences in response to antifungal therapy.45 In that study, unblinded investigators compared patients initially randomized to the newer triazole, voriconazole, to patients initially treated with amphotericin B deoxy-cholate.45 The study design was unique in that it allowed a change from the randomized drug to any other licensed antifungal therapy, without requiring that the patient be classified as a treatment failure on randomized therapy. Nearly 80% of patients randomized to receive amphotericin B deoxycholate were switched to other licensed an-tifungal therapies (mean duration 10 days) versus 36% of patients in the voriconazole arm (mean duration 77 days). The poor tolerability of amphotericin B deoxycholate was not surprising given the relatively higher dosages (1 mg/kg/day IV) and prolonged treatment courses required in the treatment of IA. At the end of the study (12 weeks), a higher proportion of patients in the voriconazole arm remained alive (70.8%) compared to amphotericin B deoxycholate-treated patients (57.9%). On the basis of these results, many experts now consider voriconazole as the initial drug of choice for IA in patients without significant contraindications (e.g., drug interactions or pre-

existing liver dysfunction) to azole therapy (see Table 84-2). Voriconazole also appears to have some efficacy in CNS aspergillosis, a form of IA with historical mortality rates approaching 100%. Itraconazole has activity against Aspergillus and is frequently used as prophylaxis, but is not considered a particularly effective treatment

option for invasive disease.

FIGURE 84-4. Pathogenesis of invasive aspergillosis (IA).

Lipid formulations ofamphotericin B, echinocandins, or posaconazole can be considered as possible alternatives to voriconazole therapy and may be preferred agents in patients with breakthrough infection on azole antifungals (including itraconazole or fluconazole). Several recent open-label case series have suggested that combination therapy, with an echinocandin and mold-active triazole such as voriconazole, may be more effective than voriconazole alone for IA that has failed amphotericin B-based 42

therapy. Once antifungal therapy has begun, the duration and intensity of antifungal therapy is directed by host-specific factors including clinical response, underlying immunosuppression, tolerability, and plans for future chemotherapy/immunosuppres-sion. In the heavily immunocompromised patient, complete eradication ofthe fungus is unlikely and suppressive therapy may be required until well after recovery of cellular immune function. Reactivation from residual infarcts or devitalized tissue in the sinus or lung harboring aspergillosis is a concern ifthe patient will receive further im-munosuppressive therapy. Therefore, surgical debridement of the sinus or excision of large lung lesions is often pursued if the patient is not profoundly thrombocytopenic. Relapsing or breakthrough Aspergillus infections respond less favorably to antifungal therapy than de novo IA and may require more aggressive measures (combination therapy, immunotherapy, or surgery) to stabilize the infection.

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