Azole resistance in a clinical isolate of Aspergillus fumigatus from Chile

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C. albicans and N. glabratus were detected earlier in the Myco bottles than in the Aero bottles, p=0.02 and p=0.018, respectively. TTD of C. parapsilosis, M. guilliermondi and P. kudriavzevii was similar in both bottles (p=0.3; p=0.8 and p=0.16, respectively). C. tropicalis was detected earlier in the Aero bottles (p=0.014). *Statistical difference." ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Leandre Carmem Wilot, Vanice Rodrigues Poester, Cecília Bittencourt Severo, Karine Ortiz Sanchotene, Bruna Muradás Esperon, Mariana Rodrigues Trápaga, David A. 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"apellidos" => "Stevens" ] 7 => array:2 [ "nombre" => "Melissa Orzechowski" "apellidos" => "Xavier" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1130140624000081?idApp=UINPBA00004N" "url" => "/11301406/0000004100000001/v1_202410040500/S1130140624000081/v1_202410040500/en/main.assets" ] "itemAnterior" => array:18 [ "pii" => "S1130140624000044" "issn" => "11301406" "doi" => "10.1016/j.riam.2024.01.001" "estado" => "S300" "fechaPublicacion" => "2024-01-01" "aid" => "644" "copyright" => "Asociación Española de Micología" "documento" => "article" "crossmark" => 1 "subdocumento" => "fla" "cita" => "Rev Iberoam Micol. 2024;41:1-6" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "en" => array:12 [ "idiomaDefecto" => true "cabecera" => "Original article" "titulo" => "Fungemia due to opportunistic fungi in patients with cancer" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => array:2 [ 0 => "en" 1 => "es" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "1" "paginaFinal" => "6" ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Fungemia por hongos oportunistas en pacientes con cáncer" ] ] "contieneResumen" => array:2 [ "en" => true "es" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Rodrigo M. Flores-Delgado, Patricia Volkow, Consuelo Velázquez-Acosta, Patricia Cornejo-Juárez" "autores" => array:4 [ 0 => array:2 [ "nombre" => "Rodrigo M." "apellidos" => "Flores-Delgado" ] 1 => array:2 [ "nombre" => "Patricia" "apellidos" => "Volkow" ] 2 => array:2 [ "nombre" => "Consuelo" "apellidos" => "Velázquez-Acosta" ] 3 => array:2 [ "nombre" => "Patricia" "apellidos" => "Cornejo-Juárez" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1130140624000044?idApp=UINPBA00004N" "url" => "/11301406/0000004100000001/v1_202410040500/S1130140624000044/v1_202410040500/en/main.assets" ] "en" => array:19 [ "idiomaDefecto" => true "cabecera" => "Original article" "titulo" => "Azole resistance in a clinical isolate of Aspergillus fumigatus from Chile" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "7" "paginaFinal" => "12" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Eduardo Álvarez Duarte, Nicolás Cepeda, Jean Miranda" "autores" => array:3 [ 0 => array:4 [ "nombre" => "Eduardo" "apellidos" => "Álvarez Duarte" "email" => array:1 [ 0 => "ealvarezd@uchile.cl" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "Nicolás" "apellidos" => "Cepeda" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] ] ] 2 => array:3 [ "nombre" => "Jean" "apellidos" => "Miranda" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] ] "afiliaciones" => array:2 [ 0 => array:3 [ "entidad" => "Laboratorio Micología, ICBM – F. de Medicina, Universidad de Chile, Chile" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Clinical Chemistry and Hematology, Hospital del Salvador, Chile" "etiqueta" => "b" "identificador" => "aff0010" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Primer aislamiento clínico de Aspergillus fumigatus resistente a azoles en Chile" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1543 "Ancho" => 1600 "Tamanyo" => 515565 ] ] "descripcion" => array:1 [ "en" => "Mutations observed in the Cyp51A sequences obtained from the isolates ChFC 132 and ChFC 104. (a) TR34 (red bar), (b) L98H (red arrow), and (c) F46Y/M172V/E427K (blue arrows)." ] ] ] "textoCompleto" => "In recent years, the number of pathogenic fungi and the incidence of mycoses have increased considerably. Among the causes that may explain this situation, the increase in the population at risk of contracting an invasive fungal disease (IFD), i.e. immunocompromised patients, those with oncohematological problems, or those with prolonged corticosteroid treatment must be mentioned.<a class="elsevierStyleCrossRef" href="#bib0435">39</a> Another cause is the improvement in both the diagnosis of mycoses and the identification of the etiological agents. Nevertheless, IFDs still have a high morbidity and mortality rate, which can reach 90% in some groups of patients.<a class="elsevierStyleCrossRefs" href="#bib0260">4,7,35,36</a>Among the different fungi capable of producing IFD, we can find two large groups of etiological agents: yeasts, with Candida albicans being the most representative, and filamentous fungi, with Aspergillus fumigatus as the most isolated microorganism.The genus Aspergillus is a diverse group of fungi comprising many species capable of producing a wide variety of pathologies. Classically, the identification of the different species has been based on the phenotypic characterization of the isolates. However, due to the improvement and development of new molecular tools in the last decades, these advanced methodologies are fundamental in the identification of the Aspergillus species. Currently, this genus contains about 446 species. However, only some of them are pathogenic for humans, being the species belonging to the sections Fumigati, Flavi, Nidulantes, Nigri, Terrei and Usti the most commonly isolated from clinical cases.<a class="elsevierStyleCrossRef" href="#bib0385">29</a>We daily inhale a large number of Aspergillus spores, most of which get trapped in the epithelium of the lower respiratory tract and are eliminated by the ciliary clearance mechanism. Only the smaller spores (between 2 and 5μm) are able to reach the pulmonary alveoli, where they will be removed by the alveolar macrophages, responsible for eliminating the conidia, and the neutrophils, responsible for destroying the few hyphae produced from the germination of the spores.<a class="elsevierStyleCrossRef" href="#bib0375">27</a> However, in immunocompromised patients, the presence of the spores can lead to colonization of the host, enabling the development of IFD.<a class="elsevierStyleCrossRefs" href="#bib0285">9,33</a>Diseases caused by species of the genus Aspergillus are generally referred to as aspergillosis. This genus is responsible for more than 200,000 cases of invasive aspergillosis (IA) per year. Besides, this genus causes more than 1.2 million additional cases of chronic pulmonary aspergillosis (CPA) and about 4.8 million cases of allergic bronchopulmonary aspergillosis (ABPA).<a class="elsevierStyleCrossRefs" href="#bib0325">17,18</a> In Chile, due to the absence of official data about IFD, cases of IA, CPA and ABPA are estimated to occur in 1.7/100,000; 6.9/100,000 and 97.9/100,000, respectively.<a class="elsevierStyleCrossRef" href="#bib0250">2</a>One of the threats related to aspergillosis is the resistance to antifungals, mainly azoles, which are the treatment of choice in these mycoses. Such resistance seems to be caused by various mutations in the Cyp51A gene, which codes for 14-α-demethylase, the target enzyme of azole drugs,<a class="elsevierStyleCrossRefs" href="#bib0410">34,45,46</a> and which would be related to high rates of therapeutic failure. The first reports of this phenomenon date back to the 1990s,<a class="elsevierStyleCrossRef" href="#bib0320">16</a> being an emerging problem widely reported in many countries around the world.The present work reports the isolation for the first time in Chile of azole resistant strains of A. fumigatus. We also prove the mutations in the Cyp51A gene.Material and methodsFungal isolates and morphological identificationTwenty-three clinical isolates obtained from March 2017 to March 2021, classified as Aspergillus spp., were received to perform the species identification. The isolates were obtained by culturing bronchoalveolar lavage samples from patients diagnosed with aspergillosis. Firstly, the isolates were identified by a phenotypical approach, evaluating their macro- and microscopic features and their ability to grow in the dark at 10°C, 25°C, 37±1°C, and 50°C on potato dextrose agar (PDA).Molecular analysisAccording to the manufacturer's instructions, the DNA was extracted using an E.Z.N.A.® Fungal DNA Mini Kit (Omega Biotek Store, USA). The universal fungal primers ITS1 and ITS4 for ITS1-5.8S-ITS2 region,<a class="elsevierStyleCrossRef" href="#bib0475">47</a> and Bt2a and Bt2b<a class="elsevierStyleCrossRef" href="#bib0360">24</a> for a partial β-tubulin gene sequence, were used. A 30μl mixture containing 17μl of BioMixTM Red (New England Biolabs), 10pM primers, and 10ng DNA was subjected to a DNA amplification technique, following a protocol of initial denaturation at 94°C for 5min, 35 cycles of denaturation at 94°C for 1min, annealing at 52°C for 1min for the ITS region, and 55°C for β-tubulin; extension at 72°C for 2min, and final extension at 72°C for 7min. The PCR product was checked on 2% agarose gel. Purification was performed following manufacturer guidelines with FavorPrep™ Gel/PCR purification Mini Kit (Favorgene, Taiwan). Sequencing was carried out in Macrogen (Macrogen, Korea). An NCBI Blastn search for each locus region was performed.<a class="elsevierStyleCrossRef" href="#bib0245">1</a> Sequences from type and reference strains were retrieved from the GenBank database. The sequences were aligned in MUSCLE software<a class="elsevierStyleCrossRef" href="#bib0340">20</a> followed by manual adjustments with a text editor. ITS sequences were used to identify isolates to the Aspergillus-section level, and partial β-tubulin sequences were used to identify to the species level.The entire sequences of the Cyp51A gene and promoter regions were amplified as previously described<a class="elsevierStyleCrossRef" href="#bib0450">42</a> in any isolate that exhibited azole resistance with the purpose of finding mutations that might explain that condition. Sequencing and analyses were carried out as formerly mentioned. The DNA sequences were compared with the wild-type susceptible A. fumigatus reference strain (GenBank <a href="ncbi-n:AF338659">AF338659</a>).Finally, the cell surface protein (CSP) encoding gene was partially sequenced<a class="elsevierStyleCrossRef" href="#bib0280">8</a> in all the isolates to perform the CSP typing according to the nomenclature reported by Klaassen et al.<a class="elsevierStyleCrossRef" href="#bib0400">32</a>Antifungal analysisThe in vitro susceptibility to itraconazole (ITZ), posaconazole (PCZ) and voriconazole (VRZ) was evaluated by the broth microdilution method performed according to the CLSI document M38M51S.<a class="elsevierStyleCrossRef" href="#bib0305">13</a> The antifungal concentration of ITZ, PCZ and VRZ ranged from 0.0156 to 8μg/mL. The inoculated plates were incubated at 35°C and observed after 24h. The lack of visual growth in each well was defined as the MIC value. Due to the absence of breakpoints for filamentous fungi in the CLSI method (except for voriconazole and A. fumigatus), the epidemiological cut-off values (ECVs) were used (1mg/L for ITZ and VRZ, 0.5mg/L for PCZ).<a class="elsevierStyleCrossRefs" href="#bib0310">14,10,22</a> In order to confirm the obtained results, the susceptibility test was performed twice. Candida parapsilosis ATCC 22019, A. fumigatus ATCC MYA-3626 and Hamigera insecticola (ex. Paecilomyces variotii) ATCC MYA-3630 were used as controls.In addition, an antifungal susceptibility test by the disk diffusion method was performed according to the CLSI M38M51S document.<a class="elsevierStyleCrossRef" href="#bib0305">13</a> Isolates were subcultured on PDA at 25°C for 5–7 days before testing. Then, the surface of a Mueller Hinton agar (MHA) plate dish was inoculated with a sterile cotton swab with the undiluted mold stock inoculum suspension. Antifungal disks (Rosco Diagnostica, Denmark) including ITZ (10μg), PCZ (5μg), and VRZ (1μg) were applied onto the surface of the inoculated media. The plates were incubated at 35°C and read after 24–48h. Zone diameters were interpreted according to CLSI M38M51S. A slight trailing or hyphal element extending into the inhibition zone was ignored.ResultsThe twenty-three strains analyzed in the present study were identified as Aspergillus section Fumigati based on their morphological and physiological characteristics: blue-green colored velutinous colonies, and abundant sporulation on PDA. The isolates showed subclavate vesicles (13–26μm), uniseriate columnar heads and flexuous conidiophore. No strain grew at 10°C, but did it at 50°C on PDA, as expected according to the literature.<a class="elsevierStyleCrossRefs" href="#bib0380">28,40</a> The analysis of the nucleotide sequences of the β-tubulin gene showed that two strains had a percent identity equal to or higher than 99% with those sequences of A. fumigatussensu stricto available in the GenBank/NCBI database (99.6% sequence of the strain >EF669851.1 NRRL 5587).Antifungal susceptibility<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> shows the antifungal susceptibility profiles obtained by means of the microdilution method and the disk diffusion method. Voriconazole and posaconazole showed the highest activity. One isolate (ChFC 132) was resistant to voriconazole with a MIC of 8μg/mL. Also, and due to a lack of clinical breakpoints, ChFC 132 was considered as non-wild type (NWT) based on the proposed ECV, exhibiting MIC values of 16μg/mL for ITZ and 1μg/mL for PCZ. The remaining 22 isolates showed MIC values of 1μg/mL, 0.5μg/mL and 0.25μg/mL for ITZ, VRZ and PCZ, respectively. Based on these results, these isolates were considered susceptible to VRZ and wild-type for ITZ and PCZ.<elsevierMultimedia ident="tbl0005"></elsevierMultimedia>The results obtained with the disk diffusion method were consistent with those observed with the microdilution broth methodology. In brief, isolate ChFC 132 showed an inhibition zone ≤17mm for all triazoles tested. According to these values, ChFC 132 was considered NWT. In the remaining 22 strains, the inhibition halos observed were greater than 17mm for VRZ, PCZ and ITZ, being considered as susceptible to all the antifungals tested. However, one of these strains (ChFC 104) exhibited inhibition halos ≥17mm for VRZ and PCZ, but ≤17mm for ITZ. Interestingly, in the halo around the ITZ disk, a trailing zone was observed, which is why it was decided to sequence the CYP51A gene in order to elucidate putative mutations.Cyp51A gene sequencing and CSP typingSequencing of the Cyp51A gene and its promoter showed the presence of the 34 bp tandem repeat (TR34) and L98H mutation in the strain ChFC 132. In addition, this analysis revealed that the second isolate (ChFC 104) harboured the F46Y/M172V/E427K mutations (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). In the remaining isolates, no mutations were observed.<elsevierMultimedia ident="fig0005"></elsevierMultimedia>The characterization of the CSP showed that our strains corresponded to types previously described in the literature. The strain ChFC 132 belongs to type t02, while the ChFC 104 was identified as type t15. The other 21 strains were classified into type t01.DiscussionInvasive aspergillosis is a very important challenge in medical mycology. An early diagnosis may be difficult to achieve, and the treatment of the disease is complex, so antifungal agents are used at the slightest suspicion of infection. In this context, the development of secondary resistance to commonly used antifungals gets facilitated. This fact is becoming a problem that is aggravated by the existence of cross-resistance between clinical triazoles and other azoles of the same family used as antifungals in agriculture.<a class="elsevierStyleCrossRef" href="#bib0355">23</a>Likewise, azole resistance is now being reported in countries worldwide.<a class="elsevierStyleCrossRefs" href="#bib0265">5,19,44</a> In Latin America, several countries have reported the presence of azole resistance in A. fumigatus, such as Colombia,<a class="elsevierStyleCrossRef" href="#bib0255">3</a> Argentina<a class="elsevierStyleCrossRef" href="#bib0390">30</a> and Peru,<a class="elsevierStyleCrossRef" href="#bib0295">11</a> among others. To our knowledge, this study describes for the first time in Chile the presence of azole resistance in A. fumigatus. Our two isolates with the mutations already mentioned were recovered from the bronchoalveolar lavage of two patients with aspergillosis. The samples were sent to our laboratory in order to check the presence of fungal organisms. Due to our passive surveillance strategy, we performed a disk diffusion test to evaluate their susceptibility patterns to some azoles. Based on the presence of halos ≤17mm (ChFC 132), as well as the presence of what appeared to be trailing (ChFC 104), the isolates were subjected to the broth microdilution method, and the sequencing of the Cyp51A gene. The first strain was harbouring the TR34/L98H mutations. These substitutions and tandem repeat sequences in the promoter region are some of the most commonly reported azole-resistance mutations.<a class="elsevierStyleCrossRefs" href="#bib0425">37,43</a> They were first described in Dutch A. fumigatus isolates, but are now spread worldwide<a class="elsevierStyleCrossRef" href="#bib0335">19</a> due to the extensive use of azole fungicides in agriculture and animals. These mutations have been related to high MIC values to azoles in several global studies, especially to itraconazole and voriconazole. Our results show MICs over 1mg/L for VRZ and ITZ, and 0.5mg/L for PCZ, allowing us to classify this isolate as resistant for voriconazole, and NWT for itraconazole/posaconazole, respectively. This finding agrees with other reports demonstrating the pan-azole resistance that confers the presence of TR34/L98H.<a class="elsevierStyleCrossRefs" href="#bib0365">25,48</a>The F46Y/M172V/E427K substitutions were observed in the second isolate. Curiously, these mutations had been identified in both azole-susceptible and resistant A. fumigatus isolates.<a class="elsevierStyleCrossRefs" href="#bib0345">21,31</a> The F46Y/M172V/E427K mutations seem to be located in a protein region that does not interact with azole compounds or, at least, does not affect the structure of the protein.<a class="elsevierStyleCrossRef" href="#bib0450">42</a> The above suggests that the mutations found might not be the molecular mechanism related to the observed resistance to azoles. In the same way, other situations, such as mutations of the HapE or Hmg1 gene, or efflux pumps, among others, could explain azole resistance in some isolates.<a class="elsevierStyleCrossRefs" href="#bib0300">12,26,38</a>In our study, three previously observed genotypes were identified. Most of the clinical strains analyzed in the present study were susceptible to all the antifungal assayed. Moreover, they were identified as the t01 genotype. Worldwide, the t01 genotype has been mostly associated with susceptible strains; however, resistant isolates have also been reported within that genotype. It seems that both susceptible and resistant isolates can be found in all genotypes. In fact, in a study carried out in the United Kingdom, no susceptible isolates were associated with the t01 genotype but with genotypes t03, t04A, t05, and t08.<a class="elsevierStyleCrossRef" href="#bib0445">41</a> With respect to the other genotypes analyzed, isolate ChFC 132 was linked to t02 genotype, commonly associated with the TR34/L98H mutations.<a class="elsevierStyleCrossRef" href="#bib0270">6</a> Likewise, the strain ChFC 104 was characterized as t15, a genotype reported in Europe and Australia. Interestingly, strains belonging to genotype t15 harboring F46Y/M172V/E427K mutations seem to be susceptible to all azoles.<a class="elsevierStyleCrossRef" href="#bib0315">15</a> As we can observe, these genotypes have been recovered in several countries around the world, exhibiting a low genetic variation compared with wild-type strains. The detection of identical genotypes in distant countries suggests the clonal expansion, presumably airborne dispersal.<a class="elsevierStyleCrossRef" href="#bib0445">41</a>ConclusionsWe report the finding of two clinical strains from Chile with mutations in the Cyp51A gene. The results obtained with both the disk diffusion method and the microdilution broth methodology were consistent. This demonstrates the usefulness and advantages of disk diffusion: its low cost and easy implementation in low complexity laboratories are the most remarkable features. Likewise, this methodology seems to predict azole resistance efficiently. Future studies involving more clinical and environmental strains are necessary to elucidate Chile's accurate picture of azole resistance.Ethical approvalNot applicable.FundingThis research received no external funding.Authors’ contributionsConceptualization, E.A.D; Methodology, E.A.D., N.C., J.M.; Investigation, E.A.D., N.C., J.M.; Writing – original draft preparation, E.A.D., N.C.; Writing – review and editing, E.A.D. All authors have read and agreed to the published version of the manuscript.Consent to participateNot applicable.Consent for publicationNot applicable.Competing interestsThe authors declare no conflict of interest.Availability of data and materialsThe data that support the findings of this study are available from the corresponding author upon reasonable request." "textoCompletoSecciones" => array:1 [ "secciones" => array:16 [ 0 => array:3 [ "identificador" => "xres2261518" "titulo" => "Abstract" "secciones" => array:5 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Background" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Aims" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Methods" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Results" ] 4 => array:2 [ "identificador" => "abst0025" "titulo" => "Conclusions" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1888128" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres2261519" "titulo" => "Resumen" "secciones" => array:5 [ 0 => array:2 [ "identificador" => "abst0030" "titulo" => "Antecedentes" ] 1 => array:2 [ "identificador" => "abst0035" "titulo" => "Objetivos" ] 2 => array:2 [ "identificador" => "abst0040" "titulo" => "Métodos" ] 3 => array:2 [ "identificador" => "abst0045" "titulo" => "Resultados" ] 4 => array:2 [ "identificador" => "abst0050" "titulo" => "Conclusiones" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec1888129" "titulo" => "Palabras clave" ] 4 => array:3 [ "identificador" => "sec0005" "titulo" => "Material and methods" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0010" "titulo" => "Fungal isolates and morphological identification" ] 1 => array:2 [ "identificador" => "sec0015" "titulo" => "Molecular analysis" ] 2 => array:2 [ "identificador" => "sec0020" "titulo" => "Antifungal analysis" ] ] ] 5 => array:3 [ "identificador" => "sec0025" "titulo" => "Results" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0030" "titulo" => "Antifungal susceptibility" ] 1 => array:2 [ "identificador" => "sec0035" "titulo" => "Cyp51A gene sequencing and CSP typing" ] ] ] 6 => array:2 [ "identificador" => "sec0040" "titulo" => "Discussion" ] 7 => array:2 [ "identificador" => "sec0045" "titulo" => "Conclusions" ] 8 => array:2 [ "identificador" => "sec0050" "titulo" => "Ethical approval" ] 9 => array:2 [ "identificador" => "sec0055" "titulo" => "Funding" ] 10 => array:2 [ "identificador" => "sec0060" "titulo" => "Authors’ contributions" ] 11 => array:2 [ "identificador" => "sec0065" "titulo" => "Consent to participate" ] 12 => array:2 [ "identificador" => "sec0070" "titulo" => "Consent for publication" ] 13 => array:2 [ "identificador" => "sec0075" "titulo" => "Competing interests" ] 14 => array:2 [ "identificador" => "sec0080" "titulo" => "Availability of data and materials" ] 15 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2023-05-10" "fechaAceptado" => "2024-04-19" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1888128" "palabras" => array:5 [ 0 => "Aspergillus fumigatus" 1 => "Antifungal resistance" 2 => "Mechanisms of antifungal resistance" 3 => "Triazoles" 4 => "cyp51A" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1888129" "palabras" => array:5 [ 0 => "Aspergillus fumigatus" 1 => "Resistencia antifúngica" 2 => "Mecanismos de resistencia a los antifúngicos" 3 => "Triazoles" 4 => "cyp51A" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:3 [ "titulo" => "Abstract" "resumen" => "BackgroundAspergillus fumigatus is a ubiquitous opportunistic pathogen. This fungus can acquire resistance to azole antifungals due to different mutations in the cyp51A gene. Azole resistance has been observed in several continents and appears to be a globally distributed phenomenon. Specific mutations in cyp51A that lead to azole resistance, such as the TR34/L98H modification, have been reported. AimsTo evaluate the azole resistance in clinically isolated A. fumigatus strains. MethodsAs a result of our passive surveillance strategy, a total of 23 A. fumigatus isolates from clinical origins were identified through a phylogenetic analysis using the ITS region and β-tubulin gene fragments, and typed with the CSP microsatellite. Azole susceptibility profiles were performed by disk diffusion and microdilution broth methodologies according to CLSI guidelines. ResultsHere we describe, for the first time, the detection of azole-resistant A. fumigatus isolates from clinical origins in Chile with mutations in the cyp51A gene. In addition to the TR34/L98H mutation, one isolate exhibited an F46Y/M172V/E427K-type mutation. Furthermore, microsatellite typing based on cell surface protein (CSP) was performed, showing the t02 (TR34/L98H), t15 (F46Y/M172V/E427K) and t01 (susceptible clinical isolates) genotypes. ConclusionsOur study demonstrates the presence of mutations related to azole resistance in A. fumigatus strains isolated from clinical samples in Chile. In order to obtain information that may help to tackle the spread of antifungal resistance among A. fumigatus populations, and to ensure the efficacy of future treatments against aspergillosis, a further research is necessary." "secciones" => array:5 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Background" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Aims" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Methods" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Results" ] 4 => array:2 [ "identificador" => "abst0025" "titulo" => "Conclusions" ] ] ] "es" => array:3 [ "titulo" => "Resumen" "resumen" => "AntecedentesAspergillus fumigatus es un patógeno oportunista ubicuo. Este hongo puede adquirir resistencia a los antifúngicos azólicos gracias a diferentes mutaciones en el gen cyp51A. La resistencia a los azoles se ha observado en varios continentes y parece ser un fenómeno de distribución mundial. Se han descrito mutaciones específicas en cyp51A para adquirir resistencia a los azoles, como la modificación TR34/L98H. ObjetivosEvaluar la resistencia a los azoles en aislamientos de A. fumigatus obtenidos de muestras clínicas. MétodosGracias a la vigilancia pasiva se identificó un total de 23 aislamientos de A. fumigatus de origen clínico a través de un análisis filogenético mediante el estudio de la región ITS y de fragmentos del gen de la β-tubulina, que se tipificaron con el microsatélite CSP. Los perfiles de sensibilidad a los azoles se realizaron mediante los métodos de difusión en disco y microdilución. ResultadosEn el presente trabajo describimos, por primera vez en Chile, la detección de aislamientos clínicos de A. fumigatus en este país resistentes a azoles, con mutaciones en el gen cyp51A. Además de la mutación TR34/L98H, un aislamiento presentó una mutación de tipo F46Y/M172V/E427K. Se realizó la tipificación por microsatélites basada en la proteína de superficie celular, que mostró los genotipos t02 (TR34/L98H), t15 (F46Y/M172V/E427K) y t01 (cepas sensibles). ConclusionesNuestro estudio demuestra la presencia de mutaciones relacionadas con la resistencia a los azoles en cepas de A. fumigatus aisladas de muestras clínicas en Chile. Para obtener información que pueda ayudar a atajar la propagación de la resistencia a los antifúngicos entre las poblaciones de A. fumigatus, y garantizar así la eficacia de futuros tratamientos contra la aspergilosis, es necesario seguir investigando." "secciones" => array:5 [ 0 => array:2 [ "identificador" => "abst0030" "titulo" => "Antecedentes" ] 1 => array:2 [ "identificador" => "abst0035" "titulo" => "Objetivos" ] 2 => array:2 [ "identificador" => "abst0040" "titulo" => "Métodos" ] 3 => array:2 [ "identificador" => "abst0045" "titulo" => "Resultados" ] 4 => array:2 [ "identificador" => "abst0050" "titulo" => "Conclusiones" ] ] ] ] "multimedia" => array:2 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1543 "Ancho" => 1600 "Tamanyo" => 515565 ] ] "descripcion" => array:1 [ "en" => "Mutations observed in the Cyp51A sequences obtained from the isolates ChFC 132 and ChFC 104. (a) TR34 (red bar), (b) L98H (red arrow), and (c) F46Y/M172V/E427K (blue arrows)." ] ] 1 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "ITZ: itraconazole; VRZ: voriconazole; PCZ: posaconazole; MIC: minimal inhibitory concentration." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td-with-role" title="\n \t\t\t\t\ttable-head\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">Genotype (n)/reference strain \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " colspan="3" align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Microdilution brothMIC (mg/L)</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " colspan="3" align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Disk diffusionDiameter (mm)</th></tr><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">ITZ \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">VRZ \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">PCZ \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">ITC \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">VRZ \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">PCZ \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">t15 (1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.25 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">17 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">27 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">22 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">t02 (1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">16 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">10 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">13 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">16 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">t01 (21) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.25–1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.25–1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.25–1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">18–21 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">25–28 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">19–23 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Candida parapsilosis ATCC 22019 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.12 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.06 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.12 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">21 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">31 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">26 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Aspergillus fumigatus ATCC MYA-3626 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.25 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.25 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.25 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">17 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">31 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">31 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Hamigera insecticola ATCC MYA-3630 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.06 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.06 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.12 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">30 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">35 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">37 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab3678494.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Antifungal susceptibility profiles obtained with the microdilution broth method and the disk diffusion method." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:48 [ 0 => array:3 [ "identificador" => "bib0245" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Basic local alignment search tool" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "S.F. 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Original article

Azole resistance in a clinical isolate of Aspergillus fumigatus from Chile

Primer aislamiento clínico de Aspergillus fumigatus resistente a azoles en Chile

Eduardo Álvarez Duartea,

Corresponding author

ealvarezd@uchile.cl

Corresponding author.

, Nicolás Cepedab, Jean Mirandaa

a Laboratorio Micología, ICBM – F. de Medicina, Universidad de Chile, Chile

b Clinical Chemistry and Hematology, Hospital del Salvador, Chile

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we can find two large groups of etiological agents&#58; yeasts&#44; with <span class="elsevierStyleItalic">Candida albicans</span> being the most representative&#44; and filamentous fungi&#44; with <span class="elsevierStyleItalic">Aspergillus fumigatus</span> as the most isolated microorganism&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">The genus <span class="elsevierStyleItalic">Aspergillus</span> is a diverse group of fungi comprising many species capable of producing a wide variety of pathologies&#46; Classically&#44; the identification of the different species has been based on the phenotypic characterization of the isolates&#46; However&#44; due to the improvement and development of new molecular tools in the last decades&#44; these advanced methodologies are fundamental in the identification of the <span class="elsevierStyleItalic">Aspergillus</span> species&#46; Currently&#44; this genus contains about 446 species&#46; However&#44; only some of them are pathogenic for humans&#44; being the species belonging to the sections Fumigati&#44; Flavi&#44; Nidulantes&#44; Nigri&#44; Terrei and Usti the most commonly isolated from clinical cases&#46;<a class="elsevierStyleCrossRef" href="#bib0385"><span class="elsevierStyleSup">29</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">We daily inhale a large number of <span class="elsevierStyleItalic">Aspergillus</span> spores&#44; most of which get trapped in the epithelium of the lower respiratory tract and are eliminated by the ciliary clearance mechanism&#46; Only the smaller spores &#40;between 2 and 5<span class="elsevierStyleHsp" style=""></span>&#956;m&#41; are able to reach the pulmonary alveoli&#44; where they will be removed by the alveolar macrophages&#44; responsible for eliminating the conidia&#44; and the neutrophils&#44; responsible for destroying the few hyphae produced from the germination of the spores&#46;<a class="elsevierStyleCrossRef" href="#bib0375"><span class="elsevierStyleSup">27</span></a> However&#44; in immunocompromised patients&#44; the presence of the spores can lead to colonization of the host&#44; enabling the development of IFD&#46;<a class="elsevierStyleCrossRefs" href="#bib0285"><span class="elsevierStyleSup">9&#44;33</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">Diseases caused by species of the genus <span class="elsevierStyleItalic">Aspergillus</span> are generally referred to as aspergillosis&#46; This genus is responsible for more than 200&#44;000 cases of invasive aspergillosis &#40;IA&#41; per year&#46; Besides&#44; this genus causes more than 1&#46;2 million additional cases of chronic pulmonary aspergillosis &#40;CPA&#41; and about 4&#46;8 million cases of allergic bronchopulmonary aspergillosis &#40;ABPA&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0325"><span class="elsevierStyleSup">17&#44;18</span></a> In Chile&#44; due to the absence of official data about IFD&#44; cases of IA&#44; CPA and ABPA are estimated to occur in 1&#46;7&#47;100&#44;000&#59; 6&#46;9&#47;100&#44;000 and 97&#46;9&#47;100&#44;000&#44; respectively&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">2</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">One of the threats related to aspergillosis is the resistance to antifungals&#44; mainly azoles&#44; which are the treatment of choice in these mycoses&#46; Such resistance seems to be caused by various mutations in the Cyp51A gene&#44; which codes for 14-&#945;-demethylase&#44; the target enzyme of azole drugs&#44;<a class="elsevierStyleCrossRefs" href="#bib0410"><span class="elsevierStyleSup">34&#44;45&#44;46</span></a> and which would be related to high rates of therapeutic failure&#46; The first reports of this phenomenon date back to the 1990s&#44;<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">16</span></a> being an emerging problem widely reported in many countries around the world&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">The present work reports the isolation for the first time in Chile of azole resistant strains of <span class="elsevierStyleItalic">A&#46; fumigatus</span>&#46; We also prove the mutations in the Cyp51A gene&#46;</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Material and methods</span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Fungal isolates and morphological identification</span><p id="par0040" class="elsevierStylePara elsevierViewall">Twenty-three clinical isolates obtained from March 2017 to March 2021&#44; classified as <span class="elsevierStyleItalic">Aspergillus</span> spp&#46;&#44; were received to perform the species identification&#46; The isolates were obtained by culturing bronchoalveolar lavage samples from patients diagnosed with aspergillosis&#46; Firstly&#44; the isolates were identified by a phenotypical approach&#44; evaluating their macro- and microscopic features and their ability to grow in the dark at 10<span class="elsevierStyleHsp" style=""></span>&#176;C&#44; 25<span class="elsevierStyleHsp" style=""></span>&#176;C&#44; 37<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1<span class="elsevierStyleHsp" style=""></span>&#176;C&#44; and 50<span class="elsevierStyleHsp" style=""></span>&#176;C on potato dextrose agar &#40;PDA&#41;&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Molecular analysis</span><p id="par0045" class="elsevierStylePara elsevierViewall">According to the manufacturer&#39;s instructions&#44; the DNA was extracted using an E&#46;Z&#46;N&#46;A&#46;&#174; Fungal DNA Mini Kit &#40;Omega Biotek Store&#44; USA&#41;&#46; The universal fungal primers ITS1 and ITS4 for ITS1-5&#46;8S-ITS2 region&#44;<a class="elsevierStyleCrossRef" href="#bib0475"><span class="elsevierStyleSup">47</span></a> and Bt2a and Bt2b<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">24</span></a> for a partial &#946;-tubulin gene sequence&#44; were used&#46; A 30<span class="elsevierStyleHsp" style=""></span>&#956;l mixture containing 17<span class="elsevierStyleHsp" style=""></span>&#956;l of BioMixTM Red &#40;New England Biolabs&#41;&#44; 10<span class="elsevierStyleHsp" style=""></span>pM primers&#44; and 10<span class="elsevierStyleHsp" style=""></span>ng DNA was subjected to a DNA amplification technique&#44; following a protocol of initial denaturation at 94<span class="elsevierStyleHsp" style=""></span>&#176;C for 5<span class="elsevierStyleHsp" style=""></span>min&#44; 35 cycles of denaturation at 94<span class="elsevierStyleHsp" style=""></span>&#176;C for 1<span class="elsevierStyleHsp" style=""></span>min&#44; annealing at 52<span class="elsevierStyleHsp" style=""></span>&#176;C for 1<span class="elsevierStyleHsp" style=""></span>min for the ITS region&#44; and 55<span class="elsevierStyleHsp" style=""></span>&#176;C for &#946;-tubulin&#59; extension at 72<span class="elsevierStyleHsp" style=""></span>&#176;C for 2<span class="elsevierStyleHsp" style=""></span>min&#44; and final extension at 72<span class="elsevierStyleHsp" style=""></span>&#176;C for 7<span class="elsevierStyleHsp" style=""></span>min&#46; The PCR product was checked on 2&#37; agarose gel&#46; Purification was performed following manufacturer guidelines with FavorPrep&#8482; Gel&#47;PCR purification Mini Kit &#40;Favorgene&#44; Taiwan&#41;&#46; Sequencing was carried out in Macrogen &#40;Macrogen&#44; Korea&#41;&#46; An NCBI Blastn search for each locus region was performed&#46;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">1</span></a> Sequences from type and reference strains were retrieved from the GenBank database&#46; The sequences were aligned in MUSCLE software<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">20</span></a> followed by manual adjustments with a text editor&#46; ITS sequences were used to identify isolates to the <span class="elsevierStyleItalic">Aspergillus</span>-section level&#44; and partial &#946;-tubulin sequences were used to identify to the species level&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">The entire sequences of the Cyp51A gene and promoter regions were amplified as previously described<a class="elsevierStyleCrossRef" href="#bib0450"><span class="elsevierStyleSup">42</span></a> in any isolate that exhibited azole resistance with the purpose of finding mutations that might explain that condition&#46; Sequencing and analyses were carried out as formerly mentioned&#46; The DNA sequences were compared with the wild-type susceptible <span class="elsevierStyleItalic">A&#46; fumigatus</span> reference strain &#40;GenBank <a href="ncbi-n:AF338659">AF338659</a>&#41;&#46;</p><p id="par0055" class="elsevierStylePara elsevierViewall">Finally&#44; the cell surface protein &#40;CSP&#41; encoding gene was partially sequenced<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">8</span></a> in all the isolates to perform the CSP typing according to the nomenclature reported by Klaassen et al&#46;<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">32</span></a></p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Antifungal analysis</span><p id="par0060" class="elsevierStylePara elsevierViewall">The in vitro susceptibility to itraconazole &#40;ITZ&#41;&#44; posaconazole &#40;PCZ&#41; and voriconazole &#40;VRZ&#41; was evaluated by the broth microdilution method performed according to the CLSI document M38M51S&#46;<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">13</span></a> The antifungal concentration of ITZ&#44; PCZ and VRZ ranged from 0&#46;0156 to 8<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;mL&#46; The inoculated plates were incubated at 35<span class="elsevierStyleHsp" style=""></span>&#176;C and observed after 24<span class="elsevierStyleHsp" style=""></span>h&#46; The lack of visual growth in each well was defined as the MIC value&#46; Due to the absence of breakpoints for filamentous fungi in the CLSI method &#40;except for voriconazole and <span class="elsevierStyleItalic">A&#46; fumigatus</span>&#41;&#44; the epidemiological cut-off values &#40;ECVs&#41; were used &#40;1<span class="elsevierStyleHsp" style=""></span>mg&#47;L for ITZ and VRZ&#44; 0&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;L for PCZ&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0310"><span class="elsevierStyleSup">14&#44;10&#44;22</span></a> In order to confirm the obtained results&#44; the susceptibility test was performed twice&#46; <span class="elsevierStyleItalic">Candida parapsilosis</span> ATCC 22019&#44; <span class="elsevierStyleItalic">A&#46; fumigatus</span> ATCC MYA-3626 and <span class="elsevierStyleItalic">Hamigera insecticola</span> &#40;ex&#46; <span class="elsevierStyleItalic">Paecilomyces variotii</span>&#41; ATCC MYA-3630 were used as controls&#46;</p><p id="par0065" class="elsevierStylePara elsevierViewall">In addition&#44; an antifungal susceptibility test by the disk diffusion method was performed according to the CLSI M38M51S document&#46;<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">13</span></a> Isolates were subcultured on PDA at 25<span class="elsevierStyleHsp" style=""></span>&#176;C for 5&#8211;7 days before testing&#46; Then&#44; the surface of a Mueller Hinton agar &#40;MHA&#41; plate dish was inoculated with a sterile cotton swab with the undiluted mold stock inoculum suspension&#46; Antifungal disks &#40;Rosco Diagnostica&#44; Denmark&#41; including ITZ &#40;10<span class="elsevierStyleHsp" style=""></span>&#956;g&#41;&#44; PCZ &#40;5<span class="elsevierStyleHsp" style=""></span>&#956;g&#41;&#44; and VRZ &#40;1<span class="elsevierStyleHsp" style=""></span>&#956;g&#41; were applied onto the surface of the inoculated media&#46; The plates were incubated at 35<span class="elsevierStyleHsp" style=""></span>&#176;C and read after 24&#8211;48<span class="elsevierStyleHsp" style=""></span>h&#46; Zone diameters were interpreted according to CLSI M38M51S&#46; A slight trailing or hyphal element extending into the inhibition zone was ignored&#46;</p></span></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Results</span><p id="par0070" class="elsevierStylePara elsevierViewall">The twenty-three strains analyzed in the present study were identified as <span class="elsevierStyleItalic">Aspergillus</span> section <span class="elsevierStyleItalic">Fumigati</span> based on their morphological and physiological characteristics&#58; blue-green colored velutinous colonies&#44; and abundant sporulation on PDA&#46; The isolates showed subclavate vesicles &#40;13&#8211;26<span class="elsevierStyleHsp" style=""></span>&#956;m&#41;&#44; uniseriate columnar heads and flexuous conidiophore&#46; No strain grew at 10<span class="elsevierStyleHsp" style=""></span>&#176;C&#44; but did it at 50<span class="elsevierStyleHsp" style=""></span>&#176;C on PDA&#44; as expected according to the literature&#46;<a class="elsevierStyleCrossRefs" href="#bib0380"><span class="elsevierStyleSup">28&#44;40</span></a> The analysis of the nucleotide sequences of the &#946;-tubulin gene showed that two strains had a percent identity equal to or higher than 99&#37; with those sequences of <span class="elsevierStyleItalic">A&#46; fumigatus</span><span class="elsevierStyleItalic">sensu stricto</span> available in the GenBank&#47;NCBI database &#40;99&#46;6&#37; sequence of the strain &#62;EF669851&#46;1 NRRL 5587&#41;&#46;</p><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Antifungal susceptibility</span><p id="par0075" class="elsevierStylePara elsevierViewall"><a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> shows the antifungal susceptibility profiles obtained by means of the microdilution method and the disk diffusion method&#46; Voriconazole and posaconazole showed the highest activity&#46; One isolate &#40;ChFC 132&#41; was resistant to voriconazole with a MIC of 8<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;mL&#46; Also&#44; and due to a lack of clinical breakpoints&#44; ChFC 132 was considered as non-wild type &#40;NWT&#41; based on the proposed ECV&#44; exhibiting MIC values of 16<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;mL for ITZ and 1<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;mL for PCZ&#46; The remaining 22 isolates showed MIC values of 1<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;mL&#44; 0&#46;5<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;mL and 0&#46;25<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;mL for ITZ&#44; VRZ and PCZ&#44; respectively&#46; Based on these results&#44; these isolates were considered susceptible to VRZ and wild-type for ITZ and PCZ&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0080" class="elsevierStylePara elsevierViewall">The results obtained with the disk diffusion method were consistent with those observed with the microdilution broth methodology&#46; In brief&#44; isolate ChFC 132 showed an inhibition zone &#8804;17<span class="elsevierStyleHsp" style=""></span>mm for all triazoles tested&#46; According to these values&#44; ChFC 132 was considered NWT&#46; In the remaining 22 strains&#44; the inhibition halos observed were greater than 17<span class="elsevierStyleHsp" style=""></span>mm for VRZ&#44; PCZ and ITZ&#44; being considered as susceptible to all the antifungals tested&#46; However&#44; one of these strains &#40;ChFC 104&#41; exhibited inhibition halos &#8805;17<span class="elsevierStyleHsp" style=""></span>mm for VRZ and PCZ&#44; but &#8804;17<span class="elsevierStyleHsp" style=""></span>mm for ITZ&#46; Interestingly&#44; in the halo around the ITZ disk&#44; a trailing zone was observed&#44; which is why it was decided to sequence the CYP51A gene in order to elucidate putative mutations&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Cyp51A gene sequencing and CSP typing</span><p id="par0085" class="elsevierStylePara elsevierViewall">Sequencing of the Cyp51A gene and its promoter showed the presence of the 34 bp tandem repeat &#40;TR34&#41; and L98H mutation in the strain ChFC 132&#46; In addition&#44; this analysis revealed that the second isolate &#40;ChFC 104&#41; harboured the F46Y&#47;M172V&#47;E427K mutations &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; In the remaining isolates&#44; no mutations were observed&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0090" class="elsevierStylePara elsevierViewall">The characterization of the CSP showed that our strains corresponded to types previously described in the literature&#46; The strain ChFC 132 belongs to type t02&#44; while the ChFC 104 was identified as type t15&#46; The other 21 strains were classified into type t01&#46;</p></span></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Discussion</span><p id="par0095" class="elsevierStylePara elsevierViewall">Invasive aspergillosis is a very important challenge in medical mycology&#46; An early diagnosis may be difficult to achieve&#44; and the treatment of the disease is complex&#44; so antifungal agents are used at the slightest suspicion of infection&#46; In this context&#44; the development of secondary resistance to commonly used antifungals gets facilitated&#46; This fact is becoming a problem that is aggravated by the existence of cross-resistance between clinical triazoles and other azoles of the same family used as antifungals in agriculture&#46;<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">23</span></a></p><p id="par0100" class="elsevierStylePara elsevierViewall">Likewise&#44; azole resistance is now being reported in countries worldwide&#46;<a class="elsevierStyleCrossRefs" href="#bib0265"><span class="elsevierStyleSup">5&#44;19&#44;44</span></a> In Latin America&#44; several countries have reported the presence of azole resistance in <span class="elsevierStyleItalic">A&#46; fumigatus</span>&#44; such as Colombia&#44;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">3</span></a> Argentina<a class="elsevierStyleCrossRef" href="#bib0390"><span class="elsevierStyleSup">30</span></a> and Peru&#44;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">11</span></a> among others&#46; To our knowledge&#44; this study describes for the first time in Chile the presence of azole resistance in <span class="elsevierStyleItalic">A&#46; fumigatus</span>&#46; Our two isolates with the mutations already mentioned were recovered from the bronchoalveolar lavage of two patients with aspergillosis&#46; The samples were sent to our laboratory in order to check the presence of fungal organisms&#46; Due to our passive surveillance strategy&#44; we performed a disk diffusion test to evaluate their susceptibility patterns to some azoles&#46; Based on the presence of halos &#8804;17<span class="elsevierStyleHsp" style=""></span>mm &#40;ChFC 132&#41;&#44; as well as the presence of what appeared to be trailing &#40;ChFC 104&#41;&#44; the isolates were subjected to the broth microdilution method&#44; and the sequencing of the Cyp51A gene&#46; The first strain was harbouring the TR34&#47;L98H mutations&#46; These substitutions and tandem repeat sequences in the promoter region are some of the most commonly reported azole-resistance mutations&#46;<a class="elsevierStyleCrossRefs" href="#bib0425"><span class="elsevierStyleSup">37&#44;43</span></a> They were first described in Dutch <span class="elsevierStyleItalic">A&#46; fumigatus</span> isolates&#44; but are now spread worldwide<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">19</span></a> due to the extensive use of azole fungicides in agriculture and animals&#46; These mutations have been related to high MIC values to azoles in several global studies&#44; especially to itraconazole and voriconazole&#46; Our results show MICs over 1<span class="elsevierStyleHsp" style=""></span>mg&#47;L for VRZ and ITZ&#44; and 0&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;L for PCZ&#44; allowing us to classify this isolate as resistant for voriconazole&#44; and NWT for itraconazole&#47;posaconazole&#44; respectively&#46; This finding agrees with other reports demonstrating the pan-azole resistance that confers the presence of TR34&#47;L98H&#46;<a class="elsevierStyleCrossRefs" href="#bib0365"><span class="elsevierStyleSup">25&#44;48</span></a></p><p id="par0105" class="elsevierStylePara elsevierViewall">The F46Y&#47;M172V&#47;E427K substitutions were observed in the second isolate&#46; Curiously&#44; these mutations had been identified in both azole-susceptible and resistant <span class="elsevierStyleItalic">A&#46; fumigatus</span> isolates&#46;<a class="elsevierStyleCrossRefs" href="#bib0345"><span class="elsevierStyleSup">21&#44;31</span></a> The F46Y&#47;M172V&#47;E427K mutations seem to be located in a protein region that does not interact with azole compounds or&#44; at least&#44; does not affect the structure of the protein&#46;<a class="elsevierStyleCrossRef" href="#bib0450"><span class="elsevierStyleSup">42</span></a> The above suggests that the mutations found might not be the molecular mechanism related to the observed resistance to azoles&#46; In the same way&#44; other situations&#44; such as mutations of the HapE or Hmg1 gene&#44; or efflux pumps&#44; among others&#44; could explain azole resistance in some isolates&#46;<a class="elsevierStyleCrossRefs" href="#bib0300"><span class="elsevierStyleSup">12&#44;26&#44;38</span></a></p><p id="par0110" class="elsevierStylePara elsevierViewall">In our study&#44; three previously observed genotypes were identified&#46; Most of the clinical strains analyzed in the present study were susceptible to all the antifungal assayed&#46; Moreover&#44; they were identified as the t01 genotype&#46; Worldwide&#44; the t01 genotype has been mostly associated with susceptible strains&#59; however&#44; resistant isolates have also been reported within that genotype&#46; It seems that both susceptible and resistant isolates can be found in all genotypes&#46; In fact&#44; in a study carried out in the United Kingdom&#44; no susceptible isolates were associated with the t01 genotype but with genotypes t03&#44; t04A&#44; t05&#44; and t08&#46;<a class="elsevierStyleCrossRef" href="#bib0445"><span class="elsevierStyleSup">41</span></a> With respect to the other genotypes analyzed&#44; isolate ChFC 132 was linked to t02 genotype&#44; commonly associated with the TR34&#47;L98H mutations&#46;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">6</span></a> Likewise&#44; the strain ChFC 104 was characterized as t15&#44; a genotype reported in Europe and Australia&#46; Interestingly&#44; strains belonging to genotype t15 harboring F46Y&#47;M172V&#47;E427K mutations seem to be susceptible to all azoles&#46;<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">15</span></a> As we can observe&#44; these genotypes have been recovered in several countries around the world&#44; exhibiting a low genetic variation compared with wild-type strains&#46; The detection of identical genotypes in distant countries suggests the clonal expansion&#44; presumably airborne dispersal&#46;<a class="elsevierStyleCrossRef" href="#bib0445"><span class="elsevierStyleSup">41</span></a></p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Conclusions</span><p id="par0115" class="elsevierStylePara elsevierViewall">We report the finding of two clinical strains from Chile with mutations in the Cyp51A gene&#46; The results obtained with both the disk diffusion method and the microdilution broth methodology were consistent&#46; This demonstrates the usefulness and advantages of disk diffusion&#58; its low cost and easy implementation in low complexity laboratories are the most remarkable features&#46; Likewise&#44; this methodology seems to predict azole resistance efficiently&#46; Future studies involving more clinical and environmental strains are necessary to elucidate Chile&#39;s accurate picture of azole resistance&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Ethical approval</span><p id="par0120" class="elsevierStylePara elsevierViewall">Not applicable&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Funding</span><p id="par0125" class="elsevierStylePara elsevierViewall">This research received no external funding&#46;</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Authors&#8217; contributions</span><p id="par0130" class="elsevierStylePara elsevierViewall">Conceptualization&#44; E&#46;A&#46;D&#59; Methodology&#44; E&#46;A&#46;D&#46;&#44; N&#46;C&#46;&#44; J&#46;M&#46;&#59; Investigation&#44; E&#46;A&#46;D&#46;&#44; N&#46;C&#46;&#44; J&#46;M&#46;&#59; Writing &#8211; original draft preparation&#44; E&#46;A&#46;D&#46;&#44; N&#46;C&#46;&#59; Writing &#8211; review and editing&#44; E&#46;A&#46;D&#46; All authors have read and agreed to the published version of the manuscript&#46;</p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Consent to participate</span><p id="par0135" class="elsevierStylePara elsevierViewall">Not applicable&#46;</p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0140">Consent for publication</span><p id="par0140" class="elsevierStylePara elsevierViewall">Not applicable&#46;</p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0145">Competing interests</span><p id="par0145" class="elsevierStylePara elsevierViewall">The authors declare no conflict of interest&#46;</p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0150">Availability of data and materials</span><p id="par0150" class="elsevierStylePara elsevierViewall">The data that support the findings of this study are available from the corresponding author upon reasonable request&#46;</p></span></span>"
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    "fechaRecibido" => "2023-05-10"
    "fechaAceptado" => "2024-04-19"
    "PalabrasClave" => array:2 [
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        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Keywords"
          "identificador" => "xpalclavsec1888128"
          "palabras" => array:5 [
            0 => "<span class="elsevierStyleItalic">Aspergillus fumigatus</span>"
            1 => "Antifungal resistance"
            2 => "Mechanisms of antifungal resistance"
            3 => "Triazoles"
            4 => "cyp51A"
          ]
        ]
      ]
      "es" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Palabras clave"
          "identificador" => "xpalclavsec1888129"
          "palabras" => array:5 [
            0 => "<span class="elsevierStyleItalic">Aspergillus fumigatus</span>"
            1 => "Resistencia antif&#250;ngica"
            2 => "Mecanismos de resistencia a los antif&#250;ngicos"
            3 => "Triazoles"
            4 => "cyp51A"
          ]
        ]
      ]
    ]
    "tieneResumen" => true
    "resumen" => array:2 [
      "en" => array:3 [
        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Background</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Aspergillus fumigatus</span> is a ubiquitous opportunistic pathogen&#46; This fungus can acquire resistance to azole antifungals due to different mutations in the cyp51A gene&#46; Azole resistance has been observed in several continents and appears to be a globally distributed phenomenon&#46; Specific mutations in cyp51A that lead to azole resistance&#44; such as the TR34&#47;L98H modification&#44; have been reported&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Aims</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">To evaluate the azole resistance in clinically isolated <span class="elsevierStyleItalic">A&#46; fumigatus</span> strains&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Methods</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">As a result of our passive surveillance strategy&#44; a total of 23 <span class="elsevierStyleItalic">A&#46; fumigatus</span> isolates from clinical origins were identified through a phylogenetic analysis using the ITS region and &#946;-tubulin gene fragments&#44; and typed with the CSP microsatellite&#46; Azole susceptibility profiles were performed by disk diffusion and microdilution broth methodologies according to CLSI guidelines&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Results</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Here we describe&#44; for the first time&#44; the detection of azole-resistant <span class="elsevierStyleItalic">A&#46; fumigatus</span> isolates from clinical origins in Chile with mutations in the cyp51A gene&#46; In addition to the TR34&#47;L98H mutation&#44; one isolate exhibited an F46Y&#47;M172V&#47;E427K-type mutation&#46; Furthermore&#44; microsatellite typing based on cell surface protein &#40;CSP&#41; was performed&#44; showing the t02 &#40;TR34&#47;L98H&#41;&#44; t15 &#40;F46Y&#47;M172V&#47;E427K&#41; and t01 &#40;susceptible clinical isolates&#41; genotypes&#46;</p></span> <span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Conclusions</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Our study demonstrates the presence of mutations related to azole resistance in <span class="elsevierStyleItalic">A&#46; fumigatus</span> strains isolated from clinical samples in Chile&#46; In order to obtain information that may help to tackle the spread of antifungal resistance among <span class="elsevierStyleItalic">A&#46; fumigatus</span> populations&#44; and to ensure the efficacy of future treatments against aspergillosis&#44; a further research is necessary&#46;</p></span>"
        "secciones" => array:5 [
          0 => array:2 [
            "identificador" => "abst0005"
            "titulo" => "Background"
          ]
          1 => array:2 [
            "identificador" => "abst0010"
            "titulo" => "Aims"
          ]
          2 => array:2 [
            "identificador" => "abst0015"
            "titulo" => "Methods"
          ]
          3 => array:2 [
            "identificador" => "abst0020"
            "titulo" => "Results"
          ]
          4 => array:2 [
            "identificador" => "abst0025"
            "titulo" => "Conclusions"
          ]
        ]
      ]
      "es" => array:3 [
        "titulo" => "Resumen"
        "resumen" => "<span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Antecedentes</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Aspergillus fumigatus</span> es un pat&#243;geno oportunista ubicuo&#46; Este hongo puede adquirir resistencia a los antif&#250;ngicos az&#243;licos gracias a diferentes mutaciones en el gen cyp51A&#46; La resistencia a los azoles se ha observado en varios continentes y parece ser un fen&#243;meno de distribuci&#243;n mundial&#46; Se han descrito mutaciones espec&#237;ficas en cyp51A para adquirir resistencia a los azoles&#44; como la modificaci&#243;n TR34&#47;L98H&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Objetivos</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Evaluar la resistencia a los azoles en aislamientos de <span class="elsevierStyleItalic">A&#46; fumigatus</span> obtenidos de muestras cl&#237;nicas&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">M&#233;todos</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Gracias a la vigilancia pasiva se identific&#243; un total de 23 aislamientos de <span class="elsevierStyleItalic">A&#46; fumigatus</span> de origen cl&#237;nico a trav&#233;s de un an&#225;lisis filogen&#233;tico mediante el estudio de la regi&#243;n ITS y de fragmentos del gen de la &#946;-tubulina&#44; que se tipificaron con el microsat&#233;lite CSP&#46; Los perfiles de sensibilidad a los azoles se realizaron mediante los m&#233;todos de difusi&#243;n en disco y microdiluci&#243;n&#46;</p></span> <span id="abst0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Resultados</span><p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">En el presente trabajo describimos&#44; por primera vez en Chile&#44; la detecci&#243;n de aislamientos cl&#237;nicos de <span class="elsevierStyleItalic">A&#46; fumigatus</span> en este pa&#237;s resistentes a azoles&#44; con mutaciones en el gen cyp51A&#46; Adem&#225;s de la mutaci&#243;n TR34&#47;L98H&#44; un aislamiento present&#243; una mutaci&#243;n de tipo F46Y&#47;M172V&#47;E427K&#46; Se realiz&#243; la tipificaci&#243;n por microsat&#233;lites basada en la prote&#237;na de superficie celular&#44; que mostr&#243; los genotipos t02 &#40;TR34&#47;L98H&#41;&#44; t15 &#40;F46Y&#47;M172V&#47;E427K&#41; y t01 &#40;cepas sensibles&#41;&#46;</p></span> <span id="abst0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Conclusiones</span><p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Nuestro estudio demuestra la presencia de mutaciones relacionadas con la resistencia a los azoles en cepas de <span class="elsevierStyleItalic">A&#46; fumigatus</span> aisladas de muestras cl&#237;nicas en Chile&#46; Para obtener informaci&#243;n que pueda ayudar a atajar la propagaci&#243;n de la resistencia a los antif&#250;ngicos entre las poblaciones de <span class="elsevierStyleItalic">A&#46; fumigatus</span>&#44; y garantizar as&#237; la eficacia de futuros tratamientos contra la aspergilosis&#44; es necesario seguir investigando&#46;</p></span>"
        "secciones" => array:5 [
          0 => array:2 [
            "identificador" => "abst0030"
            "titulo" => "Antecedentes"
          ]
          1 => array:2 [
            "identificador" => "abst0035"
            "titulo" => "Objetivos"
          ]
          2 => array:2 [
            "identificador" => "abst0040"
            "titulo" => "M&#233;todos"
          ]
          3 => array:2 [
            "identificador" => "abst0045"
            "titulo" => "Resultados"
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          4 => array:2 [
            "identificador" => "abst0050"
            "titulo" => "Conclusiones"
          ]
        ]
      ]
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    "multimedia" => array:2 [
      0 => array:7 [
        "identificador" => "fig0005"
        "etiqueta" => "Fig&#46; 1"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr1.jpeg"
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        "descripcion" => array:1 [
          "en" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Mutations observed in the Cyp51A sequences obtained from the isolates ChFC 132 and ChFC 104&#46; &#40;a&#41; TR34 &#40;red bar&#41;&#44; &#40;b&#41; L98H &#40;red arrow&#41;&#44; and &#40;c&#41; F46Y&#47;M172V&#47;E427K &#40;blue arrows&#41;&#46;</p>"
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            "identificador" => "at1"
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          "leyenda" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">ITZ&#58; itraconazole&#59; VRZ&#58; voriconazole&#59; PCZ&#58; posaconazole&#59; MIC&#58; minimal inhibitory concentration&#46;</p>"
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                  \t\t\t\t"><span class="elsevierStyleItalic">Candida parapsilosis</span> ATCC 22019&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">Aspergillus fumigatus</span> ATCC MYA-3626&nbsp;\t\t\t\t\t\t\n
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