The Antifungal Activity of an Abbreviated Regimen of Amphotericin B Deoxycholate (DAmB) For Cryptococcal Meningitis is Due to Persistence of Drug in the Brain Rather Than T-Cell Recruitment

Ref ID: 18725

Author:

J. Livermore, PhD – Research Assistant1, A. Sharp, BSc – Research Assistant 1, C. Walker, PhD – Research Assistant 1, W. Moser, PhD – Research Assistant 1, L. Gregson, MSc – Research Assistant 1, J. Goodwin, BSc – Research Associate 1, T. W. Felton,

Author address:

1The Univ. of Manchester, Manchester, United Kingdom, 2Duke Univ., Durham, NC.

Full conference title:

52nd Annual ICAAC

Date: 9 September 2014

Abstract:

Background: Cryptococcal meningitis is a leading cause of AIDS-associated morbidity and mortality. An abbreviated amphotericin B regimen produces a comparable antifungal effect to prolonged dosing in experimental cryptococcal meningitis. This may relate to either persistence of drug at the effect site or immune effectors. A further understanding is required before studies in humans can be safely performed. Methods: A well validated murine model of cryptococcal meningitis was used. Mice were treated with either 3 or 7 dosages of DAmB 3mg/kg i.p. Controls included infected and untreated mice as well as animals that were uninfected, but treated with DAmB. The % of CD3, CD4 and CD8 cells in brain tissue was measured using FACS. The concentration of amphotericin B in the plasma and brain was measured. The fungal burden in the brain was estimated using quantitative culture. Results: Progressive logarithmic growth was observed in infected, untreated mice. No growth was apparent in uninfected untreated mice. An abbreviated DAmB regimen produced the same antifungal effect compared with prolonged dosing. The % of CD3+CD4 and CD3+CD8 cells progressively increased over 7 days in the brains of infected, but untreated mice(p<0.05). The % of immune cells in all treatment groups showed no change compared to infected, untreated group throughout the 7 days. For the abbreviated regimen DAmB could be quantified in the brain for the entire experimental period and up to 4 days after the last dose was administered. Conclusions: The antifungal activity of an abbreviated regimen of DAmB is due to persistence of drug at the effect site and not related to immunological effectors. These results can now be bridged to humans to identify innovative induction regimens for use in resource poor settings.

Abstract Number: M-977

Conference Year: 2012

Link to conference website: NULL

New link: NULL

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