ORCID Profile
0000-0002-4747-0144
Current Organisations
Statens Serum Institut
,
IT University of Copenhagen
,
Rigshospitalet
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Publisher: Elsevier BV
Date: 11-2011
Publisher: Elsevier BV
Date: 11-2011
Publisher: Elsevier BV
Date: 12-2011
Publisher: American Society for Microbiology
Date: 09-2012
DOI: 10.1128/JCM.01843-12
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 05-2019
Publisher: American Society for Microbiology
Date: 05-2012
DOI: 10.1128/AAC.06369-11
Abstract: We recently observed that the micafungin MICs for some Candida glabrata fks hot spot mutant isolates are less elevated than those for the other echinocandins, suggesting that the efficacy of micafungin may be differentially dependent on such mutations. Three clinical C. glabrata isolates with or without (S3) fks hot spot mutations R83 (Fks2p-S663F) and RR24 (Fks1p-S629P) and low, medium, and high echinocandin MICs, respectively, were evaluated to assess the in vivo efficacy in an immunocompetent mouse model using three doses of each echinocandin. Drug concentrations were determined in plasma and kidneys by high-performance liquid chromatography (HPLC). A pharmacokinetic-pharmacodynamic mathematical model was used to define the area under the concentration-time curve (AUC) that produced half- and near-maximal activity. Micafungin was equally efficacious against the S3 and R83 isolates. The estimates for the AUCs of each echinocandin that induced half-maximal effect (E 50 s) were 194.2 and 53.99 mg · h/liter, respectively. In contrast, the maximum effect ( E max ) for caspofungin was higher against S3 than R83, but the estimates for E 50 were similar (187.1 and 203.5 mg · h/liter, respectively). Anidulafungin failed to induce a ≥1-log reduction for any of the isolates (AUC range, 139 to 557 mg · h/liter). None of the echinocandins were efficacious in mice challenged with the RR24 isolate despite lower virulence (reduced maximal growth, prolonged lag phase, and lower kidney burden). The AUC associated with half-maximal effect was higher than the average human exposure for all drug-dose-bug combinations except micafungin and the R83 isolate. In conclusion, differences in micafungin MICs are associated with differential antifungal activities in the animal model. This study may have implications for clinical practice and echinocandin breakpoint determination, and further studies are warranted.
Publisher: Elsevier BV
Date: 04-2014
Publisher: Elsevier BV
Date: 12-2012
Publisher: Centers for Disease Control and Prevention (CDC)
Date: 06-2015
Publisher: Elsevier BV
Date: 12-2012
Publisher: Elsevier BV
Date: 12-2012
Publisher: Oxford University Press (OUP)
Date: 25-05-2012
Abstract: Voriconazole is a first-line agent for the treatment of invasive pulmonary aspergillosis (IPA). There are increasing reports of Aspergillus fumigatus isolates with reduced susceptibility to voriconazole. An in vitro dynamic model of IPA was developed that enabled simulation of human-like voriconazole pharmacokinetics. Galactomannan was used as a biomarker. The pharmacodynamics of voriconazole against wild-type and 3 resistant strains of A. fumigatus were defined. The results were bridged to humans to provide decision support for setting breakpoints for voriconazole using Clinical Laboratory Standards Institute (CLSI) and European Committee of Antimicrobial Susceptibility Testing (EUCAST) methodologies. Isolates with higher minimum inhibitory concentrations (MICs) required higher area under the concentration time curves (AUCs) to achieve suppression of galactomannan. Using CLSI and EUCAST methodologies, the AUC:MIC values that achieved suppression of galactomannan were 55 and 32.1, respectively. Using CLSI and EUCAST methodologies, the trough concentration:MIC values that achieved suppression of galactomannan were 1.68 and 1, respectively. Potential CLSI breakpoints for voriconazole are ≤ 0.5 mg/L for susceptible and >1 mg/L for resistant. Potential EUCAST breakpoints for voriconazole are ≤1 mg/L for susceptible and >2 mg/L for resistant. This dynamic model of IPA is a useful tool to address many remaining questions related to antifungal treatment of Aspergillus spp.
Publisher: Elsevier BV
Date: 04-2014
Publisher: Elsevier BV
Date: 07-2012
Publisher: Elsevier BV
Date: 12-2013
DOI: 10.1016/J.DRUP.2014.01.001
Abstract: Candida and Aspergillus infections have emerged as significant pathogens in recent decades. During this same time, broad spectrum triazole and echinocandin antifungal agents have been developed and increasingly used. One consequence of widespread use is leading to the emergence of mutants with acquired resistance mutations. Therefore, accurate susceptibility testing and appropriate clinical breakpoints for the interpretation of susceptibility results have become increasingly important. Here we review the underlying methodology by which breakpoints have been selected by EUCAST (European Committee on Antimicrobial Susceptibility Testing). Five parameters are evaluated: dosing regimens used EUCAST MIC distributions from multiple laboratories, species and compound specific epidemiological cut off values (upper MIC limits of wild type isolates or ECOFFs), pharmacokinetic harmacodynamic relationships and targets associated with outcome and finally clinical data by species and MIC when available. The general principles are reviewed followed by a detailed review of the in idual aspects for Candida species and the three echinocandins and for Aspergillus and the three mould-active azoles. This review provides an update of the subcommittee on antifungal susceptibility testing (AFST) of the EUCAST methodology and summarises the current EUCAST breakpoints for Candida and Aspergillus. Recommendations about applicability of antifungal susceptibility testing in the routine setting are also included.
Publisher: Wiley
Date: 13-01-2014
DOI: 10.1111/MYC.12170
Abstract: The European Committee on Antimicrobial Susceptibility Testing Subcommittee on Antifungal Susceptibility Testing has determined breakpoints for micafungin and revised breakpoints for anidulafungin and fluconazole for Candida spp. This Technical Note is based on the corresponding rationale documents (www.eucast.org). The micafungin breakpoints are based on PK data, animal PK/PD data, microbiological data and clinical experience. The anidulafungin breakpoints for C. parapsilosis and fluconazole breakpoints for C. glabrata have been modified to species-specific values that categorise the wild-type as intermediate to accommodate use of these compounds in some clinical situations.
Publisher: American Society for Microbiology
Date: 07-2011
DOI: 10.1128/AAC.01686-10
Abstract: The clinical utility of the echinocandins is potentially compromised by the emergence of drug resistance. We investigated whether Candida albicans with amino acid substitutions at position Ser645 in Fks1 can be treated with either a conventional or an elevated dosage of micafungin. We studied Candida albicans (wild-type SC5314 MIC, 0.06 mg/liter) and four fks1 mutants (one FKS1 / fks1 heterozygote mutant [MIC, 0.5 mg/liter] and three fks1 / fks1 homozygous mutants [MICs for all, 2 mg/liter]) with a variety of amino acid substitutions at Ser645. The pharmacokinetic and pharmacodynamic relationships were characterized in a persistently neutropenic murine model of disseminated candidiasis. A mathematical model was fitted to all pharmacokinetic and pharmacodynamic data. This mathematical model was then used to “humanize” the murine pharmacokinetics, and the predicted antifungal effect was determined. The estimated maximal rate of growth and ultimate fungal densities in the kidney for each of the strains were similar. The administration of micafungin at 1 mg/kg of body weight to the wild type resulted in moderate antifungal activity, whereas the administration of 5 and 20 mg/kg resulted in rapid fungicidal activity. In contrast, the FKS1 / fks heterozygote was killed only with 20 mg/kg, and the homozygous fks1 mutants failed to respond to any dosage. The bridging study revealed that human dosages of 100 and 400 mg/day were active only against the wild type, with no activity against either the heterozygote or the homozygote mutants. Ser645 Fks1 Candida albicans mutants cannot be treated with either conventional or elevated dosages of micafungin and should be deemed resistant.
Publisher: Elsevier BV
Date: 07-2012
Publisher: Informa UK Limited
Date: 11-2018
DOI: 10.2147/IDR.S176384
Publisher: Elsevier BV
Date: 06-2013
Publisher: Elsevier BV
Date: 04-2014
Publisher: Elsevier BV
Date: 12-2012
Publisher: Elsevier BV
Date: 12-2012
Publisher: Elsevier BV
Date: 11-2018
DOI: 10.1016/J.IJID.2018.08.010
Abstract: Denmark has a high incidence rate of candidaemia. A Nordic study suggested a higher Danish prevalence of haematological malignancies as an underlying reason. This nationwide study ascertained clinical characteristics of Danish candidaemia patients and investigated potential factors contributing to the high incidence and mortality. Microbiological and clinical data for candidaemia patients in 2010-2011 were retrieved. 30-day mortality was estimated by hazard ratios (HR) with 95% confidence intervals (CI, Cox regression). Data were available for 912/973 candidaemia episodes (93.7%). Intensive care unit (ICU) held the largest share of patients (43.2%). Prevalent host factors were multi-morbidity (≥2 underlying diseases, 74.2%) and gastrointestinal disease (52.5%). Haematological disease was infrequent (7.8%). Risk factors included antibiotic exposure (90.5%), CVC (71.9%) and Candida colonisation (66.7%). 30-day mortality was 43.4%, and 53.6% in ICU. Mortality was lower for patients with recent abdominal surgery (HR 0.70, 95% CI: 0.54-0.92). A substantial prevalence of multi-morbidity and a high 30-day mortality was found. We hypothesise, that an increasing population of severely ill patients with prolonged supportive treatment and microbiological testing may in part explain the high candidaemia incidence in Denmark. Nationwide studies are warranted to clarify this issue.
Publisher: Elsevier BV
Date: 12-2012
Publisher: Elsevier BV
Date: 04-2014
No related grants have been discovered for Maiken Cavling Arendrup.