Studies into the epidemiology and management of invasive fungal infections with a focus on candidaemia and antifungal resistance

Abstract

Background Invasive fungal infections (IFIs) such as those caused by Candida species, the most common fungal pathogen, are associated with significant mortality despite advances in antifungal therapy and medical care. The aims of this thesis were to assess prevention in high-risk groups, examine the risk factors for candidaemia and its complications, and antifungal drug resistance. Methods The thesis employs a thesis-by-publication format, comprising four epidemiological studies followed by two laboratory-based studies. Findings In a retrospective single-centre analysis of itraconazole prophylaxis in acute myeloid leukaemia (AML), breakthrough IFI rate was low. A prospective multicentre, case-controlled study across Australia found that central venous access device (CVAD) use, end-organ failure, hepatobiliary or gastrointestinal surgery, urological instrumentation or catheterisation, intravenous drug use (IVDU) and carbapenem were risks factors for candidaemia. A case-cohort study identified age > 65 years, intensive care unit (ICU) admission, absence of prior surgery, haematological malignancy, chronic organ dysfunction, gastrointestinal or unidentifiable source and prior use of antibiotics for at least 10 days as associated with mortality, and established a predictive model. Shorter time to positivity (TTP) was associated with higher mortality, with species-specific differences. WGS of C. tropicalis demonstrated high-level fluconazole resistance present exclusively in isolates with ERG11 gene mutations in the homozygous form. An ERG3 deletion was associated with azole-resistance on comparison of two bloodstream isolates of C. albicans. Conclusions The thesis first provides support for the continued use of itraconazole prophylaxis for AML patients. The research contributed to the understanding of risk factors and outcomes associated with candidaemia and provided insights into the genomic characteristics associated with antifungal resistance