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Combination therapy with amphotericin B and fluconazole against invasive candidiasis in neutropenic-mouse and
H Sanati1, C F Ramos, A S Bayer
1Department of Internal Medicine, Harbor-UCLA Medical Center, Torrance, California 90509, USA.
Abstract:
Although there are an increasing number of new antifungal agents available, the morbidity and mortality due to invasive mycoses remain high. The high rates of polyene toxicities and the development of azole resistance have raised the issue of using antifungal agents of these classes in combination, despite theoretical concerns regarding antagonism between such agents. This study was designed to evaluate the in vivo efficacy of combined therapy with amphotericin B and fluconazole against Candida albicans. Two distinct animal models were used in this study: a neutropenic-mouse model of hematogenously disseminated candidiasis and the infective-endocarditis rabbit model. Treatment efficacy was assessed by determining reductions in mortality as well as decreases in tissue fungal densities. In the neutropenic-mouse model, amphotericin B, as well as combination therapy, significantly prolonged survival compared to untreated controls (P < 10(-5) and P = 0.001, respectively). The fungal densities in the kidneys of neutropenic mice were significantly reduced with either amphotericin B monotherapy or amphotericin B-fluconazole combined therapy compared to those of controls (P < 10(-6)). Fluconazole monotherapy also reduced fungal densities in the kidneys; however, this decrease was not statistically significant (P = 0.17). In contrast, treatment with either fluconazole alone or combined with amphotericin B (but not amphotericin B monotherapy) significantly decreased fungal densities in the brain (P = 0.025). In the rabbit endocarditis model, amphotericin B monotherapy or combined therapy significantly decreased fungal densities in cardiac vegetations (P < 0.01 versus the controls). Although no significant antagonism was seen when fluconazole was given in combination with amphotericin B, combination therapy did not augment the antifungal activity of amphotericin B.
Insights
Combination therapy with amphotericin B and fluconazole showed efficacy against invasive candidiasis in animal models. While not antagonistic, the combination did not significantly improve outcomes over amphotericin B alone.
Area of Science:
- Medical Mycology
- Infectious Diseases
- Pharmacology
Background:
- Invasive mycoses contribute significantly to morbidity and mortality.
- High polyene toxicity and azole resistance necessitate exploring combination antifungal therapies.
- Theoretical concerns exist regarding potential antagonism between different antifungal classes.
Purpose of the Study:
- To evaluate the in vivo efficacy of combined amphotericin B and fluconazole therapy against Candida albicans.
- To assess treatment efficacy using mortality reduction and tissue fungal density.
- To investigate potential antagonism between amphotericin B and fluconazole.
Main Methods:
- Utilized a neutropenic-mouse model of hematogenously disseminated candidiasis.
- Employed an infective-endocarditis rabbit model.
- Assessed efficacy by measuring survival rates and quantifying fungal burden in tissues.
Main Results:
- Amphotericin B and combination therapy significantly prolonged survival in neutropenic mice.
- Both amphotericin B monotherapy and combination therapy reduced kidney fungal densities in mice.
- Combination therapy, but not amphotericin B alone, reduced brain fungal burden in mice.
- In rabbits, amphotericin B monotherapy and combination therapy reduced cardiac fungal burden.
- No significant antagonism was observed between amphotericin B and fluconazole.
Conclusions:
- Combined amphotericin B and fluconazole therapy is effective in animal models of invasive candidiasis.
- Combination therapy did not demonstrate enhanced antifungal activity compared to amphotericin B monotherapy.
- The combination of amphotericin B and fluconazole did not result in significant antagonism.