1887

Abstract

Echinocandins are recommended as first-line agents against invasive fungal infections caused by , which still carry a high mortality rate. Dose escalation of echinocandins has been suggested to improve the clinical outcome against . To address this possibility, we performed and experiments with caspofungin against four WT clinical isolates, a drug-susceptible ATCC 90030 reference strain and two echinocandin-resistant strains with known mutations. MIC values for the clinical isolates in RPMI 1640 were ≤ 0.03 mg l but increased to 0.125–0.25 mg l in RPMI 1640+50 % serum. In RPMI 1640+50 % serum, the replication of was weaker than in RPMI 1640.Caspofungin in RPMI 1640 at 1 and 4 mg l showed a fungicidal effect within 7 h against three of the four clinical isolates but was only fungistatic at 16 and 32 mg l (paradoxically decreased killing activity). In RPMI 1640+50 % serum, caspofungin at ≥ 1 mg l was rapidly fungicidal (within 3.31 h) against three of the four isolates. In a profoundly neutropenic murine model, all caspofungin doses (1, 2, 3, 5 and 20 mg kg daily) decreased the fungal tissue burdens significantly ( < 0.05–0.001) without statistical differences between doses, but the mean fungal tissue burdens never fell below 10 cells (g tissue).The echinocandin-resistant strains were highly virulent in animal models and all doses were ineffective. These results confirm the clinical experience that caspofungin dose escalation does not improve efficacy.

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2015-09-01
2024-03-29
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