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In vitro post antibiotic effect of isavuconazole, voriconazole and amphotericin B against a strain of C. albicans with concentration-dependent pharmacokinetics in a murine model and susceptibility of strains for murine kidneys post infection

Abstract number: P2177

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

Objective: Isavuconazole (ISA) is a water soluble triazole suitable for IV and oral dosing in Phase III trials. Understanding the pharmacodynamics (PD) of antimicrobials is a essential in defining the treatment schedules for optimum outcomes. Using a strain of C. albicans used to determine the PD of ISA the post-antifungal-effect (PAE) of ISA, voriconazole (VCZ) and amphotericin B (AmB) were determined in vitro. Also the susceptibility of this C. albicans strain was determined from kidneys of mice following treatment with low or high dose ISA.

Method: PAEs were determined in RPMI broth + 2% glucose buffered with MOPS. Log phase growth cultures (106 CFU/mL) were exposed to, solvent, ISA or VCZ at 0.1, 0.5, 1, 2, 5, 10, 40 and 100 × MIC; AmB cultures were exposed at 2 × MIC. Following 3 hours of exposure all drugs were removed by serial washing prior to dilution and transfer to fresh pre-warmed media. Cultures were incubated on an orbital shaking and viable CFUs determined hourly for 8 h then at 11 and 21 h. The log10 count was plotted against time and PAE defined as the difference is the time required for the count in solvent and drug exposed cultures and to increase 1×log10 above the count following drug removal. Mice were immunocompromised with cyclophosphamide then infected with the same strain of Candida then treated 5 h post infection with vehicle 6 or 24 mg/kg of ISA. 24 h post treatment mice were culled and kidneys cultured onto Sabouraud agar plus ISA (containing 0.25–2.5 × MIC). Recovered fungi had MICs tested by CLSI M27A2.

Results: The in vitro PAE of ISA was absent at leqslant R: less-than-or-eq, slantMIC for ISA but was 2–2.5 hours for all doses geqslant R: gt-or-equal, slanted2 × MIC. The PAE was much shorter <1 hour for all doses of VCZ. As expected a much longer PAE of 11 hours was seen with AmB. The burden following infection of 2.7×105 for vehicle, 1.7×105 for 6 mg/kg and 9.5×103 for 24 mg/kg was recovered from drug free plates. ~75% of this burden was recovered from ISA containing plates following prolonged incubation. Colonies recovered from ISA containing plates had identical MICs to the input cultures indicating no generation of resistance.

Conclusions: ISA demonstrated very significant PAE at drug concentrations geqslant R: gt-or-equal, slanted2× MIC. Plasma and tissue ISA levels of >100×Candida MICs are easily attainable in humans and animal models so PAE might have a significant effect on the therapeutic response and PD. Candida recovered from organs post treatment had MICs unaffected by drug exposure.

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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