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Efficacy of isavuconazole, voriconazole and fluconazole in neutropenic murine models of disseminated Candida tropicalis and Candida krusei

Abstract number: P1914

Majithiya J.B., Sharp A., Parmar A., Denning D.W., Warn P.A.

Objectives: Isavuconazole (ISA) is the water-soluble prodrug of triazole BAL8557. We examined the dose response of ISA, voriconazole (VCZ) and fluconazole (FLU) on the tissue burden (TB) after 4 and 7 days infection in temporarily (TN) and persistently neutropenic (PN) mice with disseminated Candida tropicalis (CT) or Candida krusei (CK) infection.

Methods: Male CD1 were immunosuppressed using either 1 dose (TN) or two doses (PN) of 200 mg/kg cyclophosphamide. Mice were infected IV with 6.8 (TN) or 5.2×104 (PN) CT, or 1×107cfu/mouse CK and treated 5 hours later with solvent, oral ISA (6, 15, 30, 60, 90, 120, 150 mg/kg active compound), IV VCZ (5, 20, 40 mg/kg plus grapefruit gavage BD) or oral FLU (15, 50, 150 mg/kg) BD. 101 hours (CT and CK) or 7 days (CT) post infection mice were killed, kidneys & brains (CK only) removed for culture.

Results: Solvent controls developed a non-lethal infection with high burdens in all models (CT 1.25×107–2.1×108 in kidneys; CK 4.1×105–3.8×106 in kidneys and 1.7–4.9×106 log10cfu/g in brain.

For CT, TN model: ISA (>6 mg/kg), VCZ (>5 mg/kg) and FLU (all doses) dose dependently reduced TB (P < 0.05) after 4 and 7 days. ISA Emax was 60 mg/kg (2.3log10) was similar to FLU Emax (50 mg/kg) but was superior to VCZ (40 mg/kg). ISA >60 mg/kg was superior to all doses VRC. PN model: ISA (all doses) and FLU (all doses) dose dependently and VCZ (40 mg/kg only) reduced TB (P < 0.05) in 4 day kidney burden. For 7 day TB ISA (>30 mg/kg), VCZ (all dose >5 mg/kg) and FLU (all doses) dose dependently reduced TB. ISA Emax achieved at >60 mg/kg. No treatment sterilised kidneys.

For CK, TN model: ISA, VCZ and FLU dose dependently reduced kidney burden (P < 0.05 all doses). VCZ 40, ISA 120 & 150 were superior to other treatments in reducing kidney burden. ISA (all doses) and VCZ (40 mg/kg) reduced brain burden (P < 0.05). FLU (all doses) and VCZ (5 & 20 mg/kg) had no significant effect on brain burden. VCZ 40, ISA 120 & 150 were superior at reducing brain burden but FLU had no significant effect.

PN model: ISA (all doses), VCZ (all doses) and FLU (150 mg/kg) reduced kidney burden (p < 0.05) with ISA >90 mg/kg and VRC 40 mg/kg superior. In the brain ISA and VCZ (all doses) reduced tissue burden (p < 0.05) FLU had no significant even at 15 mg/kg.

Conclusions: ISA significantly lowered kidney (CT & CK) & brain burden (CK) and was at least as effective as VCZ. ISA was much more effective than FLU at reducing brain burden (CK). ISA had maximal effect by 60 mg/kg and was partially effective at all doses >6 mg/kg.

Session Details

Date: 19/04/2008
Time: 00:00-00:00
Session name: 18th European Congress of Clinical Microbiology and Infectious Diseases
Subject:
Location: Barcelona, Spain
Presentation type:
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