Invasive Fungal Infection

Abstract

Background: The incidence of invasive fungal infection is approximately 6 cases per 100 000 persons per year. It is estimated that only half of such infections are detected during the patient's lifetime, making this one of the more common overlooked causes of death in intensive-care patients. The low detection rate is due in part to the complexity of the diagnostic work-up, in which the clinical, radiological, and microbiological findings must be considered. Fungi with resistance to antimycotic drugs have been found to be on the rise around the world.

Methods: This review is based on pertinent publications retrieved from a selective search in PubMed, with special attention to guidelines on the diagnosis and treatment of invasive fungal infections caused by Candida spp., Aspergillus spp., Mucorales, and Fusarium spp.

Results: The clinical risk factors for invasive fungal infection include, among others, congenital immune deficiency, protracted (>10 days) marked granulocytopenia (<0.5 x 109/L), allogeneic stem-cell transplantation, and treatment with immunosuppressive drugs or corticosteroids. High-risk groups include patients in intensive care and those with structural pulmonary disease and/or compli- cated influenza. The first line of treatment, supported by the findings of randomized clinical trials, consists of echinocandins for in- fections with Candida spp. (candidemia response rates: 75.6% for anidulafungin vs. 60.2% for fluconazole) and azole antimycotic drugs for infections with Aspergillus spp. (response rates: 52.8% for voriconazole vs. 31.6% for conventional amphotericin B). The recommended first-line treatment also depends on the local epidemiology. This challenge should be met by interdisciplinary collaboration. Therapeutic decision-making should also take account of the often severe undesired effects of antimycotic drugs (including impairment of hepatic and/or renal function) and the numerous interactions that some of them have with other drugs.

Conclusion: Invasive fungal infections are often overlooked in routine hospital care. They should be incorporated into antimicro- bial stewardship programs as an essential component. There is also a pressing need for the development of new classes of antimycotic drug.

eFigure 1

Tomography in the diagnostic evaluation of invasive fungal infections Tomography can provide important pointers of an invasive fungal infection: a) nodular infiltrate with surrounding halo in invasive pulmonary aspergillosis in a patient with granulocytopenia (arrow); b) invasive pulmonary aspergillosis in granulocytopenia (the same patient as in a), luftsichel sign as an indicator of responsiveness to treatment (arrow); c) inverse halo sign in mucormycosis (arrow). d) Aspergilloma in a preformed cavity of unclear origin (arrow); e) multiple abscesses in liver and spleen in chronic disseminated candidiasis; f) bilateral sinusitis owing to Mucorales (Lichtheimia corymbifera).

eFigure 2

Years in which available antimycotics were licensed for treating invasive fungal infections

eFigure 3

Antimycotics for the treatment of invasive fungal infections Three main classes of antimycotics are mainly used for treating invasive fungal infections: polyenes, azoles, and echinocandins. Polyenes Amphotericin B, nowadays primarily given as a liposomal formulation (L-AmB), is the only polyene that can be applied systemically. L-AmB interacts with ergosterol and has a fungicidal effect thanks to extramembranous agglomeration and/or pore formation (e37). L-AmB has broad-spectrum effectiveness; acquired resistance is rare. A disadvantage is its toxicity—especially nephrotoxicity—which results in large numbers of adverse effects and discontinuation of treatment (for example, severe adverse effects in 24.3% of treated patients in (33). Azoles Azole antimycotics inhibit the cytochrome P-450-mediated biosynthesis of ergosterol. All azoles are characterized by good to very good oral bioavailability. Their fungicidal effect is due to secondary effects that result in destruction of the fungal cell membrane (40). Their effectiveness vis-à-vis different fungal species differs for the different substances (table 2). Azole antimycotics have hepatotoxic effects and also inhibit human CYP450 enzymes (especially CYP3A4), which triggers a large number of medication interactions. Echinocandins All echinocandins are identical in their effectiveness spectrum and inhibit cell wall biosynthesis by blocking the (1→3)-ß-D-glucan-synthase (GS). Echinocandins are usually well-tolerated and have a lower potential for interactions with other medications. Sufficiently high therapeutic concentrations are reached except in urine and central nervous system. In rare cases, flucytosine is used in combination therapies with other antimycotics. This substance is deaminated in fungal cells and inhibits the biosynthesis of nucleic acid..