Posaconazole versus voriconazole for primary treatment of invasive aspergillosis: a phase 3, randomised, controlled, non-inferiority trial

Maertens, Johan; Rahav, Galia; Lee, Dong Gun; Ponce-de-León, Alfredo; Sánchez, Isabel Cristina Ramírez; Климко, Н Н; Sonet, Anne; Haider, Shariq; Vélez, Juan D.; Raad, Issam; Koh, Liang-Piu; Karthaus, Meinolf; Zhang, Jianying; Ben‐Ami, Ronen; Motyl, Mary; Han, Seongah; Grandhi, Anjana; Waskin, Hetty

doi:10.1016/s0140-6736(21)00219-1

Cited by 149 publications

(162 citation statements)

References 15 publications

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“…Given the results presented in this work, as well as others, we have shown that antifungal treatment of biofilms is far less effective than treatment of conidia (Kowalski et al, 2020;Seidler et al, 2008). Mechanisms to increase efficacy of antifungal drugs in the context of A. fumigatus biofilms are of great clinical need and may even bridge the discrepancies between relatively low, but rising, rates of antifungal resistance in vitro and the relatively high rates of clinical treatment failure (Herbrecht et al, 2015;Maertens et al, 2016Maertens et al, , 2021Marr et al, 2015). Both genetic and chemical disruption of AlaA results in increased susceptibility of biofilms to echinocandin treatment, suggesting inhibition of this enzyme is a potential treatment option for clinically enhancing the efficacy of this class of antifungals.…”

Section: Discussionsupporting

confidence: 51%

“…IPA occurs primarily in individuals with a suppressed innate immune system, such as individuals undergoing solid-organ transplantation or chemotherapy (Kanj et al, 2018;Kousha et al, 2011) Tragically, antifungal therapy options for IPA remain limited and are often ineffective, with recent clinical trials reporting 12-week mortality rates of 28-45% depending on therapeutic regimen and host immune status (Herbrecht et al, 2015;Maertens et al, 2016Maertens et al, , 2021Marr et al, 2015). One class of antifungal drugs, the echinocandins, inhibits synthesis of cell wall β-glucans and are better tolerated by patients than drugs belonging to the azole or polyene classes of antifungals.…”

Section: Introductionmentioning

confidence: 99%

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An Alanine Aminotransferase is Required for Polysaccharide Regulation and Resistance of Aspergillus fumigatus Biofilms to Echinocandin Treatment

Jd¹,

et al. 2021

Preprint

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Alanine metabolism has been suggested as an adaptation strategy to oxygen limitation in organisms ranging from plants to mammals. Within the pulmonary infection microenvironment A. fumigatus forms biofilms with steep oxygen gradients defined by regions of oxygen limitation. A significant increase in alanine levels was observed in A. fumigatus cultured under oxygen limiting conditions. An alanine aminotransferase, AlaA, was observed to function in alanine catabolism and is required for several aspects of A. fumigatus biofilm physiology. Loss of alaA, or its catalytic activity, results in decreased adherence of biofilms through a defect in the maturation of the extracellular matrix polysaccharide galactosaminogalactan (GAG). Additionally, exposure of cell wall polysaccharides is also impacted by loss of alaA and loss of AlaA catalytic activity confers increased biofilm susceptibility to echinocandin treatment which is correlated with enhanced fungicidal activity. The increase in echinocandin susceptibility is specific to biofilms and chemical inhibition of alaA by the alanine aminotransferase inhibitor β-chloro-L-alanine is sufficient to sensitize A. fumigatus biofilms to echinocandin treatment. Finally, loss of alaA increases susceptibility of A. fumigatus to in vivo echinocandin treatment in a murine model of invasive pulmonary aspergillosis. Our results provide insight into the interplay of metabolism, biofilm formation, and antifungal drug resistance in A. fumigatus and describes a mechanism of increasing susceptibility of A. fumigatus biofilms to the echinocandin class of antifungal drugs.

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Section: Discussionsupporting

confidence: 51%

Section: Introductionmentioning

confidence: 99%

An Alanine Aminotransferase is Required for Polysaccharide Regulation and Resistance of Aspergillus fumigatus Biofilms to Echinocandin Treatment

Jd¹,

et al. 2021

Preprint

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“…Thus, therapeutic drug monitoring is a cornerstone for patient management, as we faced low concentrations of voriconazole in this series with a significant delay to reach the optimal therapeutic range in CAPA vs. IAPA patients. Since we faced difficulties reaching voriconazole therapeutic concentrations in CAPA patients, the use of alternative antifungal treatments such as isavuconazole or posaconazole could be envisaged in this specific population [ 33 , 34 ].…”

Section: Discussionmentioning

confidence: 99%

Influenza- and COVID-19-Associated Pulmonary Aspergillosis: Are the Pictures Different?

Reizine

Pinceaux

Léderlin

et al. 2021

JoF

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Invasive pulmonary aspergillosis (IPA) in intensive care unit patients is a major concern. Influenza-associated acute respiratory distress syndrome (ARDS) and severe COVID-19 patients are both at risk of developing invasive fungal diseases. We used the new international definitions of influenza-associated pulmonary aspergillosis (IAPA) and COVID-19-associated pulmonary aspergillosis (CAPA) to compare the demographic, clinical, biological, and radiological aspects of IAPA and CAPA in a monocentric retrospective study. A total of 120 patients were included, 71 with influenza and 49 with COVID-19-associated ARDS. Among them, 27 fulfilled the newly published criteria of IPA: 17/71 IAPA (23.9%) and 10/49 CAPA (20.4%). Kaplan–Meier curves showed significantly higher 90-day mortality for IPA patients overall (p = 0.032), whereas mortality did not differ between CAPA and IAPA patients. Radiological findings showed differences between IAPA and CAPA, with a higher proportion of features suggestive of IPA during IAPA. Lastly, a wide proportion of IPA patients had low plasma voriconazole concentrations with a higher delay to reach concentrations > 2 mg/L in CAPA vs. IAPA patients (p = 0.045). Severe COVID-19 and influenza patients appeared very similar in terms of prevalence of IPA and outcome. The dramatic consequences on the patients’ prognosis emphasize the need for a better awareness in these particular populations.

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“…Most guidelines recommend voriconazole or isavuconazole as a first line treatment option. Recently, posaconazole was shown to be non-inferior to voriconazole for the treatment of IPA [ 47 ]. The experience with isavuconazole and posaconazole in ICU patients with IPA is still limited.…”

Section: Key Questionsmentioning

confidence: 99%

Taskforce report on the diagnosis and clinical management of COVID-19 associated pulmonary aspergillosis

et al. 2021

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Purpose Invasive pulmonary aspergillosis (IPA) is increasingly reported in patients with severe coronavirus disease 2019 (COVID-19) admitted to the intensive care unit (ICU). Diagnosis and management of COVID-19 associated pulmonary aspergillosis (CAPA) are challenging and our aim was to develop practical guidance. Methods A group of 28 international experts reviewed current insights in the epidemiology, diagnosis and management of CAPA and developed recommendations using GRADE methodology. Results The prevalence of CAPA varied between 0 and 33%, which may be partly due to variable case definitions, but likely represents true variation. Bronchoscopy and bronchoalveolar lavage (BAL) remain the cornerstone of CAPA diagnosis, allowing for diagnosis of invasive Aspergillus tracheobronchitis and collection of the best validated specimen for Aspergillus diagnostics. Most patients diagnosed with CAPA lack traditional host factors, but pre-existing structural lung disease and immunomodulating therapy may predispose to CAPA risk. Computed tomography seems to be of limited value to rule CAPA in or out, and serum biomarkers are negative in 85% of patients. As the mortality of CAPA is around 50%, antifungal therapy is recommended for BAL positive patients, but the decision to treat depends on the patients’ clinical condition and the institutional incidence of CAPA. We recommend against routinely stopping concomitant corticosteroid or IL-6 blocking therapy in CAPA patients. Conclusion CAPA is a complex disease involving a continuum of respiratory colonization, tissue invasion and angioinvasive disease. Knowledge gaps including true epidemiology, optimal diagnostic work-up, management strategies and role of host-directed therapy require further study. Supplementary Information The online version contains supplementary material available at 10.1007/s00134-021-06449-4.

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Posaconazole versus voriconazole for primary treatment of invasive aspergillosis: a phase 3, randomised, controlled, non-inferiority trial

Cited by 149 publications

References 15 publications

An Alanine Aminotransferase is Required for Polysaccharide Regulation and Resistance of Aspergillus fumigatus Biofilms to Echinocandin Treatment

An Alanine Aminotransferase is Required for Polysaccharide Regulation and Resistance of Aspergillus fumigatus Biofilms to Echinocandin Treatment

Influenza- and COVID-19-Associated Pulmonary Aspergillosis: Are the Pictures Different?

Taskforce report on the diagnosis and clinical management of COVID-19 associated pulmonary aspergillosis

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