Friday, 23 January 2015

Antifungal Combination Therapy: A Step Forward


Combination therapy for IA benefits the moderately ill patients most

The first large (454 participants) randomized, double-blind, placebo-controlled multicenter trial study on combination therapy shows a 11% improvement in survival at 6 weeks (which is a 42% improvement compared with treating with voriconazole alone). All patients received voriconazole and half also received anidulafungin. All patients had hematologic malignancies or a hematopoietic cell transplant. The largest differences in outcome were seen in those with serum galactomannan levels in the low middle range of 0.5-1.5. Non-neutropenic patients also appeared to benefit (13.7% versus 33.2% mortality), whereas neutropenic patients did not.

Invasive aspergillosis in immunocompromised patients is often a fatal complication - only around 40% of patients survive. Improvements in outcome have been seen in neutropenic patients especially, with earlier diagnosis and use of voriconazole therapy.

Combination therapy has been evaluated previously - one of the first being Verweij et. al. (1994) comparing amphotericin B with or without flucytosine. Mortaliy in this study exceeded 80%. Combined amphotericin B and terbinafine increased death rates (never published) and there have been several small studies but all have been inconclusive, though some gave a encouraging results.
In the recent combination study, there was no significant difference between the outcome of the two treatments (P=0.087), there was a clear improvement (11.5 percentage points) when comparing monotherapy (voriconazole alone 27% mortality) versus combination therapy (15.5% mortality) after six weeks treatment. The results may or may not be pertinent to other patient groups such as critically ill corticosteroid treatment or solid organ transplant patients. Increasing azole resistance in northern Europe may be an argument to initiate combination therapy in certain patient groups. (ClinicalTrials.gov:  NCT00531479).

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