Browsing by Subject "Invasive Fungal Infections"
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Item Open Access Breakthrough invasive fungal infections: Who is at risk?(Mycoses, 2020-10) Jenks, Jeffrey D; Cornely, Oliver A; Chen, Sharon C-A; Thompson, George R; Hoenigl, MartinThe epidemiology of invasive fungal infections (IFIs) in immunocompromised individuals has changed over the last few decades, partially due to the increased use of antifungal agents to prevent IFIs. Although this strategy has resulted in an overall reduction in IFIs, a subset of patients develop breakthrough IFIs with substantial morbidity and mortality in this population. Here, we review the most significant risk factors for breakthrough IFIs in haematology patients, solid organ transplant recipients, and patients in the intensive care unit, focusing particularly on host factors, and highlight areas that require future investigation.Item Open Access Broad spectrum triazoles for invasive mould infections in adults: Which drug and when?(Medical mycology, 2019-04) Jenks, Jeffrey D; Mehta, Sanjay R; Hoenigl, MartinInvasive mould infections are an increasing cause of morbidity and mortality globally, mainly due to increasing numbers of immunocompromised individuals at risk for fungal infections. The introduction of broad spectrum triazoles, which are much better tolerated compared to conventional amphotericin B formulations, has increased survival, particularly in invasive mould infection. However, early initiation of appropriate antifungal treatment remains a major predictor of outcome in invasive mould infection, but despite significant advances in diagnosis of these diseases, early diagnosis remains a challenge. As a result, prophylaxis with mould-active triazoles is widely used for those patients at highest risk for invasive mould infection, including patients with prolonged neutropenia after induction chemotherapy for acute myeloid leukemia and patients with graft-versus-host-disease. Posaconazole is the recommended drug of choice for antimould prophylaxis in these high-risk patients. Voriconazole has its primary role in treatment of invasive aspergillosis but not in prophylaxis. Recently, isavuconazole has been introduced as an excellent alternative to voriconazole for primary treatment of invasive aspergillosis in patients with hematological malignancies. Compared to voriconazole, isavuconazole and posaconazole have broader activity against moulds and are therefore also an option for treatment of mucormycosis in the presence of intolerance or contraindications against liposomal amphotericin B.Item Open Access Clinical characteristics and outcomes of invasive Lomentospora prolificans infections: Analysis of patients in the FungiScope® registry.(Mycoses, 2020-05) Jenks, Jeffrey D; Seidel, Danila; Cornely, Oliver A; Chen, Sharon; van Hal, Sebastiaan; Kauffman, Carol; Miceli, Marisa H; Heinemann, Melina; Christner, Martin; Jover Sáenz, Alfredo; Burchardt, Alexander; Kemmerling, Björn; Herbrecht, Raoul; Steinmann, Joerg; Shoham, Shmuel; Gräber, Sandra; Pagano, Livio; Deeren, Dries; Slavin, Monica A; Hoenigl, MartinOBJECTIVES:Invasive fungal infections caused by Lomentospora prolificans are associated with very high mortality rates and can be challenging to treat given pan-drug resistance to available antifungal agents. The objective of this study was to describe the clinical presentation and outcomes in a cohort of patients with invasive L prolificans infections. METHODS:We performed a retrospective review of medical records of patients with invasive L prolificans infection in the FungiScope® registry of rare invasive fungal infections. Patients diagnosed between 01 January 2008 and 09 September 2019 were included in for analysis. RESULTS:The analysis included 41 patients with invasive L prolificans infection from eight different countries. Haematological/oncological malignancies were the most frequent underlying disease (66%), disseminated infection was frequent (61%), and the lung was the most commonly involved organ (44%). Most infections (59%) were breakthrough infections. Progression/deterioration/treatment failure was observed in 23/40 (58%) of patients receiving antifungal therapy. In total, 21/41 (51%) patients, and 77% of patients with underlying haematological/oncological malignancy, had a fatal outcome attributed to invasive fungal infection. Combination antifungal therapy was frequent (24/40) and associated with improved survival. In particular, treatment regimens including terbinafine were significantly associated with higher treatment success at final assessment (P = .012), with a positive trend observed for treatment regimens that included voriconazole (P = .054). CONCLUSIONS:Lomentospora prolificans infections were associated with mortality rates of 77% and above in patients with underlying haematological/oncological malignancies and those with disseminated infections. While combination therapy is the preferred option for now, the hope lies with novel antifungals currently under development.Item Open Access Let's talk about sex characteristics-As a risk factor for invasive fungal diseases.(Mycoses, 2022-06) Egger, Matthias; Hoenigl, Martin; Thompson, George R; Carvalho, Agostinho; Jenks, Jeffrey DBiological sex, which comprises differences in host sex hormone homeostasis and immune responses, can have a substantial impact on the epidemiology of infectious diseases. Comprehensive data on sex distributions in invasive fungal diseases (IFDs) are lacking. In this review, we performed a literature search of in vitro/animal studies, clinical studies, systematic reviews and meta-analyses of invasive fungal infections. Females represented 51.2% of invasive candidiasis cases, mostly matching the proportions of females among the general population in the United States and Europe (>51%). In contrast, other IFDs were overrepresented in males, including invasive aspergillosis (51% males), mucormycosis (60%), cryptococcosis (74%), coccidioidomycosis (70%), histoplasmosis (61%) and blastomycosis (66%). Behavioural variations, as well as differences related to biological sex, may only in part explain these findings. Further investigations concerning the association between biological sex/gender and the pathogenesis of IFDs are warranted.Item Open Access Looking for fungi in all the right places: screening for cryptococcal disease and other AIDS-related mycoses among patients with advanced HIV disease.(Curr Opin HIV AIDS, 2017-03) Greene, Greg; Sriruttan, Charlotte; Le, Thuy; Chiller, Tom; Govender, Nelesh PPURPOSE OF REVIEW: As HIV treatment programmes scale up to meet the UNAIDS 90-90-90 goals, care must be taken to start antiretroviral treatment safely in patients with advanced disease (CD4 counts <200 cells/μl) who are simultaneously at risk for opportunistic infections and immune reconstitution inflammatory syndrome. Invasive fungal diseases pose a great threat at this critical time point, though the development of inexpensive and highly accurate rapid diagnostic tests has changed the approach HIV programmes are taking to reduce the high mortality associated with these opportunistic infections. This article summarizes recent advances and findings in fungal opportunistic infection diagnostics with a focus on screening to prevent cryptococcal meningitis. RECENT FINDINGS: Cryptococcal antigen (CrAg) screening using a lateral flow assay platform is cost-effective and feasible to implement as either a laboratory reflex or point-of-care test. Recent CrAg screening pilots have elucidated the varying prevalence of cryptococcal antigenemia across geographic regions, which may aid programme planning. Evidence from recently completed clinical trials provides a strong motivation for the use of CrAg titer to refine treatment options for patients with subclinical cryptococcal disease. SUMMARY: Although several operational barriers to programme effectiveness still need to be addressed, the utility of CrAg screening using inexpensive and accurate antigen assays has been demonstrated in real-world HIV programmes, paving the way for development and testing of other fungal opportunistic infection screening strategies and for an integrated advanced HIV disease testing package to reduce AIDS mortality and ensure safe antiretroviral treatment initiation.Item Open Access Needles in a haystack: Extremely rare invasive fungal infections reported in FungiScopeⓇ-Global Registry for Emerging Fungal Infections.(The Journal of infection, 2020-11) Salmanton-García, Jon; Koehler, Philipp; Kindo, Anupma; Falces-Romero, Iker; García-Rodríguez, Julio; Ráčil, Zdeněk; Chen, Sharon C-A; Klimko, Nikolai; Desoubeaux, Guillaume; Thompson, George R; Benítez-Peñuela, Miguel-Ángel; Rodríguez, José-Yesid; Sheppard, Donald C; Hoenigl, Martin; Le Govic, Yohann; Badali, Hamid; Baddley, John W; Chander, Jagdish; Ingram, Paul R; Pakstis, Diana L; Mellinghoff, Sibylle C; Atıcı, Serkan; Cesaro, Simone; Chakrabarti, Arunaloke; Dupont, Damien; González, Gloria M; Hatvani, Lóránt; Herbrecht, Raoul; Klyasova, Galina; Lass-Flörl, Cornelia; Mareș, Mihai; Mullane, Kathleen; Vinh, Donald C; Wisplinghoff, Hilmar; Lackner, Michaela; Cornely, Oliver A; Seidel, Danila; ECMM/ISHAM working groupObjectives
Emerging invasive fungal infections (IFI) have become a notable challenge. Apart from the more frequently described fusariosis, lomentosporiosis, mucormycosis, scedosporiosis, and certain dematiaceae or yeasts, little is known about extremely rare IFI.Methods
Extremely rare IFI collected in the FungiScopeⓇ registry were grouped as Dematiaceae, Hypocreales, Saccharomycetales, Eurotiales, Dermatomycetes, Agaricales, and Mucorales.Results
Between 2003 and June 2019, 186 extremely rare IFI were documented in FungiScopeⓇ. Dematiaceae (35.5%), Hypocreales (23.1%), Mucorales (11.8%), and Saccharomycetales (11.3%) caused most IFI. Most patients had an underlying malignancy (38.7%) with acute leukemia accounting for 50% of cancers. Dissemination was observed in 26.9% of the patients. Complete or partial clinical response rate was 68.3%, being highest in Eurotiales (82.4%) and in Agaricales (80.0%). Overall mortality rate was 29.3%, ranging from 11.8% in Eurotiales to 50.0% in Mucorales.Conclusions
Physicians are confronted with a complex variety of fungal pathogens, for which treatment recommendations are lacking and successful outcome might be incidental. Through an international consortium of physicians and scientists, these cases of extremely rare IFI can be collected to further investigate their epidemiology and eventually identify effective treatment regimens.Item Open Access Point-of-care diagnostics for invasive aspergillosis: nearing the finish line.(Expert review of molecular diagnostics, 2020-10) Jenks, Jeffrey D; Hoenigl, MartinIntroduction
The spectrum of disease caused by Aspergillus spp. is dependent on the immune system of the host, with invasive aspergillosis (IA) its most severe manifestation. Early and reliable diagnosis of Aspergillus disease is important to decrease associated morbidity and mortality from IA.Areas covered
The following review searched Pub Med for literature published since 2007 and will give an update on the current point-of-care diagnostic strategies for the diagnosis of IA, discuss needed areas of improvement for these tests, and future directions.Expert opinion
Several new diagnostic tests for IA - including point-of-care tests - are now available to complement conventional galactomannan (GM) testing. In particular, the Aspergillus-specific Lateral Flow Device (LFD) test and the sōna Aspergillus GM Lateral Flow Assay (LFA) are promising for the diagnosis of IA in patients with hematologic malignancy, although further evaluation in the non-hematology setting is needed. In addition, a true point-of-care test, particularly for easily obtained specimens like serum or urine that can be done at the bedside or in the Clinic in a matter of minutes is needed, such as the lateral flow dipstick test, which is under current evaluation. Lastly, improved diagnostic algorithms to diagnose IA in non-neutropenic patients is needed.Item Open Access Rare mould infections caused by Mucorales, Lomentospora prolificans and Fusarium, in San Diego, CA: the role of antifungal combination therapy.(International journal of antimicrobial agents, 2018-11) Jenks, Jeffrey D; Reed, Sharon L; Seidel, Danila; Koehler, Philipp; Cornely, Oliver A; Mehta, Sanjay R; Hoenigl, MartinNon-Aspergillus invasive mould infections (IMIs) are associated with devastating morbidity and mortality rates and are increasingly diagnosed in immunocompromised hosts. The aim of this study was to describe the epidemiology and outcomes of non-Aspergillus IMIs at a university hospital in San Diego, California, USA. A retrospective chart review of the medical records of all patients with cultures growing non-Aspergillus moulds at the microbiology laboratory in the Center for Academic Laboratory Medicine, Department of Pathology, University of California, San Diego (UCSD) Health between mid-2014 and mid-2017 (3-year period) was performed. A total of 23 cases of non-Aspergillus IMI were identified, including 10 cases of mucormycosis, 8 cases of lomentosporiosis and 5 cases of fusariosis. Antifungal susceptibility testing was performed for 14 isolates, and 10/11 Fusarium and Lomentospora isolates had minimum inhibitory concentrations (MICs) of >16 µg/mL for voriconazole and/or posaconazole. Overall 180-day mortality was significantly lower among those who received combination antifungal therapy than among those who received single-agent therapy [3/13 (23%) vs. 9/10 (90%); P = 0.003]. In conclusion, Lomentospora prolificans (35% of non-Aspergillus IMIs) and Fusarium spp. (22%) accounted for high proportions of non-Aspergillus IMIs during the study period. Non-Aspergillus IMIs were detected in patients with various underlying diseases and were associated with high mortality rates, which was significantly lower in those who received antifungal combination therapy.Item Open Access Revision and Update of the Consensus Definitions of Invasive Fungal Disease From the European Organization for Research and Treatment of Cancer and the Mycoses Study Group Education and Research Consortium.(Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2020-09) Donnelly, J Peter; Chen, Sharon C; Kauffman, Carol A; Steinbach, William J; Baddley, John W; Verweij, Paul E; Clancy, Cornelius J; Wingard, John R; Lockhart, Shawn R; Groll, Andreas H; Sorrell, Tania C; Bassetti, Matteo; Akan, Hamdi; Alexander, Barbara D; Andes, David; Azoulay, Elie; Bialek, Ralf; Bradsher, Robert W; Bretagne, Stephane; Calandra, Thierry; Caliendo, Angela M; Castagnola, Elio; Cruciani, Mario; Cuenca-Estrella, Manuel; Decker, Catherine F; Desai, Sujal R; Fisher, Brian; Harrison, Thomas; Heussel, Claus Peter; Jensen, Henrik E; Kibbler, Christopher C; Kontoyiannis, Dimitrios P; Kullberg, Bart-Jan; Lagrou, Katrien; Lamoth, Frédéric; Lehrnbecher, Thomas; Loeffler, Jurgen; Lortholary, Olivier; Maertens, Johan; Marchetti, Oscar; Marr, Kieren A; Masur, Henry; Meis, Jacques F; Morrisey, C Orla; Nucci, Marcio; Ostrosky-Zeichner, Luis; Pagano, Livio; Patterson, Thomas F; Perfect, John R; Racil, Zdenek; Roilides, Emmanuel; Ruhnke, Marcus; Prokop, Cornelia Schaefer; Shoham, Shmuel; Slavin, Monica A; Stevens, David A; Thompson, George R; Vazquez, Jose A; Viscoli, Claudio; Walsh, Thomas J; Warris, Adilia; Wheat, L Joseph; White, P Lewis; Zaoutis, Theoklis E; Pappas, Peter GBackground
Invasive fungal diseases (IFDs) remain important causes of morbidity and mortality. The consensus definitions of the Infectious Diseases Group of the European Organization for Research and Treatment of Cancer and the Mycoses Study Group have been of immense value to researchers who conduct clinical trials of antifungals, assess diagnostic tests, and undertake epidemiologic studies. However, their utility has not extended beyond patients with cancer or recipients of stem cell or solid organ transplants. With newer diagnostic techniques available, it was clear that an update of these definitions was essential.Methods
To achieve this, 10 working groups looked closely at imaging, laboratory diagnosis, and special populations at risk of IFD. A final version of the manuscript was agreed upon after the groups' findings were presented at a scientific symposium and after a 3-month period for public comment. There were several rounds of discussion before a final version of the manuscript was approved.Results
There is no change in the classifications of "proven," "probable," and "possible" IFD, although the definition of "probable" has been expanded and the scope of the category "possible" has been diminished. The category of proven IFD can apply to any patient, regardless of whether the patient is immunocompromised. The probable and possible categories are proposed for immunocompromised patients only, except for endemic mycoses.Conclusions
These updated definitions of IFDs should prove applicable in clinical, diagnostic, and epidemiologic research of a broader range of patients at high-risk.Item Open Access The Antifungal Pipeline: Fosmanogepix, Ibrexafungerp, Olorofim, Opelconazole, and Rezafungin.(Drugs, 2021-10) Hoenigl, Martin; Sprute, Rosanne; Egger, Matthias; Arastehfar, Amir; Cornely, Oliver A; Krause, Robert; Lass-Flörl, Cornelia; Prattes, Juergen; Spec, Andrej; Thompson, George R; Wiederhold, Nathan; Jenks, Jeffrey DThe epidemiology of invasive fungal infections is changing, with new populations at risk and the emergence of resistance caused by the selective pressure from increased usage of antifungal agents in prophylaxis, empiric therapy, and agriculture. Limited antifungal therapeutic options are further challenged by drug-drug interactions, toxicity, and constraints in administration routes. Despite the need for more antifungal drug options, no new classes of antifungal drugs have become available over the last 2 decades, and only one single new agent from a known antifungal class has been approved in the last decade. Nevertheless, there is hope on the horizon, with a number of new antifungal classes in late-stage clinical development. In this review, we describe the mechanisms of drug resistance employed by fungi and extensively discuss the most promising drugs in development, including fosmanogepix (a novel Gwt1 enzyme inhibitor), ibrexafungerp (a first-in-class triterpenoid), olorofim (a novel dihyroorotate dehydrogenase enzyme inhibitor), opelconazole (a novel triazole optimized for inhalation), and rezafungin (an echinocandin designed to be dosed once weekly). We focus on the mechanism of action and pharmacokinetics, as well as the spectrum of activity and stages of clinical development. We also highlight the potential future role of these drugs and unmet needs.Item Open Access Voriconazole plus terbinafine combination antifungal therapy for invasive Lomentospora prolificans infections: analysis of 41 patients from the FungiScope® registry 2008-2019.(Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases, 2020-06) Jenks, JD; Seidel, D; Cornely, OA; Chen, S; van Hal, S; Kauffman, C; Miceli, MH; Heinemann, M; Christner, M; Jover Sáenz, A; Burchardt, A; Kemmerling, B; Herbrecht, R; Steinmann, J; Shoham, S; Gräber, S; Pagano, L; Deeren, D; Aslam, S; Taplitz, R; Revankar, SG; Baddley, J; Mehta, SR; Reed, S; Slavin, MA; Hoenigl, MObjectives
Lomentospora prolificans is an emerging cause of serious invasive fungal infections. Optimal treatment of these infections is unknown, although voriconazole-containing treatment regimens are considered the treatment of choice. The objective of this study was to evaluate the role of combination antifungal therapy for L. prolificans infections.Methods
We performed a retrospective review of medical records of patients with invasive L. prolificans infection diagnosed between 1 January 2008 and 9 September 2019 that were documented in the FungiScope® registry of rare invasive fungal infections. We compared clinical outcomes between antifungal treatment strategies.Results
Over the study period, 41 individuals with invasive L. prolificans infection from eight different countries were documented in the FungiScope® registry. Overall, 17/40 (43%) had treatment response/stable disease and 21/40 (53%) had a fatal outcome attributed to invasive fungal infection. Combination antifungal therapy was associated with increased 28-day survival (15/24 survived versus 4/16 receiving monotherapy; p 0.027) and the combination voriconazole plus terbinafine trended to be associated with higher rates of treatment success (10/16, 63%, 95% CI 35%-85%) compared with other antifungal treatment regimens (7/24, 29%, 95% CI 13%-51%, p 0.053). In Kaplan-Meier survival analysis there was a higher survival probability in individuals receiving the voriconazole/terbinafine combination compared with other antifungal regimens (median survival 150 days versus 17 days).Conclusions
While overall mortality was high, combination antifungal treatment, and in particular combination therapy with voriconazole plus terbinafine may be associated with improved treatment outcomes compared with other antifungal regimens for the treatment of invasive L. prolificans infections.