Potential Implication of Azole Persistence in the Treatment Failure of Two Haematological Patients Infected with Aspergillus fumigatus

Invasive aspergillosis (IA) is a major cause of morbidity and mortality in patients receiving allogeneic haematopoieticcell transplantation. The deep immunosuppression and a variety of potential additional complications developed in these patients result in IA reaching mortality rates of around 50-60%. This mortality is even higher when the patients are infected with azole-resistant isolates, demonstrating that, despite the complexity of management, adequate azole treatment can have a beneficial effect. It is therefore paramount to understand the reasons why antifungal treatment of IA infections caused by azole-susceptible isolates is often unsuccessful. In this respect, there are already various factors known to be important for treatment efficacy, for instance the drug concentrations achieved in the blood, which are thus often monitored. We hypothesize that antifungal persistence may be another important factor to consider. In this study we present two case reports of haematological patients who developed proven IA and suffered treatment failure, despite having been infected with susceptible isolates, receiving correct antifungal treatment and reaching therapeutic levels of the azole. Microbiological analysis of the recovered infective isolates showed that the patients were infected with multiple strains, several of which were persisters to voriconazole and/or isavuconazole. Therefore, we propose that azole persistence may have contributed to therapeutic failure in these patients and that this phenomenon should be considered in future studies.This research was funded by “Proyecto de I+D+I en salud-ISCIII 2022 de la Acción Estratégica en Salud Intramural (AESI)”, grant number “PI22CIII/00053”.S

Aspergillus fumigatus Can Display Persistence to the Fungicidal Drug Voriconazole

Aspergillus fumigatus is a filamentous fungus that can infect the lungs of patients with immunosuppression and/or underlying lung diseases. The mortality associated with chronic and invasive aspergillosis infections remain very high, despite availability of antifungal treatments. In the last decade, there has been a worrisome emergence and spread of resistance to the first-line antifungals, the azoles. The mortality caused by resistant isolates is even higher, and patient management is complicated as the therapeutic options are reduced. Nevertheless, treatment failure is also common in patients infected with azole-susceptible isolates, which can be due to several non-mutually exclusive reasons, such as poor drug absorption. In addition, the phenomena of tolerance or persistence, where susceptible pathogens can survive the action of an antimicrobial for extended periods, have been associated with treatment failure in bacterial infections, and their occurrence in fungal infections already proposed. Here, we demonstrate that some isolates of A. fumigatus display persistence to voriconazole. A subpopulation of the persister isolates can survive for extended periods and even grow at low rates in the presence of supra-MIC of voriconazole and seemingly other azoles. Persistence cannot be eradicated with adjuvant drugs or antifungal combinations and seemed to reduce the efficacy of treatment for certain individuals in a Galleria mellonella model of infection. Furthermore, persistence implies a distinct transcriptional profile, demonstrating that it is an active response. We propose that azole persistence might be a relevant and underestimated factor that could influence the outcome of infection in human aspergillosis. Importance: The phenomena of antibacterial tolerance and persistence, where pathogenic microbes can survive for extended periods in the presence of cidal drug concentrations, have received significant attention in the last decade. Several mechanisms of action have been elucidated, and their relevance for treatment failure in bacterial infections demonstrated. In contrast, our knowledge of antifungal tolerance and, in particular, persistence is still very limited. In this study, we have characterized the response of the prominent fungal pathogen Aspergillus fumigatus to the first-line therapy antifungal voriconazole. We comprehensively show that some isolates display persistence to this fungicidal antifungal and propose various potential mechanisms of action. In addition, using an alternative model of infection, we provide initial evidence to suggest that persistence may cause treatment failure in some individuals. Therefore, we propose that azole persistence is an important factor to consider and further investigate in A. fumigatus.J.A. is funded by an Atracción de Talento Modalidad 1 (020-T1/BMD-200) contract of the Madrid Regional Government. J.S. has been funded by a BSAC Scholarship (bsac-2016-0049). C.V. was funded by FAPESP (2108/00715-3 and 2020/01131-5). G.H.G. hasbeen funded by FAPESP (2016/07870-9 and 2021/04977-5), CNPq (301058/2019-9 and404735/2018-5) and by the NIH/NIAID (grant R01AI153356). S.G. was cofunded by the NIHR Manchester Research Centre and the Fungal Infection Trust.S

[Correspondencia de Camilo Díaz Baliño] , 1917-1936

Mss. (algúns en fotocopia) autógrafo e mecanografiadoResumen: Correspondencia recibida por Camilo Díaz Baliño entre os anos 1917-1936 relacionada con asuntos persoais e laboraisBiblioteca de GaliciaForma de ingreso: Depósito. Fuente de ingreso: Díaz Pardo, Isaac. Fecha de ingreso: 2011. Propietario: Herdeiros de Isaac Díaz PardoDixitalización Telefónica-IDP 2012Contén : Cartas de: Manuel Abelenda (1 páx.) -- Cesar Alvarez (1 páx.) -- Carlos Amigo Collía (2 páxs.) -- Banco Hispano-Americano (2 páxs.) -- Alfonso Barreiro (3 páxs.) -- Eliseo Barros Gamallo (1 páx.),(2 páxs.) -- Ramón Beade (2 páxs.) -- Benito(2 páxs.) -- Fernando Blanco(1 páx.) -- José Bouzas y Cardama (1 páx.) -- Albino Bouzó Fernández (1 páx.),(2 páxs) -- José Cabada Vázquez (4 páxs.),(1 páx.),(1 páx.) --Salvador Cabeza (1 páx.) -- Antonio Carballa (1 páx.) -- Leandro y Euxenio Carré (2 páxs.) -- V. Carro (1 páx.) -- Santiago Casares (1 páx.) -- Alvaro Cebreiro (2 páxs.) -- Centro Gallego de Buenos Aires (1 páx.),(1 páx.) -- Compostela (2 páxs.) -- Manolo: Continental (2 páxs.) -- Coral de Ruada (1 páx.),(2 páxs.) -- Amando Cotarelo(1 páx.),(1 páx.) -- Eduardo Dorado Xaneiro (8 páx.) -- Círculo Mercantil e Idustrial: Ramón Fernández (1 páx.) --Virgilio Fernández(3 páxs.) -- Ramón Fernández Mato (2 páxs.) -- B. Ferreiro(1 páx.) -- Jenaro de la Fuente (1 páx.) -- Isaac Fraga: Espéctaculos Empresa Fraga (1 páx.),(1 páx.) -- Antonio Folgar Lema(1 páx.)--Alicio Garcitoral (1 páx.) -- Cándido González Raño (1 páx.) -- Daniel González Rodriguez (2 páxs.),(2 páxs.) -- Edurardo G.del Río (1 páx.) -- Hermanos Hernández (2 páxs.),(1 páx.),(1 páx.),(1 páx.) -- José Iglesias Sánchez (2 páxs.) -- Irmandades da Fala (1 páx.) -- José Silva? (2 páxs.) -- Arturo Longa (1 páx.) -- Casimiro López (1 páx.) -- Edmundo López (1 páx.),(1 páx.) -- Eduardo R. Losada y Rebellón (2 páx.) -- Carlos Maside (1 páx.) -- Enrique Mayer (1 páx.) -- Antonio Méndez Laserna (1 páx.) -- Anselmo Padín (1 páx.) -- Xavier Pardo (1 páx.) -- Partido Republicano Radical Socialista (1 páx.) -- Pérez Bustamante (1 páx.) -- Modesto Piñeiro (2 páxs.) -- Salustiano Portela (2 páxs.) -- José Seijo Rubio (2 páxs.) -- Suarez Picallo (2 páxs.) -- Luis Losada (1 páx), (1 páx.) -- Ricardo Valdés (2 páxs.),(2 páxs.),(2 páxs.),(1 páx.) -- A.Nilo Varela (1 páx.),(2 páxs.),(2 páxs.) -- Juan Varela de Limia (1 páx.) -- Victorino? Varela (1 páx.) -- Jesús Varela (3 páxs.) -- F.Vázquez Suarez (1 páx.) -- Santiago Vidal Gimeno (1 páx.) -- Pedro Vieitez (1 páx.) -- M. Villar (2 páxs.) -- Anónima (1 páx.) -- Anónima (1 páx.