In Vitro Interactions with Fractional Inhibitory Concentration (FIC) Indices between 0.5 and 4 Are in vivo Important. A Need to Revisit FIC Index Cutoffs

Ref ID: 18749

Author:

J. Meletiadis, PhD – Lecturer1, A. Elefanti, MS – PhD student 1, L. Zerva, MD – Professor 1, P. E. Verweij, MD – Professor 2, J. W. Mouton, MD – Professor 2;

Author address:

1Attikon Univ. Gen. Hosp., Athens, Greece, 2Radboud Univ. Med. Ctr., Nijmegen, Netherlands.

Full conference title:

52nd Annual ICAAC

Date: 9 September 2014

Abstract:

Background: The FIC indices (FICi) 8804;0.5 and ≥ 4 were originally proposed to detect synergy and antagonism, respectively. However, these values are based on twofold dilution-series in checkerboards and do not take intermediate values into account, nor statistical significance. We investigated the in vivo significance of in vitro combinations of posaconazole (POS) and amphotericin B (AMB) with FIC index >0.5 and <4 in a neutropenic murine model of experimental disseminated candidiasis. Methods: Serial twofold drug dilutions of AMB (0.008-0.5 mg/L ) and POS (0.000008-0.06 mg/L) in 96-well microtitration plates (8x12 checkerboard) were inoculated with 2.5x103 CFU/ml of a Candida albicans clinical isolate, incubated for 48h at 37oC and read spectrophotometrically (405nm). MICs of AMB and POS were read at complete and prominent growth inhibition, respectively, and in the combinations as complete growth inhibition. CD1 female neutropenic mice were i.v. infected with 105 CFU/mouse and treated for 2 days. CFU/kidney were determined for 3x3 in vivo checkerboards of 3.6, 2 and 1 mg/kg ip of AMB with 0.9, 0.45 and 0.2 mg/kg po of POS. Results were analyzed with the Emax model. ED50 of drugs in combination were estimated and compared with the ED50s of the drugs alone. Results: The MIC of AMB and POS was 0.13 mg/l and 0.004 mg/l. The FICi was 0.5001 at AMB+POS concentrations of 0.06+0.00003 mg/l and an FICi of 2.5 at AMB+POS concentrations 0.25+0.015 mg/l. In vivo, the ED50 of POS and AMB alone was 0.44 (0.18-0.96) mg/kg and 1.6 (1.4-2) mg/kg, respectively. The ED50 of AMB+0.2 mg/kg POS was 2.6 (2.2-3.1) mg/kg, significantly higher than ED50 of the drugs alone (p<0.001) indicating reduction of antifungal efficacy. The ED50 of AMB+0.9 mg/kg POS was 0.09 (0.01-0.25) mg/kg significantly lower than the ED50 of the drugs alone (p=0.036) indicating enhancement of antifungal efficacy. Conclusions: In vitro FICi between 0.5 and 4 were associated with significant changes of in vivo antifungal efficacy and not predictive. The FIC index interpretation for synergy and antagonism need to be revised.

Abstract Number: E-782

Conference Year: 2012

Link to conference website: NULL

New link: NULL

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