Once-weekly dosing requires a proportionally higher dosage of micafungin for treatment of experimental disseminated candidiasis caused by Candida glabrata in persistently neutropenic rabbits

Ruta Petraitiene, Vidmantas Petraitis, Bo Bo Win Maung, Naima Skaikh, Navjot K Sekhon, William W. Hope, Thomas J. Walsh


Background: The epidemiology of candidemia is evolving with greater representation of non-albicans Candida spp., particularly C. glabrata (CG) in neutropenic patients. Its emerging resistance and higher echinocandin MICs pose a challenge to novel dosing regimens. A longer dosing interval of a once weekly (QWK) dosing schedule in patients with cancer would enable more flexible outpatient care and improve quality of life. We therefore studied the pharmacokinetics (PK) and efficacy of QWK dosing of micafungin (MFG) in the treatment of experimental disseminated candidiasis in persistently neutropenic rabbits.

Material/methods: A well established persistently neutropenic New Zeeland White rabbit model of experimental disseminated candidiasis was used for this study. Treatment with MFG started 24 h post IV inoculation of 1x1010 CG blastoconidia and continued for 14 days thereafter. Study groups consisted of treatment with MFG at 1 mg/kg/day (Q24, MFG1), 7 mg/kg/week (QWK, MFG7), 2 mg/kg/day (Q24, MFG2), 14 mg/kg/week (QWK, MFG14), 4 mg/kg/day (Q24, MFG4), and 28 mg/kg/week (QWK, MFG28), and untreated controls (UC). PK of MFG was performed on day 7 postinoculation. Blood samples for serum (13)-β-D-glucan levels were obtain every other day. Fungal burden in tissues was determined at the end of the study.

Results: Rabbits receiving MFG2, MFG4 Q24 or MFG14, and MFG28 QWK demonstrated significant decreases in residual fungal burden in liver, spleen and kidney in comparison to that of UC (p<0.05). Moreover, rabbits treated with MFG2, MFG4, MFG14, and MFG28 QWK demonstrated decreased residual fungal burden in lung, cerebrum, and vena cava. By comparison, rabbits treated with MFG1 Q24 and MFG7 QWK demonstrated no differences in comparison to that of UC. These results correlated with serum (1→3)-ß-D-glucan levels. Thus, while a proportional increase of dosage from 1 mg/kg/d to 7 mg/kg/wk was inadequate, a higher once weekly dosage of 14 or 28 mg/kg/wk was significantly effective in reducing residual fungal burden in tissues.

Conclusions: These data demonstrate that treatment regimens at higher once weekly dosages with MFG are efficacious against experimental disseminated candidiasis caused by C. glabrata in persistently neutropenic rabbits.


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26th European Congress of Clinical Microbiology and Infectious Diseases
    • ECCMID 26th (2016)