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Review
. 2003 Apr;47(4):1179-86.
doi: 10.1128/AAC.47.4.1179-1186.2003.

In vivo pharmacodynamics of antifungal drugs in treatment of candidiasis

David Andes  1
Affiliations
Review

In vivo pharmacodynamics of antifungal drugs in treatment of candidiasis

David Andes. Antimicrob Agents Chemother. 2003 Apr.
No abstract available

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Figures

FIG. 1.
FIG. 1.
Relationship between echinocandin (HMR 3270) dose and burden of C. albicans in the kidneys of neutropenic mice over time. Each datum point represents the mean Candida burden in kidneys from two animals. (Modified from reference .)
FIG. 2.
FIG. 2.
In vivo PAE of amphotericin B against C. albicans in neutropenic mice. Each datum point represents the mean Candida burden in kidneys from two animals. The black horizontal bars represent the amount of time that each of the dose levels would produce serum drug levels exceeding the MIC for the infecting organism. (Reprinted from reference .)
FIG. 3.
FIG. 3.
(A) Relationship between 24-h total fluconazole dose for three dosing intervals and fungal density in kidneys of mice in a candidiasis model. (Data from reference .) (B) Relationship between 24-h total flucytosine dose for four dosing intervals in a neutropenic candidiasis model. Each datum point represents the mean Candida burden in kidneys two animals. The solid horizontal line represents the burden of organisms in kidneys of mice at the start of therapy. (Reprinted from reference 3.) (C) Relationship between total echinocandin dose for four dosing intervals in a neutropenic candidiasis model. Each datum point represents the mean Candida burden in kidneys from two animals. The dashed horizontal line represents the burden of organisms in kidneys of mice at the start of therapy. SD, the dose necessary to produce no organism growth in the kidneys of mice relative to the burden at the start of therapy. Values in parentheses represent the 95% confidence intervals for the fungistatic dose. (Reprinted from reference .) In each panel, the letter q followed by a time indicates the frequency of dosing.
FIG. 3.
FIG. 3.
(A) Relationship between 24-h total fluconazole dose for three dosing intervals and fungal density in kidneys of mice in a candidiasis model. (Data from reference .) (B) Relationship between 24-h total flucytosine dose for four dosing intervals in a neutropenic candidiasis model. Each datum point represents the mean Candida burden in kidneys two animals. The solid horizontal line represents the burden of organisms in kidneys of mice at the start of therapy. (Reprinted from reference 3.) (C) Relationship between total echinocandin dose for four dosing intervals in a neutropenic candidiasis model. Each datum point represents the mean Candida burden in kidneys from two animals. The dashed horizontal line represents the burden of organisms in kidneys of mice at the start of therapy. SD, the dose necessary to produce no organism growth in the kidneys of mice relative to the burden at the start of therapy. Values in parentheses represent the 95% confidence intervals for the fungistatic dose. (Reprinted from reference .) In each panel, the letter q followed by a time indicates the frequency of dosing.
FIG. 4.
FIG. 4.
Impact of increasing dose and a single dosing interval (A) and three dosing intervals (B) on the interrelationship among peak/MIC, AUC/MIC, and T > MIC for flucytosine. R2 is the coefficient of determination. (Reprinted from reference with permission.)
FIG. 5.
FIG. 5.
(A) Relationship between three pharmacodynamic parameters and Candida organism burden in the kidneys of neutropenic animals treated with an echinocandin (A), flucytosine (B), and the triazole ravuconazole (C). Each symbol represents the mean organism burden in kidneys from two mice. The dashed lines represent the burden of Candida in the kidneys of mice at the start of therapy. R2 is the coefficient of determination. (The data in panels A, B, and C are from references , , and , respectively.)
FIG. 6.
FIG. 6.
Relationship between the magnitude of the 24-h AUC/MIC for a free triazole and the MIC for the infecting organism in animal models of candidiasis. The study end points associated with the triazole 24-h AUC/MIC include the dose necessary to produce 50% of maximal microbiologic efficacy and the dose associated with 80% survival in infected animals.
FIG. 7.
FIG. 7.
Impact of protein binding on the relationship between the triazole 24-h AUC/MIC and the burden of Candida spp. in the kidneys of neutropenic mice. Solid symbols, mean Candida burden in kidneys from two mice treated with fluconazole; hollow symbols, mean Candida burden in kidneys from two mice treated with ravuconazole. Data were obtained by using total drug levels (A) and free drug levels (B). (Modified from reference .)
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References

    1. Andes, D., and M. L. van Ogtrop. 1999. Characterization and quantitation of the pharmacodynamics of fluconazole in a neutropenic murine model of disseminated candidiasis model. Antimicrob. Agents Chemother. 43:2116-2120. - PMC - PubMed
    1. Andes, D., T. Stamsted, and R. Conklin. 2001. Pharmacodynamics of amphotericin B in a neutropenic murine disseminated candidiasis model. Antimicrob. Agents Chemother. 45:922-926. - PMC - PubMed
    1. Andes, D., and M. van Ogtrop. 2000. In vivo characterization of the pharmacodynamics of flucytosine in a neutropenic murine disseminated candidiasis model. Antimicrob. Agents Chemother. 44:938-942. - PMC - PubMed
    1. Andes, D., and W. A. Craig. 1998. In vivo activities of amoxicillin and amoxicillin-clavulanate against Streptococcus pneumoniae: application to breakpoint determinations. Antimicrob. Agents Chemother. 42:2375-2379. - PMC - PubMed
    1. Andes, D., K. Marchillo, L. Lowther, A. Bryskier, T. Stamstad, and R. Conklin. 2003.. In vivo pharmacodynamics of HMR 3270, a glucan synthase inhibitor, in a murine candidiasis model. Antimicrob. Agents Chemother. 47:1187-1192. - PMC - PubMed

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