Browsing by Author "Thompson, George R"
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Item Open Access A Mycoses Study Group International Prospective Study of Phaeohyphomycosis: An Analysis of 99 Proven/Probable Cases.(Open forum infectious diseases, 2017-01) Revankar, Sanjay G; Baddley, John W; Chen, Sharon C-A; Kauffman, Carol A; Slavin, Monica; Vazquez, Jose A; Seas, Carlos; Morris, Michele I; Nguyen, M Hong; Shoham, Shmuel; Thompson, George R; Alexander, Barbara D; Simkins, Jacques; Ostrosky-Zeichner, Luis; Mullane, Kathleen; Alangaden, George; Andes, David R; Cornely, Oliver A; Wahlers, Kerstin; Lockhart, Shawn R; Pappas, Peter GBackground
Phaeohyphomycosis is infection caused by dematiaceous, or darkly pigmented, fungi. The spectrum of disease is broad, and optimal therapy remains poorly defined. The Mycoses Study Group established an international case registry of patients with proven/probable phaeohyphomycosis with the goal of improving the recognition and management of these infections.Methods
Patients from 18 sites in 3 countries were enrolled from 2009-2015. Cases were categorized as local superficial, local deep (pulmonary, sinus, osteoarticular infections), and disseminated infections. End points were clinical response (partial and complete) and all-cause mortality at 30 days and end of follow-up.Results
Of 99 patients, 32 had local superficial infection, 41 had local deep infection, and 26 had disseminated infection. The most common risk factors were corticosteroids, solid organ transplantation, malignancy, and diabetes. Cultures were positive in 98% of cases. All-cause mortality was 16% at 30 days and 33% at end of follow-up, and 18 of 26 (69%) with dissemination died. Itraconazole was most commonly used for local infections, and voriconazole was used for more severe infections, often in combination with terbinafine or amphotericin B.Conclusions
Phaeohyphomycosis is an increasingly recognized infection. Culture remains the most frequently used diagnostic method. Triazoles are currently the drugs of choice, often combined with other agents. Further studies are needed to develop optimal therapies for disseminated infections.Item Open Access A randomized, double-blind, placebo-controlled clinical trial of fluconazole as early empiric treatment of coccidioidomycosis pneumonia (Valley Fever) in adults presenting with community-acquired pneumonia in endemic areas (FLEET-Valley Fever).(Contemp Clin Trials Commun, 2021-12) Messina, Julia A; Maziarz, Eileen K; Galgiani, John; Truong, Jonathan T; Htoo, Aung K; Heidari, Arash; Johnson, Royce H; Narang, Aneesh T; Donovan, Fariba M; Ewell, Marion; Catanzaro, Antonino; Thompson, George R; Ampel, Neil M; Perfect, John R; Naggie, Susanna; Walter, Emmanuel BIntroduction: Coccidioidomycosis is a fungal infection endemic in the southwestern United States (US). Primary pulmonary coccidioidomycosis (PPC) is a leading cause of community-acquired pneumonia (CAP) in this region, although its diagnosis is often delayed, leading to lag in antifungal treatment and subsequent morbidity. The impact of early empiric antifungal therapy as part of treatment for CAP in endemic areas on clinical outcomes is unknown. Methods: Phase IV randomized, double-blind, placebo-controlled trial in individuals aged 18 years or older with CAP who met all eligibility criteria in Coccidioides endemic regions in the US. Eligible participants with CAP were randomized to receive either fluconazole (400 mg daily) or matching placebo for 42 days and were subsequently monitored for clinical resolution of their illness. Objectives: The primary objective was to assess the clinical response of early empiric antifungal therapy with fluconazole through Day 22 in subjects with PPC who were adherent to the study intervention. Secondary objectives included: assessments of the impact of early empiric antifungal therapy with fluconazole through Day 22 and 43 in subjects with PPC regardless of adherence, comparisons of the clinical response and its individual components over time by treatment group in subjects with PPC, assessments of days lost from work or school, hospitalization, and all-cause mortality. Discussion: This trial was halted early due to slow enrollment (72 participants in one year, 33 received fluconazole and 39 received placebo). Of those enrolled, eight (11%) met the study definition of PPC. The study design and challenges are discussed.Item Open Access An update on current and novel molecular diagnostics for the diagnosis of invasive fungal infections(Expert Review of Molecular Diagnostics) Jenks, Jeffrey D; White, P Lewis; Kidd, Sarah E; Goshia, Tyler; Fraley, Stephanie I; Hoenigl, Martin; Thompson, George RItem 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 Coronavirus Disease 2019-Associated Invasive Fungal Infection.(Open forum infectious diseases, 2021-12) Baddley, John W; Thompson, George R; Chen, Sharon C-A; White, P Lewis; Johnson, Melissa D; Nguyen, M Hong; Schwartz, Ilan S; Spec, Andrej; Ostrosky-Zeichner, Luis; Jackson, Brendan R; Patterson, Thomas F; Pappas, Peter GCoronavirus disease 2019 (COVID-19) can become complicated by secondary invasive fungal infections (IFIs), stemming primarily from severe lung damage and immunologic deficits associated with the virus or immunomodulatory therapy. Other risk factors include poorly controlled diabetes, structural lung disease and/or other comorbidities, and fungal colonization. Opportunistic IFI following severe respiratory viral illness has been increasingly recognized, most notably with severe influenza. There have been many reports of fungal infections associated with COVID-19, initially predominated by pulmonary aspergillosis, but with recent emergence of mucormycosis, candidiasis, and endemic mycoses. These infections can be challenging to diagnose and are associated with poor outcomes. The reported incidence of IFI has varied, often related to heterogeneity in patient populations, surveillance protocols, and definitions used for classification of fungal infections. Herein, we review IFI complicating COVID-19 and address knowledge gaps related to epidemiology, diagnosis, and management of COVID-19-associated fungal infections.Item Open Access Do high MICs predict the outcome in invasive fusariosis?(The Journal of antimicrobial chemotherapy, 2021-03) Nucci, Marcio; Jenks, Jeffrey; Thompson, George R; Hoenigl, Martin; Dos Santos, Marielle Camargo; Forghieri, Fabio; Rico, Juan Carlos; Bonuomo, Valentina; López-Soria, Leyre; Lass-Flörl, Cornelia; Candoni, Anna; Garcia-Vidal, Carolina; Cattaneo, Chiara; Buil, Jochem; Rabagliati, Ricardo; Roiz, Maria Pia; Gudiol, Carlota; Fracchiolla, Nicola; Campos-Herrero, Maria Isolina; Delia, Mario; Farina, Francesca; Fortun, Jesus; Nadali, Gianpaolo; Sastre, Enric; Colombo, Arnaldo L; Pérez Nadales, Elena; Alastruey-Izquierdo, Ana; Pagano, LivioBackground
Invasive fusariosis (IF) affects mostly severely immunocompromised hosts and is associated with poor outcome. Since Fusarium species exhibit high MICs for most antifungal agents, this could explain the poor prognosis. However, a clear-cut correlation between MIC and outcome has not been established.Objective
To evaluate the correlation between MIC and outcome (6 week death rate) in patients with IF.Methods
We performed a multicentre retrospective study of patients with IF who received treatment and had MIC levels determined by EUCAST or CLSI for the drug(s) used during treatment. We compared the MIC50 and MIC distribution among survivors and patients who died within 6 weeks from the diagnosis of IF.Results
Among 88 patients with IF, 74 had haematological diseases. Primary treatment was monotherapy in 52 patients (voriconazole in 27) and combination therapy in 36 patients (liposomal amphotericin B + voriconazole in 23). The MIC50 and range for the five most frequent agents tested were: voriconazole 8 mg/L (range 0.5-64), amphotericin B 2 mg/L (range 0.25-64), posaconazole 16 mg/L (range 0.5-64), itraconazole 32 mg/L (range 4-64), and isavuconazole 32 mg/L (range 8-64). There was no difference in MIC50 and MIC distribution among survivors and patients who died. By contrast, persistent neutropenia and receipt of corticosteroids were strong predictors of 6 week mortality.Conclusions
Our study did not show any correlation between MIC and mortality at 6 weeks in patients with IF.Item Open Access Fungal Endocarditis: Pathophysiology, Epidemiology, Clinical Presentation, Diagnosis, and Management.(Clinical microbiology reviews, 2023-07) Thompson, George R; Jenks, Jeffrey D; Baddley, John W; Lewis, James S; Egger, Matthias; Schwartz, Ilan S; Boyer, Johannes; Patterson, Thomas F; Chen, Sharon C-A; Pappas, Peter G; Hoenigl, MartinFungal 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.Item Open Access Global guideline for the diagnosis and management of the endemic mycoses: an initiative of the European Confederation of Medical Mycology in cooperation with the International Society for Human and Animal Mycology.(The Lancet. Infectious diseases, 2021-12) Thompson, George R; Le, Thuy; Chindamporn, Ariya; Kauffman, Carol A; Alastruey-Izquierdo, Ana; Ampel, Neil M; Andes, David R; Armstrong-James, Darius; Ayanlowo, Olusola; Baddley, John W; Barker, Bridget M; Lopes Bezerra, Leila; Buitrago, Maria J; Chamani-Tabriz, Leili; Chan, Jasper FW; Chayakulkeeree, Methee; Cornely, Oliver A; Cunwei, Cao; Gangneux, Jean-Pierre; Govender, Nelesh P; Hagen, Ferry; Hedayati, Mohammad T; Hohl, Tobias M; Jouvion, Grégory; Kenyon, Chris; Kibbler, Christopher C; Klimko, Nikolai; Kong, David CM; Krause, Robert; Lee Lee, Low; Meintjes, Graeme; Miceli, Marisa H; Rath, Peter-Michael; Spec, Andrej; Queiroz-Telles, Flavio; Variava, Ebrahim; Verweij, Paul E; Schwartz, Ilan S; Pasqualotto, Alessandro CThe global burden of the endemic mycoses (blastomycosis, coccidioidomycosis, emergomycosis, histoplasmosis, paracoccidioidomycosis, sporotrichosis, and talaromycosis) continues to rise yearly and these infectious diseases remain a leading cause of patient morbidity and mortality worldwide. Management of the associated pathogens requires a thorough understanding of the epidemiology, risk factors, diagnostic methods and performance characteristics in different patient populations, and treatment options unique to each infection. Guidance on the management of these infections has the potential to improve prognosis. The recommendations outlined in this Review are part of the "One World, One Guideline" initiative of the European Confederation of Medical Mycology. Experts from 23 countries contributed to the development of these guidelines. The aim of this Review is to provide an up-to-date consensus and practical guidance in clinical decision making, by engaging physicians and scientists involved in various aspects of clinical management.Item Open Access Impact of climate change and natural disasters on fungal infections(The Lancet Microbe, 2024-03) Seidel, Danila; Wurster, Sebastian; Jenks, Jeffrey D; Sati, Hatim; Gangneux, Jean-Pierre; Egger, Matthias; Alastruey-Izquierdo, Ana; Ford, Nathan P; Chowdhary, Anuradha; Sprute, Rosanne; Cornely, Oliver; Thompson, George R; Hoenigl, Martin; Kontoyiannis, Dimitrios PItem 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 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 Novel antifungals and treatment approaches to tackle resistance and improve outcomes of invasive fungal disease(Clinical Microbiology Reviews) Hoenigl, Martin; Arastehfar, Amir; Arendrup, Maiken Cavling; Brüggemann, Roger; Carvalho, Agostinho; Chiller, Tom; Chen, Sharon; Egger, Matthias; Feys, Simon; Gangneux, Jean-Pierre; Gold, Jeremy AW; Groll, Andreas H; Heylen, Jannes; Jenks, Jeffrey D; Krause, Robert; Lagrou, Katrien; Lamoth, Frédéric; Prattes, Juergen; Sedik, Sarah; Wauters, Joost; Wiederhold, Nathan P; Thompson, George RSUMMARY Fungal infections are on the rise, driven by a growing population at risk and climate change. Currently available antifungals include only five classes, and their utility and efficacy in antifungal treatment are limited by one or more of innate or acquired resistance in some fungi, poor penetration into “sequestered” sites, and agent-specific side effect which require frequent patient reassessment and monitoring. Agents with novel mechanisms, favorable pharmacokinetic (PK) profiles including good oral bioavailability, and fungicidal mechanism(s) are urgently needed. Here, we provide a comprehensive review of novel antifungal agents, with both improved known mechanisms of actions and new antifungal classes, currently in clinical development for treating invasive yeast, mold (filamentous fungi), Pneumocystis jirovecii infections, and dimorphic fungi (endemic mycoses). We further focus on inhaled antifungals and the role of immunotherapy in tackling fungal infections, and the specific PK/pharmacodynamic profiles, tissue distributions as well as drug-drug interactions of novel antifungals. Finally, we review antifungal resistance mechanisms, the role of use of antifungal pesticides in agriculture as drivers of drug resistance, and detail detection methods for antifungal resistance.Item Open Access Race and ethnicity: Risk factors for fungal infections?(PLoS pathogens, 2023-01) Jenks, Jeffrey D; Aneke, Chioma Inyang; Al-Obaidi, Mohanad M; Egger, Matthias; Garcia, Lorena; Gaines, Tommi; Hoenigl, Martin; Thompson, George RRacial and ethnic identities, largely understood as social rather than biologic constructs, may impact risk for acquiring infectious diseases, including fungal infections. Risk factors may include genetic and immunologic differences such as aberrations in host immune response, host polymorphisms, and epigenomic factors stemming from environmental exposures and underlying social determinants of health. In addition, certain racial and ethnic groups may be predisposed to diseases that increase risk for fungal infections, as well as disparities in healthcare access and health insurance. In this review, we analyzed racial and ethnic identities as risk factors for acquiring fungal infections, as well as race and ethnicity as they relate to risk for severe disease from fungal infections. Risk factors for invasive mold infections such as aspergillosis largely appear related to environmental differences and underlying social determinants of health, although immunologic aberrations and genetic polymorphisms may contribute in some circumstances. Although black and African American individuals appear to be at high risk for superficial and invasive Candida infections and cryptococcosis, the reasons for this are unclear and may be related to underling social determinants of health, disparities in access to healthcare, and other socioeconomic disparities. Risk factors for all the endemic fungi are likely largely related to underlying social determinants of health, socioeconomic, and health disparities, although immunologic mechanisms likely play a role as well, particularly in disseminated coccidioidomycosis.Item Open Access Real-world Use of Mold-Active Triazole Prophylaxis in the Prevention of Invasive Fungal Diseases: Results From a Subgroup Analysis of a Multicenter National Registry.(Open forum infectious diseases, 2023-09) Nguyen, M Hong; Ostrosky-Zeichner, Luis; Pappas, Peter G; Walsh, Thomas J; Bubalo, Joseph; Alexander, Barbara D; Miceli, Marisa H; Jiang, Jeanette; Song, Yi; Thompson, George RBackground
Antifungal prophylaxis can prevent invasive fungal diseases (IFDs) in high-risk, immunocompromised patients. This study assessed the real-world use of mold-active triazoles (MATs) for the prevention of IFDs.Methods
This subgroup analysis of a multicenter, observational, prospective registry in the United States from March 2017 to April 2020 included patients who received MATs for prophylaxis (isavuconazole, posaconazole, and voriconazole) at study index/enrollment. The primary objective was to describe patient characteristics and patterns of MAT use. Exploratory assessments included the frequency of breakthrough IFDs and MAT-related adverse drug reactions (ADRs).Results
A total of 1177 patients (256 isavuconazole, 397 posaconazole, 272 voriconazole, and 252 multiple/sequenced MATs at/after index/enrollment) were included in the prophylaxis subgroup analysis. Patient characteristics were similar across MAT groups, but risk factors varied. Hematological malignancy predominated (76.5%) across all groups. Breakthrough IFDs occurred in 7.1% (73/1030) of patients with an investigator's assessment (5.0% [11/221] isavuconazole; 5.3% [20/374] posaconazole; 4.0% [9/226] voriconazole; and 15.8% [33/209] multiple/sequenced MATs). Aspergillus (29.5% [18/61]) and Candida (36.1% [22/61]) species were the most common breakthrough pathogens recovered. ADRs were reported in 14.1% of patients, and discontinuation of MATs due to ADRs was reported in 11.1% of patients (2.0% [5/245] isavuconazole; 8.2% [30/368] posaconazole; and 10.1% [27/267] voriconazole).Conclusions
Breakthrough IFDs were uncommon in patients who received MATs for prophylaxis. Candida and Aspergillus species were the most commonly reported breakthrough pathogens. The discontinuation of MATs due to ADRs was infrequent. These findings support prophylactic strategies with isavuconazole, posaconazole, and voriconazole in high-risk patients.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 Social determinants of health as drivers of fungal disease(eClinicalMedicine, 2023-12-01) Jenks, Jeffrey D; Prattes, Juergen; Wurster, Sebastian; Sprute, Rosanne; Seidel, Danila; Oliverio, Matteo; Egger, Matthias; Del Rio, Carlos; Sati, Hatim; Cornely, Oliver A; Thompson, George R; Kontoyiannis, Dimitrios P; Hoenigl, MartinDisparities in social determinants of health (SDOH) play a significant role in causing health inequities globally. The physical environment, including housing and workplace environment, can increase the prevalence and spread of fungal infections. A number of professions are associated with increased fungal infection risk and are associated with low pay, which may be linked to crowded and sub-optimal living conditions, exposure to fungal organisms, lack of access to quality health care, and risk for fungal infection. Those involved and displaced from areas of armed conflict have an increased risk of invasive fungal infections. Lastly, a number of fungal plant pathogens already threaten food security, which will become more problematic with global climate change. Taken together, disparities in SDOH are associated with increased risk for contracting fungal infections. More emphasis needs to be placed on systematic approaches to better understand the impact and reducing the health inequities associated with these disparities.Item Open Access Study protocol: A randomized, double-blind, placebo-controlled trial of isavuconazole prophylaxis for the prevention of covid-19-associated pulmonary aspergillosis.(Contemporary clinical trials communications, 2024-06) Jenks, Jeffrey D; Hoenigl, Martin; Thompson, George RDuring the early stages of the coronavirus disease 2019 (COVID-19) pandemic, those with severe COVID-19 infection were at risk for a number of opportunistic infections including COVID-19-associated pulmonary aspergillosis (CAPA). We initiated a randomized clinical trial to evaluate whether isavuconazole, a triazole antifungal, could prevent CAPA and improve survival in patients admitted to the ICU with severe COVID-19 infection. We designed a phase III/IV randomized, double-blind, two-arm, placebo-controlled trial evaluating standard of care (SOC) plus isavuconazole versus SOC plus placebo and were to enroll participants admitted to the ICU with severe COVID-19 infection at three medical centers in California, United States. The projected sample size was 162 participants. Due to poor enrollment and the declining number of COVID-19 cases over time, the study was terminated after 7 participants were enrolled, all enrolled at one study site (UC San Diego Health). CAPA was suspected in two participants and they were started on open-label isavuconazole. One was withdrawn due to possible isavuconazole-related adverse side effects. Enrollment was slower-than-expected due to multiple factors, including competing COVID-19-related studies and hesitancy from potential study participants or their families to join the study. Our experience highlights some of the difficulties in planning and running a clinical trial focused on fungal superinfections involving severely ill patients during the height of the COVID-19 pandemic. Lessons learned from this study will help in the design of proposed studies examining antifungal prophylaxis against aspergillosis following other severe respiratory viral infections.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 Treatment of Fusarium Infection of the Central Nervous System: A Review of Past Cases to Guide Therapy for the Ongoing 2023 Outbreak in the United States and Mexico.(Mycopathologia, 2023-08) Hoenigl, Martin; Jenks, Jeffrey D; Egger, Matthias; Nucci, Marcio; Thompson, George RIntroduction
Fusariosis of the central nervous system (CNS) is extremely uncommon. Treatment and outcome data from previously published cases may provide some guidance in light of the ongoing fungal meningitis outbreak in 2023 involving Fusarium spp. in the United States and Mexico.Methods
We reviewed the published literature describing cases of invasive fusariosis of the (CNS) that included data on patient demographic characteristics, treatment, and outcome.Results
Twenty-six cases met inclusion criteria. The mean age was 36 years, 55% involved females, 60% had underlying hematologic malignancy, and another 16% were on immunosuppressants. The majority of infections were from Fusarium solani species complex. Overall 72% of patients died. The majority received monotherapy with amphotericin B, although some received voriconazole monotherapy or combination therapy with amphotericin B plus voriconazole with or without adjuvant surgery. Among the survivors, 3 received amphotericin B monotherapy, 2 voriconazole monotherapy, 1 combination therapy of both, and one surgery only.Conclusion
The overall mortality rate in published cases of fusariosis of the CNS was high, although-unlike during the current outbreak-the preponderance of patients were severely immunocompromised. While historically the majority were treated with amphotericin B monotherapy, some recent patients were treated with voriconazole monotherapy or combination therapy with amphotericin B plus voriconazole. Current guidelines recommend monotherapy with voriconazole or lipid formulations of amphotericin B or combination of both for the treatment of invasive fusariosis, which is in line with the findings from our literature review and should be considered during the ongoing 2023 outbreak.