Invasive Fungal Infection
New treatments to meet new challenges
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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 complicated influenza. The first line of treatment, supported by the findings of randomized clinical trials, consists of echinocandins for infections 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 antimicrobial stewardship programs as an essential component. There is also a pressing need for the development of new classes of antimycotic drug.
Since the start of the new millennium, fungal infections have drastically increased in different ecosystems (1). Bat populations in North America have undergone a 70% reduction as a result of fungal infections; several species of amphibians have become extinct (e1, e2). Overall no group of microorganisms causes species extinction as frequently as fungi (1). Fungal infections are also among the most important causes for crop failures (e3). In spite of this ecological relevance, invasive fungal infections in humans are rare.
According to estimates, more than 10% of Germany’s population is affected by fungal infections. Superficial skin and nail mycoses are most common in this setting. Data on life-threatening infections are lacking, and valid conclusions can therefore not be drawn (2). On the basis of discharge diagnoses, in France the total incidence of invasive fungal infections has been found to be 5.9/100 000 cases/year, with a mortality of 27.6%, Both the incidence and mortality increased during the observation period (2001–2010) (3).
Yeasts of the Candida genus are the most common pathogens causing invasive fungal infections in Germany (2). They are responsible for a relevant proportion of all nosocomial bloodstream infections. According to data from the German nosocomial infection surveillance system (Krankenhaus-Infektions-Surveillance-System, KISS), 6.5% of bloodstream infections in intensive care wards are caused by this pathogen (4) (Table 1). Apart from Candida albicans, Candida glabrata is most commonly implicated (e4).
Infections with Aspergillus spp. are the most common mold infections in Germany. They mostly occur in patients with cell-mediated immune defects (Table 1) (2). Review articles of autopsy studies showed that invasive aspergillosis is one of the most commonly overlooked diagnoses and that according to estimates, only about half of all invasive fungal infections are diagnosed pre-death (5, 6) (Table 1). In addition to Aspergillus fumigatus (>80%) other species have been found in locally varying but clearly lower numbers. Determining the species is relevant because of partly varying resistance profiles.
Different pathogens from the large group of Mucorales, as well as Fusarium spp., rarely cause invasive infections, but always present a therapeutic challenge because of numerous resistances. It is not possible to give data on case numbers as these infections are very rare. Fusarium spp. are also the most common pathogens causing fungal keratitis, which in about half of all affected patients has severe sequelae, including the loss of the affected eye (in 3 out of 15 cases in a German case series) (7). Furthermore, there are numerous descriptions of invasive fungal infections caused by rare or undescribed pathogens. In 2018, the National Reference Center for Invasive Fungal Infections (Nationales Referenzzentrum für invasive Mykosen, NRZMyk) documented some 80 different species obtained from clinical specimens. The present article focuses on invasive infections caused by Candida spp., aspergillosis, mucormycosis, and fusariosis as the most common invasive fungal infections in Germany. Because of the particularities of the treatment, we exempted Pneumocystis jirovecii from this study. The same holds true for Cryptococcus neoformans, a pathogen that is highly prevalent especially in Africa, but occurs only very rarely in Germany (e5).
The therapeutic challenges associated with invasive fungal infections have changed over the past 20 years (8):
- Since the mid-1990s, Aspergillus fumigatus isolates with resistance to azoles have been increasingly identified. Azole-resistant isolates have also been identified in Germany and at individual centers were responsible for a substantial proportion of invasive infections (9).
- With the increased use of echinocandins, resistant Candida isolates started to be seen worldwide (e6).
- Since 2009, the new species Candida auris has spread globally. Nosocomial transmissions of this pathogen have caused institutions of the public healthcare system to issue warnings (e7).
New therapeutic options have become available to meet these challenges. Since the start of the new millennium, the portfolio of antimycotics has expanded (eFigure 2). For the fungal infections that are the subject of this review article, three main classes of substance are available: polyenes, azoles, and echinocandins (eFigure 3). In this article, the authors aim to provide—on the basis of the recent literature and guidelines—an overview of the diagnostic evaluation and therapy of invasive fungal infections.
The safe and early diagnosis of invasive fungal infections is the central challenge in routine clinical practice and forms the crucial basis for targeted treatment (10–17). The diagnosis of an invasive fungal infection is based on three elements: the clinical examination, imaging, and confirmation/proof of the causative agent.
The clinical diagnostic criteria for invasive fungal infections were defined by an international working group (the (EORTC/MSG Study Group). These criteria selectively apply to immunosuppressed patients and were conceived primarily for clinical studies (18). In addition to congenital immunodeficiencies (Table 1), the relevant clinical risk factors include:
- Prolonged (>10 days) deep granulocytopenia (<0.55 × 109/L)
- Allogeneic stem cell transplantation
- Medication-induced immunosuppression, or
- Treatment with prednisone (the equivalent of at least 0.3 mg/kg/d for a minimum of 3 weeks).
This list is by no means complete and excludes important but less well-defined risk groups. Examples include patients in intensive care wards, patients with structural lung disease, and patients with severe influenza (Table 1) (19, 20).
Tomography imaging yields crucial clues (eFigure 1). Infections of the respiratory tract require computed tomography (CT), neurological infections require magnetic resonance imaging (MRI), and abdominal infections require CT or MRI scanning in order to identify abscesses that are characteristic for the special variety of hepatolienal candidiasis. Abdominal infections can also be visualized by using sonography.
Where a diagnosis is suspected, the next step will be confirmation of the pathogen (eTable 1). Bloodstream infections with Candida spp. are almost exclusively confirmed by blood cultures. The identification of Candida in specimens taken from the respiratory tract does not indicate an invasive infection (21); for other, non-sterile specimens, a decision always has to be made on the basis of the individual clinical situation as to whether it is a case of colonization or a clinically relevant situation. Because of their wide environmental spread, the confirmation of molds from physiologically non-sterile material should be interpreted with caution; this is also the case for all specimens from the respiratory tract.
For serological diagnostic evaluation, Candida antigen/antibody confirmation is not recommended in current guidelines because of the lack of pertinent studies. Beta D-glucan (BDG) is not specific for Candida , but it does indicate an invasive fungal infection. A patient’s risk profile, symptoms, and imaging results will narrow down this differential diagnosis, however. The sensitivity and specificity of this marker vary substantially between different patient populations and depend on the test system used (e8–e10). To confirm A. fumigatus, galactomannan (“aspergillus antigen”) is available—in addition to BDG—which can be determined from serum and bronchial secretions (and, if applicable, cerebrospinal fluid). The sensitivity for serum is about 78%, the specificity is 85%, depending on the cut-off value and the patient population (22). To confirm invasive aspergillosis, furthermore, reference protocols for molecular diagnostics have been developed that function as examples for molecular diagnostic evaluation of infections and, in combination with other methods, contribute to improved diagnostics (23–25).
Resistances and testing for resistance
In recent years, increasing rates of resistant pathogens have been confirmed worldwide. In Candida spp., acquired echinocandin resistance now occurs, in addition to the long familiar fluconazole resistance (at least in Candida glabrata). In Denmark, the rates of resistant C. glabrata from blood cultures rose from 0.9% (2008/2009) to 3.1% (2012/2013) (e6). In the US, resistant C. glabrata is already much more common; one center posted a rise in the resistance rate from 4.9% in 2001 to 12.3% in 2010 (e11). In Germany, such strains are currently still rare. Because of lacking data, concrete resistance rates cannot be reliably determined. Most guidelines, meanwhile, are recommending testing all “clinically relevant” isolates of Candida spp. for sensitivity/susceptibility to azoles. For echinocandins, EUCAST recommends because of the lacking reproducibility of the caspofungin test to test only for anidulafungin or micafungin. If the isolate proves susceptible to these two substances on testing, treatment can also consist of administering caspofungin.
Since the 1990s, azole-resistant strains of A. fumigatus have been described in particular in the Netherlands and in Great Britain (26). The European Society of Clinical Microbiology and Infectious Diseases (ESCMID) recommends testing for resistance to azole antimycotics (16). Overall, we hold that resistance in Germany is currently not a problem. However, raised resistance rates have been found in patients with cystic fibrosis who were chronically colonized with A. fumigatus (e12). Only where rates of azole resistant A. fumigatus have increased locally, consideration should be given to whether, until a susceptible pathogen has been confirmed, a treatment should be selected that includes strains with azole resistance. In Essen, Germany, for example, a resistance rate of 30% in cases of invasive aspergillosis was found in isolates of A. fumigatus that were detected on culture (9). A recent Dutch guideline recommends—in view of the high rates of azole resistant A. fumigatus in the Netherlands (12.9%)—for the first time treatment with a combination of voriconazole and either echinocandin or liposomal amphotericin B (L-AmB) until sensitivity/susceptibility has been confirmed (e13).
Depending on the indication, a choice needs to be made between prophylactic treatment, empirical treatment, or pre-emptive treatment. Antimycotic prophylaxis is recommended primarily for hematology/oncology patients (27). After allogeneic stem cell transplantation, prophylaxis against yeasts is usually sufficient. By contrast, a high-risk constellation—such as granulocytopenia after myelosuppressive induction therapy or graft-versus-host disease—requires prophylaxis that is effective against molds. Data for other patient populations are less clear-cut. For patients with complications after abdominal surgery, for patients requiring intensive care and who have relevant risk factors, and for patients who have undergone lung transplantation surgery, prophylaxis can make sense (12). However, these indications are not sufficiently supported by study results. Empirical therapy is used if an invasive fungal infection is suspected. The therapeutic approach described in the following section is based on confirmation of the pathogen and should follow available guidelines (eTable 2). Essentially, the main therapeutic options are substances from three classes of antimycotic drugs (Table 2).
Invasive Candida infection
Several guidelines are available to support the selection of treatment of invasive Candida infections (eTable 2). The therapeutic schemes depend on the underlying disease and organ involvement (12–14, 17, 28, 29). Determining the species is extremely important because of intrinsic resistance patterns (Table 2). In most clinical situations, echinocandins are the treatment of choice in adult patients. In a randomized study of the treatment of candidemia, anidulafungin was at least equivalent to fluconazole; a secondary analysis even found that it was superior (response rate for fluconazole 60.2%, for anidulafungin 75.6%, difference 15.4% [95% confidence interval: 3.9; 27.0]). For this reason, fluconazole should be used only in patients without critical illness and at a high initial dosage (800 mg/d) (12). Fluconazole is, however, still relevant for oral treatment continuation after successful initial treatment with an echinocandin. L-AmB constitutes an alternative where resistance to other classes of substances is confirmed. Furthermore, L-AmB is important in treating chronically disseminated candidosis/candidiasis, endocarditis due to Candida, and in pediatric patients (12, 13). Voriconazole usually does not provide any additional benefits over fluconazole—with the exception of infection with C. krusei or where additionally a mold infection is suspected.
Candidemia should be treated for at least two weeks after the bloodstream infection has disappeared (28). The exact treatment duration can be defined only after follow-up blood cultures have been produced. In continuing symptoms or granulocytopenia, the treatment should be continued for longer. Chronically disseminated candidosis should be treated for a minimum of 8–12 weeks, and in some cases for several months, until the lesions have resolved (12, 14, 17, 28). Central venous catheters should be removed if at all possible. If this is not possible then the patient should be treated with an echinocandin or L-AmB, because of their effectiveness against biofilms in vitro (12, 14, 17, 28). Because of possible relocation of the pathogen into the eyes, funduscopy is recommended during intravenous therapy (12, 14, 17, 28).
The prognosis for invasive aspergillosis has improved substantially over the past decade. The treatment of choice usually consists of the administration of voriconazole or isavuconazole. Both azoles are effective fungicides against A. fumigatus (16, 31, 32) (e14) (Table 2). In a randomized controlled study, voriconazole was superior to treatment with conventional amphotericin B (21.2% greater response [52.8% versus 31.6%], 95% confidence interval [10.4; 32.9]; longer survival rates for voriconazole (33). Voriconazole reaches effective concentrations even for neurological infections (Table 2) (e15). In a randomized controlled clinical trial of the treatment of invasive mold infections, isavuconazole was non-inferior to treatment with voriconazole (34). L-AmB is an alternative—after taking into consideration prior prophylactic administration of azoles (the class should be changed), comorbidities, resistance of the pathogen, medication interactions, and local epidemiology. L-AmB is also recommended for initial therapy if co-infection with Mucorales is suspected. The value of combination therapy (for example, using voriconazole plus echinocandin) is unclear (e16). In addition to systemic administration, local instillation of L-AmB may make sense, for example in aspergillosis of the central nervous system (e17). In all cases, surgical treatment should be considered in addition to medication treatment (16, 31). Supportive measures include the administration of granulocyte colony stimulating factor (G-CSF) or, in long-term granulocytopenia, granulocyte transfusions (16, 31).
The duration of treatment depends on the patient’s individual clinical development while taking into account the type and extent of immunosuppression (16); it usually takes about 6–12 weeks (31). Radiological checkups make sense, but the guidelines currently do not provide any indication of optimal time points (35). After the start of the treatment and especially after granulocyte levels have risen in patients with neutropenia, the radiological imaging will usually show an increase in lesion size. But a week after the start of therapy, lesions should not enlarge any more but can be expected to shrink until day 14 (35). In order to undertake these checkups, serial CT scans at the start of therapy and one and two weeks subsequently are our current recommendation. Changes to the galactomannan titer during treatment also provide information about the course (e18).
Rare invasive mycoses
No randomized controlled trials exist of the treatment of invasive mycoses caused by rare pathogens. Therapy is guided by the broad spectrum effectiveness of the antimycotics and by case series (Table 2). Mycormycoses are caused by a large group of different pathogens with different sensitivity/susceptibility profiles. To treat these, L-AmB (at a minimum dosage of 5 mg/kg; 10 mg/kg if the central nervous system is affected) and azoles with effectiveness against Mucorales (isovuconazole, posaconazole) are the medications of choice (11). The surgical resection of infected tissue is an essential component of the therapeutic concept (11).
Invasive infections with Fusarium spp. should be treated with voriconazole or L-AmB—in combination until the results of sensitivity/susceptibility testing become available—with posaconazole available as second-line treatment (15). Surgical removal of infected tissue should be considered, and possible immunosuppression should be lowered. Keratitis caused by Fusarium spp. requires local therapy using natamycin (eyedrops 5%) and systemic therapy with voriconazole (e19–e21). A Cochrane review found that local therapy with natamycin 5% was superior to other treatments (36). The benefits of systemic treatment with voriconazole was shown in a randomized controlled clinical trial (e20). In spite of antimycotic therapy, penetrating keratoplasty will be required in many cases (for example, in two thirds of cases in ). Individual guidelines also comment on the treatment of further, rare pathogens (10, 15). The search engine www.FungiQuest.net provides a web based tool that lists case histories for extremely rare invasive mycoses. However, this cannot be a substitute for expert consultation.
Conclusions and outlook
The number and heterogeneity of patients at risk for invasive fungal infections have increased. For example, the number of stem cell transplantations in Europe almost doubled between 2000 and 2016 (e22, e23). At the same time, new at-risk populations were identified—examples include hospital inpatients with severe influenza or chronic obstructive pulmonary disease (19, 20). The emergence of new and/or resistant pathogens is matched by a growing repertoire of antimycotics. Antimycotic treatment needs to be initiated more frequently, and the selection of the optimal therapeutic strategy has become more complex. Additional classes of antimycotics are therefore well overdue (37) (e24). These trends have added to the challenges for mycological diagnostics, for example with regard to resistance testing. The treatment of fungal infections should be anchored in antimicrobial stewardship programs. Resistance development in fungal pathogens will need to be integrated into national action plans, such as the German Antimicrobial Resistance Strategy (Deutsche Antibiotika Resistenzstrategie, DART). Restricting such programs to bacterial infections means enabling the further spread of resistance to antimycotics.
The work of the National Reference Center for Invasive Fungal Infections (NRZMyk) is supported by the Robert Koch-Institute using funding from Germany’s Federal Ministry of Health (funding reference 1369–240). Research projects at the NRZMyk are supported by the German Federal Ministry of Education and Research in the context of the consortium InfectControl 2020 (Programm Zwanzig20—Partnerschaft für InnovationProgramme [Program Twenty20—a Partnership for Innovation program]). The activities of the authors (HE, OK) are supported by the German Research Foundation (DFG) in the context of the collaborative research center Transregio FungiNet (TR124, projects A2 and C3).
Conflict of interest statement
Professor Lilienfeld-Toal received consultancy fees from Gilead and MSD. Conference delegate fees and travel expenses were paid on her behalf by Gilead and Astellas. She received lecture honoraria from Gilead, MSD, Pfizer, Astellas, and Chugai. She received third-party funding from Gilead.
PD Dr Wagener received study support (third-party funding) from Fujifilm Wako Chemicals Europe and Euroimmun Medizinische Labordiagnostika [which provides immunodiagnostic laboratory solutions].
Prof. Cornely received consultancy fees from Actelion, Allecra Therapeutics, Amplyx, Astellas, Basilea, Biosys IK Limited, Cidara, Da Volterra, Entasis, F2G, Gilead, IQVIA, Matinas, MedPace, Menarini Ricerche, Merck/MSD, Octapharma, Paratek Pharmaceuticals, Pfizer, PSI, Rempex, Scynexis, Seres Therapeutics, Tetraphas, and Vical. He received study support (third-party funding) from Actelion, Amplyx, Astellas, Basilea, Cidara, Da Volterra, F2G, Gilead, Janssen Pharmaceuticals, Medicines Company, MedPace, Melinta Therapeutics, Pfizer, Scynexis, and Merck/MSD. He received conference delegate fees and reimbursement of travel expenses and consultancy fees from Astellas, Basilea, Gilead, Merck/MSD, and Pfizer.
Professor Kurzai received consultancy fees from Basilea. He received reviewer honoraria relating to the subject of the article from BG Chemische Industrie. He received lecture honoraria from Heidelberg Engineering GmbH, Pfizer, and Astellas. He received study support from Astellas, Pfizer, MSD, Gilead, Virotech, Novartis, and Fujifilm Wako Chemicals.
Professor Einsele declares that no conflict of interest exists.
Manuscript received on 29 June 2018, revised version accepted on 14 February 2019.
Translated from the original German by Birte Twisselmann, PhD.
Prof. Dr. med. Oliver Kurzai
Institut für Hygiene und Mikrobiologie
Lehrstuhl für Medizinische Mikrobiologie und Mykologie
97080 Würzburg, Germany
Cite this as:
von Lilienfeld-Toal M, Wagener J, Einsele H, Cornely OA, Kurzai O:
Invasive fungal infection—new treatments to meet new challenges.
Dtsch Arztebl Int 2019; 116: 271–8. DOI: 10.3238/arztebl.2019.0271
For eReferences please refer to:
HIV-associated cryptococcal meningitis: an updated analysis. Lancet Infect Dis 2017; 17: 873–81 CrossRef
PD Dr. med. Johannes Wagener, Prof. Dr. med. Oliver Kurzai
Clinic of Internal Medicine II, University Hospital Jena:
Prof. Dr. med. Marie von Lilienfeld-Toal
Institute for Hygiene and Microbiology, University of Würzburg,
Chair of Medical Microbiology and Mycology, Würzburg:
PD Dr. med. Johannes Wagener, Prof. Dr. med. Oliver Kurzai
Department of Internal Medicine II, University Hospital of Würzburg: Prof. Dr. med. Hermann Einsele
InfectControl 2020, Jena/Würzburg:
Prof. Dr. med. Hermann Einsele, Prof. Dr. med. Oliver Kurzai
Cologne Excellence Cluster on Cellular Stress Responses
in Aging-Associated Diseases (CECAD), Department I of Internal Medicine, at the University Hospital of Cologne,
European Excellence Center for Medical Mycology (ECMM),
DGerman Center for Infection Research(DZIF)
Partner Site Bonn Köln, Cologne University:
Prof. Dr. med. Oliver A. Cornely
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