Caracterização molecular e prospecção de combinações antifúngicas sinérgicas “in vitro” frente a Trichosporon asahii, antes e após exposição prolongada ao fluconazol
Autor(a) principal: | |
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Data de Publicação: | 2016 |
Tipo de documento: | Tese |
Idioma: | por |
Título da fonte: | Biblioteca Digital de Teses e Dissertações do UFSM |
Texto Completo: | http://repositorio.ufsm.br/handle/1/17973 |
Resumo: | The occurence of invasive fungal infections caused by emerging fungal pathogens has increased considerably in the last decades. The genus Trichosporon comprises species relevant in this context, due to reduced susceptibility to amphotericin B (AMB) and echinocandins, as well as the emergence of resistant strains to azole antifungals, especially to fluconazole (FCZ). Among the strategies to combat the therapeutic failures, the combination of drugs with different mechanisms of action has deserved attention. This study aimed to identify genotypically clinical isolates (n = 30), and to evaluate the susceptibility in vitro of T. asahii, before and after induction the resistance to fluconazole, to antifungal agents: AMB, FCZ, itraconazole (ITZ), voriconazole (VCZ), caspofungin (CPF), micafungin (MCF) and anidulafungin (AND), and non-antifungal compounds: tacrolimus (FK 506), diphenyl diselenide (DPDS), and ebselen (EBS), by determining the minimum inhibitory concentrations (MICs), as M27-A3 (CLSI, 2008). T. asahii was the most prevalent specie among isolates from urine and blood identified. The results MICs confirm the intrinsic resistance of T. asahii to echinocandins (MICs ≥ 4 μg mL-1), and the superiority of the triazole compounds against this specie. Moreover, it was observed that, other than AMB (MIC90 = 1 μg mL-1), the fluconazole-resistant isolates (FR) were less sensitive to azoles than fluconazole-sensitive group (FS), and this cross-resistance phenomenon is more significant forward to ITZ (90%), followed by the POS (36.67%) and VCZ (10%). The results of the antifungal associations and non-antifungal compounds against T. asahii FS and FR were evaluated by microdilution checkerboard method. FK506 (MICs > 64 μg mL-1) and the DPDS (MICs ≥ 8 μg mL-1), did not show satisfactory antifungal activity against T. asahii FS and FR. However, high percentages of synergistic interactions were exibited in the association of AMB + FK506 (96.67%), CPF + FK506 (73.33%) and AMB + DPDS (90%) against FS isolates, as well against the T. asahii FR group: CAS + DPDS (96.67%), AMB + DPDS (93.33%), FCZ + DPDS (86.67%), and ITZ + DPDS (83.33%). On the other hand, the organic compound EBS stood out by the low MIC values (0.25 to 8 μg mL-1) when tested alone, and a strong synergism in combination with AMB (90%) against T. asahii FR. Additionally, were tested combinations of AMB and echinocandins or FCZ, and CPF + FCZ against FR isolates that, other than CPF + FCZ combination (66.67% synergistic interactions), resulted in predominantly indifferent activity. Antagonistic interactions were not observed in the associations of antifungals. In this context, the in vitro exposure to increasing concentrations of fluconazole is an important factor for the emergence of resistance in T. asahii, this phenomenon brings consequences for the susceptibility profile of this specie. Moreover, the synergism observed in vitro is promising for the development of new studies to understand the activity of FK506 and organoselenium compounds against T. asahii for future application as a complementary role in the treatment of tricosporonosis. |
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2019-08-20T16:15:25Z2019-08-20T16:15:25Z2016-11-17http://repositorio.ufsm.br/handle/1/17973The occurence of invasive fungal infections caused by emerging fungal pathogens has increased considerably in the last decades. The genus Trichosporon comprises species relevant in this context, due to reduced susceptibility to amphotericin B (AMB) and echinocandins, as well as the emergence of resistant strains to azole antifungals, especially to fluconazole (FCZ). Among the strategies to combat the therapeutic failures, the combination of drugs with different mechanisms of action has deserved attention. This study aimed to identify genotypically clinical isolates (n = 30), and to evaluate the susceptibility in vitro of T. asahii, before and after induction the resistance to fluconazole, to antifungal agents: AMB, FCZ, itraconazole (ITZ), voriconazole (VCZ), caspofungin (CPF), micafungin (MCF) and anidulafungin (AND), and non-antifungal compounds: tacrolimus (FK 506), diphenyl diselenide (DPDS), and ebselen (EBS), by determining the minimum inhibitory concentrations (MICs), as M27-A3 (CLSI, 2008). T. asahii was the most prevalent specie among isolates from urine and blood identified. The results MICs confirm the intrinsic resistance of T. asahii to echinocandins (MICs ≥ 4 μg mL-1), and the superiority of the triazole compounds against this specie. Moreover, it was observed that, other than AMB (MIC90 = 1 μg mL-1), the fluconazole-resistant isolates (FR) were less sensitive to azoles than fluconazole-sensitive group (FS), and this cross-resistance phenomenon is more significant forward to ITZ (90%), followed by the POS (36.67%) and VCZ (10%). The results of the antifungal associations and non-antifungal compounds against T. asahii FS and FR were evaluated by microdilution checkerboard method. FK506 (MICs > 64 μg mL-1) and the DPDS (MICs ≥ 8 μg mL-1), did not show satisfactory antifungal activity against T. asahii FS and FR. However, high percentages of synergistic interactions were exibited in the association of AMB + FK506 (96.67%), CPF + FK506 (73.33%) and AMB + DPDS (90%) against FS isolates, as well against the T. asahii FR group: CAS + DPDS (96.67%), AMB + DPDS (93.33%), FCZ + DPDS (86.67%), and ITZ + DPDS (83.33%). On the other hand, the organic compound EBS stood out by the low MIC values (0.25 to 8 μg mL-1) when tested alone, and a strong synergism in combination with AMB (90%) against T. asahii FR. Additionally, were tested combinations of AMB and echinocandins or FCZ, and CPF + FCZ against FR isolates that, other than CPF + FCZ combination (66.67% synergistic interactions), resulted in predominantly indifferent activity. Antagonistic interactions were not observed in the associations of antifungals. In this context, the in vitro exposure to increasing concentrations of fluconazole is an important factor for the emergence of resistance in T. asahii, this phenomenon brings consequences for the susceptibility profile of this specie. Moreover, the synergism observed in vitro is promising for the development of new studies to understand the activity of FK506 and organoselenium compounds against T. asahii for future application as a complementary role in the treatment of tricosporonosis.A ocorrência de micoses invasivas causadas por patógenos fúngicos emergentes tem aumentado consideravelmente nas últimas décadas. O gênero Trichosporon compreende espécies relevantes neste cenário, devido à reduzida suscetibilidade à anfotericina B (AMB) e às equinocandinas, bem como o aparecimento de cepas resistentes aos antifúngicos azólicos, em especial ao fluconazol (FCZ). Dentre as estratégias para combater as falhas terapêuticas, a combinação de fármacos com distintos mecanismos de ação tem merecido atenção. Este estudo objetivou identificar genotipicamente os isolados clínicos (n=30), bem como avaliar a suscetibilidade in vitro de T. asahii, antes e após exposição prolongada ao fluconazol. Os agentes testados foram os antifúngicos AMB, FCZ, itraconazol (ITZ), voriconazol (VCZ), posaconazol (POS), caspofungina (CPF), micafungina (MCF) e anidulafungina (AND), e compostos não antifúngicos tacrolimus (FK506), disseleneto de difenila (DPDS) e ebselen (EBS); todos testes foram realizados pela determinação das concentrações inibitórias mínimas (CIMs), conforme o protocolo M27-A3 (CLSI, 2008). T. asahii apresentou-se como a única espécie identificada molecularmente dentre os isolados provenientes de amostras de urina e sangue caracterizados. As CIMs confirmaram a resistência intrínsica de T. asahii às equinocandinas (CIMs ≥ 4 μg/mL), bem como a superioridade dos compostos triazólicos frente a essa espécie. Ademais, foi possível observar que, com exceção da AMB (CIM90 = 1 μg/mL), os isolados FCZ-resistentes (FR) foram menos sensíveis aos azólicos do que o grupo FCZ-sensível (FS), sendo esse fenômeno de resistência cruzada mais expressivo frente ao ITZ (90%), seguido do POS (36,67%) e VCZ (10%). Os resultados das associações de antifúngicos e não antifúngicos frente aos grupos de T. asahii FS e FR foram avaliados pelo método de microdiluição checkerboard. O FK506 (CIMs > 64 μg/mL), assim como o DPDS (CIMs ≥ 8 μg/mL), não demonstraram satisfatória ação antifúngica frente T. asahii FS e FR. Entretanto, consideráveis percentuais de interações sinérgicas foram exibidos na associação de AMB + FK506 (96,67%), CPF + FK506 (73,33%) e AMB + DPDS (90%) frente aos isolados FS, assim como frente ao grupo de T. asahii FR: CAS + DPDS (96.67%), AMB + DPDS (93.33%), FCZ + DPDS (86.67%), and ITZ + DPDS (83.33%). Por outro lado, o organocomposto EBS destacou-se pelos baixos valores de CIMs (0,25 - 8 μg/mL) quando testado isoladamente, além do sinergismo na associação com AMB (90%) sobre T. asahii FR. Adicionalmente, foram testadas combinações AMB e equinocandinas ou FCZ, e CPF + FCZ frente aos isolados FR que, com exceção da combinação CPF + FCZ (66,67% de sinergismo), resultaram em predomínio de atividade indiferente. Interações antagônicas não foram observadas nas associações entre antifúngicos. Neste contexto, a exposição in vitro a concentrações crescentes de fluconazol é um fator importante para a emergência de resistência em T. asahii, fenômeno este que agrega consequências para o perfil de suscetibilidade desta espécie. Além disso, os sinergismos observados in vitro, são promissores para o desenvolvimento de estudos in vivo, bem como elucidar a atividade do FK506 e organocompostos de selênio contra T. asahii.porUniversidade Federal de Santa MariaCentro de Ciências da SaúdePrograma de Pós-Graduação em Ciências FarmacêuticasUFSMBrasilFarmacologiaAttribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessResistênciaSuscetibilidadeTacrolimusDisseleneto de difenilaEbselenResistanceSusceptibilityTacrolimusDiphenyl diselenideCNPQ::CIENCIAS BIOLOGICAS::FARMACOLOGIACaracterização molecular e prospecção de combinações antifúngicas sinérgicas “in vitro” frente a Trichosporon asahii, antes e após exposição prolongada ao fluconazolMolecular characterization and "in vitro" prospection of synergistic antifungal combinations for Trichosporon asahii before and after prolonged exposure to fluconazoleinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/doctoralThesisAlves, Sydney Hartzhttp://lattes.cnpq.br/0330782478769631Zanette, Régis Adrielhttp://lattes.cnpq.br/3166371422900794Mario, Débora Alves Nuneshttp://lattes.cnpq.br/0731595522786356Peres, Paulo Edelvar Corrêahttp://lattes.cnpq.br/1363957298527005Trindade, Priscila de Arrudahttp://lattes.cnpq.br/0124362929241308http://lattes.cnpq.br/0657276243683382Kubiça, Thaís Felli201000000000600bfe6016c-9c1e-42ca-ab1d-db5453ed090cae616355-6ce5-4530-90c0-ae103708eef2a54b7e0a-0ca7-42cd-9ccc-4852c6fb9e318a8a3af4-9c5c-4e0d-9fa6-78508c19a6fdc6a2e8c9-7434-4e54-b28a-10f7da532df1cfc2887a-ae7d-4e03-9984-f2ccfe8fc1fdreponame:Biblioteca Digital de Teses e Dissertações do UFSMinstname:Universidade Federal de Santa Maria (UFSM)instacron:UFSMORIGINALTES_PPGCF_2016_KUBICA_THAIS.pdfTES_PPGCF_2016_KUBICA_THAIS.pdfTese de Doutoradoapplication/pdf2353849http://repositorio.ufsm.br/bitstream/1/17973/1/TES_PPGCF_2016_KUBICA_THAIS.pdfa0f80e74d19912764f4a1fe3371e2e65MD51CC-LICENSElicense_rdflicense_rdfapplication/rdf+xml; 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dc.title.por.fl_str_mv |
Caracterização molecular e prospecção de combinações antifúngicas sinérgicas “in vitro” frente a Trichosporon asahii, antes e após exposição prolongada ao fluconazol |
dc.title.alternative.eng.fl_str_mv |
Molecular characterization and "in vitro" prospection of synergistic antifungal combinations for Trichosporon asahii before and after prolonged exposure to fluconazole |
title |
Caracterização molecular e prospecção de combinações antifúngicas sinérgicas “in vitro” frente a Trichosporon asahii, antes e após exposição prolongada ao fluconazol |
spellingShingle |
Caracterização molecular e prospecção de combinações antifúngicas sinérgicas “in vitro” frente a Trichosporon asahii, antes e após exposição prolongada ao fluconazol Kubiça, Thaís Felli Resistência Suscetibilidade Tacrolimus Disseleneto de difenila Ebselen Resistance Susceptibility Tacrolimus Diphenyl diselenide CNPQ::CIENCIAS BIOLOGICAS::FARMACOLOGIA |
title_short |
Caracterização molecular e prospecção de combinações antifúngicas sinérgicas “in vitro” frente a Trichosporon asahii, antes e após exposição prolongada ao fluconazol |
title_full |
Caracterização molecular e prospecção de combinações antifúngicas sinérgicas “in vitro” frente a Trichosporon asahii, antes e após exposição prolongada ao fluconazol |
title_fullStr |
Caracterização molecular e prospecção de combinações antifúngicas sinérgicas “in vitro” frente a Trichosporon asahii, antes e após exposição prolongada ao fluconazol |
title_full_unstemmed |
Caracterização molecular e prospecção de combinações antifúngicas sinérgicas “in vitro” frente a Trichosporon asahii, antes e após exposição prolongada ao fluconazol |
title_sort |
Caracterização molecular e prospecção de combinações antifúngicas sinérgicas “in vitro” frente a Trichosporon asahii, antes e após exposição prolongada ao fluconazol |
author |
Kubiça, Thaís Felli |
author_facet |
Kubiça, Thaís Felli |
author_role |
author |
dc.contributor.advisor1.fl_str_mv |
Alves, Sydney Hartz |
dc.contributor.advisor1Lattes.fl_str_mv |
http://lattes.cnpq.br/0330782478769631 |
dc.contributor.referee1.fl_str_mv |
Zanette, Régis Adriel |
dc.contributor.referee1Lattes.fl_str_mv |
http://lattes.cnpq.br/3166371422900794 |
dc.contributor.referee2.fl_str_mv |
Mario, Débora Alves Nunes |
dc.contributor.referee2Lattes.fl_str_mv |
http://lattes.cnpq.br/0731595522786356 |
dc.contributor.referee3.fl_str_mv |
Peres, Paulo Edelvar Corrêa |
dc.contributor.referee3Lattes.fl_str_mv |
http://lattes.cnpq.br/1363957298527005 |
dc.contributor.referee4.fl_str_mv |
Trindade, Priscila de Arruda |
dc.contributor.referee4Lattes.fl_str_mv |
http://lattes.cnpq.br/0124362929241308 |
dc.contributor.authorLattes.fl_str_mv |
http://lattes.cnpq.br/0657276243683382 |
dc.contributor.author.fl_str_mv |
Kubiça, Thaís Felli |
contributor_str_mv |
Alves, Sydney Hartz Zanette, Régis Adriel Mario, Débora Alves Nunes Peres, Paulo Edelvar Corrêa Trindade, Priscila de Arruda |
dc.subject.por.fl_str_mv |
Resistência Suscetibilidade Tacrolimus Disseleneto de difenila Ebselen |
topic |
Resistência Suscetibilidade Tacrolimus Disseleneto de difenila Ebselen Resistance Susceptibility Tacrolimus Diphenyl diselenide CNPQ::CIENCIAS BIOLOGICAS::FARMACOLOGIA |
dc.subject.eng.fl_str_mv |
Resistance Susceptibility Tacrolimus Diphenyl diselenide |
dc.subject.cnpq.fl_str_mv |
CNPQ::CIENCIAS BIOLOGICAS::FARMACOLOGIA |
description |
The occurence of invasive fungal infections caused by emerging fungal pathogens has increased considerably in the last decades. The genus Trichosporon comprises species relevant in this context, due to reduced susceptibility to amphotericin B (AMB) and echinocandins, as well as the emergence of resistant strains to azole antifungals, especially to fluconazole (FCZ). Among the strategies to combat the therapeutic failures, the combination of drugs with different mechanisms of action has deserved attention. This study aimed to identify genotypically clinical isolates (n = 30), and to evaluate the susceptibility in vitro of T. asahii, before and after induction the resistance to fluconazole, to antifungal agents: AMB, FCZ, itraconazole (ITZ), voriconazole (VCZ), caspofungin (CPF), micafungin (MCF) and anidulafungin (AND), and non-antifungal compounds: tacrolimus (FK 506), diphenyl diselenide (DPDS), and ebselen (EBS), by determining the minimum inhibitory concentrations (MICs), as M27-A3 (CLSI, 2008). T. asahii was the most prevalent specie among isolates from urine and blood identified. The results MICs confirm the intrinsic resistance of T. asahii to echinocandins (MICs ≥ 4 μg mL-1), and the superiority of the triazole compounds against this specie. Moreover, it was observed that, other than AMB (MIC90 = 1 μg mL-1), the fluconazole-resistant isolates (FR) were less sensitive to azoles than fluconazole-sensitive group (FS), and this cross-resistance phenomenon is more significant forward to ITZ (90%), followed by the POS (36.67%) and VCZ (10%). The results of the antifungal associations and non-antifungal compounds against T. asahii FS and FR were evaluated by microdilution checkerboard method. FK506 (MICs > 64 μg mL-1) and the DPDS (MICs ≥ 8 μg mL-1), did not show satisfactory antifungal activity against T. asahii FS and FR. However, high percentages of synergistic interactions were exibited in the association of AMB + FK506 (96.67%), CPF + FK506 (73.33%) and AMB + DPDS (90%) against FS isolates, as well against the T. asahii FR group: CAS + DPDS (96.67%), AMB + DPDS (93.33%), FCZ + DPDS (86.67%), and ITZ + DPDS (83.33%). On the other hand, the organic compound EBS stood out by the low MIC values (0.25 to 8 μg mL-1) when tested alone, and a strong synergism in combination with AMB (90%) against T. asahii FR. Additionally, were tested combinations of AMB and echinocandins or FCZ, and CPF + FCZ against FR isolates that, other than CPF + FCZ combination (66.67% synergistic interactions), resulted in predominantly indifferent activity. Antagonistic interactions were not observed in the associations of antifungals. In this context, the in vitro exposure to increasing concentrations of fluconazole is an important factor for the emergence of resistance in T. asahii, this phenomenon brings consequences for the susceptibility profile of this specie. Moreover, the synergism observed in vitro is promising for the development of new studies to understand the activity of FK506 and organoselenium compounds against T. asahii for future application as a complementary role in the treatment of tricosporonosis. |
publishDate |
2016 |
dc.date.issued.fl_str_mv |
2016-11-17 |
dc.date.accessioned.fl_str_mv |
2019-08-20T16:15:25Z |
dc.date.available.fl_str_mv |
2019-08-20T16:15:25Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/doctoralThesis |
format |
doctoralThesis |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://repositorio.ufsm.br/handle/1/17973 |
url |
http://repositorio.ufsm.br/handle/1/17973 |
dc.language.iso.fl_str_mv |
por |
language |
por |
dc.relation.cnpq.fl_str_mv |
201000000000 |
dc.relation.confidence.fl_str_mv |
600 |
dc.relation.authority.fl_str_mv |
bfe6016c-9c1e-42ca-ab1d-db5453ed090c ae616355-6ce5-4530-90c0-ae103708eef2 a54b7e0a-0ca7-42cd-9ccc-4852c6fb9e31 8a8a3af4-9c5c-4e0d-9fa6-78508c19a6fd c6a2e8c9-7434-4e54-b28a-10f7da532df1 cfc2887a-ae7d-4e03-9984-f2ccfe8fc1fd |
dc.rights.driver.fl_str_mv |
Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/ info:eu-repo/semantics/openAccess |
rights_invalid_str_mv |
Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/ |
eu_rights_str_mv |
openAccess |
dc.publisher.none.fl_str_mv |
Universidade Federal de Santa Maria Centro de Ciências da Saúde |
dc.publisher.program.fl_str_mv |
Programa de Pós-Graduação em Ciências Farmacêuticas |
dc.publisher.initials.fl_str_mv |
UFSM |
dc.publisher.country.fl_str_mv |
Brasil |
dc.publisher.department.fl_str_mv |
Farmacologia |
publisher.none.fl_str_mv |
Universidade Federal de Santa Maria Centro de Ciências da Saúde |
dc.source.none.fl_str_mv |
reponame:Biblioteca Digital de Teses e Dissertações do UFSM instname:Universidade Federal de Santa Maria (UFSM) instacron:UFSM |
instname_str |
Universidade Federal de Santa Maria (UFSM) |
instacron_str |
UFSM |
institution |
UFSM |
reponame_str |
Biblioteca Digital de Teses e Dissertações do UFSM |
collection |
Biblioteca Digital de Teses e Dissertações do UFSM |
bitstream.url.fl_str_mv |
http://repositorio.ufsm.br/bitstream/1/17973/1/TES_PPGCF_2016_KUBICA_THAIS.pdf http://repositorio.ufsm.br/bitstream/1/17973/2/license_rdf http://repositorio.ufsm.br/bitstream/1/17973/3/license.txt http://repositorio.ufsm.br/bitstream/1/17973/4/TES_PPGCF_2016_KUBICA_THAIS.pdf.txt http://repositorio.ufsm.br/bitstream/1/17973/5/TES_PPGCF_2016_KUBICA_THAIS.pdf.jpg |
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bitstream.checksumAlgorithm.fl_str_mv |
MD5 MD5 MD5 MD5 MD5 |
repository.name.fl_str_mv |
Biblioteca Digital de Teses e Dissertações do UFSM - Universidade Federal de Santa Maria (UFSM) |
repository.mail.fl_str_mv |
atendimento.sib@ufsm.br||tedebc@gmail.com |
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1791086207434752000 |