{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,3]],"date-time":"2026-02-03T18:03:36Z","timestamp":1770141816884,"version":"3.49.0"},"reference-count":37,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,1,17]],"date-time":"2023-01-17T00:00:00Z","timestamp":1673913600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell. Infect. Microbiol."],"abstract":"<jats:p>Azole resistance in <jats:italic>Aspergillus fumigatus<\/jats:italic> (Af) has become a widespread threat and a major concern for optimal management of patients with invasive aspergillosis (IA). Combination of echinocandins with azoles is an attractive alternative option for the treatment of IA due to azole-resistant Af strains. The aim of this study was to evaluate the <jats:italic>in vitro<\/jats:italic> and <jats:italic>in vivo<\/jats:italic> combination of caspofungin (CAS) with either voriconazole (VRZ) or posaconazole (PSZ). <jats:italic>In vitro<\/jats:italic> interactions were assessed by two methods, and an animal model of IA in <jats:italic>Galleria mellonella<\/jats:italic> was used for <jats:italic>in vivo<\/jats:italic> evaluation. Assessment of efficacy was based on larvae mortality. Groups of 10 larvae were infected by 3 clinical strains of Af (azole susceptible, AfS; PSZ resistant, AfR1; VRZ and PSZ resistant strain, AfR2). <jats:italic>In vitro<\/jats:italic>, combination of CAS and azoles was indifferent against AfS, and AfR2, and a synergy was found for AfR1. When compared to VRZ monotherapy, the combination of VRZ at 4 \u00b5g\/larva with CAS at 4 \u00b5g\/larva improved survival of AfR2-infected larvae (p=0.0066). Combination of PSZ at 4\u00b5g\/larva with CAS at 4 \u00b5g\/larva improved survival of AfR1-infected larvae compared to CAS (p=0.0002) and PSZ (0.0024) monotherapy. Antagonism was never observed. In conclusion, the combination of caspofungin with azoles is a promising alternative for the treatment of azole resistant strains of Af.<\/jats:p>","DOI":"10.3389\/fcimb.2022.1038342","type":"journal-article","created":{"date-parts":[[2023,1,17]],"date-time":"2023-01-17T06:07:21Z","timestamp":1673935641000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":10,"title":["In vitro and in vivo evaluation of antifungal combinations against azole-resistant Aspergillus fumigatus isolates"],"prefix":"10.3389","volume":"12","author":[{"given":"Sana","family":"Jemel","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yannick","family":"Raveloarisaona","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anne-Laure","family":"Bidaud","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elie","family":"Djenontin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aicha","family":"Kallel","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jacques","family":"Guillot","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kalthoum","family":"Kallel","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fran\u00e7oise","family":"Botterel","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eric","family":"Dannaoui","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2023,1,17]]},"reference":[{"key":"B1","article-title":"Method for the determination of broth dilution minimum inhibitory concentrations of antifungal agents for conidia forming moulds","author":"Arendrup","year":"2017","journal-title":"EUCAST definitive document"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.3390\/jof7020113","article-title":"Techniques for the assessment of in vitro and in vivo antifungal combinations","volume":"7","author":"Bidaud","year":"2021","journal-title":"J. Fungi (Basel)"},{"key":"B3","doi-asserted-by":"publisher","first-page":"1232","DOI":"10.1128\/AAC.49.3.1232-1235.2005","article-title":"Combined activity in vitro of caspofungin, amphotericin b, and azole agents against itraconazole-resistant clinical isolates of aspergillus fumigatus","volume":"49","author":"Cuenca-Estrella","year":"2005","journal-title":"Antimicrob. Agents Chemother."},{"key":"B4","doi-asserted-by":"publisher","first-page":"970","DOI":"10.1128\/AAC.48.3.970-978.2004","article-title":"In vitro evaluation of double and triple combinations of antifungal drugs against aspergillus fumigatus and aspergillus terreus","volume":"48","author":"Dannaoui","year":"2004","journal-title":"Antimicrob. Agents Chemother."},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1128\/mSphere.00416-19","article-title":"The aspergillus fumigatus mismatch repair MSH2 homolog is important for virulence and azole resistance","volume":"4","author":"Dos Reis","year":"2019","journal-title":"mSphere"},{"key":"B6","doi-asserted-by":"publisher","first-page":"1065","DOI":"10.1128\/CMR.00095-16","article-title":"Molecular tools for the detection and deduction of azole antifungal drug resistance phenotypes in aspergillus species","volume":"30","author":"Dudakova","year":"2017","journal-title":"Clin. Microbiol. Rev."},{"key":"B7","doi-asserted-by":"publisher","first-page":"511","DOI":"10.1016\/j.ijantimicag.2015.07.007","article-title":"In vivo efficacy of voriconazole and posaconazole therapy in a novel invertebrate model of aspergillus fumigatus infection","volume":"46","author":"Forastiero","year":"2015","journal-title":"Int. J. Antimicrob. Agents"},{"key":"B8","doi-asserted-by":"publisher","first-page":"180","DOI":"10.1016\/S2213-2600(21)00442-2","article-title":"Fungal infections in mechanically ventilated patients with COVID-19 during the first wave: The French multicentre MYCOVID study","volume":"10","author":"Gangneux","year":"2022","journal-title":"Lancet Respir. Med."},{"key":"B9","doi-asserted-by":"publisher","first-page":"5180","DOI":"10.1128\/AAC.01111-12","article-title":"Combination of voriconazole and anidulafungin for treatment of triazole-resistant aspergillus fumigatus in an in vitro model of invasive pulmonary aspergillosis","volume":"56","author":"Jeans","year":"2012","journal-title":"Antimicrob. Agents Chemother."},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.3390\/microorganisms8030390","article-title":"Galleria mellonella for the evaluation of antifungal efficacy against medically important fungi, a narrative review","volume":"8","author":"Jemel","year":"2020","journal-title":"Microorganisms"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.3390\/jof7121012","article-title":"In vivo efficacy of voriconazole in a galleria mellonella model of invasive infection due to azole-susceptible or resistant aspergillus fumigatus isolates","volume":"7","author":"Jemel","year":"2021","journal-title":"J. Fungi (Basel)"},{"key":"B12","doi-asserted-by":"publisher","first-page":"2564","DOI":"10.1128\/AAC.46.8.2564-2568.2002","article-title":"Efficacy of caspofungin alone and in combination with voriconazole in a Guinea pig model of invasive aspergillosis","volume":"46","author":"Kirkpatrick","year":"2002","journal-title":"Antimicrob. Agents Chemother."},{"key":"B13","doi-asserted-by":"publisher","first-page":"e00140","DOI":"10.1128\/CMR.00140-18","article-title":"Aspergillus fumigatus and aspergillosis in 2019","volume":"33","author":"Latge","year":"2020","journal-title":"Clin. Microbiol. Rev."},{"key":"B14","doi-asserted-by":"publisher","first-page":"5438","DOI":"10.1128\/AAC.00833-13","article-title":"Impact of in vivo triazole and echinocandin combination therapy for invasive pulmonary aspergillosis: Enhanced efficacy against Cyp51 mutant isolates","volume":"57","author":"Lepak","year":"2013","journal-title":"Antimicrob. Agents Chemother."},{"key":"B15","doi-asserted-by":"publisher","first-page":"1463","DOI":"10.1093\/cid\/ciy859","article-title":"Voriconazole resistance and mortality in invasive aspergillosis: A multicenter retrospective cohort study","volume":"68","author":"Lestrade","year":"2019","journal-title":"Clin. Infect. Dis."},{"key":"B16","doi-asserted-by":"publisher","first-page":"799","DOI":"10.1016\/j.cmi.2018.11.027","article-title":"Triazole resistance in aspergillus fumigatus: Recent insights and challenges for patient management","volume":"25","author":"Lestrade","year":"2019","journal-title":"Clin. Microbiol. Infect."},{"key":"B17","doi-asserted-by":"publisher","first-page":"3697","DOI":"10.1128\/AAC.49.9.3697-3701.2005","article-title":"Efficacy of caspofungin and voriconazole combinations in experimental aspergillosis","volume":"49","author":"MacCallum","year":"2005","journal-title":"Antimicrob. Agents Chemother."},{"key":"B18","doi-asserted-by":"publisher","first-page":"591","DOI":"10.1080\/21505594.2015.1045183","article-title":"Galleria mellonella as a host model to study aspergillus terreus virulence and amphotericin b resistance","volume":"6","author":"Maurer","year":"2015","journal-title":"Virulence"},{"key":"B19","doi-asserted-by":"publisher","first-page":"1738","DOI":"10.1128\/AAC.04469-14","article-title":"The strength of synergistic interaction between posaconazole and caspofungin depends on the underlying azole resistance mechanism of aspergillus fumigatus","volume":"59","author":"Mavridou","year":"2015","journal-title":"Antimicrob. Agents Chemother."},{"key":"B20","doi-asserted-by":"publisher","first-page":"133","DOI":"10.1080\/13693780410001731547","article-title":"Assessing in vitro combinations of antifungal drugs against yeasts and filamentous fungi: Comparison of different drug interaction models","volume":"43","author":"Meletiadis","year":"2005","journal-title":"Med. Mycol"},{"key":"B21","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1093\/jac\/dkg301","article-title":"Synergy, antagonism, and what the chequerboard puts between them","volume":"52","author":"Odds","year":"2003","journal-title":"J. Antimicrob. Chemother."},{"key":"B22","doi-asserted-by":"publisher","first-page":"980","DOI":"10.1111\/myc.13341","article-title":"A review of significance of aspergillus detection in airways of ICU COVID-19 patients","volume":"64","author":"Pasquier","year":"2021","journal-title":"Mycoses"},{"key":"B23","doi-asserted-by":"publisher","first-page":"e1","DOI":"10.1093\/cid\/ciw326","article-title":"Practice guidelines for the diagnosis and management of aspergillosis: 2016 update by the infectious diseases society of America","volume":"63","author":"Patterson","year":"2016","journal-title":"Clin. Infect. Dis."},{"key":"B24","doi-asserted-by":"publisher","first-page":"3572","DOI":"10.1128\/AAC.49.8.3572-3574.2005","article-title":"In vitro synergy testing of anidulafungin with itraconazole, voriconazole, and amphotericin b against aspergillus spp. and fusarium spp","volume":"49","author":"Philip","year":"2005","journal-title":"Antimicrob. Agents Chemother."},{"key":"B25","doi-asserted-by":"publisher","first-page":"4500","DOI":"10.1128\/AAC.00045-12","article-title":"In vitro combination of anidulafungin and voriconazole against intrinsically azole-susceptible and -resistant aspergillus spp","volume":"56","author":"Planche","year":"2012","journal-title":"Antimicrob. Agents Chemother."},{"key":"B26","doi-asserted-by":"publisher","first-page":"e01382","DOI":"10.1128\/AAC.01382-17","article-title":"In vitro combination of isavuconazole with echinocandins against azole-susceptible and -resistant aspergillus spp","volume":"62","author":"Raffetin","year":"2018","journal-title":"Antimicrob. Agents Chemother."},{"key":"B27","doi-asserted-by":"publisher","first-page":"2759","DOI":"10.1093\/jac\/dkz258","article-title":"Prevalence of voriconazole-resistant invasive aspergillosis and its impact on mortality in haematology patients","volume":"74","author":"Resendiz-Sharpe","year":"2019","journal-title":"J.\u00a0Antimicrob. Chemother."},{"key":"B28","doi-asserted-by":"publisher","first-page":"835","DOI":"10.1093\/jac\/dky517","article-title":"Emerging threat of triazole-resistant aspergillus fumigatus","volume":"74","author":"Rybak","year":"2019","journal-title":"J. Antimicrob. Chemother."},{"key":"B29","doi-asserted-by":"publisher","first-page":"782","DOI":"10.1016\/S2213-2600(18)30274-1","article-title":"Invasive aspergillosis in patients admitted to the intensive care unit with severe influenza: A retrospective cohort study","volume":"6","author":"Schauwvlieghe","year":"2018","journal-title":"Lancet Respir. Med."},{"key":"B30","doi-asserted-by":"publisher","first-page":"385","DOI":"10.1093\/jac\/dks402","article-title":"Efficacy and pharmacodynamics of voriconazole combined with anidulafungin in azole-resistant invasive aspergillosis","volume":"68","author":"Seyedmousavi","year":"2013","journal-title":"J.\u00a0Antimicrob. Chemother."},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1128\/spectrum.02007-21","article-title":"vivo interactions of TOR inhibitor AZD8055 and azoles against pathogenic fungi","volume":"10","author":"Sun","year":"2022","journal-title":"In Vitro Microbiol. Spectr."},{"key":"B32","doi-asserted-by":"publisher","first-page":"1496","DOI":"10.1056\/NEJMra2027424","article-title":"Aspergillus infections","volume":"385","author":"Thompson","year":"2021","journal-title":"N Engl. J. Med."},{"key":"B33","doi-asserted-by":"publisher","first-page":"e1","DOI":"10.1016\/j.cmi.2018.01.002","article-title":"Diagnosis and management of aspergillus diseases: Executive summary of the 2017 ESCMID-ECMM-ERS guideline","volume":"24","author":"Ullmann","year":"2018","journal-title":"Clin. Microbiol. Infect."},{"key":"B34","doi-asserted-by":"publisher","first-page":"30","DOI":"10.1016\/j.drup.2015.08.001","article-title":"International expert opinion on the management of infection caused by azole-resistant aspergillus fumigatus","author":"Verweij","year":"2015","journal-title":"Drug Resist. Update"},{"key":"B35","doi-asserted-by":"publisher","first-page":"1524","DOI":"10.1007\/s00134-020-06091-6","article-title":"Review of influenza-associated pulmonary aspergillosis in ICU patients and proposal for a case definition: an expert opinion","volume":"46","author":"Verweij","year":"2020","journal-title":"Intensive Care Med."},{"key":"B36","doi-asserted-by":"publisher","first-page":"143","DOI":"10.1385\/1-59259-943-5:143","article-title":"Antifungal combinations","volume":"118","author":"Vitale","year":"2005","journal-title":"Methods Mol. Med."},{"key":"B37","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1007\/s11046-013-9719-z","article-title":"Efficacy of the combination of voriconazole and caspofungin in experimental pulmonary aspergillosis by different aspergillus species","volume":"177","author":"Zhang","year":"2014","journal-title":"Mycopathologia"}],"container-title":["Frontiers in Cellular and Infection Microbiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcimb.2022.1038342\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,17]],"date-time":"2023-01-17T06:07:26Z","timestamp":1673935646000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcimb.2022.1038342\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,1,17]]},"references-count":37,"alternative-id":["10.3389\/fcimb.2022.1038342"],"URL":"https:\/\/doi.org\/10.3389\/fcimb.2022.1038342","relation":{},"ISSN":["2235-2988"],"issn-type":[{"value":"2235-2988","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,1,17]]},"article-number":"1038342"}}