Posaconazole Salvage in Invasive Aspergillosis
Abstract & Commentary
By Stan Deresinski, MD, FACP, Clinical Professor of Medicine, Stanford, Associate Chief of Infectious Diseases, Santa Clara Valley Medical Center, is Editor for Infectious Disease Alert.
Source: Walsh TJ, et al. Treatment of invasive aspergillosis with posaconazole in patients who are refractory to or intolerant of conventional therapy: an externally controlled trial. Clin Infect Dis. 2007;44:2-12.
Synopsis: Salvage therapy of invasive aspergillosis with posaconazole was associated with a 42% response rate, compared to only 26% in an external control group.
In a multicenter international open-label study, patients with proven or probable invasive aspergillosis (IA) that was refractory to standard antifungal therapy or who were intolerant to such therapy were treated with posaconazole in a total daily amount of 800 mg administered in divided doses. In addition to the 107 posaconazole recipients meeting criteria for analysis, 86 control subjects with proven or probable IA who received other salvage therapies were included in the assessment. Among the latter group, salvage treatments were approximately evenly distributed among amphotericin B, itraconazole, a combination of the 2, and other agents. The median duration of posaconazole therapy was 56 days, while controls received their salvage therapy for only 22 days. Patients of either group receiving mechanical ventilation at baseline or who died within 72 hours were excluded from the analysis.
Three-fourths of patients had a hematological malignancy and approximately one-half of the total population had received a hematopoietic stem cell transplant, most of which were allogeneic. Twelve percent of posaconazole recipients and 21% of controls had been intolerant of standard antifungal therapy, while the remainder had suffered from infections refractory to treatment. Infection was confined to the lungs in approximately three-fourths of cases.
Success of antifungal therapy was achieved in 42% of posaconazole recipients and 26% of control subjects (OR, 4.06; 95% CI, 1.50 to 11.04; P =0.06). Success was associated with higher posaconazole serum concentrations, ranging from 24% in those whose concentrations fell into the lowest quartile (mean Cmax of 142 ng/ml) to 75% in those in the highest quartile (mean Cmax of 1489 ng/ml). Only 4 of 14 (29%) of patients with Aspergillus terreus infection responded to salvage with posaconazole as did only 2 of 13 (15%) receiving alternative salvage therapies, however.
Posaconazole therapy was also associated with greater survival than were the other salvage therapies received by control group members. Posaconazole was well tolerated with gastrointestinal disturbances being the most frequently reported adverse events.
Commentary
The 42% rate of success in patients with IA receiving salvage treatment with posaconazole may seem low but is, in fact, remarkably similar to the results of salvage therapy with other antifungals, which have ranged from 38% with voriconazole to 45% with caspofungin. Furthermore, the response rate to posaconazole therapy in this study was superior to that of an external prospectively selected control group. Thus, posaconazole appears to be an effective salvage agent in patients with IA. However, voriconazole, on the basis of the results of a randomized clinical trial demonstrating its superiority to amphotericin B deoxycholate,1 remains the initial treatment of choice for most patients with IA. In addition, clinical practice at many centers has evolved toward the use of combination therapy with the addition of an echinocandin, most commonly caspofungin, to voriconazole in that setting. Of note is that none of the patients in this study received either voriconazole or an echinocandin as part of their initial failed regimen.
The low response rate in patients infected with A. terreus is consistent with results seen with other antifungals. This organism appears to be emerging as a problem pathogen because of its relative refractoriness to antifungal therapy. This poor response to therapy is true despite the fact that the MIC90 of many antifungals against this species is similar to that of species that exhibit higher rates of response to therapy.2 Thus, the posaconazole MIC90 of A. terreus is reported to be 1000 ng/ml while that of A. fumigatus is only one dilution lower at 500 ng/ml.2 As indicated above, a higher posaconazole Cmax (mean of 1489 ng/ml in the highest quartile) was associated with better outcomes.
Posaconazole is only available as an oral suspension and its bioavailability is maximized by split dosing and by administration with food. The finding of an association of improved responses with higher serum concentrations of this drug demonstrate a need to pay attention to these factors in order to optimize bioavailability. In addition, the apparent dose response seen in this study suggests the possibility that pushing the dose beyond that currently recommended may prove beneficial, but the efficacy and safety of such an approach requires further study.
References
- Herbrecht R, et al. Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis. N Engl J Med. 2002; 347:408-415.
- Diekema D, et al. Activities of caspofungin, itraconazole, posaconazole, ravuconazole, voriconazole, and amphotericin B against 448 recent clinical isolates of filamentous fungi. J Clin Microbiol. 2003;41:3623-3626 .
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