Dose escalation studies with caspofungin against Candida glabrata.
J Med Microbiol. 2015 Jun 30;
Authors: Domán M, Kovács R, Perlin DS, Kardos G, Gesztelyi R, Juhász B, Bozó A, Majoros L
Echinocandins are recommended as first line agents against invasive fungal infections due to C. glabrata, which still carry a high mortality rate. Dose escalation of echinocandins has been suggested to improve the clinical outcome against C. glabrata. To address this possibility, we performed in vitro and in vivo experiments with caspofungin against four wild-type C. glabrata clinical isolates, a drug susceptible ATCC 90030 reference strain and two echinocandin resistant strains with known FKS 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 50% serum. In 50% serum, the replication of C. glabrata was weaker than in RPMI-1640. Caspofungin in RPMI-1640 at 1 and 4 mg/L showed fungicidal effect within 7 hours against three out of four clinical isolates, but was only fungistatic at 16 and 32 mg/L (paradoxically decreased killing activity). In 50% serum, caspofungin at ≥1 mg/L was rapidly fungicidal (within 3.31 hours) against three out of four isolates. In a profoundly neutropenic murine model all caspofungin doses (daily 1, 2, 3, 5 and 20 mg/kg) decreased the fungal tissue burdens significantly (P<0.05-0.001) without statistical differences between doses, but the mean fungal tissue burdens never fell below 105 cells per gram 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.
PMID: 26296340 [PubMed - as supplied by publisher]