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Related Experiment Videos

Interactions between triazoles and amphotericin B against Cryptococcus neoformans.

F Barchiesi1, A M Schimizzi, F Caselli

  • 1Istituto di Malattie Infettive e Medicina Pubblica, Italy. cmalinf@popsci.unian.it

Antimicrobial Agents and Chemotherapy
|August 22, 2000
PubMed
Summary

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This study found that combining amphotericin B (AmB) with azole antifungals like fluconazole (FLC) shows enhanced activity against Cryptococcus neoformans. In vivo, FLC-AmB combination therapy improved survival and reduced fungal burden in mice, demonstrating a positive interaction.

Area of Science:

  • Mycology and Infectious Diseases
  • Pharmacology and Drug Interactions
  • Antifungal Resistance Mechanisms

Background:

  • The combined use of amphotericin B (AmB) and azole antifungal agents for treating fungal infections remains a subject of debate.
  • Cryptococcus neoformans is a significant fungal pathogen, and understanding drug interactions is crucial for effective treatment strategies.
  • Previous studies have yielded conflicting results regarding the synergistic or antagonistic effects of AmB and azoles.

Purpose of the Study:

  • To investigate the in vitro interactions between amphotericin B (AmB) and three azole antifungal agents (fluconazole, itraconazole, and SCH 56592) against clinical isolates of Cryptococcus neoformans.
  • To evaluate the in vivo efficacy of the combination therapy of AmB and fluconazole (FLC) in a murine model of systemic cryptococcosis.
  • To explore potential drug resistance mechanisms and the impact of sequential drug exposure.

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Main Methods:

  • A checkerboard titration broth microdilution method, following National Committee for Clinical Laboratory Standards guidelines, was employed for in vitro interaction studies.
  • Fractional Inhibitory Concentration (FIC) index was calculated to determine synergy, additivism, indifference, or antagonism.
  • A systemic cryptococcosis model in BALB/c mice was established to assess the in vivo effects of combination therapy, including survival and tissue burden studies.

Main Results:

  • In vitro, SCH 56592-AmB demonstrated synergy in 33% of isolates, while FLC-AmB and ITC-AmB showed synergy in 7% of isolates. Additivism was the most common interaction for all combinations.
  • In vivo, FLC-AmB combination therapy was more effective than FLC alone and at least as effective as AmB monotherapy in a murine model, improving survival and reducing fungal burden.
  • Pre-exposure of C. neoformans to FLC in vitro led to increased resistance to AmB, abolishing its fungicidal activity. However, this antagonism was not observed in vivo, where sequential FLC-AmB treatment showed reciprocal potentiation.

Conclusions:

  • The combination of triazoles and AmB exhibits significantly enhanced activity against Cryptococcus neoformans in vitro compared to monotherapy.
  • Concomitant or sequential administration of fluconazole and amphotericin B results in a positive therapeutic interaction for systemic murine cryptococcosis.
  • In vitro observations of drug antagonism do not always translate to in vivo outcomes, highlighting the complexity of drug interactions in a physiological context.