In-Vitro Synergy Between Terbinafine and Voriconazole against Scedosporium prolificans.



Background: Management of invasive infections caused by Scedosporium prolificans has become an emerging clinical problem, especially in cases of septic arthritis and osteomyelitis. This fungus is notoriously resistant to antifungal therapy, surgical resection is often required and treatment failures are common. In vitro testing has demonstrated multi-resistance to current anti-fungal agents and limited activity with the novel triazoles and echinocandins. We examined the in-vitro activity of amphotericin B, itraconazole, voriconazole and terbinafine individually and the combinations of terbinafine/voriconazole and terbinafine/itraconazole against 38 clinical isolates of S. prolificans. Method: All isolates were tested by micro-dilution according to the NCCLS M38P method to obtain single MIC's. Synergy studies were performed using a two-dimensional two-agent micro-dilution checkerboard method. MIC's were read at 48 and 72 hours and the end points taken at 50% or greater inhibition than the growth control. Results: Single drug MIC90 were amphotericin B = 16 ug/ml, terbinafine = 8 ug/ml, itraconazole = >16 ug/ml and voriconazole = 8 ug/ml. In combination with terbinafine the MIC's for both voriconazole and itraconazole were dramatically reduced. Thirty-one of the 38 isolates demonstrated synergy with the terbinafine/voriconazole combination, while 7 isolates showed partial synergy. The terbinafine/itraconazole combination resulted in synergy for 18 isolates, while 16 isolates showed partial synergy and 4 indifference. No antagonism was observed. Conclusion: Terbinafine appears to be synergistic with voriconazole and itraconazole against most isolates of S. prolificans. The MIC's of both terbinafine/itraconazole and terbinafine/voriconazole combinations appear to be within achievable plasma ranges. Although in-vitro results have not yet been directly correlated with therapeutic outcome, checkerboard synergy testing may provide valuable information to the treating clinician.

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42nd Interscience Conference on Antimicrobial Agents and Chemotherapy
    • ICAAC 42nd