Simvastatin inhibits planktonic cells and biofilms of Candida and Cryptococcus species | The Brazilian Journal of Infectious Diseases

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"documento" => "article" "crossmark" => 1 "licencia" => "http://creativecommons.org/licenses/by-nc-nd/4.0/" "subdocumento" => "fla" "cita" => "Braz J Infect Dis. 2015;19:466-72" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:2 [ "total" => 1906 "formatos" => array:3 [ "EPUB" => 171 "HTML" => 1248 "PDF" => 487 ] ] "en" => array:12 [ "idiomaDefecto" => true "cabecera" => "Original article" "titulo" => "Molecular epidemiology of heteroresistant vancomycin-intermediate Staphylococcus aureus in Brazil" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => "en" "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "466" "paginaFinal" => "472" ] ] "contieneResumen" => array:1 [ "en" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "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" => 1885 "Ancho" => 3210 "Tamanyo" => 313992 ] ] "descripcion" => array:1 [ "en" => "Growth curves of the twelve isolates characterized as hVISA compared to the standard strain Mu3. All isolates showed an AUC/Mu3 AUC ratio greater than 0.9. For clarity, bacterial growth was expressed in log10 CFU/mL. Nine concentrations of vancomycin (0, 0.5, 1.0, 2.0, 3.0, 4.0, 5.0, 6.0 and 8μg/mL) were used. Graph A depicts isolates S4, S11 and S13. Graph B shows isolates L10, L43 and L36. Graph C shows isolates L54, L69 and L74. Graph D shows isolates L80, L84 and L92. The reference strain Mu3 is shown in all graphs." ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Alessandro Conrado de Oliveira Silveira, Gabriela Rosa da Cunha, Juliana Caierão, Caio Mauricio Mendes de Cordova, Pedro Alves d’Azevedo" "autores" => array:5 [ 0 => array:2 [ "nombre" => "Alessandro Conrado de Oliveira" "apellidos" => "Silveira" ] 1 => array:2 [ "nombre" => "Gabriela Rosa" "apellidos" => "da Cunha" ] 2 => array:2 [ "nombre" => "Juliana" "apellidos" => "Caierão" ] 3 => array:2 [ "nombre" => "Caio Mauricio Mendes" "apellidos" => "de Cordova" ] 4 => array:2 [ "nombre" => "Pedro Alves" "apellidos" => "d’Azevedo" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1413867015001385?idApp=UINPBA00003Y" "url" => "/14138670/0000001900000005/v1_201510011125/S1413867015001385/v1_201510011125/en/main.assets" ] "itemAnterior" => array:19 [ "pii" => "S1413867015001294" "issn" => "14138670" "doi" => "10.1016/j.bjid.2015.05.008" "estado" => "S300" "fechaPublicacion" => "2015-09-01" "aid" => "481" "copyright" => "Elsevier Editora Ltda." 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The treatment led to an increase in gene expression of IFNγ (*p<0.05) at day 5. The Kruskal–Wallis test was used to compare the results between groups." ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Camila Michele Appolinario, Susan Dora Allendorf, Marina Gea Peres, Clovis Reynaldo Fonseca, Acacia Ferreira Vicente, João Marcelo Azevedo de Paula Antunes, José Carlos Figueiredo Pantoja, Jane Megid" "autores" => array:8 [ 0 => array:2 [ "nombre" => "Camila Michele" "apellidos" => "Appolinario" ] 1 => array:2 [ "nombre" => "Susan Dora" "apellidos" => "Allendorf" ] 2 => array:2 [ "nombre" => "Marina Gea" "apellidos" => "Peres" ] 3 => array:2 [ "nombre" => "Clovis Reynaldo" "apellidos" => "Fonseca" ] 4 => array:2 [ "nombre" => "Acacia Ferreira" "apellidos" => "Vicente" ] 5 => array:2 [ "nombre" => "João Marcelo Azevedo de Paula" "apellidos" => "Antunes" ] 6 => array:2 [ "nombre" => "José Carlos Figueiredo" "apellidos" => "Pantoja" ] 7 => array:2 [ "nombre" => "Jane" "apellidos" => "Megid" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1413867015001294?idApp=UINPBA00003Y" "url" => "/14138670/0000001900000005/v1_201510011125/S1413867015001294/v1_201510011125/en/main.assets" ] "en" => array:19 [ "idiomaDefecto" => true "cabecera" => "Original article" "titulo" => "Simvastatin inhibits planktonic cells and biofilms of Candida and Cryptococcus species" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "459" "paginaFinal" => "465" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Raimunda Sâmia Nogueira Brilhante, Erica Pacheco Caetano, Jonathas Sales de Oliveira, Débora de Souza Collares Maia Castelo-Branco, Elizabeth Ribeiro Yokobatake Souza, Lucas Pereira de Alencar, Rossana de Aguiar Cordeiro, Tereza de Jesus Pinheiro Gomes Bandeira, José Júlio Costa Sidrim, Marcos Fábio Gadelha Rocha" "autores" => array:10 [ 0 => array:4 [ "nombre" => "Raimunda Sâmia Nogueira" "apellidos" => "Brilhante" "email" => array:1 [ 0 => "brilhante@ufc.br" ] "referencia" => array:3 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "Erica Pacheco" "apellidos" => "Caetano" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] 2 => array:3 [ "nombre" => "Jonathas Sales" "apellidos" => "de Oliveira" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] 3 => array:3 [ "nombre" => "Débora de Souza Collares Maia" "apellidos" => "Castelo-Branco" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] 4 => array:3 [ "nombre" => "Elizabeth Ribeiro Yokobatake" "apellidos" => "Souza" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] 5 => array:3 [ "nombre" => "Lucas Pereira" "apellidos" => "de Alencar" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] 6 => array:3 [ "nombre" => "Rossana de Aguiar" "apellidos" => "Cordeiro" "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] ] ] 7 => array:3 [ "nombre" => "Tereza de Jesus Pinheiro Gomes" "apellidos" => "Bandeira" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] 8 => array:3 [ "nombre" => "José Júlio Costa" "apellidos" => "Sidrim" "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] ] ] 9 => array:3 [ "nombre" => "Marcos Fábio Gadelha" "apellidos" => "Rocha" "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "c" "identificador" => "aff0015" ] ] ] ] "afiliaciones" => array:3 [ 0 => array:3 [ "entidad" => "Centro Especializado em Micologia Médica, Programa de Pós-Graduação em Microbiologia Médica, Universidade Federal do Ceará (UFC), Fortaleza, CE, Brazil" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Programa de Pós-Graduação em Ciências Médicas, Universidade Federal do Ceará (UFC), Fortaleza, CE, Brazil" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Programa de Pós-Graduação em Ciências Veterinárias, Universidade Estadual do Ceará (UECE), Fortaleza, CE, Brazil" "etiqueta" => "c" "identificador" => "aff0015" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author at: Rua Barão de Canindé, 210, Montese, CEP: 60425-540 Fortaleza, CE, Brazil." ] ] ] ] "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" => 1633 "Tamanyo" => 115989 ] ] "descripcion" => array:1 [ "en" => "In vitro effect of simvastatin (SIM), amphotericin B (AMB), and itraconazole (ITC) at 3 different concentrations on biofilm formation (A) and mature biofilm (B) of Candida spp. Black bars: positive control; MIC: minimum inhibitory concentration. Absorbance of XTT (492nm). *Represents statistically significant difference (p<0.05) when compared to the positive control. Data expressed as mean±SEM." ] ] ] "textoCompleto" => "IntroductionThe incidence of invasive fungal infections, especially those caused by opportunistic fungi of the genus Candida and Cryptococcus, has proportionally increased with the increase in the number of hosts with impaired immunity.<a class="elsevierStyleCrossRefs" href="#bib0210">1–4</a> In addition, in vitro resistance to antifungal drugs among Candida spp. and Cryptococcus spp. strains recovered from humans and animals has been reported.<a class="elsevierStyleCrossRefs" href="#bib0230">5–11</a>This scenario motivates the search for new compounds with antifungal potential. Originally, the first statins were described as metabolites of microorganisms with the ability to lower blood cholesterol.<a class="elsevierStyleCrossRef" href="#bib0265">12</a> Later, it was demonstrated that these compounds reduce the growth of several fungal species,<a class="elsevierStyleCrossRefs" href="#bib0270">13–15</a> including the yeasts Candida spp. and Cryptococcus neoformans<a class="elsevierStyleCrossRef" href="#bib0285">16</a> and the filamentous fungi Mucor spp. and Rhizopus spp.<a class="elsevierStyleCrossRef" href="#bib0290">17</a> In addition, it has also been reported that the administration of statins to hospitalized patients increases survival<a class="elsevierStyleCrossRef" href="#bib0295">18</a> and decreases Candida burden in diabetic patients.<a class="elsevierStyleCrossRef" href="#bib0300">19</a>Although the antifungal potential of statins has already been addressed in previous reports, studies involving the effect of statins on fungal biofilms are needed to obtain a better knowledge on the antifungal potential of these compounds. Hence, this study evaluated the effect of the statins simvastatin, atorvastatin, and pravastatin on planktonic cells of Candida spp. and Cryptococcus spp. Considering that the best results were obtained for simvastatin, this drug was evaluated in combination with antifungal drugs against planktonic growth. In addition, simvastatin was tested against biofilms of Candida spp. and Cryptococcus spp.Materials and methodsMicroorganismsFor this study, 51 strains of Candida spp. (16 Candida albicans; 12 Candida tropicalis; 11 Candida krusei; 12 Candida parapsilosis sensu lato), and 25 strains of Cryptococcus spp. (13 C. neoformans – serotypes A, D and AD; and 12 Cryptococcus gattii – serotypes B and C) isolated from animals were used. The isolates belong to the culture collection of the Specialized Medical Mycology Center, Brazil. The purity and identity of the Candida spp. strains were confirmed by growth on chromogenic medium and microscopical and biochemical features.<a class="elsevierStyleCrossRef" href="#bib0305">20</a> For the Cryptococcus spp. strains, capsule formation, melanin production, and biochemical testing were evaluated and the serotype of each strain was assessed by PCR.<a class="elsevierStyleCrossRef" href="#bib0310">21</a>Susceptibility testing of planktonic cellsSusceptibility assays were performed using the broth microdilution method, as described by the document M27-A3 of the Clinical and Laboratory Standards Institute.<a class="elsevierStyleCrossRef" href="#bib0315">22</a> The tests were performed in duplicate and visually read after 48h of incubation at 35°C. The strains C. parapsilosis ATCC 22019 and C. krusei ATCC 6258 were included as quality control for all tests.<a class="elsevierStyleCrossRef" href="#bib0315">22</a>Inocula were prepared to obtain a final concentration of 0.5–2.5×103cellsmL−1.<a class="elsevierStyleCrossRef" href="#bib0315">22</a> The statins simvastatin (Medley Indústria Farmacêutica Ltda, Campinas, SP, Brazil), atorvastatin (Laboratórios Pfizer Ltda, São Paulo, SP, Brazil), and pravastatin (Bristol-Myers-Squibb, Nova York, NY, USA) and the antifungal drugs amphotericin B (Sigma Chemical Corporation, St Louis, USA), itraconazole (Janssen Pharmaceutica, Beerse, Belgium), and fluconazole (Pfizer Pharmaceuticals, New York, USA) were tested against all strains.To obtain the stock-solutions of each drug, atorvastatin, pravastatin, and fluconazole were diluted with sterile distilled water, and amphotericin B and itraconazole were diluted with dimethylsulfoxide (DMSO). Simvastatin was activated from its lactone prodrug form through hydrolysis in ethanolic NaOH (15% (v/v) ethanol, 0.25% (w/v) NaOH), at 60°C, for 1h.<a class="elsevierStyleCrossRef" href="#bib0280">15</a> The concentration range tested was 3.9–2000μgmL−1 for simvastatin, 19.5–10,000μgmL−1 for atorvastatin, 97.6–50,000μgmL−1 for pravastatin, 0.0312–64μgmL−1 for amphotericin B and itraconazole, and 0.25–256μgmL−1 for fluconazole. The minimum inhibitory concentration (MIC) was defined as the lowest drug concentration able to inhibit 100% of fungal growth for amphotericin B and 50% inhibition of fungal growth when compared to the free-drug azoles<a class="elsevierStyleCrossRef" href="#bib0315">22</a> and statins control.As simvastatin provided the best antifungal results, we evaluated the interaction between this drug and the antifungal drugs against the tested yeasts. For drug interaction studies, simvastatin was tested with each azole by broth microdilution method, using the MIC of each tested drug alone as the highest concentrations tested in combination. The concentrations of the drugs in combination ranged from 0.03 to 1000, 0.00024 to 2, 0.00006 to 64 and 0.00048 to 256μgmL−1 for simvastatin, amphotericin B, itraconazole and fluconazole, respectively. The reading criteria were the same as for the antifungal drugs alone, namely 100% inhibition when combined with amphotericin B and 50% inhibition when combined with azoles. The interaction between the drugs was analyzed by calculating the fractional inhibitory concentration index (FICI), with values ≤0.5 indicating synergism.<a class="elsevierStyleCrossRef" href="#bib0320">23</a>Susceptibility test of sessile cellsSimvastatin was tested against growing biofilms and mature biofilms of Candida spp. and Cryptococcus spp. Amphotericin B and itraconazole were used in all tests as control drugs for biofilm inhibition. The tests were performed in triplicate using one biofilm-producing strain of each tested fungal species (C. albicans, C. tropicalis, C. parapsilosis, C. krusei, C. neoformans and C. gattii), according to the methodology described by Chatzimoschou et al.,<a class="elsevierStyleCrossRef" href="#bib0325">24</a> with some modifications. Briefly, strains were grown on Sabouraud dextrose agar for 48h at 30°C and then subcultured into Sabouraud dextrose broth for 24h, at 30°C, under agitation at 150rpm. After this period, the suspensions were centrifuged at 3000rpm for 10min, the supernatant was discarded, and the pellet was washed twice with sterile PBS. Then, the pellet was resuspended in RPMI 1640 medium (Gibco-BRL, USA), reaching a concentration of 1×106cellsmL−1. Tests were performed in 96-well polystyrene plates.To evaluate the effect of simvastatin, amphotericin B, and itraconazole on growing biofilm, 100μL of the fungal suspension was exposed to 100μL of simvastatin and incubated at 35°C for 48h. The tested concentrations were based on the MIC obtained for each drug against fungal planktonic growth, including MIC, 10xMIC and 50xMIC. On the other hand, to evaluate the effect of simvastatin and the antifungals alone against mature biofilm, 100μL of the fungal suspension was added to 100μL of RPMI 1640 medium and incubated at 35°C for 48h. Then, the mature biofilms were exposed to simvastatin, amphotericin B, and itraconazole and incubated at 35°C for 48h. The tested concentrations against mature biofilms were 10xMIC, 50xMIC and 100xMIC. For all tests, drug-free growth control for each strain was included.After 48h of drug exposure, the growing and mature biofilms were submitted to the following procedures: supernatants were collected and reserved for further analysis, and plates were washed twice with sterile PBS Tween 20 (0.05%, v/v) solution to remove non-adhered cells. Then, the biofilm viability was evaluated through XTT assay, according to Martinez and Casadevall,<a class="elsevierStyleCrossRef" href="#bib0330">25</a> with modifications. Stock solutions of XTT (1mgmL−1) were previously prepared, filtrated and stocked at −20°C, until used. Menadione (Sigma) (0.4mM in acetone) was prepared at the moment of use. Afterwards, 50μL of sterile PBS, 75μL of XTT solution, and 6μL of menadione solution were added to each well. Plates were incubated at 35°C during 5h, in the dark, and then XTT was all transferred to a new plate and read in a spectrophotometer at 492nm.Statistical analysisFor analysis of the MIC data of drugs against planktonic cells, Student's t test for independent and paired samples was used. To check the variation of the MIC values of the drugs in combination, as well as the FICI value, Student's t test for paired samples was also used. Regarding the biofilm assay, all tests were made in triplicate and results were evaluated by ANOVA and Tukey's multiple comparison post-test. p-Values<0.05 were considered statistically significant.ResultsSusceptibility test of planktonic cellsAmong the tested statins, simvastatin showed the lowest MIC, with geometric means varying from 29.45 to 567.16 and from 62.5 to 500mgL−1 against the genera Candida and Cryptococcus, respectively (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>). Atorvastatin showed better results against Candida species, when compared to Cryptococcus spp., with MIC geometric means varying from 52.06 to 1682.37mgL−1 against Candida spp. and from 3886.02 to >10,000μgmL−1 against Cryptococcus spp. (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>). As for pravastatin, the MIC geometric means varied from 2159.24 to >50,000mgL−1 against Candida spp. and from 44079.56 to >50,000mgL−1 against Cryptococcus (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>). MIC geometric means for the classic antifungals against Candida spp. varied from 0.343 to 1.624mgL−1 for amphotericin B, from 0.046 to 15.021mgL−1 for itraconazole, and from 0.659 to 82.346mgL−1 for fluconazole. MIC geometric means for classic antifungals against Cryptococcus spp. varied from 0.125 to 0.735mgL−1 for amphotericin B, from 0.189 to 1mgL−1 for itraconazole, and from 6.498 to 64mgL−1 for fluconazole (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>).<elsevierMultimedia ident="tbl0005"></elsevierMultimedia>Results for the in vitro interaction between simvastatin and antifungal drugs against these yeasts are shown in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>. In general, a synergistic interaction was observed between simvastatin and both azoles against C. albicans (n=10/10), C. tropicalis (n=11/11) and C. parapsilosis sensu lato (n=12/12) (p<0.05). Concerning C. krusei, only the combination of simvastatin and itraconazole was synergistic (n=9/10) (p<0.05). As for Cryptococcus spp., synergistic interactions were observed between simvastatin and the three antifungals tested against C. gattii (simvastatin/amphotericin B and simvastatin/fluconazole: n=7/7; simvastatin/itraconazole: n=5/7) and C. neoformans (simvastatin/amphotericin B: n=11/11; simvastatin/itraconazole: n=9/11; simvastatin/fluconazole: n=10/11) (p<0.05).<elsevierMultimedia ident="tbl0010"></elsevierMultimedia>Susceptibility test of sessile cellsRegarding the action of simvastatin against biofilm of Candida spp., simvastatin inhibited growing biofilms at concentrations greater than 10xMIC (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). Amphotericin B caused significant decrease in metabolic activity of growing biofilms at 10xMIC and 50xMIC, while itraconazole caused inhibition at all tested concentrations (p<0.05). As for mature biofilms, simvastatin caused significant decrease in metabolic activity (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>) (p<0.05), at concentrations above 50xMIC. Amphotericin B inhibited mature biofilms at all tested concentrations, while itraconazole only at 50xMIC and 100xMIC (p<0.05).<elsevierMultimedia ident="fig0005"></elsevierMultimedia>Regarding the genus Cryptococcus, simvastatin inhibited growing biofilms at all tested concentrations (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>) (p<0.05), similar to what was observed when amphotericin B and itraconazole were used (p<0.05). Concerning mature biofilms, simvastatin caused significant decrease in metabolic activity of Cryptococcus biofilm at 50xMIC and 100xMIC (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>) (p<0.05). Amphotericin B inhibited mature biofilms at all tested concentrations (p<0.05), while itraconazole did not decrease biofilm metabolic activity at any tested concentration.<elsevierMultimedia ident="fig0010"></elsevierMultimedia>DiscussionThis study shows the inhibitory activity of simvastatin on the growth of yeasts of the genera Candida and Cryptococcus with an inhibitory effect against both planktonic cells and biofilms. The MICs of simvastatin against C. albicans and C. tropicalis were similar to the serum levels of the drug, when administered to control blood cholesterol.<a class="elsevierStyleCrossRef" href="#bib0335">26</a>C. albicans and C. tropicalis are important fungal pathogens commonly isolated from candidemia.<a class="elsevierStyleCrossRefs" href="#bib0340">27,28</a> Simvastatin and atorvastatin have been described inhibiting Candida spp. and the filamentous fungus Aspergillus fumigatus.<a class="elsevierStyleCrossRef" href="#bib0270">13</a> This work confirms the action of these two drugs, especially simvastatin against Candida spp. and Cryptococcus spp. However, the growth of these fungi was not inhibited by pravastatin. The use of statins deregulates cellular production of isoprenoid,<a class="elsevierStyleCrossRef" href="#bib0270">13</a> which leads to mitochondrial dysfunction, respiratory deficit,<a class="elsevierStyleCrossRef" href="#bib0350">29</a> and changes in lipid structure and in the dynamics of plasma membrane of C. albicans cells.<a class="elsevierStyleCrossRef" href="#bib0355">30</a>There is no synergistic interaction when simvastatin is associated with amphotericin B against most Candida spp. strains. Statins reduce the amount of fungal ergosterol, which may lead to decreased activity of amphotericin B, since ergosterol is the target molecule for this antifungal drug and a decrease in the amount of this molecule is one of the mechanisms developed by amphotericin B resistant Candida spp. However, synergism between simvastatin and amphotericin B was observed against strains of Cryptococcus spp., in line with previous reports with the filamentous fungi Rhizopus oryzae and Aspergillus flavus.<a class="elsevierStyleCrossRef" href="#bib0360">31</a> These contradictory findings still need to be elucidated.In general, when simvastatin is associated with azoles (i.e. itraconazole or fluconazole) there is synergism against strains of Candida spp. and Cryptococcus spp. However, probably due to the intrinsic resistance of C. krusei to fluconazole, synergism between simvastatin and fluconazole was not observed against this Candida species. The interaction between statins and azoles has been reported against the yeasts Saccharomyces cerevisiae<a class="elsevierStyleCrossRef" href="#bib0365">32</a> and Candida spp.,<a class="elsevierStyleCrossRef" href="#bib0370">33</a> and the filamentous fungi Aspergillus spp., Mucor spp. and Rhizopus spp.<a class="elsevierStyleCrossRefs" href="#bib0290">17,33</a> Synergism between these two pharmacological groups is most likely associated with the combined action of the drugs in reducing fungal ergosterol, by acting at different moments in the pathway of ergosterol biosynthesis.<a class="elsevierStyleCrossRef" href="#bib0260">11</a> In addition, the reduction of endogenous sterol due to the action of statins increases cell membrane permeability in order to increase absorption of exogenous sterol, as a compensatory mechanism, and, simultaneously, the entrance of azoles in the cell is facilitated.<a class="elsevierStyleCrossRef" href="#bib0375">34</a>Biofilm production is considered an important virulence factor of Candida spp.<a class="elsevierStyleCrossRef" href="#bib0380">35</a> and it contributes for the persistence of infections.<a class="elsevierStyleCrossRef" href="#bib0385">36</a> It has been demonstrated that simvastatin also inhibits growing and mature biofilms of Candida spp. and Cryptococcus spp. strains when used alone. Liu et al.<a class="elsevierStyleCrossRef" href="#bib0390">37</a> showed that simvastatin inhibited biofilm production of C. albicans after 16-h-incubation, suggesting that at least one mechanism of inhibition involves interference with ergosterol biosynthesis. On the other hand, there are no reports of the effect of simvastatin on biofilms of Cryptococcus spp. Additional studies are needed to better understand the action of simvastatin against yeast biofilms.Studies have shown that amphotericin B inhibits fungal biofilms<a class="elsevierStyleCrossRefs" href="#bib0330">25,38</a> causing apoptosis of the cells in Candida biofilms.<a class="elsevierStyleCrossRef" href="#bib0400">39</a> In our study, growing and mature biofilms of Candida spp. and Cryptococcus spp. were inhibited by amphotericin B. Although many authors have reported that azoles do not inhibit fungal biofilms,<a class="elsevierStyleCrossRefs" href="#bib0330">25,38</a> the present study demonstrated the inhibition of growing and mature biofilms of Candida spp. by itraconazole. As for Cryptococcus spp., itraconazole only inhibited growing biofilms.Although several reports have demonstrated in vitro activity of statins agents against many clinical relevant yeast and mold species, as well as the synergistic effect of statins with different antifungal drugs, clinical studies are scarce.<a class="elsevierStyleCrossRef" href="#bib0405">40</a> Spanakis et al.<a class="elsevierStyleCrossRef" href="#bib0300">19</a> showed that use of statins decreased the incidence of cultures positive for Candida species among patients with type 2 diabetes mellitus who underwent gastrointestinal surgery. In contrast, no beneficial effects were observed for statins in a study of patients with candidemia.<a class="elsevierStyleCrossRef" href="#bib0410">41</a> However, these studies were performed with different patient groups and were inconclusive. Thus, further studies aiming to evaluate the benefits of statin in antifungal therapy are required.The present study showed the activity of statins against Candida and Cryptococcus species, with particular emphasis on simvastatin, isolated and combined with classical antifungals. In addition, it was also demonstrated that simvastatin was able to inhibit growing and mature biofilms of Candida spp. and Cryptococcus spp.Conflicts of interestThe authors declare no conflicts of interest." "textoCompletoSecciones" => array:1 [ "secciones" => array:8 [ 0 => array:3 [ "identificador" => "xres561578" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec577977" "titulo" => "Keywords" ] 2 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 3 => array:3 [ "identificador" => "sec0010" "titulo" => "Materials and methods" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Microorganisms" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "Susceptibility testing of planktonic cells" ] 2 => array:2 [ "identificador" => "sec0025" "titulo" => "Susceptibility test of sessile cells" ] 3 => array:2 [ "identificador" => "sec0030" "titulo" => "Statistical analysis" ] ] ] 4 => array:3 [ "identificador" => "sec0035" "titulo" => "Results" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0040" "titulo" => "Susceptibility test of planktonic cells" ] 1 => array:2 [ "identificador" => "sec0045" "titulo" => "Susceptibility test of sessile cells" ] ] ] 5 => array:2 [ "identificador" => "sec0050" "titulo" => "Discussion" ] 6 => array:2 [ "identificador" => "sec0055" "titulo" => "Conflicts of interest" ] 7 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2015-04-02" "fechaAceptado" => "2015-06-01" "PalabrasClave" => array:1 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec577977" "palabras" => array:5 [ 0 => "Candida" 1 => "Cryptococcus" 2 => "Simvastatin" 3 => "Antifungal activity" 4 => "Biofilm" ] ] ] ] "tieneResumen" => true "resumen" => array:1 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "The antifungal activity of some statins against different fungal species has been reported. Thus, at the first moment, the in vitro antifungal activity of simvastatin, atorvastatin and pravastatin was tested against Candida spp. and Cryptococcus spp. Then, in a second approach, considering that the best results were obtained for simvastatin, this drug was evaluated in combination with antifungal drugs against planktonic growth and tested against biofilms of Candida spp. and Cryptococcus spp. Drug susceptibility testing was performed using the microdilution broth method, as described by the Clinical and Laboratory Standards Institute. The interaction between simvastatin and antifungals against planktonic cells was analyzed by calculating the fractional inhibitory concentration index. Regarding biofilm susceptibility, simvastatin was tested against growing biofilm and mature biofilm of one strain of each tested yeast species. Simvastatin showed inhibitory effect against Candida spp. and Cryptococcus spp. with minimum inhibitory concentration values ranging from 15.6 to 1000mgL−1 and from 62.5 to 1000mgL−1, respectively. The combination of simvastatin with itraconazole and fluconazole showed synergism against Candida spp. and Cryptococcus spp., while the combination of simvastatin with amphotericin B was synergistic only against Cryptococcus spp. Concerning the biofilm assays, simvastatin was able to inhibit both growing biofilm and mature biofilm of Candida spp. and Cryptococcus spp. The present study showed that simvastatin inhibits planktonic cells and biofilms of Candida and Cryptococcus species." ] ] "multimedia" => array:4 [ 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" => 1633 "Tamanyo" => 115989 ] ] "descripcion" => array:1 [ "en" => "In vitro effect of simvastatin (SIM), amphotericin B (AMB), and itraconazole (ITC) at 3 different concentrations on biofilm formation (A) and mature biofilm (B) of Candida spp. Black bars: positive control; MIC: minimum inhibitory concentration. Absorbance of XTT (492nm). *Represents statistically significant difference (p<0.05) when compared to the positive control. Data expressed as mean±SEM." ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1585 "Ancho" => 1643 "Tamanyo" => 113724 ] ] "descripcion" => array:1 [ "en" => "In vitro effect of simvastatin (SIM), amphotericin B (AMB), and itraconazole (ITC) at 3 different concentrations on biofilm formation (A) and mature biofilm (B) of Cryptococcus spp. strains. Black bars: positive control; MIC, minimum inhibitory concentration. Absorbance of XTT (492nm). *Represents statistical significant difference (p<0.05) when compared to the positive control. Data expressed as mean±SEM." ] ] 2 => array:7 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "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" title="table-head " align="left" valign="top" scope="col">Strains (n) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " colspan="6" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">MIC geometric mean (μgmL−1)</th></tr><tr title="table-row"><th class="td" title="table-head " align="" valign="top" scope="col"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " colspan="3" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Statins</th><th class="td" title="table-head " colspan="3" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Antifungals</th></tr><tr title="table-row"><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Simvastatin \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Atorvastatin \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Pravastatin \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Amphotericin B \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Itraconazole \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Fluconazole \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry " colspan="7" align="left" valign="top">Candidaspecies</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">C. albicans (16) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">29.45 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">52.06 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2159.24 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.561 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">5.992 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">21.357 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">C. tropicalis (12) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">70.12 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">165.34 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">21022.41 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.343 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">15.021 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">82.346 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">C. krusei (11) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">567.16 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">755.06 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">>50,000 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1.624 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.072 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">12.126 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">C. parapsilosis sensu lato (12) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">235.97 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1491.37 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">>50,000 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.707 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.059 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.891 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="7" align="left" valign="top">Cryptococcusspecies</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">C. neoformans A<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> (11) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">500 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">3886.02 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">44079.56 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.536 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.189 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">6.498 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">C. neoformans D (1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">250 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">>10,000 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">>50,000 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.25 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.25 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">8 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">C. neoformans AD (1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">62.5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">>10,000 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">>50,000 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.125 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">8 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">C. gatti B (11) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">500 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">5325.21 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">44079.56 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.735 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.315 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">34.562 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">C. gatti C (1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">500 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">>10,000 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">>50,000 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">64 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab909228.png" ] ] ] "notaPie" => array:1 [ 0 => array:3 [ "identificador" => "tblfn0005" "etiqueta" => "a" "nota" => "Serotypes." ] ] ] "descripcion" => array:1 [ "en" => "Geometric means of the minimum inhibitory concentrations (MIC) of statins and antifungal agents against Candida spp. and Cryptococcus spp." ] ] 3 => array:7 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "SIM, simvastatin; AMB, amphotericin B; ITC, itraconazole; FLC, fluconazole; MIC, minimum inhibitory concentration; FICI, fractional inhibitory concentration index." "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" title="table-head " align="left" valign="top" scope="col">Species (n) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="center" valign="top" scope="col">Drugs \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " colspan="2" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">MIC (isolated) (μgmL−1)</th><th class="td" title="table-head " colspan="2" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">MIC (combination) (μgmL−1)</th><th class="td" title="table-head " align="center" valign="top" scope="col">FICI \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="center" valign="top" scope="col">Number of strains showing synergism \t\t\t\t\t\t\n \t\t\t\t</th></tr><tr title="table-row"><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">SIM \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Antifungal \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">SIM \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Antifungal \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry " colspan="8" align="left" valign="top">Candida albicans (10)</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">SIM/AMB \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">29.11 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.616 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">24.06 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.595 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1.741 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0/10 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">SIM/ITC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">29.11 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">9.189 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1.042 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.329 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.071 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">10/10 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">SIM/FLC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">29.11 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">21.112 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1.695 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.116 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.116 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">10/10 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="8" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="8" align="left" valign="top">Candida tropicalis (11)</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">SIM/AMB \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">75.47 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.3426 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">55.637 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.354 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1.37 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1/11 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">SIM/ITC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">75.47 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">15.021 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1.327 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.266 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.035 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">11/11 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">SIM/FLC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">75.47 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">82.347 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">4.425 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">4.832 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.117 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">11/11 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="8" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="8" align="left" valign="top">Candida krusei (10)</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">SIM/AMB \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">574.35 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1.624 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">435.28 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1.231 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1.515 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0/10 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">SIM/ITC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">574.35 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.072 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">116.61 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.014 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.416 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">9/10 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">SIM/FLC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">574.35 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">12.126 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">233.26 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">4.925 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.812 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">3/10 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="8" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="8" align="left" valign="top">Candida parapsilosis sensu lato (12)</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">SIM/AMB \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">235.97 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.707 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">78.74 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.236 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.667 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">7/12 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">SIM/ITC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">235.97 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.059 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">41.68 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.010 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.353 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">12/12 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">SIM/FLC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">235.97 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.891 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">49.58 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.187 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.420 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">12/12 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="8" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="8" align="left" valign="top">Cryptococcus neoformans (11)</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Serotypes: A(9); D(1); AD(1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">SIM/AMB \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">388.6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.4139 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">35.42 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.0377 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.182 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">11/11 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">SIM/ITC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">388.6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.1943 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">70.86 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.0354 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.365 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">9/11 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">SIM/FLC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">388.6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">6.622 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">21.38 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.3648 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.11 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">10/11 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="8" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="8" align="left" valign="top">Cryptococcus gattii (7)</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Serotypes: B(6); C(1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">SIM/AMB \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">500 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.8203 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">19.025 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.0312 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.076 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">7/7 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">SIM/ITC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">500 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.4102 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">84.0803 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.0689 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.336 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">5/7 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">SIM/FLC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">500 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">39.008 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">38.051 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2.972 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.152 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">7/7 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab909229.png" ] ] ] ] "descripcion" => array:1 [ "en" => 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Simvastatin inhibits planktonic cells and biofilms of Candida and Cryptococcus species

Raimunda Sâmia Nogueira Brilhantea,b,

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brilhante@ufc.br

Corresponding author at: Rua Barão de Canindé, 210, Montese, CEP: 60425-540 Fortaleza, CE, Brazil.

, Erica Pacheco Caetanoa, Jonathas Sales de Oliveiraa, Débora de Souza Collares Maia Castelo-Brancoa, Elizabeth Ribeiro Yokobatake Souzaa, Lucas Pereira de Alencara, Rossana de Aguiar Cordeiroa,b, Tereza de Jesus Pinheiro Gomes Bandeiraa, José Júlio Costa Sidrima,b, Marcos Fábio Gadelha Rochaa,c

a Centro Especializado em Micologia Médica, Programa de Pós-Graduação em Microbiologia Médica, Universidade Federal do Ceará (UFC), Fortaleza, CE, Brazil

b Programa de Pós-Graduação em Ciências Médicas, Universidade Federal do Ceará (UFC), Fortaleza, CE, Brazil

c Programa de Pós-Graduação em Ciências Veterinárias, Universidade Estadual do Ceará (UECE), Fortaleza, CE, Brazil

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            "en" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Growth curves of the twelve isolates characterized as hVISA compared to the standard strain Mu3&#46; All isolates showed an AUC&#47;Mu3 AUC ratio greater than 0&#46;9&#46; For clarity&#44; bacterial growth was expressed in log<span class="elsevierStyleInf">10</span> CFU&#47;mL&#46; Nine concentrations of vancomycin &#40;0&#44; 0&#46;5&#44; 1&#46;0&#44; 2&#46;0&#44; 3&#46;0&#44; 4&#46;0&#44; 5&#46;0&#44; 6&#46;0 and 8<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;mL&#41; were used&#46; Graph A depicts isolates S4&#44; S11 and S13&#46; Graph B shows isolates L10&#44; L43 and L36&#46; Graph C shows isolates L54&#44; L69 and L74&#46; Graph D shows isolates L80&#44; L84 and L92&#46; The reference strain Mu3 is shown in all graphs&#46;</p>"
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Originally&#44; the first statins were described as metabolites of microorganisms with the ability to lower blood cholesterol&#46;<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">12</span></a> Later&#44; it was demonstrated that these compounds reduce the growth of several fungal species&#44;<a class="elsevierStyleCrossRefs" href="#bib0270"><span class="elsevierStyleSup">13&#8211;15</span></a> including the yeasts <span class="elsevierStyleItalic">Candida</span> spp&#46; and <span class="elsevierStyleItalic">Cryptococcus neoformans</span><a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">16</span></a> and the filamentous fungi <span class="elsevierStyleItalic">Mucor</span> spp&#46; and <span class="elsevierStyleItalic">Rhizopus</span> spp&#46;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">17</span></a> In addition&#44; it has also been reported that the administration of statins to hospitalized patients increases survival<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">18</span></a> and decreases <span class="elsevierStyleItalic">Candida</span> burden in diabetic patients&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">19</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">Although the antifungal potential of statins has already been addressed in previous reports&#44; studies involving the effect of statins on fungal biofilms are needed to obtain a better knowledge on the antifungal potential of these compounds&#46; Hence&#44; this study evaluated the effect of the statins simvastatin&#44; atorvastatin&#44; and pravastatin on planktonic cells of <span class="elsevierStyleItalic">Candida</span> spp&#46; and <span class="elsevierStyleItalic">Cryptococcus</span> spp&#46; Considering that the best results were obtained for simvastatin&#44; this drug was evaluated in combination with antifungal drugs against planktonic growth&#46; In addition&#44; simvastatin was tested against biofilms of <span class="elsevierStyleItalic">Candida</span> spp&#46; and <span class="elsevierStyleItalic">Cryptococcus</span> spp&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Materials and methods</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Microorganisms</span><p id="par0020" class="elsevierStylePara elsevierViewall">For this study&#44; 51 strains of <span class="elsevierStyleItalic">Candida</span> spp&#46; &#40;16 <span class="elsevierStyleItalic">Candida albicans</span>&#59; 12 <span class="elsevierStyleItalic">Candida tropicalis</span>&#59; 11 <span class="elsevierStyleItalic">Candida krusei</span>&#59; 12 <span class="elsevierStyleItalic">Candida parapsilosis sensu lato</span>&#41;&#44; and 25 strains of <span class="elsevierStyleItalic">Cryptococcus</span> spp&#46; &#40;13 <span class="elsevierStyleItalic">C&#46; neoformans</span> &#8211; serotypes A&#44; D and AD&#59; and 12 <span class="elsevierStyleItalic">Cryptococcus gattii</span> &#8211; serotypes B and C&#41; isolated from animals were used&#46; The isolates belong to the culture collection of the Specialized Medical Mycology Center&#44; Brazil&#46; The purity and identity of the <span class="elsevierStyleItalic">Candida</span> spp&#46; strains were confirmed by growth on chromogenic medium and microscopical and biochemical features&#46;<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">20</span></a> For the <span class="elsevierStyleItalic">Cryptococcus</span> spp&#46; strains&#44; capsule formation&#44; melanin production&#44; and biochemical testing were evaluated and the serotype of each strain was assessed by PCR&#46;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">21</span></a></p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Susceptibility testing of planktonic cells</span><p id="par0025" class="elsevierStylePara elsevierViewall">Susceptibility assays were performed using the broth microdilution method&#44; as described by the document M27-A3 of the Clinical and Laboratory Standards Institute&#46;<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">22</span></a> The tests were performed in duplicate and visually read after 48<span class="elsevierStyleHsp" style=""></span>h of incubation at 35<span class="elsevierStyleHsp" style=""></span>&#176;C&#46; The strains <span class="elsevierStyleItalic">C&#46; parapsilosis</span> ATCC 22019 and <span class="elsevierStyleItalic">C&#46; krusei</span> ATCC 6258 were included as quality control for all tests&#46;<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">22</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">Inocula were prepared to obtain a final concentration of 0&#46;5&#8211;2&#46;5<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleSup">3</span><span class="elsevierStyleHsp" style=""></span>cells<span class="elsevierStyleHsp" style=""></span>mL<span class="elsevierStyleSup">&#8722;1</span>&#46;<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">22</span></a> The statins simvastatin &#40;Medley Ind&#250;stria Farmac&#234;utica Ltda&#44; Campinas&#44; SP&#44; Brazil&#41;&#44; atorvastatin &#40;Laborat&#243;rios Pfizer Ltda&#44; S&#227;o Paulo&#44; SP&#44; Brazil&#41;&#44; and pravastatin &#40;Bristol-Myers-Squibb&#44; Nova York&#44; NY&#44; USA&#41; and the antifungal drugs amphotericin B &#40;Sigma Chemical Corporation&#44; St Louis&#44; USA&#41;&#44; itraconazole &#40;Janssen Pharmaceutica&#44; Beerse&#44; Belgium&#41;&#44; and fluconazole &#40;Pfizer Pharmaceuticals&#44; New York&#44; USA&#41; were tested against all strains&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">To obtain the stock-solutions of each drug&#44; atorvastatin&#44; pravastatin&#44; and fluconazole were diluted with sterile distilled water&#44; and amphotericin B and itraconazole were diluted with dimethylsulfoxide &#40;DMSO&#41;&#46; Simvastatin was activated from its lactone prodrug form through hydrolysis in ethanolic NaOH &#40;15&#37; &#40;v&#47;v&#41; ethanol&#44; 0&#46;25&#37; &#40;w&#47;v&#41; NaOH&#41;&#44; at 60<span class="elsevierStyleHsp" style=""></span>&#176;C&#44; for 1<span class="elsevierStyleHsp" style=""></span>h&#46;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">15</span></a> The concentration range tested was 3&#46;9&#8211;2000<span class="elsevierStyleHsp" style=""></span>&#956;g<span class="elsevierStyleHsp" style=""></span>mL<span class="elsevierStyleSup">&#8722;1</span> for simvastatin&#44; 19&#46;5&#8211;10&#44;000<span class="elsevierStyleHsp" style=""></span>&#956;g<span class="elsevierStyleHsp" style=""></span>mL<span class="elsevierStyleSup">&#8722;1</span> for atorvastatin&#44; 97&#46;6&#8211;50&#44;000<span class="elsevierStyleHsp" style=""></span>&#956;g<span class="elsevierStyleHsp" style=""></span>mL<span class="elsevierStyleSup">&#8722;1</span> for pravastatin&#44; 0&#46;0312&#8211;64<span class="elsevierStyleHsp" style=""></span>&#956;g<span class="elsevierStyleHsp" style=""></span>mL<span class="elsevierStyleSup">&#8722;1</span> for amphotericin B and itraconazole&#44; and 0&#46;25&#8211;256<span class="elsevierStyleHsp" style=""></span>&#956;g<span class="elsevierStyleHsp" style=""></span>mL<span class="elsevierStyleSup">&#8722;1</span> for fluconazole&#46; The minimum inhibitory concentration &#40;MIC&#41; was defined as the lowest drug concentration able to inhibit 100&#37; of fungal growth for amphotericin B and 50&#37; inhibition of fungal growth when compared to the free-drug azoles<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">22</span></a> and statins control&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">As simvastatin provided the best antifungal results&#44; we evaluated the interaction between this drug and the antifungal drugs against the tested yeasts&#46; For drug interaction studies&#44; simvastatin was tested with each azole by broth microdilution method&#44; using the MIC of each tested drug alone as the highest concentrations tested in combination&#46; The concentrations of the drugs in combination ranged from 0&#46;03 to 1000&#44; 0&#46;00024 to 2&#44; 0&#46;00006 to 64 and 0&#46;00048 to 256<span class="elsevierStyleHsp" style=""></span>&#956;g<span class="elsevierStyleHsp" style=""></span>mL<span class="elsevierStyleSup">&#8722;1</span> for simvastatin&#44; amphotericin B&#44; itraconazole and fluconazole&#44; respectively&#46; The reading criteria were the same as for the antifungal drugs alone&#44; namely 100&#37; inhibition when combined with amphotericin B and 50&#37; inhibition when combined with azoles&#46; The interaction between the drugs was analyzed by calculating the fractional inhibitory concentration index &#40;FICI&#41;&#44; with values &#8804;0&#46;5 indicating synergism&#46;<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">23</span></a></p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Susceptibility test of sessile cells</span><p id="par0045" class="elsevierStylePara elsevierViewall">Simvastatin was tested against growing biofilms and mature biofilms of <span class="elsevierStyleItalic">Candida</span> spp&#46; and <span class="elsevierStyleItalic">Cryptococcus</span> spp&#46; Amphotericin B and itraconazole were used in all tests as control drugs for biofilm inhibition&#46; The tests were performed in triplicate using one biofilm-producing strain of each tested fungal species &#40;<span class="elsevierStyleItalic">C&#46; albicans</span>&#44; <span class="elsevierStyleItalic">C&#46; tropicalis</span>&#44; <span class="elsevierStyleItalic">C&#46; parapsilosis</span>&#44; <span class="elsevierStyleItalic">C&#46; krusei</span>&#44; <span class="elsevierStyleItalic">C&#46; neoformans</span> and <span class="elsevierStyleItalic">C&#46; gattii</span>&#41;&#44; according to the methodology described by Chatzimoschou et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">24</span></a> with some modifications&#46; Briefly&#44; strains were grown on Sabouraud dextrose agar for 48<span class="elsevierStyleHsp" style=""></span>h at 30<span class="elsevierStyleHsp" style=""></span>&#176;C and then subcultured into Sabouraud dextrose broth for 24<span class="elsevierStyleHsp" style=""></span>h&#44; at 30<span class="elsevierStyleHsp" style=""></span>&#176;C&#44; under agitation at 150<span class="elsevierStyleHsp" style=""></span>rpm&#46; After this period&#44; the suspensions were centrifuged at 3000<span class="elsevierStyleHsp" style=""></span>rpm for 10<span class="elsevierStyleHsp" style=""></span>min&#44; the supernatant was discarded&#44; and the pellet was washed twice with sterile PBS&#46; Then&#44; the pellet was resuspended in RPMI 1640 medium &#40;Gibco-BRL&#44; USA&#41;&#44; reaching a concentration of 1<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleSup">6</span><span class="elsevierStyleHsp" style=""></span>cells<span class="elsevierStyleHsp" style=""></span>mL<span class="elsevierStyleSup">&#8722;1</span>&#46; Tests were performed in 96-well polystyrene plates&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">To evaluate the effect of simvastatin&#44; amphotericin B&#44; and itraconazole on growing biofilm&#44; 100<span class="elsevierStyleHsp" style=""></span>&#956;L of the fungal suspension was exposed to 100<span class="elsevierStyleHsp" style=""></span>&#956;L of simvastatin and incubated at 35<span class="elsevierStyleHsp" style=""></span>&#176;C for 48<span class="elsevierStyleHsp" style=""></span>h&#46; The tested concentrations were based on the MIC obtained for each drug against fungal planktonic growth&#44; including MIC&#44; 10xMIC and 50xMIC&#46; On the other hand&#44; to evaluate the effect of simvastatin and the antifungals alone against mature biofilm&#44; 100<span class="elsevierStyleHsp" style=""></span>&#956;L of the fungal suspension was added to 100<span class="elsevierStyleHsp" style=""></span>&#956;L of RPMI 1640 medium and incubated at 35<span class="elsevierStyleHsp" style=""></span>&#176;C for 48<span class="elsevierStyleHsp" style=""></span>h&#46; Then&#44; the mature biofilms were exposed to simvastatin&#44; amphotericin B&#44; and itraconazole and incubated at 35<span class="elsevierStyleHsp" style=""></span>&#176;C for 48<span class="elsevierStyleHsp" style=""></span>h&#46; The tested concentrations against mature biofilms were 10xMIC&#44; 50xMIC and 100xMIC&#46; For all tests&#44; drug-free growth control for each strain was included&#46;</p><p id="par0055" class="elsevierStylePara elsevierViewall">After 48<span class="elsevierStyleHsp" style=""></span>h of drug exposure&#44; the growing and mature biofilms were submitted to the following procedures&#58; supernatants were collected and reserved for further analysis&#44; and plates were washed twice with sterile PBS Tween 20 &#40;0&#46;05&#37;&#44; v&#47;v&#41; solution to remove non-adhered cells&#46; Then&#44; the biofilm viability was evaluated through XTT assay&#44; according to Martinez and Casadevall&#44;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">25</span></a> with modifications&#46; Stock solutions of XTT &#40;1<span class="elsevierStyleHsp" style=""></span>mg<span class="elsevierStyleHsp" style=""></span>mL<span class="elsevierStyleSup">&#8722;1</span>&#41; were previously prepared&#44; filtrated and stocked at &#8722;20<span class="elsevierStyleHsp" style=""></span>&#176;C&#44; until used&#46; Menadione &#40;Sigma&#41; &#40;0&#46;4<span class="elsevierStyleHsp" style=""></span>mM in acetone&#41; was prepared at the moment of use&#46; Afterwards&#44; 50<span class="elsevierStyleHsp" style=""></span>&#956;L of sterile PBS&#44; 75<span class="elsevierStyleHsp" style=""></span>&#956;L of XTT solution&#44; and 6<span class="elsevierStyleHsp" style=""></span>&#956;L of menadione solution were added to each well&#46; Plates were incubated at 35<span class="elsevierStyleHsp" style=""></span>&#176;C during 5<span class="elsevierStyleHsp" style=""></span>h&#44; in the dark&#44; and then XTT was all transferred to a new plate and read in a spectrophotometer at 492<span class="elsevierStyleHsp" style=""></span>nm&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Statistical analysis</span><p id="par0060" class="elsevierStylePara elsevierViewall">For analysis of the MIC data of drugs against planktonic cells&#44; Student&#39;s <span class="elsevierStyleItalic">t</span> test for independent and paired samples was used&#46; To check the variation of the MIC values of the drugs in combination&#44; as well as the FICI value&#44; Student&#39;s <span class="elsevierStyleItalic">t</span> test for paired samples was also used&#46; Regarding the biofilm assay&#44; all tests were made in triplicate and results were evaluated by ANOVA and Tukey&#39;s multiple comparison post-test&#46; <span class="elsevierStyleItalic">p</span>-Values<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05 were considered statistically significant&#46;</p></span></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Results</span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Susceptibility test of planktonic cells</span><p id="par0065" class="elsevierStylePara elsevierViewall">Among the tested statins&#44; simvastatin showed the lowest MIC&#44; with geometric means varying from 29&#46;45 to 567&#46;16 and from 62&#46;5 to 500<span class="elsevierStyleHsp" style=""></span>mg<span class="elsevierStyleHsp" style=""></span>L<span class="elsevierStyleSup">&#8722;1</span> against the genera <span class="elsevierStyleItalic">Candida</span> and <span class="elsevierStyleItalic">Cryptococcus</span>&#44; respectively &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46; Atorvastatin showed better results against <span class="elsevierStyleItalic">Candida</span> species&#44; when compared to <span class="elsevierStyleItalic">Cryptococcus</span> spp&#46;&#44; with MIC geometric means varying from 52&#46;06 to 1682&#46;37<span class="elsevierStyleHsp" style=""></span>mg<span class="elsevierStyleHsp" style=""></span>L<span class="elsevierStyleSup">&#8722;1</span> against <span class="elsevierStyleItalic">Candida</span> spp&#46; and from 3886&#46;02 to &#62;10&#44;000<span class="elsevierStyleHsp" style=""></span>&#956;g<span class="elsevierStyleHsp" style=""></span>mL<span class="elsevierStyleSup">&#8722;1</span> against <span class="elsevierStyleItalic">Cryptococcus</span> spp&#46; &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46; As for pravastatin&#44; the MIC geometric means varied from 2159&#46;24 to &#62;50&#44;000<span class="elsevierStyleHsp" style=""></span>mg<span class="elsevierStyleHsp" style=""></span>L<span class="elsevierStyleSup">&#8722;1</span> against <span class="elsevierStyleItalic">Candida</span> spp&#46; and from 44079&#46;56 to &#62;50&#44;000<span class="elsevierStyleHsp" style=""></span>mg<span class="elsevierStyleHsp" style=""></span>L<span class="elsevierStyleSup">&#8722;1</span> against <span class="elsevierStyleItalic">Cryptococcus</span> &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46; MIC geometric means for the classic antifungals against <span class="elsevierStyleItalic">Candida</span> spp&#46; varied from 0&#46;343 to 1&#46;624<span class="elsevierStyleHsp" style=""></span>mg<span class="elsevierStyleHsp" style=""></span>L<span class="elsevierStyleSup">&#8722;1</span> for amphotericin B&#44; from 0&#46;046 to 15&#46;021<span class="elsevierStyleHsp" style=""></span>mg<span class="elsevierStyleHsp" style=""></span>L<span class="elsevierStyleSup">&#8722;1</span> for itraconazole&#44; and from 0&#46;659 to 82&#46;346<span class="elsevierStyleHsp" style=""></span>mg<span class="elsevierStyleHsp" style=""></span>L<span class="elsevierStyleSup">&#8722;1</span> for fluconazole&#46; MIC geometric means for classic antifungals against <span class="elsevierStyleItalic">Cryptococcus</span> spp&#46; varied from 0&#46;125 to 0&#46;735<span class="elsevierStyleHsp" style=""></span>mg<span class="elsevierStyleHsp" style=""></span>L<span class="elsevierStyleSup">&#8722;1</span> for amphotericin B&#44; from 0&#46;189 to 1<span class="elsevierStyleHsp" style=""></span>mg<span class="elsevierStyleHsp" style=""></span>L<span class="elsevierStyleSup">&#8722;1</span> for itraconazole&#44; and from 6&#46;498 to 64<span class="elsevierStyleHsp" style=""></span>mg<span class="elsevierStyleHsp" style=""></span>L<span class="elsevierStyleSup">&#8722;1</span> for fluconazole &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0070" class="elsevierStylePara elsevierViewall">Results for the <span class="elsevierStyleItalic">in vitro</span> interaction between simvastatin and antifungal drugs against these yeasts are shown in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#46; In general&#44; a synergistic interaction was observed between simvastatin and both azoles against <span class="elsevierStyleItalic">C&#46; albicans</span> &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>10&#47;10&#41;&#44; <span class="elsevierStyleItalic">C&#46; tropicalis</span> &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>11&#47;11&#41; and <span class="elsevierStyleItalic">C</span>&#46; <span class="elsevierStyleItalic">parapsilosis sensu lato</span> &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>12&#47;12&#41; &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#46; Concerning <span class="elsevierStyleItalic">C&#46; krusei</span>&#44; only the combination of simvastatin and itraconazole was synergistic &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>9&#47;10&#41; &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#46; As for <span class="elsevierStyleItalic">Cryptococcus</span> spp&#46;&#44; synergistic interactions were observed between simvastatin and the three antifungals tested against <span class="elsevierStyleItalic">C&#46; gattii</span> &#40;simvastatin&#47;amphotericin B and simvastatin&#47;fluconazole&#58; <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>7&#47;7&#59; simvastatin&#47;itraconazole&#58; <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>5&#47;7&#41; and <span class="elsevierStyleItalic">C&#46; neoformans</span> &#40;simvastatin&#47;amphotericin B&#58; <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>11&#47;11&#59; simvastatin&#47;itraconazole&#58; <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>9&#47;11&#59; simvastatin&#47;fluconazole&#58; <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>10&#47;11&#41; &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Susceptibility test of sessile cells</span><p id="par0075" class="elsevierStylePara elsevierViewall">Regarding the action of simvastatin against biofilm of <span class="elsevierStyleItalic">Candida</span> spp&#46;&#44; simvastatin inhibited growing biofilms at concentrations greater than 10xMIC &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; Amphotericin B caused significant decrease in metabolic activity of growing biofilms at 10xMIC and 50xMIC&#44; while itraconazole caused inhibition at all tested concentrations &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#46; As for mature biofilms&#44; simvastatin caused significant decrease in metabolic activity &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41; &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#44; at concentrations above 50xMIC&#46; Amphotericin B inhibited mature biofilms at all tested concentrations&#44; while itraconazole only at 50xMIC and 100xMIC &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0080" class="elsevierStylePara elsevierViewall">Regarding the genus <span class="elsevierStyleItalic">Cryptococcus</span>&#44; simvastatin inhibited growing biofilms at all tested concentrations &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41; &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#44; similar to what was observed when amphotericin B and itraconazole were used &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#46; Concerning mature biofilms&#44; simvastatin caused significant decrease in metabolic activity of <span class="elsevierStyleItalic">Cryptococcus</span> biofilm at 50xMIC and 100xMIC &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41; &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#46; Amphotericin B inhibited mature biofilms at all tested concentrations &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#44; while itraconazole did not decrease biofilm metabolic activity at any tested concentration&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia></span></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Discussion</span><p id="par0085" class="elsevierStylePara elsevierViewall">This study shows the inhibitory activity of simvastatin on the growth of yeasts of the genera <span class="elsevierStyleItalic">Candida</span> and <span class="elsevierStyleItalic">Cryptococcus</span> with an inhibitory effect against both planktonic cells and biofilms&#46; The MICs of simvastatin against <span class="elsevierStyleItalic">C&#46; albicans</span> and <span class="elsevierStyleItalic">C&#46; tropicalis</span> were similar to the serum levels of the drug&#44; when administered to control blood cholesterol&#46;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">26</span></a><span class="elsevierStyleItalic">C</span>&#46; <span class="elsevierStyleItalic">albicans</span> and <span class="elsevierStyleItalic">C&#46; tropicalis</span> are important fungal pathogens commonly isolated from candidemia&#46;<a class="elsevierStyleCrossRefs" href="#bib0340"><span class="elsevierStyleSup">27&#44;28</span></a> Simvastatin and atorvastatin have been described inhibiting <span class="elsevierStyleItalic">Candida</span> spp&#46; and the filamentous fungus <span class="elsevierStyleItalic">Aspergillus fumigatus</span>&#46;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">13</span></a> This work confirms the action of these two drugs&#44; especially simvastatin against <span class="elsevierStyleItalic">Candida</span> spp&#46; and <span class="elsevierStyleItalic">Cryptococcus</span> spp&#46; However&#44; the growth of these fungi was not inhibited by pravastatin&#46; The use of statins deregulates cellular production of isoprenoid&#44;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">13</span></a> which leads to mitochondrial dysfunction&#44; respiratory deficit&#44;<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">29</span></a> and changes in lipid structure and in the dynamics of plasma membrane of <span class="elsevierStyleItalic">C&#46; albicans</span> cells&#46;<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">30</span></a></p><p id="par0090" class="elsevierStylePara elsevierViewall">There is no synergistic interaction when simvastatin is associated with amphotericin B against most <span class="elsevierStyleItalic">Candida</span> spp&#46; strains&#46; Statins reduce the amount of fungal ergosterol&#44; which may lead to decreased activity of amphotericin B&#44; since ergosterol is the target molecule for this antifungal drug and a decrease in the amount of this molecule is one of the mechanisms developed by amphotericin B resistant <span class="elsevierStyleItalic">Candida</span> spp&#46; However&#44; synergism between simvastatin and amphotericin B was observed against strains of <span class="elsevierStyleItalic">Cryptococcus</span> spp&#46;&#44; in line with previous reports with the filamentous fungi <span class="elsevierStyleItalic">Rhizopus oryzae</span> and <span class="elsevierStyleItalic">Aspergillus flavus</span>&#46;<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">31</span></a> These contradictory findings still need to be elucidated&#46;</p><p id="par0095" class="elsevierStylePara elsevierViewall">In general&#44; when simvastatin is associated with azoles &#40;i&#46;e&#46; itraconazole or fluconazole&#41; there is synergism against strains of <span class="elsevierStyleItalic">Candida</span> spp&#46; and <span class="elsevierStyleItalic">Cryptococcus</span> spp&#46; However&#44; probably due to the intrinsic resistance of <span class="elsevierStyleItalic">C</span>&#46; <span class="elsevierStyleItalic">krusei</span> to fluconazole&#44; synergism between simvastatin and fluconazole was not observed against this <span class="elsevierStyleItalic">Candida</span> species&#46; The interaction between statins and azoles has been reported against the yeasts <span class="elsevierStyleItalic">Saccharomyces cerevisiae</span><a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">32</span></a> and <span class="elsevierStyleItalic">Candida</span> spp&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">33</span></a> and the filamentous fungi <span class="elsevierStyleItalic">Aspergillus</span> spp&#46;&#44; <span class="elsevierStyleItalic">Mucor</span> spp&#46; and <span class="elsevierStyleItalic">Rhizopus</span> spp&#46;<a class="elsevierStyleCrossRefs" href="#bib0290"><span class="elsevierStyleSup">17&#44;33</span></a> Synergism between these two pharmacological groups is most likely associated with the combined action of the drugs in reducing fungal ergosterol&#44; by acting at different moments in the pathway of ergosterol biosynthesis&#46;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">11</span></a> In addition&#44; the reduction of endogenous sterol due to the action of statins increases cell membrane permeability in order to increase absorption of exogenous sterol&#44; as a compensatory mechanism&#44; and&#44; simultaneously&#44; the entrance of azoles in the cell is facilitated&#46;<a class="elsevierStyleCrossRef" href="#bib0375"><span class="elsevierStyleSup">34</span></a></p><p id="par0100" class="elsevierStylePara elsevierViewall">Biofilm production is considered an important virulence factor of <span class="elsevierStyleItalic">Candida</span> spp&#46;<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">35</span></a> and it contributes for the persistence of infections&#46;<a class="elsevierStyleCrossRef" href="#bib0385"><span class="elsevierStyleSup">36</span></a> It has been demonstrated that simvastatin also inhibits growing and mature biofilms of <span class="elsevierStyleItalic">Candida</span> spp&#46; and <span class="elsevierStyleItalic">Cryptococcus</span> spp&#46; strains when used alone&#46; Liu et al&#46;<a class="elsevierStyleCrossRef" href="#bib0390"><span class="elsevierStyleSup">37</span></a> showed that simvastatin inhibited biofilm production of <span class="elsevierStyleItalic">C&#46; albicans</span> after 16-h-incubation&#44; suggesting that at least one mechanism of inhibition involves interference with ergosterol biosynthesis&#46; On the other hand&#44; there are no reports of the effect of simvastatin on biofilms of <span class="elsevierStyleItalic">Cryptococcus</span> spp&#46; Additional studies are needed to better understand the action of simvastatin against yeast biofilms&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">Studies have shown that amphotericin B inhibits fungal biofilms<a class="elsevierStyleCrossRefs" href="#bib0330"><span class="elsevierStyleSup">25&#44;38</span></a> causing apoptosis of the cells in <span class="elsevierStyleItalic">Candida</span> biofilms&#46;<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">39</span></a> In our study&#44; growing and mature biofilms of <span class="elsevierStyleItalic">Candida</span> spp&#46; and <span class="elsevierStyleItalic">Cryptococcus</span> spp&#46; were inhibited by amphotericin B&#46; Although many authors have reported that azoles do not inhibit fungal biofilms&#44;<a class="elsevierStyleCrossRefs" href="#bib0330"><span class="elsevierStyleSup">25&#44;38</span></a> the present study demonstrated the inhibition of growing and mature biofilms of <span class="elsevierStyleItalic">Candida</span> spp&#46; by itraconazole&#46; As for <span class="elsevierStyleItalic">Cryptococcus</span> spp&#46;&#44; itraconazole only inhibited growing biofilms&#46;</p><p id="par0110" class="elsevierStylePara elsevierViewall">Although several reports have demonstrated <span class="elsevierStyleItalic">in vitro</span> activity of statins agents against many clinical relevant yeast and mold species&#44; as well as the synergistic effect of statins with different antifungal drugs&#44; clinical studies are scarce&#46;<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">40</span></a> Spanakis et al&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">19</span></a> showed that use of statins decreased the incidence of cultures positive for <span class="elsevierStyleItalic">Candida</span> species among patients with type 2 diabetes mellitus who underwent gastrointestinal surgery&#46; In contrast&#44; no beneficial effects were observed for statins in a study of patients with candidemia&#46;<a class="elsevierStyleCrossRef" href="#bib0410"><span class="elsevierStyleSup">41</span></a> However&#44; these studies were performed with different patient groups and were inconclusive&#46; Thus&#44; further studies aiming to evaluate the benefits of statin in antifungal therapy are required&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">The present study showed the activity of statins against <span class="elsevierStyleItalic">Candida</span> and <span class="elsevierStyleItalic">Cryptococcus</span> species&#44; with particular emphasis on simvastatin&#44; isolated and combined with classical antifungals&#46; In addition&#44; it was also demonstrated that simvastatin was able to inhibit growing and mature biofilms of <span class="elsevierStyleItalic">Candida</span> spp&#46; and <span class="elsevierStyleItalic">Cryptococcus</span> spp&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Conflicts of interest</span><p id="par0120" class="elsevierStylePara elsevierViewall">The authors declare no conflicts of interest&#46;</p></span></span>"
    "textoCompletoSecciones" => array:1 [
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          "identificador" => "xres561578"
          "titulo" => "Abstract"
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              "identificador" => "abst0005"
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        1 => array:2 [
          "identificador" => "xpalclavsec577977"
          "titulo" => "Keywords"
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        2 => array:2 [
          "identificador" => "sec0005"
          "titulo" => "Introduction"
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        3 => array:3 [
          "identificador" => "sec0010"
          "titulo" => "Materials and methods"
          "secciones" => array:4 [
            0 => array:2 [
              "identificador" => "sec0015"
              "titulo" => "Microorganisms"
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            1 => array:2 [
              "identificador" => "sec0020"
              "titulo" => "Susceptibility testing of planktonic cells"
            ]
            2 => array:2 [
              "identificador" => "sec0025"
              "titulo" => "Susceptibility test of sessile cells"
            ]
            3 => array:2 [
              "identificador" => "sec0030"
              "titulo" => "Statistical analysis"
            ]
          ]
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        4 => array:3 [
          "identificador" => "sec0035"
          "titulo" => "Results"
          "secciones" => array:2 [
            0 => array:2 [
              "identificador" => "sec0040"
              "titulo" => "Susceptibility test of planktonic cells"
            ]
            1 => array:2 [
              "identificador" => "sec0045"
              "titulo" => "Susceptibility test of sessile cells"
            ]
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        5 => array:2 [
          "identificador" => "sec0050"
          "titulo" => "Discussion"
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        6 => array:2 [
          "identificador" => "sec0055"
          "titulo" => "Conflicts of interest"
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        7 => array:1 [
          "titulo" => "References"
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    "pdfFichero" => "main.pdf"
    "tienePdf" => true
    "fechaRecibido" => "2015-04-02"
    "fechaAceptado" => "2015-06-01"
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            0 => "<span class="elsevierStyleItalic">Candida</span>"
            1 => "<span class="elsevierStyleItalic">Cryptococcus</span>"
            2 => "Simvastatin"
            3 => "Antifungal activity"
            4 => "Biofilm"
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        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">The antifungal activity of some statins against different fungal species has been reported&#46; Thus&#44; at the first moment&#44; the <span class="elsevierStyleItalic">in vitro</span> antifungal activity of simvastatin&#44; atorvastatin and pravastatin was tested against <span class="elsevierStyleItalic">Candida</span> spp&#46; and <span class="elsevierStyleItalic">Cryptococcus</span> spp&#46; Then&#44; in a second approach&#44; considering that the best results were obtained for simvastatin&#44; this drug was evaluated in combination with antifungal drugs against planktonic growth and tested against biofilms of <span class="elsevierStyleItalic">Candida</span> spp&#46; and <span class="elsevierStyleItalic">Cryptococcus</span> spp&#46; Drug susceptibility testing was performed using the microdilution broth method&#44; as described by the Clinical and Laboratory Standards Institute&#46; The interaction between simvastatin and antifungals against planktonic cells was analyzed by calculating the fractional inhibitory concentration index&#46; Regarding biofilm susceptibility&#44; simvastatin was tested against growing biofilm and mature biofilm of one strain of each tested yeast species&#46; Simvastatin showed inhibitory effect against <span class="elsevierStyleItalic">Candida</span> spp&#46; and <span class="elsevierStyleItalic">Cryptococcus</span> spp&#46; with minimum inhibitory concentration values ranging from 15&#46;6 to 1000<span class="elsevierStyleHsp" style=""></span>mg<span class="elsevierStyleHsp" style=""></span>L<span class="elsevierStyleSup">&#8722;1</span> and from 62&#46;5 to 1000<span class="elsevierStyleHsp" style=""></span>mg<span class="elsevierStyleHsp" style=""></span>L<span class="elsevierStyleSup">&#8722;1</span>&#44; respectively&#46; The combination of simvastatin with itraconazole and fluconazole showed synergism against <span class="elsevierStyleItalic">Candida</span> spp&#46; and <span class="elsevierStyleItalic">Cryptococcus</span> spp&#46;&#44; while the combination of simvastatin with amphotericin B was synergistic only against <span class="elsevierStyleItalic">Cryptococcus</span> spp&#46; Concerning the biofilm assays&#44; simvastatin was able to inhibit both growing biofilm and mature biofilm of <span class="elsevierStyleItalic">Candida</span> spp&#46; and <span class="elsevierStyleItalic">Cryptococcus</span> spp&#46; The present study showed that simvastatin inhibits planktonic cells and biofilms of <span class="elsevierStyleItalic">Candida</span> and <span class="elsevierStyleItalic">Cryptococcus</span> species&#46;</p></span>"
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          "en" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">In vitro</span> effect of simvastatin &#40;SIM&#41;&#44; amphotericin B &#40;AMB&#41;&#44; and itraconazole &#40;ITC&#41; at 3 different concentrations on biofilm formation &#40;A&#41; and mature biofilm &#40;B&#41; of <span class="elsevierStyleItalic">Candida</span> spp&#46; Black bars&#58; positive control&#59; MIC&#58; minimum inhibitory concentration&#46; Absorbance of XTT &#40;492<span class="elsevierStyleHsp" style=""></span>nm&#41;&#46; &#42;Represents statistically significant difference &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41; when compared to the positive control&#46; Data expressed as mean<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>SEM&#46;</p>"
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          "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">In vitro</span> effect of simvastatin &#40;SIM&#41;&#44; amphotericin B &#40;AMB&#41;&#44; and itraconazole &#40;ITC&#41; at 3 different concentrations on biofilm formation &#40;A&#41; and mature biofilm &#40;B&#41; of <span class="elsevierStyleItalic">Cryptococcus</span> spp&#46; strains&#46; Black bars&#58; positive control&#59; MIC&#44; minimum inhibitory concentration&#46; Absorbance of XTT &#40;492<span class="elsevierStyleHsp" style=""></span>nm&#41;&#46; &#42;Represents statistical significant difference &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41; when compared to the positive control&#46; Data expressed as mean<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>SEM&#46;</p>"
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                  <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" title="table-head  " align="left" valign="top" scope="col">Strains &#40;<span class="elsevierStyleItalic">n</span>&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " colspan="6" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">MIC geometric mean &#40;&#956;g<span class="elsevierStyleHsp" style=""></span>mL<span class="elsevierStyleSup">&#8722;1</span>&#41;</th></tr><tr title="table-row"><th class="td" title="table-head  " align="" valign="top" scope="col">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " colspan="3" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Statins</th><th class="td" title="table-head  " colspan="3" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Antifungals</th></tr><tr title="table-row"><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Simvastatin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Atorvastatin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Pravastatin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Amphotericin B&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Itraconazole&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Fluconazole&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " colspan="7" align="left" valign="top"><span class="elsevierStyleItalic"><span class="elsevierStyleBold">Candida</span></span><span class="elsevierStyleBold">species</span></td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">C&#46; albicans</span> &#40;16&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">29&#46;45&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">52&#46;06&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2159&#46;24&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;561&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">5&#46;992&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">21&#46;357&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">C&#46; tropicalis</span> &#40;12&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">70&#46;12&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">165&#46;34&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">21022&#46;41&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;343&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">15&#46;021&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">82&#46;346&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">C&#46; krusei</span> &#40;11&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">567&#46;16&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">755&#46;06&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#62;50&#44;000&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&#46;624&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;072&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">12&#46;126&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">C&#46; parapsilosis sensu lato</span> &#40;12&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">235&#46;97&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1491&#46;37&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#62;50&#44;000&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;707&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;059&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;891&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="7" align="left" valign="top"><span class="elsevierStyleItalic"><span class="elsevierStyleBold">Cryptococcus</span></span><span class="elsevierStyleBold">species</span></td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">C&#46; neoformans</span> A<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a> &#40;11&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">500&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3886&#46;02&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">44079&#46;56&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;536&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;189&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">6&#46;498&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">C&#46; neoformans</span> D &#40;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">250&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#62;10&#44;000&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#62;50&#44;000&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;25&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;25&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">C&#46; neoformans</span> AD &#40;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">62&#46;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#62;10&#44;000&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#62;50&#44;000&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;125&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">C&#46; gatti</span> B &#40;11&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">500&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5325&#46;21&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">44079&#46;56&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;735&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;315&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">34&#46;562&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">C&#46; gatti</span> C &#40;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">500&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#62;10&#44;000&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#62;50&#44;000&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">64&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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              "identificador" => "tblfn0005"
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          "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Geometric means of the minimum inhibitory concentrations &#40;MIC&#41; of statins and antifungal agents against <span class="elsevierStyleItalic">Candida</span> spp&#46; and <span class="elsevierStyleItalic">Cryptococcus</span> spp&#46;</p>"
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          "leyenda" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">SIM&#44; simvastatin&#59; AMB&#44; amphotericin B&#59; ITC&#44; itraconazole&#59; FLC&#44; fluconazole&#59; MIC&#44; minimum inhibitory concentration&#59; FICI&#44; fractional inhibitory concentration index&#46;</p>"
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            0 => array:2 [
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                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" title="table-head  " align="left" valign="top" scope="col">Species &#40;<span class="elsevierStyleItalic">n</span>&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col">Drugs&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " colspan="2" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">MIC &#40;isolated&#41; &#40;&#956;g<span class="elsevierStyleHsp" style=""></span>mL<span class="elsevierStyleSup">&#8722;1</span>&#41;</th><th class="td" title="table-head  " colspan="2" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">MIC &#40;combination&#41; &#40;&#956;g<span class="elsevierStyleHsp" style=""></span>mL<span class="elsevierStyleSup">&#8722;1</span>&#41;</th><th class="td" title="table-head  " align="center" valign="top" scope="col">FICI&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col">Number of strains showing synergism&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr><tr title="table-row"><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">SIM&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Antifungal&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">SIM&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Antifungal&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " colspan="8" align="left" valign="top"><span class="elsevierStyleItalic">Candida albicans</span> &#40;10&#41;</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">SIM&#47;AMB&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">29&#46;11&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;616&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">24&#46;06&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;595&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&#46;741&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#47;10&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">SIM&#47;ITC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">29&#46;11&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">9&#46;189&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&#46;042&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;329&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;071&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">10&#47;10&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">SIM&#47;FLC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">29&#46;11&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">21&#46;112&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&#46;695&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;116&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;116&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">10&#47;10&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="8" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="8" align="left" valign="top"><span class="elsevierStyleItalic">Candida tropicalis</span> &#40;11&#41;</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">SIM&#47;AMB&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">75&#46;47&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;3426&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">55&#46;637&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;354&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&#46;37&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#47;11&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">SIM&#47;ITC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">75&#46;47&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">15&#46;021&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&#46;327&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;266&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;035&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">11&#47;11&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">SIM&#47;FLC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">75&#46;47&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">82&#46;347&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">4&#46;425&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">4&#46;832&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;117&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">11&#47;11&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="8" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="8" align="left" valign="top"><span class="elsevierStyleItalic">Candida krusei</span> &#40;10&#41;</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">SIM&#47;AMB&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">574&#46;35&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&#46;624&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">435&#46;28&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&#46;231&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&#46;515&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#47;10&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">SIM&#47;ITC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">574&#46;35&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;072&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">116&#46;61&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;014&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;416&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">9&#47;10&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">SIM&#47;FLC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">574&#46;35&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">12&#46;126&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">233&#46;26&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">4&#46;925&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;812&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3&#47;10&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="8" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="8" align="left" valign="top"><span class="elsevierStyleItalic">Candida parapsilosis sensu lato</span> &#40;12&#41;</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">SIM&#47;AMB&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">235&#46;97&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;707&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">78&#46;74&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;236&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;667&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">7&#47;12&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">SIM&#47;ITC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">235&#46;97&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;059&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">41&#46;68&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;010&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;353&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">12&#47;12&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">SIM&#47;FLC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">235&#46;97&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;891&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">49&#46;58&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;187&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;420&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">12&#47;12&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="8" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="8" align="left" valign="top"><span class="elsevierStyleItalic">Cryptococcus neoformans</span> &#40;11&#41;</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Serotypes&#58; A&#40;9&#41;&#59; D&#40;1&#41;&#59; AD&#40;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">SIM&#47;AMB&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">388&#46;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;4139&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">35&#46;42&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">11&#47;11&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">SIM&#47;ITC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">388&#46;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;1943&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">70&#46;86&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">388&#46;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">6&#46;622&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;3648&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;11&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">10&#47;11&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="8" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="8" align="left" valign="top"><span class="elsevierStyleItalic">Cryptococcus gattii</span> &#40;7&#41;</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Serotypes&#58; B&#40;6&#41;&#59; C&#40;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">SIM&#47;AMB&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">500&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;8203&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">19&#46;025&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;0312&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;076&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">7&#47;7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">SIM&#47;ITC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">500&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;4102&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">84&#46;0803&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;0689&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;336&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5&#47;7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">SIM&#47;FLC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">500&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">39&#46;008&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">38&#46;051&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2&#46;972&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;152&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">7&#47;7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Geometric means of the minimum inhibitory concentrations &#40;MIC&#41; of the combination of simvastatin and the antifungal amphotericin B&#44; itraconazole&#44; or fluconazole against <span class="elsevierStyleItalic">Candida</span> spp&#46; and <span class="elsevierStyleItalic">Cryptococcus</span> spp&#46;</p>"
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                            4 => "A&#46;J&#46; Monteiro"
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                      "titulo" => "Detection of <span class="elsevierStyleItalic">Candida</span> species resistant to azoles in the microbiota of rheas &#40;<span class="elsevierStyleItalic">Rhea americana</span>&#41;&#58; possible implications for human and animal health"
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Article information

ISSN: 14138670
Original language: English

DOI:10.1016/j.bjid.2015.06.001

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2024 July	89	37	126
2024 June	40	24	64
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2023 December	45	29	74
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2023 October	59	66	125
2023 September	71	33	104
2023 August	26	16	42
2023 July	27	15	42
2023 June	28	17	45
2023 May	38	25	63
2023 April	17	7	24
2023 March	54	21	75
2023 February	34	17	51
2023 January	15	18	33
2022 December	39	24	63
2022 November	35	29	64
2022 October	28	28	56
2022 September	18	15	33
2022 August	19	17	36
2022 July	26	38	64
2022 June	13	25	38
2022 May	15	23	38
2022 April	19	26	45
2022 March	17	30	47
2022 February	23	29	52
2022 January	17	33	50
2021 December	17	37	54
2021 November	29	33	62
2021 October	16	20	36
2021 September	14	23	37
2021 August	14	30	44
2021 July	13	11	24
2021 June	18	19	37
2021 May	21	41	62
2021 April	24	54	78
2021 March	26	32	58
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2020 December	21	16	37
2020 November	12	10	22
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2020 September	11	15	26
2020 August	13	12	25
2020 July	15	14	29
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2020 April	10	10	20
2020 March	21	12	33
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2020 January	28	11	39
2019 December	16	11	27
2019 November	17	16	33
2019 October	6	4	10
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2019 August	27	24	51
2019 July	17	10	27
2019 June	19	14	33
2019 May	26	19	45
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2019 March	13	16	29
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2018 November	72	19	91
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2018 July	3	1	4
2018 May	6	3	9
2018 April	26	9	35
2018 March	12	4	16
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2018 January	14	5	19
2017 December	23	10	33
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2017 October	19	13	32
2017 September	18	9	27
2017 August	13	6	19
2017 July	20	13	33
2017 June	30	11	41
2017 May	25	5	30
2017 April	21	5	26
2017 March	25	8	33
2017 February	14	4	18
2017 January	15	10	25
2016 December	33	13	46
2016 November	31	9	40
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