Amphotericin B and Fluconazole, a Potent Combination Therapy for Cryptococcal Meningitis

Larsen, Robert A.; Bauer, Madeline; Thomas, Ann; Graybill, John R.

doi:10.1128/aac.48.3.985-991.2004

Cited by 78 publications

(44 citation statements)

References 25 publications

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“…Local nonparametric regression as described previously (5-8) was used to estimate the in vitro fluconazole concentration-response curve. Ninety-nine percent confidence intervals (99% CIs) based on the fitted regression were used as described previously (3,12) to assess the magnitude, variation, and significance of the effects of fluconazole. If the 99% CIs do not overlap, then the difference in response is significant at the 0.01 level.…”

Section: Materials and Methods Test Isolatementioning

confidence: 99%

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Correspondence of In Vitro and In Vivo Fluconazole Dose-Response Curves for Cryptococcus neoformans

Larsen

Bauer

Thomas

et al. 2005

Antimicrob Agents Chemother

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We conducted in vitro experiments to evaluate the susceptibility of a clinical isolate of Cryptococcus neoformans to a wide range of concentrations of fluconazole. In vitro susceptibility was tested using broth macrodilution methods modified to provide a numeric count of viable organisms. The association between the quantitative in vitro response and fluconazole drug concentrations was estimated using local nonparametric regression. Regression analysis was used to assess the correspondence between the in vitro fluconazole concentration-response curve and the murine dose-response curve observed in our previously reported murine model. The regression model was then used to predict the murine response. There was a strong correspondence between in vitro measures of response to fluconazole alone and the previously reported biologic effects seen in the mouse. In vitro antifungal drug susceptibility testing can reliably predict the murine response to fluconazole.The goal of in vitro susceptibility testing is to predict the clinical outcome. Having an in vitro measure that can reliably predict the response following 2 weeks of treatment would permit physicians to select the drug(s) with the greatest activity, extend intensive treatments past 2 weeks, and/or use combination drug therapy. During the last 20 years, considerable effort has been expended to establish a reproducible standard for in vitro testing of yeast susceptibility to antifungal drugs. This standard has been most useful for testing Candida species causing oral thrush (14,18,20). Limited data suggest this method might also be useful for Cryptococcus neoformans; however, no interpretive guidelines or breakpoints have been identified (16,19). The usual approach to identifying breakpoints has been to measure outcome as a categorical response (e.g., sterile cerebrospinal fluid [CSF] versus nonsterile CSF) (1,11,24). This approach forces the search for a breakpoint into a search for a drug concentration that predicts an outcome measure that takes on just two values, "sterile CSF" versus "nonsterile CSF." This search is greatly confounded by the wide range in the severity of meningitis that occurs in clinical practice (21, 24).In our previously published murine model, we used a clinical isolate of C. neoformans to evaluate the effects of fluconazole (12). The response was the number of CFU per gram of brain recovered at day 16. By using this quantitative response and by testing fluconazole over a wide range of doses, we could use regression methods to estimate the dose-response curve for fluconazole. In the present paper, we report the in vitro susceptibility of this same isolate to fluconazole tested over a wide range of concentrations. MATERIALS AND METHODS Test isolate. The Cryptococcus neoformans var. neoformans isolate (USC 1597)was obtained from a patient with AIDS-associated cryptococcal meningitis that responded promptly to treatment with fluconazole plus flucytosine. The isolate was stored in 20% skim milk at Ϫ70°C and subcultured on Sabouraud's dextros...

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Section: Materials and Methods Test Isolatementioning

confidence: 99%

“…In our previously published murine model, we used a clinical isolate of C. neoformans to evaluate the effects of fluconazole (12). The response was the number of CFU per gram of brain recovered at day 16.…”

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confidence: 99%

Correspondence of In Vitro and In Vivo Fluconazole Dose-Response Curves for Cryptococcus neoformans

Larsen

Bauer

Thomas

et al. 2005

Antimicrob Agents Chemother

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“…Fluconazole should be introduced for consolidation regimen whenever the mental status recovered, fever, headache and meningeal symptoms disappear, and/or yeast culture results are negative at the second week. Despite the theoretic antagonism between amphotericin B and fluconazole, most animal model data suggests that both drugs together are a very effective combination against C. neoformans (Menichetti et al, 1996;Larsen et al, 2004;Larsen et al, 2005;Pappas et al, 2009;Perfect et al, 2010).…”

Section: Cryptococcosis and Aidsmentioning

confidence: 99%

An Overview on Cryptococcal Meningitis

Melhem¹,

Pappalardo²

2012

Meningitis

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“…Present work in cryptococcal meningitis combination antifungal therapy has continued to examine a polyene and azole together. 26 There have been favorable animal model studies with this combination and certainly an azole following polyene induction therapy in sequence has been widely and successfully used. 27 However, the combination of an azole plus polyene for induction therapy still represents second-line therapy.…”

Section: Challenge Recommendationmentioning

confidence: 99%