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2.
Drugs ; 81(15): 1703-1729, 2021 Oct.
Article in English | MEDLINE | ID: covidwho-1491481

ABSTRACT

The 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.


Subject(s)
Antifungal Agents/pharmacology , Fungi/drug effects , Invasive Fungal Infections/drug therapy , Animals , Antifungal Agents/adverse effects , Antifungal Agents/classification , Drug Development , Drug Interactions , Drug Resistance, Fungal , Humans , Invasive Fungal Infections/microbiology
3.
Mycoses ; 64(10): 1197-1202, 2021 Oct.
Article in English | MEDLINE | ID: covidwho-1305495

ABSTRACT

BACKGROUND: Detection of galactomannan (GM) from bronchoalveolar lavage fluid (BALF) or serum is broadly used for diagnosis of invasive aspergillosis (IA), although the sensitivity of GM from serum is lower in non-neutropenic patients. We evaluated the Aspergillus galactomannan Lateral Flow assay (LFA) with digital readout from serum in a mixed cohort of patients. METHODS: We performed a retrospective two-centre study evaluating the LFA from serum of patients with clinical suspicion of IA obtained between 2015 and 2021 at the University of California San Diego and the Medical University of Graz. The sensitivity and specificity was calculated for proven/probable aspergillosis versus no aspergillosis. Correlation with same-sample GM was calculated using Spearman correlation analysis and kappa statistics. RESULTS: In total, 122 serum samples from 122 patients were analysed, including proven IA (n = 1), probable IA or coronavirus-associated pulmonary aspergillosis (CAPA) (n = 27), and no IA/CAPA/non-classifiable (n = 94). At a 0.5 ODI cut-off, the sensitivity and specificity of the LFA was 78.6% and 80.5%. Spearman correlation analysis showed a strong correlation between serum LFA ODI and serum GM ODI (ρ 0.459, p < .0001). Kappa was 0.611 when both LFA and GM were used with a 0.5 ODI cut-off, showing substantial agreement (p < .001). DISCUSSION: The LFA with digital read out from serum showed good performance for the diagnosis of probable/proven aspergillosis, with substantial agreement to GM from serum. Like the LFA from BALF, the LFA from serum may serve as a more rapid test compared to conventional GM, particularly in settings where GM is not readily available.


Subject(s)
Antigens, Fungal/blood , Immunoassay/methods , Invasive Pulmonary Aspergillosis/diagnosis , Mannans/blood , Adult , Aged , Aged, 80 and over , Aspergillus/isolation & purification , Automation, Laboratory , Bronchoalveolar Lavage Fluid/chemistry , Diagnostic Tests, Routine/methods , Female , Galactose/analogs & derivatives , Humans , Male , Middle Aged , Retrospective Studies , Sensitivity and Specificity , Young Adult
5.
Mycoses ; 64(9): 1002-1014, 2021 Sep.
Article in English | MEDLINE | ID: covidwho-1148083

ABSTRACT

Invasive aspergillosis (IA) is an increasingly recognised phenomenon in critically ill patients in the intensive care unit, including in patients with severe influenza and severe coronavirus disease 2019 (COVID-19) infection. To date, there are no consensus criteria on how to define IA in the ICU population, although several criteria are used, including the AspICU criteria and new consensus criteria to categorise COVID-19-associated pulmonary aspergillosis (CAPA). In this review, we describe the epidemiology of IA in critically ill patients, most common definitions used to define IA in this population, and most common clinical specimens obtained for establishing a mycological diagnosis of IA in the critically ill. We also review the most common diagnostic tests used to diagnose IA in this population, and lastly discuss the most common clinical presentation and imaging findings of IA in the critically ill and discuss areas of further needed investigation.


Subject(s)
Aspergillus/genetics , COVID-19/complications , Diagnostic Techniques and Procedures/standards , Intensive Care Units/standards , Invasive Pulmonary Aspergillosis/classification , Invasive Pulmonary Aspergillosis/diagnosis , Practice Guidelines as Topic , Adult , Aged , Aged, 80 and over , Aspergillus/isolation & purification , COVID-19/microbiology , Critical Illness/classification , Female , Humans , Invasive Pulmonary Aspergillosis/physiopathology , Male , Mannans/blood , Middle Aged , Polymerase Chain Reaction , SARS-CoV-2
6.
Open Forum Infect Dis ; 7(7): ofaa242, 2020 Jul.
Article in English | MEDLINE | ID: covidwho-846374

ABSTRACT

Pulmonary aspergillosis has been increasingly reported following severe respiratory viral infections. Millions have been infected by SARS-CoV-2, placing large numbers of patients at-risk for COVID-19 associated pulmonary aspergillosis (CAPA). Prompt recognition of this syndrome and is paramount to improve outcomes.

7.
J Fungi (Basel) ; 6(2)2020 Jun 24.
Article in English | MEDLINE | ID: covidwho-613241

ABSTRACT

Like 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.

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