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Characterization of the Paradoxical Growth Effect of Candida albicans Exposed to Caspofungin

  • Author / Creator
    Delorme, Amy E
  • Candida albicans is an opportunistic pathogen and major cause of invasive fungal infections. Choice of antifungal therapy is complicated by the underlying associated diseases of patients infected, other drug interactions, and in vitro susceptibility of the isolate. Echinocandins are emerging as a preferred first line therapy in candidiasis, as they have few drug interactions or patient side effects, and have a fungal specific mode of action. However, in vitro susceptibility testing of caspofungin by broth microdilution has revealed an unexplained paradoxical growth (PG) effect in which there is noticeable growth at concentrations above the minimum inhibitory concentration (MIC) of susceptible isolates. This effect has not been fully characterized, but is believed to be a strictly in vitro phenomenon. The incidence of the PG effect varies between Candida strains, species, and growth forms and is affected my growth medium composition. My objectives were to more fully understand this effect by evaluating factors that affect in vitro growth with the echinocandin caspofungin (CASPO), including inoculum density and medium carbon source. I demonstrated that all C. albicans demonstrate the PG effect while C. glabrata, suggesting an intrinsic difference between species that demonstrate PG. Sequence and phylogenetic evaluation of the echinocandin target, glucan synthase, does not correlate with MIC or PG. Further in vitro evaluation by time kill analysis determined that medium carbon source modulates the PG effect. My research findings contribute to the growing body of evidence that suggests the action of echinocandins is not entirely concentration dependent and highlights the significant physiological differences between yeast grown at PG and inhibitory CASPO concentrations.

  • Subjects / Keywords
  • Graduation date
    2015-06
  • Type of Item
    Thesis
  • Degree
    Doctor of Philosophy
  • DOI
    https://doi.org/10.7939/R3DF6K80Z
  • License
    This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.
  • Language
    English
  • Institution
    University of Alberta
  • Degree level
    Doctoral
  • Department
    • Medical Sciences-Laboratory Medicine and Pathology
  • Supervisor / co-supervisor and their department(s)
    • Rennie, Robert (Laboratory Medicine and Pathology)
    • Tyrrell, Greg (Laboratory Medicine and Pathology)
  • Examining committee members and their departments
    • Laverdiere, Michel (Microbiology and Infectious Diseases)
    • Fuller, Jeff (Laboratory Medicine and Pathology)
    • Bundle, David (Chemistry)