Fungal Endocarditis: Pathophysiology, Epidemiology, Clinical Presentation, Diagnosis, and Management.

Fungal endocarditis accounts for 1% to 3% of all infective endocarditis cases, is associated with high morbidity and mortality (>70%), and presents numerous challenges during clinical care. Candida spp. are the most common causes of fungal endocarditis, implicated in over 50% of cases, followed by Aspergillus and Histoplasma spp. Important risk factors for fungal endocarditis include prosthetic valves, prior heart surgery, and injection drug use. The signs and symptoms of fungal endocarditis are nonspecific, and a high degree of clinical suspicion coupled with the judicious use of diagnostic tests is required for diagnosis. In addition to microbiological diagnostics (e.g., blood culture for Candida spp. or galactomannan testing and PCR for Aspergillus spp.), echocardiography remains critical for evaluation of potential infective endocarditis, although radionuclide imaging modalities such as 18F-fluorodeoxyglucose positron emission tomography/computed tomography are increasingly being used. A multimodal treatment approach is necessary: surgery is usually required and should be accompanied by long-term systemic antifungal therapy, such as echinocandin therapy for Candida endocarditis or voriconazole therapy for Aspergillus endocarditis.

Core Recommendations for Antifungal Stewardship: A Statement of the Mycoses Study Group Education and Research Consortium.

In recent years, the global public health community has increasingly recognized the importance of antimicrobial stewardship (AMS) in the fight to improve outcomes, decrease costs, and curb increases in antimicrobial resistance around the world. However, the subject of antifungal stewardship (AFS) has received less attention. While the principles of AMS guidelines likely apply to stewarding of antifungal agents, there are additional considerations unique to AFS and the complex field of fungal infections that require specific recommendations. In this article, we review the literature on AMS best practices and discuss AFS through the lens of the global core elements of AMS. We offer recommendations for best practices in AFS based on a synthesis of this evidence by an interdisciplinary expert panel of members of the Mycoses Study Group Education and Research Consortium. We also discuss research directions in this rapidly evolving field. AFS is an emerging and important component of AMS, yet requires special considerations in certain areas such as expertise, education, interventions to optimize utilization, therapeutic drug monitoring, and data analysis and reporting.

US database study: burden and healthcare resource utilization in adults with systemic endemic mycoses and aspergillosis.

Aim: This study evaluated burden of illness in immunocompromised patients with systemic mycoses (SM) eligible for itraconazole treatment, specifically, histoplasmosis, blastomycosis and aspergillosis. Methods: A cross-sectional study used an electronic medical record network integrating information from 30 US hospitals, including >34 million patients, to evaluate burden and healthcare resource utilization over 6 months following initiation of antifungal therapy. Results: Symptomatic burden experienced by each of the otherwise healthy or age >65 or immunosuppressed cohorts receiving antifungal therapy for SM was comparable but significantly greater in cancer or HIV patients and transplant recipients. Across groups, there was substantially higher healthcare resource utilization in patients with SM versus matched controls without SM. Conclusion: The total impact of SM is particularly severe in high-risk or vulnerable populations.

Molecular mechanisms of posaconazole- and itraconazole-induced pseudohyperaldosteronism and assessment of other systemically used azole antifungals.

Recent reports described cases of severe hypertension and hypokalemia accompanied by low renin and aldosterone levels during antifungal therapy with posaconazole and itraconazole. These conditions represent characteristics of secondary endocrine hypertension caused by mineralocorticoid excess. Different mechanisms can cause mineralocorticoid excess, including inhibition of the adrenal steroidogenic enzymes CYP17A1 and CYP11B1, inhibition of the peripheral cortisol oxidizing enzyme 11ß-hydroxysteroid dehydrogenase type 2 (11ß-HSD2) or direct activation of the mineralocorticoid receptor (MR). Compared to previous experiments revealing a threefold more potent inhibition of 11ß-HSD2 by itraconazole than with posaconazole, the current study found sevenfold stronger CYP11B1 inhibition by posaconazole over itraconazole. Both compounds most potently inhibited CYP11B2. The major pharmacologically active itraconazole metabolite hydroxyitraconazole (OHI) resembled the effects of itraconazole but was considerably less active. Molecular modeling calculations assessed the binding of posaconazole, itraconazole and OHI to 11ß-HSD2 and the relevant CYP enzymes, and predicted important interactions not formed by the other systemically used azole antifungals, thus providing an initial explanation for the observed inhibitory activities. Together with available clinical observations, the presented data suggest that itraconazole primarily causes pseudohyperaldosteronism through cortisol-induced MR activation due to 11ß-HSD2 inhibition, and posaconazole by CYP11B1 inhibition and accumulation of the mineralocorticoids 11-deoxycorticosterone and 11-deoxycortisol because of hypothalamus-pituitary-adrenal axis (HPA) feedback activation. Therapeutic drug monitoring and introduction of upper plasma target levels may help preventing the occurrence of drug-induced hypertension and hypokalemia. Furthermore, the systemically used azole antifungals voriconazole, isavuconazole and fluconazole did not affect any of the mineralocorticoid excess targets, offering alternative therapeutic options.

Treatment of Primary Pulmonary Aspergillosis: An Assessment of the Evidence.

Aspergillus spp. are a group of filamentous molds that were first described due to a perceived similarity to an aspergillum, or liturgical device used to sprinkle holy water, when viewed under a microscope. Although commonly inhaled due to their ubiquitous nature within the environment, an invasive fungal infection (IFI) is a rare outcome that is often reserved for those patients who are immunocompromised. Given the potential for significant morbidity and mortality within this patient population from IFI due to Aspergillus spp., along with the rise in the use of therapies that confer immunosuppression, there is an increasing need for appropriate initial clinical suspicion leading to accurate diagnosis and effective treatment. Voriconazole remains the first line agent for therapy; however, the use of polyenes, novel triazole agents, or voriconazole in combination with an echinocandin may also be utilized. Consideration as to which particular agent and for what duration should be made in the individual context for each patient based upon underlying immunosuppression, comorbidities, and overall tolerance of therapy.

Correction: Stewart, E.R.; Thompson, G.R. Treatment of Primary Pulmonary Aspergillosis: An Assessment of the Evidence. J. Fungi 2016, 2, 25.

The authors of the published paper [1] would like to correct Table 1.[...].

Fluoride excess in coccidioidomycosis patients receiving long-term antifungal therapy: an assessment of currently available triazoles.

The use of voriconazole, a trifluorinated antifungal, has been associated with the development of fluoride excess and periostitis/exostoses. We evaluated a cohort of patients on long-term triazole therapy and found that other fluorinated triazoles (fluconazole and posaconazole) conferred no risk for the development of hyperfluorosis and its complications in our cohort.