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


Other title
paradoxical growth effect
candida albicans
Type of item
Degree grantor
University of Alberta
Author or creator
Delorme, Amy E
Supervisor and department
Tyrrell, Greg (Laboratory Medicine and Pathology)
Rennie, Robert (Laboratory Medicine and Pathology)
Examining committee member and department
Laverdiere, Michel (Microbiology and Infectious Diseases)
Fuller, Jeff (Laboratory Medicine and Pathology)
Bundle, David (Chemistry)
Medical Sciences-Laboratory Medicine and Pathology

Date accepted
Graduation date
Doctor of Philosophy
Degree level
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.
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