Browsing by Author "Lass-Flörl, Cornelia"
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Item Open Access COVID-19 Associated Pulmonary Aspergillosis (CAPA)-From Immunology to Treatment.(Journal of fungi (Basel, Switzerland), 2020-06) Arastehfar, Amir; Carvalho, Agostinho; van de Veerdonk, Frank L; Jenks, Jeffrey D; Koehler, Philipp; Krause, Robert; Cornely, Oliver A; S Perlin, David; Lass-Flörl, Cornelia; Hoenigl, MartinLike severe influenza, coronavirus disease-19 (COVID-19) resulting in acute respiratory distress syndrome (ARDS) has emerged as an important disease that predisposes patients to secondary pulmonary aspergillosis, with 35 cases of COVID-19 associated pulmonary aspergillosis (CAPA) published until June 2020. The release of danger-associated molecular patterns during severe COVID-19 results in both pulmonary epithelial damage and inflammatory disease, which are predisposing risk factors for pulmonary aspergillosis. Moreover, collateral effects of host recognition pathways required for the activation of antiviral immunity may, paradoxically, contribute to a highly permissive inflammatory environment that favors fungal pathogenesis. Diagnosis of CAPA remains challenging, mainly because bronchoalveolar lavage fluid galactomannan testing and culture, which represent the most sensitive diagnostic tests for aspergillosis in the ICU, are hindered by the fact that bronchoscopies are rarely performed in COVID-19 patients due to the risk of disease transmission. Similarly, autopsies are rarely performed, which may result in an underestimation of the prevalence of CAPA. Finally, the treatment of CAPA is complicated by drug-drug interactions associated with broad spectrum azoles, renal tropism and damage caused by SARS-CoV-2, which may challenge the use of liposomal amphotericin B, as well as the emergence of azole-resistance. This clinical reality creates an urgency for new antifungal drugs currently in advanced clinical development with more promising pharmacokinetic and pharmacodynamic profiles.Item Open Access Defining and managing COVID-19-associated pulmonary aspergillosis: the 2020 ECMM/ISHAM consensus criteria for research and clinical guidance.(The Lancet. Infectious diseases, 2021-06) Koehler, Philipp; Bassetti, Matteo; Chakrabarti, Arunaloke; Chen, Sharon CA; Colombo, Arnaldo Lopes; Hoenigl, Martin; Klimko, Nikolay; Lass-Flörl, Cornelia; Oladele, Rita O; Vinh, Donald C; Zhu, Li-Ping; Böll, Boris; Brüggemann, Roger; Gangneux, Jean-Pierre; Perfect, John R; Patterson, Thomas F; Persigehl, Thorsten; Meis, Jacques F; Ostrosky-Zeichner, Luis; White, P Lewis; Verweij, Paul E; Cornely, Oliver A; European Confederation of Medical Mycology; International Society for Human Animal Mycology; Asia Fungal Working Group; INFOCUS LATAM/ISHAM Working Group; ISHAM Pan Africa Mycology Working Group; European Society for Clinical Microbiology; Infectious Diseases Fungal Infection Study Group; ESCMID Study Group for Infections in Critically Ill Patients; Interregional Association of Clinical Microbiology and Antimicrobial Chemotherapy; Medical Mycology Society of Nigeria; Medical Mycology Society of China Medicine Education Association; Infectious Diseases Working Party of the German Society for Haematology and Medical Oncology; Association of Medical Microbiology; Infectious Disease CanadaSevere acute respiratory syndrome coronavirus 2 causes direct damage to the airway epithelium, enabling aspergillus invasion. Reports of COVID-19-associated pulmonary aspergillosis have raised concerns about it worsening the disease course of COVID-19 and increasing mortality. Additionally, the first cases of COVID-19-associated pulmonary aspergillosis caused by azole-resistant aspergillus have been reported. This article constitutes a consensus statement on defining and managing COVID-19-associated pulmonary aspergillosis, prepared by experts and endorsed by medical mycology societies. COVID-19-associated pulmonary aspergillosis is proposed to be defined as possible, probable, or proven on the basis of sample validity and thus diagnostic certainty. Recommended first-line therapy is either voriconazole or isavuconazole. If azole resistance is a concern, then liposomal amphotericin B is the drug of choice. Our aim is to provide definitions for clinical research and up-to-date recommendations for clinical management of the diagnosis and treatment of COVID-19-associated pulmonary aspergillosis.Item Open Access Diagnosis of Breakthrough Fungal Infections in the Clinical Mycology Laboratory: An ECMM Consensus Statement.(Journal of fungi (Basel, Switzerland), 2020-10) Jenks, Jeffrey D; Gangneux, Jean-Pierre; Schwartz, Ilan S; Alastruey-Izquierdo, Ana; Lagrou, Katrien; Thompson Iii, George R; Lass-Flörl, Cornelia; Hoenigl, Martin; European Confederation of Medical Mycology (ECMM) Council InvestigatorsBreakthrough invasive fungal infections (bIFI) cause significant morbidity and mortality. Their diagnosis can be challenging due to reduced sensitivity to conventional culture techniques, serologic tests, and PCR-based assays in patients undergoing antifungal therapy, and their diagnosis can be delayed contributing to poor patient outcomes. In this review, we provide consensus recommendations on behalf of the European Confederation for Medical Mycology (ECMM) for the diagnosis of bIFI caused by invasive yeasts, molds, and endemic mycoses, to guide diagnostic efforts in patients receiving antifungals and support the design of future clinical trials in the field of clinical mycology. The cornerstone of lab-based diagnosis of breakthrough infections for yeast and endemic mycoses remain conventional culture, to accurately identify the causative pathogen and allow for antifungal susceptibility testing. The impact of non-culture-based methods are not well-studied for the definite diagnosis of breakthrough invasive yeast infections. Non-culture-based methods have an important role for the diagnosis of breakthrough invasive mold infections, in particular invasive aspergillosis, and a combination of testing involving conventional culture, antigen-based assays, and PCR-based assays should be considered. Multiple diagnostic modalities, including histopathology, culture, antibody, and/or antigen tests and occasionally PCR-based assays may be required to diagnose breakthrough endemic mycoses. A need exists for diagnostic tests that are effective, simple, cheap, and rapid to enable the diagnosis of bIFI in patients taking antifungals.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 Drug-Resistant Fungi: An Emerging Challenge Threatening Our Limited Antifungal Armamentarium.(Antibiotics (Basel, Switzerland), 2020-12) Arastehfar, Amir; Gabaldón, Toni; Garcia-Rubio, Rocio; Jenks, Jeffrey D; Hoenigl, Martin; Salzer, Helmut JF; Ilkit, Macit; Lass-Flörl, Cornelia; Perlin, David SThe high clinical mortality and economic burden posed by invasive fungal infections (IFIs), along with significant agricultural crop loss caused by various fungal species, has resulted in the widespread use of antifungal agents. Selective drug pressure, fungal attributes, and host- and drug-related factors have counteracted the efficacy of the limited systemic antifungal drugs and changed the epidemiological landscape of IFIs. Species belonging to Candida, Aspergillus, Cryptococcus, and Pneumocystis are among the fungal pathogens showing notable rates of antifungal resistance. Drug-resistant fungi from the environment are increasingly identified in clinical settings. Furthermore, we have a limited understanding of drug class-specific resistance mechanisms in emerging Candida species. The establishment of antifungal stewardship programs in both clinical and agricultural fields and the inclusion of species identification, antifungal susceptibility testing, and therapeutic drug monitoring practices in the clinic can minimize the emergence of drug-resistant fungi. New antifungal drugs featuring promising therapeutic profiles have great promise to treat drug-resistant fungi in the clinical setting. Mitigating antifungal tolerance, a prelude to the emergence of resistance, also requires the development of effective and fungal-specific adjuvants to be used in combination with systemic antifungals.Item Open Access Immune Parameters for Diagnosis and Treatment Monitoring in Invasive Mold Infection.(Journal of fungi (Basel, Switzerland), 2019-12) Jenks, Jeffrey D; Rawlings, Stephen A; Garcia-Vidal, Carol; Koehler, Philipp; Mercier, Toine; Prattes, Juergen; Lass-Flörl, Cornelia; Martin-Gomez, M Teresa; Buchheidt, Dieter; Pagano, Livio; Gangneux, Jean-Pierre; van de Veerdonk, Frank L; Netea, Mihai G; Carvalho, Agostinho; Hoenigl, MartinInfections caused by invasive molds, including Aspergillus spp., can be difficult to diagnose and remain associated with high morbidity and mortality. Thus, early diagnosis and targeted systemic antifungal treatment remains the most important predictive factor for a successful outcome in immunocompromised individuals with invasive mold infections. Diagnosis remains difficult due to low sensitivities of diagnostic tests including culture and other mycological tests for mold pathogens, particularly in patients on mold-active antifungal prophylaxis. As a result, antifungal treatment is rarely targeted and reliable markers for treatment monitoring and outcome prediction are missing. Thus, there is a need for improved markers to diagnose invasive mold infections, monitor response to treatment, and assist in determining when antifungal therapy should be escalated, switched, or can be stopped. This review focuses on the role of immunologic markers and specifically cytokines in diagnosis and treatment monitoring of invasive mold infections.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 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.