Effect of first-line antifungal treatment on ocular complication risk in Candida or yeast blood stream infection

ObjectivesOcular candidiasis (OC) can complicate Candida bloodstream infection (BSI). Antifungal treatment improves the prognosis of patients with BSI, but the effects of choice and timing of first-line medication on OC risk are incompletely understood. We explored the early treatments, risk factors and ocular presentations in Candida BSI.Methods and analysisAll patients (n=304) with Candida BSI during 2008–2017 at Oulu University Hospital were included. Those patients in whom clinical condition was appropriate for ocular examination (OE), including biomicroscopy (n=103), were carefully analysed by ophthalmologists. Criteria for patient selection were considered. Candida and yeast species, antifungal medications, echocardiography, underlying diseases and clinical properties of the patients with Candida BSI were analysed.ResultsClinical condition in 103 patients had been considered appropriate for OE. OC was diagnosed in 33 of the 103 patients. Candida albicans was the most common finding (88%) in OC. Patients in intensive care, alcohol-related conditions or poor prognosis were less frequently examined. Persistent candidemia increased the risk of OC. Chorioretinitis and endophthalmitis were diagnosed in 94% and 48% of the patients with OC, respectively. Any early antifungal treatment decreased the endophthalmitis risk. Echinocandin lowered the OC risk in those with central venous catheters (CVCs) or abdominal malignancy.ConclusionCritical condition of patients with Candida BSI affects the selection and results of OE. OC was associated with C. albicans BSI especially among those with persistent candidemia, CVC or abdominal malignancy. Any early antifungal treatment reduced endophthalmitis risk. Early echinocandin treatment may reduce the risk of OC in selected patients.

Candida Endocarditis in Patients with Candidemia: A Single-Center Experience of 14 Cases

A retrospective, single-center analysis of 14 cases of Candida endocarditis (from 355 candidemia cases during the years 2012–2019) revealed a high in-hospital mortality (57.1%), a high proportion of healthcare-associated infections (13/14) and a high treatment preference for echinocandins. Transthoracic echocardiography and 18F-FDG PET/CT had a sensitivity of 54.5% and 57.1%, respectively. Patients were older than previously described and most patients with Candida endocarditis had persistent candidemia for ≥ 3 days despite antifungal therapy.

Emerging echinocandin-resistant Candida albicans and glabrata in Switzerland

Echinocandins represent the first-line therapy of candidemia. Echinocandin resistance among Candida spp. is mainly due to acquired FKS mutations. In this study, we report the emergence of FKS-mutant Candida albicans/glabrata in Switzerland and provide the microbiological and clinical characteristics of 9 candidemic episodes. All patients were previously exposed to echinocandins (median 26 days; range 15–77). Five patients received initial echinocandin therapy with persistent candidemia in 4 of them. Overall mortality was 33%.

Clearing the FoG: Antifungal tolerance is a subpopulation effect that is distinct from resistance and is associated with persistent candidemia

Drug susceptibility, defined by the minimal inhibitory concentration (MIC), often does not predict whether fungal infections will respond to therapy in the clinic. Tolerance at supra-MIC antifungal drug concentrations is rarely quantified and current clinical recommendations suggest it be ignored. Here, we measured and characterized drug-response variables that could influence the outcomes of fungal infections and be generalizable across major clades ofCandida albicans, one of the most frequently isolated human fungal pathogens. We quantified antifungal tolerance as the fraction of growth (FoG) above the MIC and found that it is clearly distinct from susceptibility/resistance measured as MIC. Instead, tolerance is due to the slow growth of subpopulations of cells that overcome drug stress more efficiently than the rest of the population, and correlates inversely with the accumulation of intracellular drug. Importantly, many adjuvant drugs used together with fluconazole, a fungistatic drug, reduce tolerance without affecting resistance. These include inhibitors of major stress response hubs such as Hsp90, calcineurin, PKC1 and TOR. Accordingly, in an invertebrate infection model, adjuvant combination therapy was significantly more effective than fluconazole alone in treating highly tolerant isolates and did not improve the treatment of isolates with low tolerance levels. Furthermore, isolates recovered from immunocompetent patients with persistent candidemia displayed significantly higher tolerance than isolates that were readily cleared by fluconazole. Thus, tolerance correlates with the response to fluconazole therapy in patients and may help predict whether infections will respond to fluconazole alone. Similarly, measuring tolerance may provide a useful clinical parameter for choosing appropriate therapeutic strategies to overcome persistent clinical candidemia.