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James A. Dowell – One of the best experts on this subject based on the ideXlab platform.

  • in vitro and in vivo studies to characterize the clearance mechanism and potential cytochrome p450 interactions of Anidulafungin
    Antimicrobial Agents and Chemotherapy, 2009
    Co-Authors: Bharat Damle, James A. Dowell, Robert L Walsky, Gregory L Weber, Martin Stogniew, Philip B. Inskeep

    Abstract:

    Anidulafungin is a novel semisynthetic echinocandin with potent activity against Candida (including azole-resistant isolates) and Aspergillus spp. and is used for serious systemic fungal infections. The purpose of these studies was to characterize the clearance mechanism and potential for drug interactions of Anidulafungin. Experiments included in vitro degradation of Anidulafungin in buffer and human plasma, a bioassay for antifungal activity, in vitro human cytochrome P450 inhibition studies, in vitro incubation with rat and human hepatocytes, and mass balance studies in rats and humans. Clearance of Anidulafungin appeared to be primarily due to slow chemical degradation, with no evidence of hepatic-mediated metabolism (phase 1 or 2). Under physiological conditions, further degradation of the primary degradant appears to take place. The primary degradation product does not retain antifungal activity. Anidulafungin was not an inhibitor of cytochrome P450 enzymes commonly involved in drug metabolism. Mass balance studies showed that Anidulafungin was eliminated in the feces predominantly as degradation products, with only a small fraction (10%) eliminated as unchanged drug; fecal elimination likely occurred via biliary excretion. Only negligible renal involvement in the drug’s elimination was observed. In conclusion, the primary biotransformation of Anidulafungin is mediated by slow chemical degradation, with no evidence for hepatic enzymatic metabolism or renal elimination.

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  • Pharmacokinetics and Tissue Distribution of Anidulafungin in Rats
    Antimicrobial agents and chemotherapy, 2008
    Co-Authors: Bharat Damle, Martin Stogniew, James A. Dowell

    Abstract:

    This study assessed the tissue distribution of Anidulafungin in rats. Anidulafungin rapidly distributed into tissues, achieving peak concentrations within 30 min, and maintained levels above MICs for common pathogens over 72 h. In tissues susceptible to fungal infection (liver, lung, spleen, kidney), exposure was 9- to 12-fold higher than in plasma.

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  • Lack of pharmacokinetic interaction between Anidulafungin and tacrolimus.
    Journal of clinical pharmacology, 2007
    Co-Authors: James A. Dowell, Martin Stogniew, David Krause, Timothy Henkel, Bharat Damle

    Abstract:

    The safety and pharmacokinetics of Anidulafungin coadministered with tacrolimus were investigated using a single-sequence, open-label design. Healthy volunteers received 5 mg tacrolimus orally on days 1 and 13 of the study. Anidulafungin (200 mg) was administered intravenously on day 4, followed by 100-mg doses on days 5 through 13. Key pharmacokinetic parameters, including C(max), AUC, t((1/2)), CL, and V(ss), were derived from concentration-time data. The 90% confidence intervals (CIs) of the ratios of mean pharmacokinetic parameters of Anidulafungin plus tacrolimus to each drug alone were well within the 80% to 125% bioequivalence range, indicating no pharmacokinetic interaction. This ratio was 101.6 (90% CI: 92.77-111.22) for tacrolimus AUC(0-infinity) and 107.2 (90% CI: 105.1-109.4) for Anidulafungin AUC(ss). The 2 drugs were well tolerated, and no drug-related serious adverse events were reported. Because of its lack of pharmacokinetic interaction with key immunosuppressive agents, Anidulafungin is an important option for the prevention and treatment of invasive fungal infections in transplant recipients.

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Michael A Pfaller – One of the best experts on this subject based on the ideXlab platform.

  • use of Anidulafungin as a surrogate marker to predict susceptibility and resistance to caspofungin among 4 290 clinical isolates of candida by using clsi methods and interpretive criteria
    Journal of Clinical Microbiology, 2014
    Co-Authors: Michael A Pfaller, Daniel J. Diekema, Ronald N. Jones, S A Messer, Mariana Castanheira

    Abstract:

    This study addressed the application of Anidulafungin as a surrogate marker to predict the susceptibility of Candida to caspofungin due to unacceptably high interlaboratory variation of caspofungin MIC values. CLSI reference broth microdilution methods and species-specific interpretive criteria were used to test 4,290 strains of Candida (eight species), including 71 strains with documented fks mutations. Caspofungin MIC values were compared with those of Anidulafungin to determine the percentage of categorical agreement (CA) and very major (VME), major (ME), and minor error rates, as well as the ability to detect fks mutants. For all 4,290 isolates the CA was 97.1% (0.2% VME and ME, 2.5% minor errors) using Anidulafungin as the surrogate. Among the 62 isolates of Candida albicans (4 isolates), C. tropicalis (5 isolates), C. krusei (4 isolates), C. kefyr (2 isolates), and C. glabrata (47 isolates) that were nonsusceptible (NS; either intermediate [I] or resistant [R]) to both caspofungin and Anidulafungin, 52 (83.8%) contained a mutation in fks1 or fks2. Eight mutants of C. glabrata, two of C. albicans, and one each of C. tropicalis and C. krusei were classified as susceptible (S) to both antifungal agents. The remaining 7 mutants (2 C. albicans and 5 C. glabrata) were susceptible to one of the agents and either intermediate or resistant to the other. Using the epidemiological cutoff value (ECV) of 0.12 μg/ml for both caspofungin and Anidulafungin to differentiate wild-type (WT) from non-WT strains of C. glabrata, 42 of the 55 (76.4%) C. glabrata mutants were non-WT and 8 of the 55 (14.5%) were WT for both agents (90.9% concordance). Anidulafungin can accurately serve as a surrogate marker to predict S and R of Candida to caspofungin.

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  • In vivo pharmacodynamic characterization of Anidulafungin in a neutropenic murine candidiasis model.
    Antimicrobial agents and chemotherapy, 2007
    Co-Authors: David R. Andes, Michael A Pfaller, Daniel J. Diekema, R. A. Prince, Karen Marchillo, J. Ashbeck, J. Hou

    Abstract:

    Multiple in vivo studies have characterized the pharmacodynamics of drugs from the triazole and polyene antifungal drug classes. Fewer studies have investigated these pharmacodynamic relationships for the echinocandin drug class. We used a neutropenic murine model of disseminated Candida albicans , Candida tropicalis , and Candida glabrata infection to characterize the time course of activity of the new echinocandin Anidulafungin. The pharmacokinetic-pharmacodynamic (PK-PD) indices (the percentage of time that the drug concentration was above the MIC, the ratio of the area under the concentration-time curve from 0 to 24 h [AUC 0-24 ] to the MIC, and the ratio of the maximum serum drug concentration [ C max ] to the MIC) were correlated with in vivo efficacy, as measured by organism numbers in kidney cultures after 96 h of therapy. The kinetics following intraperitoneal Anidulafungin dosing in neutropenic infected mice were monitored. Peak levels and AUCs were linear over the 16-fold dose range studied. The drug elimination half-life in serum ranged from 14 to 24 h. Single-dose postantifungal-effect studies demonstrated prolonged suppression of organism regrowth after serum Anidulafungin levels had fallen below the MIC. Of the four dosing intervals studied, treatment with the more widely spaced dosing regimens was most efficacious, suggesting the C max /MIC ratio as the PK-PD index most predictive of efficacy. Nonlinear regression analysis suggested that both the C max /MIC and AUC/MIC ratios were strongly predictive of treatment success. Studies were then conducted with 13 additional C. albicans , C. tropicalis , and C. glabrata isolates with various Anidulafungin susceptibilities (MICs of Anidulafungin for these strains, 0.015 to 2.0 μg/ml) to determine if similar C max /MIC and AUC 0-24 /MIC ratios for these isolates were associated with efficacy. The Anidulafungin exposures associated with efficacy were similar among Candida species.

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  • in vitro activities of Anidulafungin against more than 2 500 clinical isolates of candida spp including 315 isolates resistant to fluconazole
    Journal of Clinical Microbiology, 2005
    Co-Authors: Michael A Pfaller, Linda Boyken, Richard J Hollis, Shawn A. Messer, S. Tendolkar, Daniel J. Diekema

    Abstract:

    Anidulafungin is an echinocandin antifungal agent with potent activity against Candida spp. We assessed the in vitro activity of Anidulafungin against 2,235 clinical isolates of Candida spp. using the CLSI broth microdilution method. Anidulafungin was very active against Candida spp. (the MIC at which 90% of strains are inhibited [MIC90] was 2 μg/ml when MIC endpoint criteria of partial inhibition [MIC-2] were used). Candida albicans, C. glabrata, C. tropicalis, C. krusei, and C. kefyr were the most susceptible species of Candida (MIC90, 0.06 to 0.12 μg/ml), and C. parapsilosis, C. lusitaniae, and C. guilliermondii were the least susceptible (MIC90, 0.5 to 2 μg/ml). In addition, 315 fluconazole-resistant isolates were tested, and 99% were inhibited by ≤1 μg/ml of Anidulafungin. These results provide further evidence for the spectrum and potency of Anidulafungin activity against a large and geographically diverse collection of clinically important isolates of Candida spp.

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Soňa Kucharikova – One of the best experts on this subject based on the ideXlab platform.

  • Anidulafungin increases the antibacterial activity of tigecycline in polymicrobial candida albicans staphylococcus aureus biofilms on intraperitoneally implanted foreign bodies
    Journal of Antimicrobial Chemotherapy, 2018
    Co-Authors: Ona Rogiers, Michelle Holtappels, Wafi Siala, Mohamed Lamkanfi, Francoise Van Bambeke, Katrien Lagrou, Patrick Van Dijck, Soňa Kucharikova

    Abstract:

    Objectives: We aimed to establish a novel murine intra-abdominal foreign body infection model to study the activity of anidulafung in and tigecycline against dual species Candida albicans/Staphylococcus aureus biofirrns.
    Methods: In vitro and in vivo single and dual species biofilms were developed inside serum-coated triple-lumen catheters placed in 24-well plates or implanted intraperitoneally in BALB/c mice. The effect of tigecycline and Anidulafungin alone and in combination was tested using clinically relevant concentrations. Scanning electron microscopy was used to visualize the mature biofilm structure developed intraperitoneally. Flow cytometry was used to determine the immunological response upon infection, Immunoblot analysis allowed us to determine the effect of Anidulafungin on poly-beta-(1,6)-N-acetylglucosamine in in vitro-grown S. aureus biofirms.
    Results: We determined the MIC, MBC and in vitro susceptibility profile for Anidulafungin and tigecycline against C. albicans and S. aureus in mixed and single species biofilms. We demonstrated that a nidulafungin acts synergistically when combined with tigecycline against in vivo intra-abdominal biofilms, Moreover, we reveal that a nidulafungin reduces the abundance of S. aureus poly-beta-(1,6)-N-acetylglucosamine. The influx of neutrophils is much increased when infected with mixed biofilms compared with single species biofilms.
    Conclusions: Currently, treatment of intra-abdominal infections, in particular polymicrobial catheter-associated peritonitis, is ineffective, To the best of our knowledge, this is the first study that provides insight into new possible options for treatment of C. albicans/S. aureus biofilms present in the abdominal cavity.

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  • in vivo efficacy of Anidulafungin against mature candida albicans biofilms in a novel rat model of catheter associated candidiasis
    Antimicrobial Agents and Chemotherapy, 2010
    Co-Authors: Soňa Kucharikova, Michelle Holtappels, Patrick Van Dijck, Helene Tournu, Katrien Lagrou

    Abstract:

    The present study demonstrates the efficacy of Anidulafungin on mature Candida albicans biofilms in vivo. One hundred fifty-seven catheter fragments challenged with C. albicans were implanted subcutaneously in rats. After formation of biofilms, rats were treated with daily intraperitoneal injections of Anidulafungin for 7 days. Catheters retrieved from treated animals showed reduced cell numbers compared to those retrieved from untreated and fluconazole-treated animals. Systemic administration of Anidulafungin is promising for the treatment of mature C. albicans biofilms.

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