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Journal Article

Danish medical journal

Dan.Med.J.

Nov

60

11

B4698

JID: 101576205; 0 (Antifungal Agents); 0 (Echinocandins); 7XU7A7DROE (Amphotericin B); 8VZV102JFY (Fluconazole); ppublish

Denmark

2245-1919; 2245-1919

PMID: 24192246

eng

Journal Article; Review; IM

B4698 [pii]

Unknown(0)

24192246

In our part of the world invasive fungal infections include invasive yeast infections with Candida as the absolutely dominating pathogen and invasive mould infections with Aspergillus as the main organism. Yeasts are part of our normal micro-flora and invasive infections arise only when barrier leakage or impaired immune function occurs. On the contrary, moulds are ubiquitous in the nature and environment and their conidia inhaled at a daily basis. Hence invasive mould infections typically arise from the airways whereas invasive yeast infections typically enter the bloodstream causing fungaemia. Candida is by far the most common fungal blood stream pathogen; hence this genus has been the main focus of this thesis. As neither the Danish epidemiology nor the susceptibility of fungal pathogens was well described when we initiated our studies we initially wanted to be able to include animal models in our work. Therefore, a comprehensive animal study was undertaken comparing the virulence in a haematogenous mouse model of eight different Candida species including the five most common ones in human infections (C. albicans, C. glabrata, C. krusei, C. parapsilosis and C. tropicalis and in addition three rarer species C. guilliermondii, C. lusitaniae and C. kefyr). We found remarkable differences in the virulence among these species and were able to group the species according to decreasing virulence in three groups I: C. albicans and C. tropicalis, II: C. glabrata, C. lusitaniae and C. kefyr, and III: C. krusei, C. parapsilosis and C. guilliermondii. Apart from being necessary for our subsequent animal experiments exploring in vivo antifungal susceptibility, these findings also helped us understand at least part of the reason for the differences in the epidemiology and the pitfalls associated with the establishment of genus rather than species specific breakpoints. In example, it was less surprising that C. albicans has been the dominant pathogen and associated with a significantly higher mortality than C. parapsilosis and that C. glabrata and C. krusei mainly emerged in the post fluconazole era and in settings with azole selection pressure. Moreover, it was less surprising that infections due to mutant C. albicans isolates with echinocandin MICs of 1-2 mg/l were not good targets for the echinocandins despite the fact that the outcome for infections involving wild type C. parapsilosis for which similar echinocandin MICs were similar was not inferior. This last observation highlights the importance of providing optimal, reproducible and sensitive reference susceptibility testing methods and notably accompanied by appropriate breakpoints that allow a separation and detection of susceptible and resistant isolates against which the commercial tests can be validated. Correct detection of resistant isolates is for obvious reasons crucial in order to avoid inappropriate treatment. And if the test method cannot correctly identify resistant isolates it makes little sense performing susceptibility testing at all. On the other hand misclassification of susceptible isolates as resistant is also an issue as the patient is thereby deprived an appropriate treatment option among the few available. These comments may seem very basic; nevertheless, it has taken a lot of effort and patience to optimise the susceptibility tests, understand the variability issue for caspofungin testing, to provide appropriate breakpoints that reduced misclassifications to a minimum and not the least to facilitate a harmonisation of breakpoints across the Atlantic sea. We initially realised that the CLSI method and echinocandin breakpoint misclassified resistant isolates. This was due to the endorsement of a single susceptibility breakpoint across all Candida species and the three echinocandins and therefore set as high as 2 mg/l in order to include and not bisect the C. parapsilosis population. Through our comprehensive comparisons of echinocandin susceptibility testing u

Arendrup,M.C.