Comparison of amphotericin B lipid complex, deoxycholate amphotericin B, fluconazole, and anidulafungin activity against Candida albicans biofilm isolated from breakthrough candidemia | Enfermedades Infecciosas y Microbiología Clínica (English Edition)

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HIV, Human immunodeficiency virus; PLWH, people living with HIV." ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Pep Coll, Inma Jarrín, Esteban Martínez, José Manuel Martínez-Sesmero, Raquel Domínguez-Hernández, Antonio Castro-Gómez, Miguel ÿngel Casado" "autores" => array:7 [ 0 => array:2 [ "nombre" => "Pep" "apellidos" => "Coll" ] 1 => array:2 [ "nombre" => "Inma" "apellidos" => "Jarrín" ] 2 => array:2 [ "nombre" => "Esteban" "apellidos" => "Martínez" ] 3 => array:2 [ "nombre" => "José Manuel" "apellidos" => "Martínez-Sesmero" ] 4 => array:2 [ "nombre" => "Raquel" "apellidos" => "Domínguez-Hernández" ] 5 => array:2 [ "nombre" => "Antonio" "apellidos" => "Castro-Gómez" ] 6 => array:2 [ "nombre" => "Miguel ÿngel" "apellidos" => "Casado" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2529993X23000308?idApp=UINPBA00004N" "url" => "/2529993X/0000004100000010/v1_202312041411/S2529993X23000308/v1_202312041411/en/main.assets" ] "en" => array:21 [ "idiomaDefecto" => true "cabecera" => "Original article" "titulo" => "Comparison of amphotericin B lipid complex, deoxycholate amphotericin B, fluconazole, and anidulafungin activity against Candida albicans biofilm isolated from breakthrough candidemia" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "596" "paginaFinal" => "603" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Letícia Kraft, Victoria Stadler Tasca Ribeiro, Geiziane Aparecida Gonçalves, Paula Hansen Suss, Felipe Francisco Tuon" "autores" => array:5 [ 0 => array:2 [ "nombre" => "Letícia" "apellidos" => "Kraft" ] 1 => array:2 [ "nombre" => "Victoria Stadler Tasca" "apellidos" => "Ribeiro" ] 2 => array:2 [ "nombre" => "Geiziane Aparecida" "apellidos" => "Gonçalves" ] 3 => array:2 [ "nombre" => "Paula Hansen" "apellidos" => "Suss" ] 4 => array:4 [ "nombre" => "Felipe Francisco" "apellidos" => "Tuon" "email" => array:1 [ 0 => "felipe.tuon@pucpr.br" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] ] "afiliaciones" => array:1 [ 0 => array:2 [ "entidad" => "Laboratory of Emerging Infectious Diseases, School of Medicine, Department of Health Sciences, Pontifícia Universidade Católica do Paraná, Curitiba, Paraná, Brazil" "identificador" => "aff0005" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Comparación de la actividad del complejo lipídico de anfotericina B, anfotericina B desoxicolato, fluconazol y anidulafungina frente al biofilrm de Candida albicans aisladas de candidemia de brecha" ] ] "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" => 1659 "Ancho" => 2928 "Tamanyo" => 655123 ] ] "descripcion" => array:1 [ "en" => "Images obtained through scanning electronic microscopy (SEM) of biofilms formed by Candida albicans isolated from breakthrough and non-breakthrough candidemia strains on polystyrene discs, at a 1000× magnification. Images A: strain 269, B: strain 307, C: strain 332, and D: strain 334, all representing breakthrough strains obtained from a location closer to the edges of the polystyrene disk, where the biofilm was denser and it is possible to observe the predominance of intertwined pseudohyphae and/or blastoconids. Images E: strain 300, F: strain 328, G: strain 347, and H: strain 358, all representing non-breakthrough candidemia." ] ] ] "textoCompleto" => "IntroductionThe incidence of invasive fungal diseases (IFDs) has increased in the last two decades being one the major causes of death in immunosuppressed patients. The incidence of candidemia follows the same tendency of other IFD. Among the complications of candidemia is the breakthrough candidemia. Breakthrough candidemia is characterized when Candida spp. is recovered in the blood culture after three days of an adequate systemic antifungal therapy.<a class="elsevierStyleCrossRef" href="#bib0230">1</a>The occurrence of breakthrough candidemia contributes to unfavorable outcomes, which are aggravated by the ability of the microorganisms to form biofilms in medical devices. This interferes with appropriate infection management, reducing treatment efficacy and increasing mortality.<a class="elsevierStyleCrossRefs" href="#bib0235">2,3</a> The incidence of breakthrough candidemia ranges from 9% to 18% in large hospitals.<a class="elsevierStyleCrossRefs" href="#bib0235">2–4</a> However, the incidence can reach 52% in patients with severe hematological diseases.<a class="elsevierStyleCrossRef" href="#bib0250">5</a>The pathogenicity of these microorganisms is measured by several virulence factors, including their ability to adhere to devices and biofilm formation.<a class="elsevierStyleCrossRef" href="#bib0255">6</a> These mechanisms are complex and multifactorial. However, microorganisms use biofilms to survive and overcome hostile conditions in order to colonize and establish in new environments.<a class="elsevierStyleCrossRef" href="#bib0260">7</a>The main groups of antifungal agents used in candidemia are azoles, echinocandins, and amphotericins. Among the azoles, fluconazole is the most used drug and is currently the second choice for the treatment of candidemia, after the discovery of echinocandins.<a class="elsevierStyleCrossRef" href="#bib0265">8</a> Currently, echinocandins (micafungin, anidulafungin, and caspofungin) are the drugs of choice for the treatment of candidemia, and a study has demonstrated the clinical superiority of anidulafungin.<a class="elsevierStyleCrossRef" href="#bib0270">9</a> Amphotericin is widely used in the treatment of severe candidemia. However, owing to nephrotoxicity, it has become an alternative drug to echinocandins and fluconazole. It is still indicated for use in refractory candidemia and resistance to azoles and echinocandins.<a class="elsevierStyleCrossRefs" href="#bib0275">10,11</a> To decrease the risk of nephrotoxicity, lipid formulations of amphotericin, including the lipid complex, have been developed and can be successfully used in candidemia.<a class="elsevierStyleCrossRef" href="#bib0285">12</a> Therefore, these drugs were selected for the present study.Several studies have assessed the risk factors associated with the development of breakthrough candidemia.<a class="elsevierStyleCrossRefs" href="#bib0290">13–15</a> However, little is known about the mechanism by which the microorganism achieves breakthrough from previous antifungal treatments. The present study investigated the hypothesis that strains of Candida albicans isolated from patients with breakthrough candidemia differ from those isolated from patients with non-breakthrough candidemia in terms of biofilm production capacity and response to antifungal agents, such as fluconazole, deoxycholate amphotericin B (dAMB), amphotericin B lipid complex (ABLC), and anidulafungin.MethodsExperimental study designEight strains of C. albicans were studied from patients aged>18 years and admitted to the Hospital de Clínicas Complex of the Federal University of Paraná (CHC-UFPR) between January 2011 and December 2017 with acute myeloid leukemia. This study was approved by the ethics committee (under CAAE number 40592915.2.000.0096 of Universidade Federal do Paraná). Written informed consent was obtained from all patients.The C. albicans strains were divided into two groups, i.e., (a) C. albicans from breakthrough candidemia (numbers 269, 307, 332, and 334) and (b) C. albicans isolated from blood culture patients that presented with non-breakthrough candidemia (identified by numbers 300, 328, 347, and 358). The identification of all isolates was confirmed by matrix-assisted laser desorption ionization/time-of-flight (MALDI-TOF) mass spectrometry (bioMérieux, Marcy l’Etoile, France) with a score value≥2.000.Minimal inhibitory concentration (MIC) determinationFour antifungal drugs were used: dAMB (Sigma-Aldrich, St. Louis, MI), ABLC (Teva, São Paulo, Brazil), fluconazole (Sigma–Aldrich, St. Louis, MO), and anidulafungin (Wyeth-Pfizer, Kalamazoo, MI). The MIC was determined in accordance with the Clinical and Laboratory Standards Institute guidelines, using broth microdilution according to the protocol M27-S4.<a class="elsevierStyleCrossRef" href="#bib0305">16</a>Biofilm productionA suspension of 1.5×106CFU/mL of each yeast was prepared using RPMI 1640, and 200μL was discharged into each well of a 96-well microplate (flat bottom). The microplate was then incubated for 24h at 36°C on a shaker at 120rpm after sealing with adhesive seal. The positive control (growth) was prepared using 200μL of each yeast suspension, whereas the negative control (sterility) was prepared using 200μL of RPMI 1640.<a class="elsevierStyleCrossRefs" href="#bib0310">17,18</a> Next, the biofilms of each strain were subjected to antifungal susceptibility tests.After the biofilm formation step, the medium of each well was aspirated, and 200μL of RPMI 1640 was prepared at concentrations of 0.25–16, 0.25–64, 0.125–32, and 0.25–32mg/L of dAMB, ABCL, fluconazole, and anidulafungin, respectively. All antifungal solutions were prepared in RPMI 1640. The microplates containing the biofilm and each antifungal with respective concentrations were then incubated for 24h at 36°C on a shaker at 120rpm. Next, the medium was aspirated, and the resulting biofilm was washed with 200μL of PBS (pH 7.5) to remove planktonic/nonadherent cells.Determination of minimum biofilm eradication concentration (MBEC)After the antifungal treatment and washing step (as mentioned above), 200μL of PBS (pH 7.5) was added to each well. The 96-well microplates were sealed with an adhesive seal and then sonicated in an ultrasonic bath for 5min at 37°C and 40kHz (Sanders Medical, Santa Rita do Sapucaí, Minas Gerais, Brazil) to disrupt the biofilm matrix cells. Serial dilutions were made using sterile saline, which was poured onto Sabouraud dextrose agar plates. The plates were then incubated for 24h at 36°C. The CFU count was determined and the results were calculated as CFU per area unit (log10 CFU/cm2), where MBEC is the minimum concentration in milligram per liter of each antifungal capable of reducing biofilm cells by 2 log10 per cm2.<a class="elsevierStyleCrossRef" href="#bib0255">6</a>Estimation of metabolic activity by the MTT reduction assayThe biofilms were incubated in a 96-well microplate filled with 200μL MTT [3-(4,5-dimethylthiazol-2yl)-2,5-diphenyl tetrazolium bromide] (Sigma-Aldrich, St. Louis, MO, USA) at a concentration of 1mg/mL at 36°C for 2h. After incubation, MTT was aspirated, and the wells were washed thrice using PBS (pH 7.5). The resulting product (formazan) formed inside the cells was dissolved in 200μL of isopropanol and homogenized. Next, 100μL of this solution was transferred to a new 96-well microplate. Absorbance was measured using a Versa-Max microplate ELISA reader adjusted to a wavelength of 570nm.<a class="elsevierStyleCrossRef" href="#bib0320">19</a> Biofilm classification was based on optical density (OD) according to a previous criteria.<a class="elsevierStyleCrossRef" href="#bib0310">17</a> The results of the MTT assay were expressed as a percentage relative to the positive control (PC), which was considered 100%.Estimation of biomass by crystal violet retentionBiofilms were fixed in a 96-well microplate using methanol (200μL) for 15min. Next, methanol was aspirated, and the wells were dried at room temperature. Thereafter, 200μL of 1% crystal violet was added to each well and the microplate was incubated at 36°C for 5min. The wells were carefully washed thrice with ultrapure water. Then, 200μL of 33% acetic acid was added to dissolve the stain, which was then homogenized. Next, 100μL of the solution was transferred to a new 96-well microplate and the total biomass was quantified using a Versa-Max microplate ELISA reader (Molecular Devices, Sunnyvale, CA) at a wavelength of 570nm. The results were stored as a percentage of biomass reduction.Biofilm analysis using scanning electronic microscopy (SEM)To evaluate the structure and biofilm adherence in vitro, SEM was performed using polystyrene discs (16mm×2mm). This method allows the capture of high-resolution images of a sample's surface and is largely used to observe the biofilm structure. Images were obtained at magnification of 1000× for each strain of each group.Statistical analysisAll tests were performed in triplicate. Qualitative data are described as percentages, and quantitative data are expressed as medians with 10% and 90% percentiles. To compare the results between isolated samples from patients with breakthrough candidemia and non-breakthrough candidemia, the Mann–Whitney U test was used to compare medians. Statistical significance was set at p<0.05. The Shapiro–Wilk normality test showed a non-normal distribution of data, justifying the usage of a non-parametric test.ResultsIdentification of C. albicans strains and biofilm characterizationThe ability to adhere, grow, and produce biofilms was observed for all isolates from the two groups. Biofilm production in isolates from breakthrough candidemia was four times higher than in isolates from non-breakthrough candidemia using violet crystal (measured in optical density). Therefore, all isolates were classified as strong biofilm producers (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>).<elsevierMultimedia ident="tbl0005"></elsevierMultimedia>In addition to this classification, the architectural structure was observed through SEM, confirming that all strains of C. albicans produced mature and structurally organized biofilms after 48h on the discs (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). At 1000× magnification, the biofilm was found to be adhered to the flat and smooth surfaces of the polystyrene discs in the presence of blastoconids and interlaced hyphae. <a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>A–D represents C. albicans from breakthrough candidemia (numbers 269, 307, 332, and 334, respectively) and 1E–H represent C. albicans isolated from blood culture patients that presented with non-breakthrough candidemia (identified by numbers 300, 328, 347, and 358, respectively).<elsevierMultimedia ident="fig0005"></elsevierMultimedia>Susceptibility of planktonic cells to antifungalsThe MICs are presented in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>. All the drugs tested showed good activity against planktonic/free cells. For dAMB and ABLC, MICs varied between 0.25 and 1mg/L. MICs varied from 0.125 to 2mg/L for fluconazole (all susceptible to fluconazole). For anidulafungin, all MICs were ≤0.03mg/L.<elsevierMultimedia ident="tbl0010"></elsevierMultimedia>Susceptibility of sessile cells to antifungalsAfter biofilm production, three complementary techniques were used to evaluate the susceptibility to antifungals: MBEC, estimating metabolic activity by reducing MTT, and evaluating biomass by crystal violet retention. All detailed data of MBEC, MTT and biomass are included in the supplement material (S1).Fluconazole and anidulafungin were unable to eradicate the biofilm (p>0.05). ABLC decreased the cell concentration by 1 log10 for breakthrough candidemia isolates (p=0.09), but not for non-breakthrough candidemia isolates. When dAMB was evaluated, a 2 log10 reduction was observed in the biofilm cells at 16mg/L of this antifungal (p<0.05 for breakthrough candidemia isolates as well as for non-breakthrough candidemia isolates) (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>).<elsevierMultimedia ident="fig0010"></elsevierMultimedia>Metabolic activity by the MTT reduction assayFluconazole and anidulafungin did not reduce metabolic activity in cells (p>0.05). Only dAMB and ABLC showed antifungal activity against the biofilms. dAMB reduced the metabolic activity by approximately 50% at 0.5mg/L of the drug, and 75% at 16mg/L (p<0.05). ABLC reduced metabolic activity by approximately 50% at 0.25mg/L, the lowest dose tested, and by 75% at 1mg/L (p<0.05) (<a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>).<elsevierMultimedia ident="fig0015"></elsevierMultimedia>Crystal violet retentionNo significant reduction was observed in biomass (p>0.05) when testing fluconazole and anidulafungin. dAMB exhibited better antifungal activity toward the biofilm, thus reducing 52% of the biomass at a concentration of 0.5mg/L in the strains from breakthrough candidemia (p<0.05) at 4 and 16mg/L concentrations of the antifungal agent. For non-breakthrough candidemia isolates, a 54% reduction was observed in biomass at 4mg/L, with p<0.05, for concentrations of 8 and 16mg/L. Using ABCL, a 50% reduction was observed at 2mg/L in the breakthrough candidemia group. In comparison with the non-breakthrough candidemia group, a maximum reduction of approximately 25% was observed at concentrations of 32 and 64mg/L (<a class="elsevierStyleCrossRef" href="#fig0020">Fig. 4</a>).<elsevierMultimedia ident="fig0020"></elsevierMultimedia>When analyzing the groups by evaluating the techniques and antifungals separately, regardless of the concentration of the tested drug, no statistical difference was observed between C. albicans isolated from breakthrough and non-breakthrough candidemia in the tests: MBEC technique using dAMB (p=0.312), ABLC (p=0.112), and anidulafungin (p=0.911); MTT reduction using dAMB (p=0.203), ABLC (p=0.103), and fluconazole (p=0.197), and biomass analysis when using dAMB (p=0.459), ABLC (p=0.245), and fluconazole (p=0.154). A statistically significant difference was observed between the groups in the MBEC technique using fluconazole (p<0.001) and MTT and biomass when tested with anidulafungin (p=0.004 and p=0.001, respectively).DiscussionThe insertion of a catheter is a risk factor for developing candidemia, as the manipulation of these devices contributes to contamination and development of biofilms caused by yeasts such as Candida spp.<a class="elsevierStyleCrossRef" href="#bib0325">20</a> Our results corroborate previous findings that described the biofilm produced by C. albicans as having a heterogeneous architecture comprising multilayered yeasts and hyphae.<a class="elsevierStyleCrossRef" href="#bib0330">21</a> These structures formed by C. albicans are difficult to eradicate and have greater stability and resistance to most antifungals.<a class="elsevierStyleCrossRef" href="#bib0335">22</a> In addition, candidemia due to biofilm-producing strains has been associated with increased patient mortality.<a class="elsevierStyleCrossRef" href="#bib0340">23</a> We found that biofilm production in breakthrough candidemia isolates was higher than in those isolates from non-breakthrough candidemia. Biofilm producing is an independent virulence factor in Candida spp.<a class="elsevierStyleCrossRef" href="#bib0345">24</a> Furthermore, clinical studies have shown that biofilm-producers isolates increase the mortality rate.<a class="elsevierStyleCrossRef" href="#bib0350">25</a>All isolates from the present study were susceptible to the antifungals tested, but not biofilms. For dAMB, planktonic cells obtained a maximum MIC of 1mg/L, whereas under sessile conditions, 16mg/L was required to eradicate the biofilm in both groups. Other studies have demonstrated a high prevalence of antifungal resistance in biofilms formed by C. albicans.<a class="elsevierStyleCrossRef" href="#bib0355">26</a> This resistance can be attributed to several mechanisms, such as ineffective penetration of the drug through the extracellular matrix of the biofilm, decreased growth rate of C. albicans, cell persistence, and expression of resistance genes induced by the community.Azoles have been shown to have poor activity against Candida spp.<a class="elsevierStyleCrossRef" href="#bib0360">27</a> Choi et al. (2007) observed a reduction in cellular metabolism and reported that biofilms were resistant to fluconazole at concentrations>1024mg/L.<a class="elsevierStyleCrossRef" href="#bib0365">28</a> Melo et al., in accordance with the present study, reported that the isolates were susceptible to fluconazole in planktonic form, but resistant in their sessile form.<a class="elsevierStyleCrossRef" href="#bib0360">27</a> Time-dependent resistance was associated with the expression of genes related to efflux pumps after drug induction.Of the three antifungal classes currently used to treat candidemia, only polyenes and echinocandins have shown consistent in vitro activity against biofilms of C. albicans.<a class="elsevierStyleCrossRef" href="#bib0370">29</a>We observed unexpected results regarding the use of anidulafungin. Other studies have reported that echinocandins have a good effect on C. albicans biofilms in vitro and in vivo and significantly reduce the number of cells at higher doses than those found for planktonic cells.<a class="elsevierStyleCrossRefs" href="#bib0375">30,31</a> Simultaneously, Rosato et al. (2013) described that anidulafungin has a paradoxical growth effect (PGE) on C. albicans.<a class="elsevierStyleCrossRef" href="#bib0385">32</a> These studies reported reduced microbial growth at low concentrations of the antifungal agent and a resurgence of growth at concentrations above the MIC. To date, the clinical significance of the PGE remains unclear. One explanation for PGE includes involvement of the calcineurin pathway and upregulation of the protein kinase-C cell wall integrity pathway.<a class="elsevierStyleCrossRef" href="#bib0390">33</a> Even though PGE has been described with fluconazole, this phenomenon is more common with echinocandins.<a class="elsevierStyleCrossRef" href="#bib0395">34</a>In comparison, amphotericin B, with or without the lipid complex, showed greater antifungal activity against the biofilms. A 50% reduction in biomass was achieved in the breakthrough candidemia group at 0.5 and 2mg/L for dAMB and ABLC, respectively. Several studies have reported that a 50% reduction is used to determine an important antifungal effect on biofilms.<a class="elsevierStyleCrossRef" href="#bib0370">29</a> However, biofilm eradication was only achieved using 16mg/L of dAMB. The MTT assay was used to evaluate cell viability in biofilms, and crystal violet was used to evaluate biomass. These are classical tests for analyzing biofilms. It is important to discriminate between the two methods when evaluating the anti-biofilm activity of antifungal drugs. In the present work, we propose the use of the tetrazolium salt assay (MTT assay), which is a frequent procedure for determining the number of eukaryotic cells in studies where the viability of cells in culture is essential. Mitochondrial enzymes cleave the yellow tetrazolium salt (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, MTT) to formazan, and the resulting product forms a purple solution when dissolved in the appropriate reagents.<a class="elsevierStyleCrossRef" href="#bib0400">35</a> The MTT assay has been successfully applied to evaluate the size of microbial populations growing in biofilms. Formazan formation by biofilms is a manifestation of respiratory enzyme activity in the cell walls of bacteria and/or dehydrogenase activity in filamentous fungi and yeast.<a class="elsevierStyleCrossRef" href="#bib0405">36</a>dAMB was once considered a gold standard among antifungals due to its broader antifungal spectrum. However, lipid formulations have been developed in an attempt to reduce its toxicity.<a class="elsevierStyleCrossRef" href="#bib0255">6</a> Kuhn et al. (2002) determined that the exposure of planktonic cells to subinhibitory concentrations of ABLC inhibited subsequent biofilm formation.<a class="elsevierStyleCrossRef" href="#bib0370">29</a> In addition, the authors reported that despite the large size of the ABLC molecule, it penetrates the extracellular matrix to reach the fungal cells within the biofilm, although its dispersion in phospholipids can facilitate passage through the polysaccharide.Although dAMB eradicated the biofilm at 16mg/L, the mean peak plasma concentrations ranged from 0.5 to 2mg/L in adults receiving repeated doses of approximately 0.5mg/kg/day. In osteomyelitis, it may be exposed to a higher concentration of amphotericin B, thereby presenting a greater antifungal effect on the biofilm.<a class="elsevierStyleCrossRef" href="#bib0410">37</a> It has been shown that dAMB presents high activity against C. albicans biofilm in an in vitro model.<a class="elsevierStyleCrossRef" href="#bib0415">38</a> Moreover, the use of dAMB in silicon catheters demonstrated complete growth and biofilm formation inhibition.<a class="elsevierStyleCrossRef" href="#bib0420">39</a> Other studies have pointed out that cases of catheter-related C. albicans infections could be treated with dAMB at 2–2.5mg/L, allowing to save the catheter and a patient treated with a concentration of 5mg/L could be cured.<a class="elsevierStyleCrossRefs" href="#bib0425">40–42</a>The techniques applied for evaluation of biofilms may pose challenges, as subtle changes such as temperature, rotation, pipetting, and washing processes can interfere with the amount of biofilm produced and analyzed.<a class="elsevierStyleCrossRef" href="#bib0440">43</a> Furthermore, in vitro and in vivo methods can produce different results due to a less controlled environment and interference with host immunity.<a class="elsevierStyleCrossRef" href="#bib0445">44</a> Nevertheless, in other study, the formation of the in vitro biofilm of C. albicans correlated well with the biofilm models in vivo, obtaining similar time in the growth phases as well as the architectural structure of the biofilms recovered from patients with infection.<a class="elsevierStyleCrossRef" href="#bib0450">45</a>The major limitation of this study was the number of isolates included. However, the anti-biofilm activity was evaluated by three methods with three antifungal classes. A higher concentration of echinocandin and fluconazole could be tested, however, the values would not be useful in clinical conditions, unless if used as lock-therapy.In conclusion, isolates from breakthrough candidemia produced more biofilm than controls from non-breakthrough candidemia. Only the dAMB and ABLC formulations exhibited antifungal effects in sessile cells. For a broader understanding of the hypothesis that breakthrough candidemia isolates could differ from non-breakthrough candidemia isolates in terms of their ability to produce biofilms and their susceptibility to antifungals, a greater number of isolates should be studied.Authors’ contributionConceptualization: L. Kraft, F.F. Tuon.Methodology: L. Kraft, V.S.T. Ribeiro, G.A. Gonçalves, P.H. Suss.Formal analysis: L. Kraft, F.F. Tuon.Writing: Original draft preparation – L. Kraft, F.F. Tuon.Writing: Review and editing – L. Kraft, V.S.T. Ribeiro, G.A. Gonçalves, P.H. Suss.Supervision: F.F. Tuon.Ethical statementThis study was approved by the ethics committee (CAAE number 40592915.2.000.0096 of Universidade Federal do Paraná).Data availabilityAll data have been used in this paper, and raw data are available upon request.FundingNone.Conflicts of interestF.F. Tuon is a CNPq researcher. The other authors declare no conflicts of interest." "textoCompletoSecciones" => array:1 [ "secciones" => array:15 [ 0 => array:3 [ "identificador" => "xres2039813" "titulo" => "Abstract" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Introduction" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusion" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1744060" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres2039812" "titulo" => "Resumen" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Introducción" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Métodos" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusión" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec1744061" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:3 [ "identificador" => "sec0010" "titulo" => "Methods" "secciones" => array:8 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Experimental study design" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "Minimal inhibitory concentration (MIC) determination" ] 2 => array:2 [ "identificador" => "sec0025" "titulo" => "Biofilm production" ] 3 => array:2 [ "identificador" => "sec0030" "titulo" => "Determination of minimum biofilm eradication concentration (MBEC)" ] 4 => array:2 [ "identificador" => "sec0035" "titulo" => "Estimation of metabolic activity by the MTT reduction assay" ] 5 => array:2 [ "identificador" => "sec0040" "titulo" => "Estimation of biomass by crystal violet retention" ] 6 => array:2 [ "identificador" => "sec0045" "titulo" => "Biofilm analysis using scanning electronic microscopy (SEM)" ] 7 => array:2 [ "identificador" => "sec0050" "titulo" => "Statistical analysis" ] ] ] 6 => array:3 [ "identificador" => "sec0055" "titulo" => "Results" "secciones" => array:5 [ 0 => array:2 [ "identificador" => "sec0060" "titulo" => "Identification of C. albicans strains and biofilm characterization" ] 1 => array:2 [ "identificador" => "sec0065" "titulo" => "Susceptibility of planktonic cells to antifungals" ] 2 => array:2 [ "identificador" => "sec0070" "titulo" => "Susceptibility of sessile cells to antifungals" ] 3 => array:2 [ "identificador" => "sec0075" "titulo" => "Metabolic activity by the MTT reduction assay" ] 4 => array:2 [ "identificador" => "sec0080" "titulo" => "Crystal violet retention" ] ] ] 7 => array:2 [ "identificador" => "sec0085" "titulo" => "Discussion" ] 8 => array:2 [ "identificador" => "sec0090" "titulo" => "Authors’ contribution" ] 9 => array:2 [ "identificador" => "sec0095" "titulo" => "Ethical statement" ] 10 => array:2 [ "identificador" => "sec0100" "titulo" => "Data availability" ] 11 => array:2 [ "identificador" => "sec0105" "titulo" => "Funding" ] 12 => array:2 [ "identificador" => "sec0110" "titulo" => "Conflicts of interest" ] 13 => array:2 [ "identificador" => "xack711158" "titulo" => "Acknowledgments" ] 14 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2022-04-20" "fechaAceptado" => "2022-07-19" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1744060" "palabras" => array:5 [ 0 => "Antifungals" 1 => "Candida" 2 => "Candidemia" 3 => "Breakthrough candidemia" 4 => "Biofilms" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1744061" "palabras" => array:5 [ 0 => "Antifúngico" 1 => "Candida" 2 => "Candidemia" 3 => "Candidemia de brecha" 4 => "Biofilms" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:3 [ "titulo" => "Abstract" "resumen" => "IntroductionBiofilm formation causes virulence and resistance in Candida albicans. However, little is known about breakthrough candidemia isolates. We evaluated the antifungal activity of fluconazole, anidulafungin, deoxycholate amphotericin B (dAMB), and amphotericin B lipid complex (ABLC) against biofilms of C. albicans isolated from patients with breakthrough candidemia. MethodsThe present study used strains of C. albicans isolated from breakthrough and non-breakthrough candidemia patients (control group). The susceptibility of planktonic cells to amphotericin B, anidulafungin, and fluconazole was determined by broth microdilution. Antifungal activity in sessile cells was evaluated using the minimum biofilm eradication concentration (MBEC), metabolic activity was estimated by reducing MTT, and biomass was estimated using crystal violet retention. ResultsThe planktonic strains were susceptible to amphotericin B, anidulafungin, and fluconazole, with minimum inhibitory concentrations of 1, ≤0.03, and 2mg/L, respectively. However, fluconazole and anidulafungin did not exert an antifungal effect on biofilms. Additionally, dAMB and ABCL reduced the metabolic activity and biomass. However, eradication was only achieved using 16mg/L dAMB. C. albicans isolates of breakthrough candidemia exhibited strong biofilm production, and the in vitro activity of available therapeutic options was poor. ConclusionIn the present study, only dAMB and ABCL exhibited antibiofilm effects against sessile breakthrough candidemia isolates." "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Introduction" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusion" ] ] ] "es" => array:3 [ "titulo" => "Resumen" "resumen" => "IntroducciónLa formación de biofilm se asocia con la virulencia y la resistencia al tratamiento de Candida albicans (C. albicans) sin embargo, son poco conocidas las características de los aislamientos procedentes de pacientes con candidemias de brecha. Evaluamos la actividad antifúngica de fluconazol, anidulafungina, anfotericina B desoxicolato (dAMB) y el complejo lipídico de la anfotericina B (ABLC) frente a biofilms de C. albicans aisladas de pacientes con candidemia de brecha. MétodosSe utilizaron cepas de C. albicans aisladas de candidemias de brecha y de otras candidemias (grupo control). La sensibilidad de las células planctónicas a la anfotericina B, la anidulafungina y el fluconazol se determinó mediante el método de microdilución en caldo. En células sésiles, la actividad antifúngica se evaluó mediante la concentración miníma de erradicación de biofilm (MBEC), la actividad metabólica se estimó mediante la reducción de MTT y la biomasa mediante la retención de cristal violeta. ResultadosLas cepas en forma planctónica fueron sensibles a la anfotericina B, anidulafungina y fluconazol, con CMI de 1 mg/L, ≤ 0,03 y 2 mg/L, respectivamente; sin embargo, no se observó efecto antifúngico sobre los biofilms con fluconazol o anidulafungina. Con dAMB y ABCL se observó una reducción de la actividad metabólica y de la biomasa, pero la erradicación solo se consiguió con 16 mg/L de dAMB. Las cepas de C. albicans que causan candidemia de brecha producen abundante biofilm y las opciones terapéuticas disponibles no son activas in vitro frente a ellas. ConclusiónSolo dAMB y ABCL exhibieron efecto antibiofilm frente a los aislamientos de C. albicans sésiles y planctónicos." "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Introducción" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Métodos" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusión" ] ] ] ] "apendice" => array:1 [ 0 => array:1 [ "seccion" => array:1 [ 0 => array:4 [ "apendice" => "The following are the supplementary data to this article:<elsevierMultimedia ident="upi0005"></elsevierMultimedia>" "etiqueta" => "Appendix A" "titulo" => "Supplementary data" "identificador" => "sec0120" ] ] ] ] "multimedia" => array:7 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1659 "Ancho" => 2928 "Tamanyo" => 655123 ] ] "descripcion" => array:1 [ "en" => "Images obtained through scanning electronic microscopy (SEM) of biofilms formed by Candida albicans isolated from breakthrough and non-breakthrough candidemia strains on polystyrene discs, at a 1000× magnification. Images A: strain 269, B: strain 307, C: strain 332, and D: strain 334, all representing breakthrough strains obtained from a location closer to the edges of the polystyrene disk, where the biofilm was denser and it is possible to observe the predominance of intertwined pseudohyphae and/or blastoconids. Images E: strain 300, F: strain 328, G: strain 347, and H: strain 358, all representing non-breakthrough candidemia." ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 2281 "Ancho" => 2514 "Tamanyo" => 266539 ] ] "descripcion" => array:1 [ "en" => "Minimal biofilm eradication concentration (MBEC) for fluconazole, deoxycholate amphotericin B, anidulafungin, and amphotericin B lipid complex (ABLC) of Candida albicans isolates from blood culture in patients with breakthrough (n=4) and non-breakthrough (n=4) candidemia. The X axis is the antifungal concentration (mg/L). * p<0.05 in comparison with control." ] ] 2 => array:7 [ "identificador" => "fig0015" "etiqueta" => "Fig. 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 2312 "Ancho" => 2933 "Tamanyo" => 353139 ] ] "descripcion" => array:1 [ "en" => "Candida albicans biofilm cell viability using MTT method for fluconazole, deoxycholate amphotericin B, anidulafungin, and amphotericin B lipid complex (ABLC) in breakthrough (n=4) and non-breakthrough (n=4) candidemia. The box plot represents min, max, and interquartile range at 25% and 75%. The values are expressed as percentage in relation to positive control (PC). The X axis is the antifungal concentration (mg/L). * p<0.05 in comparison with control." ] ] 3 => array:7 [ "identificador" => "fig0020" "etiqueta" => "Fig. 4" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr4.jpeg" "Alto" => 2331 "Ancho" => 2933 "Tamanyo" => 337235 ] ] "descripcion" => array:1 [ "en" => "Candida albicans biomass after progressive concentrations of fluconazole, deoxycholate amphotericin B, anidulafungin, and amphotericin B lipid complex (ABLC) in breakthrough (n=4) and non-breakthrough (n=4) candidemia. The box plot represents min, max, and interquartile range at 25% and 75%. The values are expressed as percentage in relation to positive control (PC). The X axis is the antifungal concentration (mg/L). * p<0.05 in comparison with control." ] ] 4 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:1 [ "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="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Group \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Strain ID \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">ODC \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">ODB \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Classification \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="4" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Breakthrough</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">269 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.158 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1.770 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Strong biofilm producer \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">307 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.158 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2.620 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Strong biofilm producer \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">332 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.163 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2.777 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Strong biofilm producer \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">334 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.168 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3.371 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Strong biofilm producer \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="5" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"></td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="4" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Non-breakthrough</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">300 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.135 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.626 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Strong biofilm producer \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">328 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.110 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2.707 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Strong biofilm producer \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">347 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.108 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1.306 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Strong biofilm producer \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">358 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.107 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2.975 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Strong biofilm producer \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab3382561.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Classification of biofilm production of Candida albicans isolates using crystal violet measured by optical density (OD) from breakthrough (ODB) and non-breakthrough (ODC) candidemia." ] ] 5 => array:8 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at2" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:1 [ "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="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Group \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Strain ID \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Amphotericin BMIC (mg/L) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Lipid complex Amphotericin BMIC (mg/L) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">FluconazoleMIC (mg/L) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">AnidulafunginMIC (mg/L) \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="4" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Breakthrough</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">269 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.25 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.25 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.25 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">≤0.03 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">307 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.25 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.25 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">≤0.03 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">332 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.25 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.25 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.125 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">≤0.03 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">334 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.25 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.25 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.25 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">≤0.03 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="6" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"></td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="4" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Nonbreakthrough</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">300 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.125 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">≤0.03 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">328 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.25 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">≤0.03 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">347 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.25 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">≤0.03 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">358 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.125 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">≤0.03 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab3382560.png" ] ] ] ] "descripcion" => array:1 [ "en" => "MICs (mg/L) of antifungals against planktonic cells from breakthrough and non-breakthrough candidemia strains." ] ] 6 => array:5 [ "identificador" => "upi0005" "tipo" => "MULTIMEDIAECOMPONENTE" "mostrarFloat" => false "mostrarDisplay" => true "Ecomponente" => array:2 [ "fichero" => "mmc1.pdf" "ficheroTamanyo" => 68643 ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:45 [ 0 => array:3 [ "identificador" => "bib0230" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Risk factors for breakthrough candidemia" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "M. Nucci" 1 => "A.L. Colombo" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1007/s10096-002-0697-1" "Revista" => array:6 [ "tituloSerie" => "Eur J Clin Microbiol Infect Dis" "fecha" => "2002" "volumen" => "21" "paginaInicial" => "209" "paginaFinal" => "211" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11957023" "web" => "Medline" ] ] ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0235" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Breakthrough candidemia in children: clinical and microbiological characteristics, therapeutic strategies and impact on outcomes" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "M.Y. Lai" 1 => "J.F. Hsu" 2 => "S.M. Chu" 3 => "I.H. Wu" 4 => "H.R. Huang" 5 => "C.C. 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Comparison of amphotericin B lipid complex, deoxycholate amphotericin B, fluconazole, and anidulafungin activity against Candida albicans biofilm isolated from breakthrough candidemia

Comparación de la actividad del complejo lipídico de anfotericina B, anfotericina B desoxicolato, fluconazol y anidulafungina frente al biofilrm de Candida albicans aisladas de candidemia de brecha

Letícia Kraft, Victoria Stadler Tasca Ribeiro, Geiziane Aparecida Gonçalves, Paula Hansen Suss, Felipe Francisco Tuon

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felipe.tuon@pucpr.br

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Laboratory of Emerging Infectious Diseases, School of Medicine, Department of Health Sciences, Pontifícia Universidade Católica do Paraná, Curitiba, Paraná, Brazil

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    "titulo" => "Comparison of amphotericin B lipid complex&#44; deoxycholate amphotericin B&#44; fluconazole&#44; and anidulafungin activity against <span class="elsevierStyleItalic">Candida albicans</span> biofilm isolated from breakthrough candidemia"
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        "titulo" => "Comparaci&#243;n de la actividad del complejo lip&#237;dico de anfotericina B&#44; anfotericina B desoxicolato&#44; fluconazol y anidulafungina frente al biofilrm de <span class="elsevierStyleItalic">Candida albicans</span> aisladas de candidemia de brecha"
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          "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Images obtained through scanning electronic microscopy &#40;SEM&#41; of biofilms formed by <span class="elsevierStyleItalic">Candida albicans</span> isolated from breakthrough and non-breakthrough candidemia strains on polystyrene discs&#44; at a 1000&#215; magnification&#46; Images A&#58; strain 269&#44; B&#58; strain 307&#44; C&#58; strain 332&#44; and D&#58; strain 334&#44; all representing breakthrough strains obtained from a location closer to the edges of the polystyrene disk&#44; where the biofilm was denser and it is possible to observe the predominance of intertwined pseudohyphae and&#47;or blastoconids&#46; Images E&#58; strain 300&#44; F&#58; strain 328&#44; G&#58; strain 347&#44; and H&#58; strain 358&#44; all representing non-breakthrough candidemia&#46;</p>"
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">The incidence of invasive fungal diseases &#40;IFDs&#41; has increased in the last two decades being one the major causes of death in immunosuppressed patients&#46; The incidence of candidemia follows the same tendency of other IFD&#46; Among the complications of candidemia is the breakthrough candidemia&#46; Breakthrough candidemia is characterized when <span class="elsevierStyleItalic">Candida</span> spp&#46; is recovered in the blood culture after three days of an adequate systemic antifungal therapy&#46;<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">1</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">The occurrence of breakthrough candidemia contributes to unfavorable outcomes&#44; which are aggravated by the ability of the microorganisms to form biofilms in medical devices&#46; This interferes with appropriate infection management&#44; reducing treatment efficacy and increasing mortality&#46;<a class="elsevierStyleCrossRefs" href="#bib0235"><span class="elsevierStyleSup">2&#44;3</span></a> The incidence of breakthrough candidemia ranges from 9&#37; to 18&#37; in large hospitals&#46;<a class="elsevierStyleCrossRefs" href="#bib0235"><span class="elsevierStyleSup">2&#8211;4</span></a> However&#44; the incidence can reach 52&#37; in patients with severe hematological diseases&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">5</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">The pathogenicity of these microorganisms is measured by several virulence factors&#44; including their ability to adhere to devices and biofilm formation&#46;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">6</span></a> These mechanisms are complex and multifactorial&#46; However&#44; microorganisms use biofilms to survive and overcome hostile conditions in order to colonize and establish in new environments&#46;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">7</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">The main groups of antifungal agents used in candidemia are azoles&#44; echinocandins&#44; and amphotericins&#46; Among the azoles&#44; fluconazole is the most used drug and is currently the second choice for the treatment of candidemia&#44; after the discovery of echinocandins&#46;<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">8</span></a> Currently&#44; echinocandins &#40;micafungin&#44; anidulafungin&#44; and caspofungin&#41; are the drugs of choice for the treatment of candidemia&#44; and a study has demonstrated the clinical superiority of anidulafungin&#46;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">9</span></a> Amphotericin is widely used in the treatment of severe candidemia&#46; However&#44; owing to nephrotoxicity&#44; it has become an alternative drug to echinocandins and fluconazole&#46; It is still indicated for use in refractory candidemia and resistance to azoles and echinocandins&#46;<a class="elsevierStyleCrossRefs" href="#bib0275"><span class="elsevierStyleSup">10&#44;11</span></a> To decrease the risk of nephrotoxicity&#44; lipid formulations of amphotericin&#44; including the lipid complex&#44; have been developed and can be successfully used in candidemia&#46;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">12</span></a> Therefore&#44; these drugs were selected for the present study&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">Several studies have assessed the risk factors associated with the development of breakthrough candidemia&#46;<a class="elsevierStyleCrossRefs" href="#bib0290"><span class="elsevierStyleSup">13&#8211;15</span></a> However&#44; little is known about the mechanism by which the microorganism achieves breakthrough from previous antifungal treatments&#46; The present study investigated the hypothesis that strains of <span class="elsevierStyleItalic">Candida albicans</span> isolated from patients with breakthrough candidemia differ from those isolated from patients with non-breakthrough candidemia in terms of biofilm production capacity and response to antifungal agents&#44; such as fluconazole&#44; deoxycholate amphotericin B &#40;dAMB&#41;&#44; amphotericin B lipid complex &#40;ABLC&#41;&#44; and anidulafungin&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Methods</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Experimental study design</span><p id="par0030" class="elsevierStylePara elsevierViewall">Eight strains of <span class="elsevierStyleItalic">C&#46; albicans</span> were studied from patients aged<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>18 years and admitted to the Hospital de Cl&#237;nicas Complex of the Federal University of Paran&#225; &#40;CHC-UFPR&#41; between January 2011 and December 2017 with acute myeloid leukemia&#46; This study was approved by the ethics committee &#40;under CAAE number 40592915&#46;2&#46;000&#46;0096 of Universidade Federal do Paran&#225;&#41;&#46; Written informed consent was obtained from all patients&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">The <span class="elsevierStyleItalic">C&#46; albicans</span> strains were divided into two groups&#44; <span class="elsevierStyleItalic">i&#46;e&#46;</span>&#44; &#40;a&#41; <span class="elsevierStyleItalic">C&#46; albicans</span> from breakthrough candidemia &#40;numbers 269&#44; 307&#44; 332&#44; and 334&#41; and &#40;b&#41; <span class="elsevierStyleItalic">C&#46; albicans</span> isolated from blood culture patients that presented with non-breakthrough candidemia &#40;identified by numbers 300&#44; 328&#44; 347&#44; and 358&#41;&#46; The identification of all isolates was confirmed by matrix-assisted laser desorption ionization&#47;time-of-flight &#40;MALDI-TOF&#41; mass spectrometry &#40;bioM&#233;rieux&#44; Marcy l&#8217;Etoile&#44; France&#41; with a score value<span class="elsevierStyleHsp" style=""></span>&#8805;<span class="elsevierStyleHsp" style=""></span>2&#46;000&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Minimal inhibitory concentration &#40;MIC&#41; determination</span><p id="par0040" class="elsevierStylePara elsevierViewall">Four antifungal drugs were used&#58; dAMB &#40;Sigma-Aldrich&#44; St&#46; Louis&#44; MI&#41;&#44; ABLC &#40;Teva&#44; S&#227;o Paulo&#44; Brazil&#41;&#44; fluconazole &#40;Sigma&#8211;Aldrich&#44; St&#46; Louis&#44; MO&#41;&#44; and anidulafungin &#40;Wyeth-Pfizer&#44; Kalamazoo&#44; MI&#41;&#46; The MIC was determined in accordance with the Clinical and Laboratory Standards Institute guidelines&#44; using broth microdilution according to the protocol M27-S4&#46;<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">16</span></a></p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Biofilm production</span><p id="par0045" class="elsevierStylePara elsevierViewall">A suspension of 1&#46;5<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleSup">6</span><span class="elsevierStyleHsp" style=""></span>CFU&#47;mL of each yeast was prepared using RPMI 1640&#44; and 200<span class="elsevierStyleHsp" style=""></span>&#956;L was discharged into each well of a 96-well microplate &#40;flat bottom&#41;&#46; The microplate was then incubated for 24<span class="elsevierStyleHsp" style=""></span>h at 36<span class="elsevierStyleHsp" style=""></span>&#176;C on a shaker at 120<span class="elsevierStyleHsp" style=""></span>rpm after sealing with adhesive seal&#46; The positive control &#40;growth&#41; was prepared using 200<span class="elsevierStyleHsp" style=""></span>&#956;L of each yeast suspension&#44; whereas the negative control &#40;sterility&#41; was prepared using 200<span class="elsevierStyleHsp" style=""></span>&#956;L of RPMI 1640&#46;<a class="elsevierStyleCrossRefs" href="#bib0310"><span class="elsevierStyleSup">17&#44;18</span></a> Next&#44; the biofilms of each strain were subjected to antifungal susceptibility tests&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">After the biofilm formation step&#44; the medium of each well was aspirated&#44; and 200<span class="elsevierStyleHsp" style=""></span>&#956;L of RPMI 1640 was prepared at concentrations of 0&#46;25&#8211;16&#44; 0&#46;25&#8211;64&#44; 0&#46;125&#8211;32&#44; and 0&#46;25&#8211;32<span class="elsevierStyleHsp" style=""></span>mg&#47;L of dAMB&#44; ABCL&#44; fluconazole&#44; and anidulafungin&#44; respectively&#46; All antifungal solutions were prepared in RPMI 1640&#46; The microplates containing the biofilm and each antifungal with respective concentrations were then incubated for 24<span class="elsevierStyleHsp" style=""></span>h at 36<span class="elsevierStyleHsp" style=""></span>&#176;C on a shaker at 120<span class="elsevierStyleHsp" style=""></span>rpm&#46; Next&#44; the medium was aspirated&#44; and the resulting biofilm was washed with 200<span class="elsevierStyleHsp" style=""></span>&#956;L of PBS &#40;pH 7&#46;5&#41; to remove planktonic&#47;nonadherent cells&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Determination of minimum biofilm eradication concentration &#40;MBEC&#41;</span><p id="par0055" class="elsevierStylePara elsevierViewall">After the antifungal treatment and washing step &#40;as mentioned above&#41;&#44; 200<span class="elsevierStyleHsp" style=""></span>&#956;L of PBS &#40;pH 7&#46;5&#41; was added to each well&#46; The 96-well microplates were sealed with an adhesive seal and then sonicated in an ultrasonic bath for 5<span class="elsevierStyleHsp" style=""></span>min at 37<span class="elsevierStyleHsp" style=""></span>&#176;C and 40<span class="elsevierStyleHsp" style=""></span>kHz &#40;Sanders Medical&#44; Santa Rita do Sapuca&#237;&#44; Minas Gerais&#44; Brazil&#41; to disrupt the biofilm matrix cells&#46; Serial dilutions were made using sterile saline&#44; which was poured onto Sabouraud dextrose agar plates&#46; The plates were then incubated for 24<span class="elsevierStyleHsp" style=""></span>h at 36<span class="elsevierStyleHsp" style=""></span>&#176;C&#46; The CFU count was determined and the results were calculated as CFU per area unit &#40;log<span class="elsevierStyleInf">10</span> CFU&#47;cm<span class="elsevierStyleSup">2</span>&#41;&#44; where MBEC is the minimum concentration in milligram per liter of each antifungal capable of reducing biofilm cells by 2 log<span class="elsevierStyleInf">10</span> per cm<span class="elsevierStyleSup">2</span>&#46;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">6</span></a></p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Estimation of metabolic activity by the MTT reduction assay</span><p id="par0060" class="elsevierStylePara elsevierViewall">The biofilms were incubated in a 96-well microplate filled with 200<span class="elsevierStyleHsp" style=""></span>&#956;L MTT &#91;3-&#40;4&#44;5-dimethylthiazol-2yl&#41;-2&#44;5-diphenyl tetrazolium bromide&#93; &#40;Sigma-Aldrich&#44; St&#46; Louis&#44; MO&#44; USA&#41; at a concentration of 1<span class="elsevierStyleHsp" style=""></span>mg&#47;mL at 36<span class="elsevierStyleHsp" style=""></span>&#176;C for 2<span class="elsevierStyleHsp" style=""></span>h&#46; After incubation&#44; MTT was aspirated&#44; and the wells were washed thrice using PBS &#40;pH 7&#46;5&#41;&#46; The resulting product &#40;formazan&#41; formed inside the cells was dissolved in 200<span class="elsevierStyleHsp" style=""></span>&#956;L of isopropanol and homogenized&#46; Next&#44; 100<span class="elsevierStyleHsp" style=""></span>&#956;L of this solution was transferred to a new 96-well microplate&#46; Absorbance was measured using a Versa-Max microplate ELISA reader adjusted to a wavelength of 570<span class="elsevierStyleHsp" style=""></span>nm&#46;<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">19</span></a> Biofilm classification was based on optical density &#40;OD&#41; according to a previous criteria&#46;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">17</span></a> The results of the MTT assay were expressed as a percentage relative to the positive control &#40;PC&#41;&#44; which was considered 100&#37;&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Estimation of biomass by crystal violet retention</span><p id="par0065" class="elsevierStylePara elsevierViewall">Biofilms were fixed in a 96-well microplate using methanol &#40;200<span class="elsevierStyleHsp" style=""></span>&#956;L&#41; for 15<span class="elsevierStyleHsp" style=""></span>min&#46; Next&#44; methanol was aspirated&#44; and the wells were dried at room temperature&#46; Thereafter&#44; 200<span class="elsevierStyleHsp" style=""></span>&#956;L of 1&#37; crystal violet was added to each well and the microplate was incubated at 36<span class="elsevierStyleHsp" style=""></span>&#176;C for 5<span class="elsevierStyleHsp" style=""></span>min&#46; The wells were carefully washed thrice with ultrapure water&#46; Then&#44; 200<span class="elsevierStyleHsp" style=""></span>&#956;L of 33&#37; acetic acid was added to dissolve the stain&#44; which was then homogenized&#46; Next&#44; 100<span class="elsevierStyleHsp" style=""></span>&#956;L of the solution was transferred to a new 96-well microplate and the total biomass was quantified using a Versa-Max microplate ELISA reader &#40;Molecular Devices&#44; Sunnyvale&#44; CA&#41; at a wavelength of 570<span class="elsevierStyleHsp" style=""></span>nm&#46; The results were stored as a percentage of biomass reduction&#46;</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Biofilm analysis using scanning electronic microscopy &#40;SEM&#41;</span><p id="par0070" class="elsevierStylePara elsevierViewall">To evaluate the structure and biofilm adherence <span class="elsevierStyleItalic">in vitro&#44;</span> SEM was performed using polystyrene discs &#40;16<span class="elsevierStyleHsp" style=""></span>mm<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>2<span class="elsevierStyleHsp" style=""></span>mm&#41;&#46; This method allows the capture of high-resolution images of a sample&#39;s surface and is largely used to observe the biofilm structure&#46; Images were obtained at magnification of 1000&#215; for each strain of each group&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Statistical analysis</span><p id="par0075" class="elsevierStylePara elsevierViewall">All tests were performed in triplicate&#46; Qualitative data are described as percentages&#44; and quantitative data are expressed as medians with 10&#37; and 90&#37; percentiles&#46; To compare the results between isolated samples from patients with breakthrough candidemia and non-breakthrough candidemia&#44; the Mann&#8211;Whitney <span class="elsevierStyleItalic">U</span> test was used to compare medians&#46; Statistical significance was set at <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#46; The Shapiro&#8211;Wilk normality test showed a non-normal distribution of data&#44; justifying the usage of a non-parametric test&#46;</p></span></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Results</span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Identification of <span class="elsevierStyleItalic">C&#46; albicans</span> strains and biofilm characterization</span><p id="par0080" class="elsevierStylePara elsevierViewall">The ability to adhere&#44; grow&#44; and produce biofilms was observed for all isolates from the two groups&#46; Biofilm production in isolates from breakthrough candidemia was four times higher than in isolates from non-breakthrough candidemia using violet crystal &#40;measured in optical density&#41;&#46; Therefore&#44; all isolates were classified as strong biofilm producers &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0085" class="elsevierStylePara elsevierViewall">In addition to this classification&#44; the architectural structure was observed through SEM&#44; confirming that all strains of <span class="elsevierStyleItalic">C&#46; albicans</span> produced mature and structurally organized biofilms after 48<span class="elsevierStyleHsp" style=""></span>h on the discs &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; At 1000&#215; magnification&#44; the biofilm was found to be adhered to the flat and smooth surfaces of the polystyrene discs in the presence of blastoconids and interlaced hyphae&#46; <a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>A&#8211;D represents <span class="elsevierStyleItalic">C&#46; albicans</span> from breakthrough candidemia &#40;numbers 269&#44; 307&#44; 332&#44; and 334&#44; respectively&#41; and 1E&#8211;H represent <span class="elsevierStyleItalic">C&#46; albicans</span> isolated from blood culture patients that presented with non-breakthrough candidemia &#40;identified by numbers 300&#44; 328&#44; 347&#44; and 358&#44; respectively&#41;&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Susceptibility of planktonic cells to antifungals</span><p id="par0090" class="elsevierStylePara elsevierViewall">The MICs are presented in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#46; All the drugs tested showed good activity against planktonic&#47;free cells&#46; For dAMB and ABLC&#44; MICs varied between 0&#46;25 and 1<span class="elsevierStyleHsp" style=""></span>mg&#47;L&#46; MICs varied from 0&#46;125 to 2<span class="elsevierStyleHsp" style=""></span>mg&#47;L for fluconazole &#40;all susceptible to fluconazole&#41;&#46; For anidulafungin&#44; all MICs were &#8804;0&#46;03<span class="elsevierStyleHsp" style=""></span>mg&#47;L&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Susceptibility of sessile cells to antifungals</span><p id="par0095" class="elsevierStylePara elsevierViewall">After biofilm production&#44; three complementary techniques were used to evaluate the susceptibility to antifungals&#58; MBEC&#44; estimating metabolic activity by reducing MTT&#44; and evaluating biomass by crystal violet retention&#46; All detailed data of MBEC&#44; MTT and biomass are included in the supplement material &#40;S1&#41;&#46;</p><p id="par0100" class="elsevierStylePara elsevierViewall">Fluconazole and anidulafungin were unable to eradicate the biofilm &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#46; ABLC decreased the cell concentration by 1 log<span class="elsevierStyleInf">10</span> for breakthrough candidemia isolates &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;09&#41;&#44; but not for non-breakthrough candidemia isolates&#46; When dAMB was evaluated&#44; a 2 log<span class="elsevierStyleInf">10</span> reduction was observed in the biofilm cells at 16<span class="elsevierStyleHsp" style=""></span>mg&#47;L of this antifungal &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05 for breakthrough candidemia isolates as well as for non-breakthrough candidemia isolates&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Metabolic activity by the MTT reduction assay</span><p id="par0105" class="elsevierStylePara elsevierViewall">Fluconazole and anidulafungin did not reduce metabolic activity in cells &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#46; Only dAMB and ABLC showed antifungal activity against the biofilms&#46; dAMB reduced the metabolic activity by approximately 50&#37; at 0&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;L of the drug&#44; and 75&#37; at 16<span class="elsevierStyleHsp" style=""></span>mg&#47;L &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#46; ABLC reduced metabolic activity by approximately 50&#37; at 0&#46;25<span class="elsevierStyleHsp" style=""></span>mg&#47;L&#44; the lowest dose tested&#44; and by 75&#37; at 1<span class="elsevierStyleHsp" style=""></span>mg&#47;L &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>&#41;&#46;</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0140">Crystal violet retention</span><p id="par0110" class="elsevierStylePara elsevierViewall">No significant reduction was observed in biomass &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41; when testing fluconazole and anidulafungin&#46; dAMB exhibited better antifungal activity toward the biofilm&#44; thus reducing 52&#37; of the biomass at a concentration of 0&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;L in the strains from breakthrough candidemia &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41; at 4 and 16<span class="elsevierStyleHsp" style=""></span>mg&#47;L concentrations of the antifungal agent&#46; For non-breakthrough candidemia isolates&#44; a 54&#37; reduction was observed in biomass at 4<span class="elsevierStyleHsp" style=""></span>mg&#47;L&#44; with <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#44; for concentrations of 8 and 16<span class="elsevierStyleHsp" style=""></span>mg&#47;L&#46; Using ABCL&#44; a 50&#37; reduction was observed at 2<span class="elsevierStyleHsp" style=""></span>mg&#47;L in the breakthrough candidemia group&#46; In comparison with the non-breakthrough candidemia group&#44; a maximum reduction of approximately 25&#37; was observed at concentrations of 32 and 64<span class="elsevierStyleHsp" style=""></span>mg&#47;L &#40;<a class="elsevierStyleCrossRef" href="#fig0020">Fig&#46; 4</a>&#41;&#46;</p><elsevierMultimedia ident="fig0020"></elsevierMultimedia><p id="par0115" class="elsevierStylePara elsevierViewall">When analyzing the groups by evaluating the techniques and antifungals separately&#44; regardless of the concentration of the tested drug&#44; no statistical difference was observed between <span class="elsevierStyleItalic">C&#46; albicans</span> isolated from breakthrough and non-breakthrough candidemia in the tests&#58; MBEC technique using dAMB &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;312&#41;&#44; ABLC &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;112&#41;&#44; and anidulafungin &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;911&#41;&#59; MTT reduction using dAMB &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;203&#41;&#44; ABLC &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;103&#41;&#44; and fluconazole &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;197&#41;&#44; and biomass analysis when using dAMB &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;459&#41;&#44; ABLC &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;245&#41;&#44; and fluconazole &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;154&#41;&#46; A statistically significant difference was observed between the groups in the MBEC technique using fluconazole &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41; and MTT and biomass when tested with anidulafungin &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;004 and <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#44; respectively&#41;&#46;</p></span></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0145">Discussion</span><p id="par0120" class="elsevierStylePara elsevierViewall">The insertion of a catheter is a risk factor for developing candidemia&#44; as the manipulation of these devices contributes to contamination and development of biofilms caused by yeasts such as <span class="elsevierStyleItalic">Candida</span> spp&#46;<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">20</span></a> Our results corroborate previous findings that described the biofilm produced by <span class="elsevierStyleItalic">C&#46; albicans</span> as having a heterogeneous architecture comprising multilayered yeasts and hyphae&#46;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">21</span></a> These structures formed by <span class="elsevierStyleItalic">C&#46; albicans</span> are difficult to eradicate and have greater stability and resistance to most antifungals&#46;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">22</span></a> In addition&#44; candidemia due to biofilm-producing strains has been associated with increased patient mortality&#46;<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">23</span></a> We found that biofilm production in breakthrough candidemia isolates was higher than in those isolates from non-breakthrough candidemia&#46; Biofilm producing is an independent virulence factor in <span class="elsevierStyleItalic">Candida</span> spp&#46;<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">24</span></a> Furthermore&#44; clinical studies have shown that biofilm-producers isolates increase the mortality rate&#46;<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">25</span></a></p><p id="par0125" class="elsevierStylePara elsevierViewall">All isolates from the present study were susceptible to the antifungals tested&#44; but not biofilms&#46; For dAMB&#44; planktonic cells obtained a maximum MIC of 1<span class="elsevierStyleHsp" style=""></span>mg&#47;L&#44; whereas under sessile conditions&#44; 16<span class="elsevierStyleHsp" style=""></span>mg&#47;L was required to eradicate the biofilm in both groups&#46; Other studies have demonstrated a high prevalence of antifungal resistance in biofilms formed by <span class="elsevierStyleItalic">C&#46; albicans</span>&#46;<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">26</span></a> This resistance can be attributed to several mechanisms&#44; such as ineffective penetration of the drug through the extracellular matrix of the biofilm&#44; decreased growth rate of <span class="elsevierStyleItalic">C&#46; albicans</span>&#44; cell persistence&#44; and expression of resistance genes induced by the community&#46;</p><p id="par0130" class="elsevierStylePara elsevierViewall">Azoles have been shown to have poor activity against <span class="elsevierStyleItalic">Candida</span> spp&#46;<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">27</span></a> Choi et al&#46; &#40;2007&#41; observed a reduction in cellular metabolism and reported that biofilms were resistant to fluconazole at concentrations<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>1024<span class="elsevierStyleHsp" style=""></span>mg&#47;L&#46;<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">28</span></a> Melo et al&#46;&#44; in accordance with the present study&#44; reported that the isolates were susceptible to fluconazole in planktonic form&#44; but resistant in their sessile form&#46;<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">27</span></a> Time-dependent resistance was associated with the expression of genes related to efflux pumps after drug induction&#46;</p><p id="par0135" class="elsevierStylePara elsevierViewall">Of the three antifungal classes currently used to treat candidemia&#44; only polyenes and echinocandins have shown consistent <span class="elsevierStyleItalic">in vitro</span> activity against biofilms of <span class="elsevierStyleItalic">C&#46; albicans&#46;</span><a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">29</span></a></p><p id="par0140" class="elsevierStylePara elsevierViewall">We observed unexpected results regarding the use of anidulafungin&#46; Other studies have reported that echinocandins have a good effect on <span class="elsevierStyleItalic">C&#46; albicans</span> biofilms <span class="elsevierStyleItalic">in vitro</span> and <span class="elsevierStyleItalic">in vivo</span> and significantly reduce the number of cells at higher doses than those found for planktonic cells&#46;<a class="elsevierStyleCrossRefs" href="#bib0375"><span class="elsevierStyleSup">30&#44;31</span></a> Simultaneously&#44; Rosato et al&#46; &#40;2013&#41; described that anidulafungin has a paradoxical growth effect &#40;PGE&#41; on <span class="elsevierStyleItalic">C&#46; albicans</span>&#46;<a class="elsevierStyleCrossRef" href="#bib0385"><span class="elsevierStyleSup">32</span></a> These studies reported reduced microbial growth at low concentrations of the antifungal agent and a resurgence of growth at concentrations above the MIC&#46; To date&#44; the clinical significance of the PGE remains unclear&#46; One explanation for PGE includes involvement of the calcineurin pathway and upregulation of the protein kinase-C cell wall integrity pathway&#46;<a class="elsevierStyleCrossRef" href="#bib0390"><span class="elsevierStyleSup">33</span></a> Even though PGE has been described with fluconazole&#44; this phenomenon is more common with echinocandins&#46;<a class="elsevierStyleCrossRef" href="#bib0395"><span class="elsevierStyleSup">34</span></a></p><p id="par0145" class="elsevierStylePara elsevierViewall">In comparison&#44; amphotericin B&#44; with or without the lipid complex&#44; showed greater antifungal activity against the biofilms&#46; A 50&#37; reduction in biomass was achieved in the breakthrough candidemia group at 0&#46;5 and 2<span class="elsevierStyleHsp" style=""></span>mg&#47;L for dAMB and ABLC&#44; respectively&#46; Several studies have reported that a 50&#37; reduction is used to determine an important antifungal effect on biofilms&#46;<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">29</span></a> However&#44; biofilm eradication was only achieved using 16<span class="elsevierStyleHsp" style=""></span>mg&#47;L of dAMB&#46; The MTT assay was used to evaluate cell viability in biofilms&#44; and crystal violet was used to evaluate biomass&#46; These are classical tests for analyzing biofilms&#46; It is important to discriminate between the two methods when evaluating the anti-biofilm activity of antifungal drugs&#46; In the present work&#44; we propose the use of the tetrazolium salt assay &#40;MTT assay&#41;&#44; which is a frequent procedure for determining the number of eukaryotic cells in studies where the viability of cells in culture is essential&#46; Mitochondrial enzymes cleave the yellow tetrazolium salt &#40;3-&#40;4&#44;5-dimethylthiazol-2-yl&#41;-2&#44;5-diphenyltetrazolium bromide&#44; MTT&#41; to formazan&#44; and the resulting product forms a purple solution when dissolved in the appropriate reagents&#46;<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">35</span></a> The MTT assay has been successfully applied to evaluate the size of microbial populations growing in biofilms&#46; Formazan formation by biofilms is a manifestation of respiratory enzyme activity in the cell walls of bacteria and&#47;or dehydrogenase activity in filamentous fungi and yeast&#46;<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">36</span></a></p><p id="par0150" class="elsevierStylePara elsevierViewall">dAMB was once considered a gold standard among antifungals due to its broader antifungal spectrum&#46; However&#44; lipid formulations have been developed in an attempt to reduce its toxicity&#46;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">6</span></a> Kuhn et al&#46; &#40;2002&#41; determined that the exposure of planktonic cells to subinhibitory concentrations of ABLC inhibited subsequent biofilm formation&#46;<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">29</span></a> In addition&#44; the authors reported that despite the large size of the ABLC molecule&#44; it penetrates the extracellular matrix to reach the fungal cells within the biofilm&#44; although its dispersion in phospholipids can facilitate passage through the polysaccharide&#46;</p><p id="par0155" class="elsevierStylePara elsevierViewall">Although dAMB eradicated the biofilm at 16<span class="elsevierStyleHsp" style=""></span>mg&#47;L&#44; the mean peak plasma concentrations ranged from 0&#46;5 to 2<span class="elsevierStyleHsp" style=""></span>mg&#47;L in adults receiving repeated doses of approximately 0&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;day&#46; In osteomyelitis&#44; it may be exposed to a higher concentration of amphotericin B&#44; thereby presenting a greater antifungal effect on the biofilm&#46;<a class="elsevierStyleCrossRef" href="#bib0410"><span class="elsevierStyleSup">37</span></a> It has been shown that dAMB presents high activity against <span class="elsevierStyleItalic">C&#46; albicans</span> biofilm in an <span class="elsevierStyleItalic">in vitro</span> model&#46;<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">38</span></a> Moreover&#44; the use of dAMB in silicon catheters demonstrated complete growth and biofilm formation inhibition&#46;<a class="elsevierStyleCrossRef" href="#bib0420"><span class="elsevierStyleSup">39</span></a> Other studies have pointed out that cases of catheter-related <span class="elsevierStyleItalic">C&#46; albicans</span> infections could be treated with dAMB at 2&#8211;2&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;L&#44; allowing to save the catheter and a patient treated with a concentration of 5<span class="elsevierStyleHsp" style=""></span>mg&#47;L could be cured&#46;<a class="elsevierStyleCrossRefs" href="#bib0425"><span class="elsevierStyleSup">40&#8211;42</span></a></p><p id="par0160" class="elsevierStylePara elsevierViewall">The techniques applied for evaluation of biofilms may pose challenges&#44; as subtle changes such as temperature&#44; rotation&#44; pipetting&#44; and washing processes can interfere with the amount of biofilm produced and analyzed&#46;<a class="elsevierStyleCrossRef" href="#bib0440"><span class="elsevierStyleSup">43</span></a> Furthermore&#44; <span class="elsevierStyleItalic">in vitro</span> and <span class="elsevierStyleItalic">in vivo</span> methods can produce different results due to a less controlled environment and interference with host immunity&#46;<a class="elsevierStyleCrossRef" href="#bib0445"><span class="elsevierStyleSup">44</span></a> Nevertheless&#44; in other study&#44; the formation of the <span class="elsevierStyleItalic">in vitro</span> biofilm of <span class="elsevierStyleItalic">C&#46; albicans</span> correlated well with the biofilm models <span class="elsevierStyleItalic">in vivo</span>&#44; obtaining similar time in the growth phases as well as the architectural structure of the biofilms recovered from patients with infection&#46;<a class="elsevierStyleCrossRef" href="#bib0450"><span class="elsevierStyleSup">45</span></a></p><p id="par0165" class="elsevierStylePara elsevierViewall">The major limitation of this study was the number of isolates included&#46; However&#44; the anti-biofilm activity was evaluated by three methods with three antifungal classes&#46; A higher concentration of echinocandin and fluconazole could be tested&#44; however&#44; the values would not be useful in clinical conditions&#44; unless if used as lock-therapy&#46;</p><p id="par0170" class="elsevierStylePara elsevierViewall">In conclusion&#44; isolates from breakthrough candidemia produced more biofilm than controls from non-breakthrough candidemia&#46; Only the dAMB and ABLC formulations exhibited antifungal effects in sessile cells&#46; For a broader understanding of the hypothesis that breakthrough candidemia isolates could differ from non-breakthrough candidemia isolates in terms of their ability to produce biofilms and their susceptibility to antifungals&#44; a greater number of isolates should be studied&#46;</p></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0150">Authors&#8217; contribution</span><p id="par0175" class="elsevierStylePara elsevierViewall">Conceptualization&#58; L&#46; Kraft&#44; F&#46;F&#46; Tuon&#46;</p><p id="par0180" class="elsevierStylePara elsevierViewall">Methodology&#58; L&#46; Kraft&#44; V&#46;S&#46;T&#46; Ribeiro&#44; G&#46;A&#46; Gon&#231;alves&#44; P&#46;H&#46; Suss&#46;</p><p id="par0185" class="elsevierStylePara elsevierViewall">Formal analysis&#58; L&#46; Kraft&#44; F&#46;F&#46; Tuon&#46;</p><p id="par0190" class="elsevierStylePara elsevierViewall">Writing&#58; Original draft preparation &#8211; L&#46; Kraft&#44; F&#46;F&#46; Tuon&#46;</p><p id="par0195" class="elsevierStylePara elsevierViewall">Writing&#58; Review and editing &#8211; L&#46; Kraft&#44; V&#46;S&#46;T&#46; Ribeiro&#44; G&#46;A&#46; Gon&#231;alves&#44; P&#46;H&#46; Suss&#46;</p><p id="par0200" class="elsevierStylePara elsevierViewall">Supervision&#58; F&#46;F&#46; Tuon&#46;</p></span><span id="sec0095" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0155">Ethical statement</span><p id="par0205" class="elsevierStylePara elsevierViewall">This study was approved by the ethics committee &#40;CAAE number 40592915&#46;2&#46;000&#46;0096 of Universidade Federal do Paran&#225;&#41;&#46;</p></span><span id="sec0100" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0160">Data availability</span><p id="par0210" class="elsevierStylePara elsevierViewall">All data have been used in this paper&#44; and raw data are available upon request&#46;</p></span><span id="sec0105" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0165">Funding</span><p id="par0215" class="elsevierStylePara elsevierViewall">None&#46;</p></span><span id="sec0110" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0170">Conflicts of interest</span><p id="par0220" class="elsevierStylePara elsevierViewall">F&#46;F&#46; Tuon is a CNPq researcher&#46; The other authors declare no conflicts of interest&#46;</p></span></span>"
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              "titulo" => "Introducci&#243;n"
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              "titulo" => "Minimal inhibitory concentration &#40;MIC&#41; determination"
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              "titulo" => "Determination of minimum biofilm eradication concentration &#40;MBEC&#41;"
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              "titulo" => "Estimation of metabolic activity by the MTT reduction assay"
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              "titulo" => "Identification of C&#46; albicans strains and biofilm characterization"
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              "titulo" => "Susceptibility of planktonic cells to antifungals"
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            2 => array:2 [
              "identificador" => "sec0070"
              "titulo" => "Susceptibility of sessile cells to antifungals"
            ]
            3 => array:2 [
              "identificador" => "sec0075"
              "titulo" => "Metabolic activity by the MTT reduction assay"
            ]
            4 => array:2 [
              "identificador" => "sec0080"
              "titulo" => "Crystal violet retention"
            ]
          ]
        ]
        7 => array:2 [
          "identificador" => "sec0085"
          "titulo" => "Discussion"
        ]
        8 => array:2 [
          "identificador" => "sec0090"
          "titulo" => "Authors&#8217; contribution"
        ]
        9 => array:2 [
          "identificador" => "sec0095"
          "titulo" => "Ethical statement"
        ]
        10 => array:2 [
          "identificador" => "sec0100"
          "titulo" => "Data availability"
        ]
        11 => array:2 [
          "identificador" => "sec0105"
          "titulo" => "Funding"
        ]
        12 => array:2 [
          "identificador" => "sec0110"
          "titulo" => "Conflicts of interest"
        ]
        13 => array:2 [
          "identificador" => "xack711158"
          "titulo" => "Acknowledgments"
        ]
        14 => array:1 [
          "titulo" => "References"
        ]
      ]
    ]
    "pdfFichero" => "main.pdf"
    "tienePdf" => true
    "fechaRecibido" => "2022-04-20"
    "fechaAceptado" => "2022-07-19"
    "PalabrasClave" => array:2 [
      "en" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Keywords"
          "identificador" => "xpalclavsec1744060"
          "palabras" => array:5 [
            0 => "Antifungals"
            1 => "<span class="elsevierStyleItalic">Candida</span>"
            2 => "Candidemia"
            3 => "Breakthrough candidemia"
            4 => "Biofilms"
          ]
        ]
      ]
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        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Palabras clave"
          "identificador" => "xpalclavsec1744061"
          "palabras" => array:5 [
            0 => "Antif&#250;ngico"
            1 => "<span class="elsevierStyleItalic">Candida</span>"
            2 => "Candidemia"
            3 => "Candidemia de brecha"
            4 => "Biofilms"
          ]
        ]
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    "tieneResumen" => true
    "resumen" => array:2 [
      "en" => array:3 [
        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Introduction</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Biofilm formation causes virulence and resistance in <span class="elsevierStyleItalic">Candida albicans&#46;</span> However&#44; little is known about breakthrough candidemia isolates&#46; We evaluated the antifungal activity of fluconazole&#44; anidulafungin&#44; deoxycholate amphotericin B &#40;dAMB&#41;&#44; and amphotericin B lipid complex &#40;ABLC&#41; against biofilms of <span class="elsevierStyleItalic">C&#46; albicans</span> isolated from patients with breakthrough candidemia&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">The present study used strains of <span class="elsevierStyleItalic">C&#46; albicans</span> isolated from breakthrough and non-breakthrough candidemia patients &#40;control group&#41;&#46; The susceptibility of planktonic cells to amphotericin B&#44; anidulafungin&#44; and fluconazole was determined by broth microdilution&#46; Antifungal activity in sessile cells was evaluated using the minimum biofilm eradication concentration &#40;MBEC&#41;&#44; metabolic activity was estimated by reducing MTT&#44; and biomass was estimated using crystal violet retention&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">The planktonic strains were susceptible to amphotericin B&#44; anidulafungin&#44; and fluconazole&#44; with minimum inhibitory concentrations of 1&#44; &#8804;0&#46;03&#44; and 2<span class="elsevierStyleHsp" style=""></span>mg&#47;L&#44; respectively&#46; However&#44; fluconazole and anidulafungin did not exert an antifungal effect on biofilms&#46; Additionally&#44; dAMB and ABCL reduced the metabolic activity and biomass&#46; However&#44; eradication was only achieved using 16<span class="elsevierStyleHsp" style=""></span>mg&#47;L dAMB&#46; <span class="elsevierStyleItalic">C&#46; albicans</span> isolates of breakthrough candidemia exhibited strong biofilm production&#44; and the <span class="elsevierStyleItalic">in vitro</span> activity of available therapeutic options was poor&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusion</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">In the present study&#44; only dAMB and ABCL exhibited antibiofilm effects against sessile breakthrough candidemia isolates&#46;</p></span>"
        "secciones" => array:4 [
          0 => array:2 [
            "identificador" => "abst0005"
            "titulo" => "Introduction"
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          1 => array:2 [
            "identificador" => "abst0010"
            "titulo" => "Methods"
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          2 => array:2 [
            "identificador" => "abst0015"
            "titulo" => "Results"
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            "identificador" => "abst0020"
            "titulo" => "Conclusion"
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      "es" => array:3 [
        "titulo" => "Resumen"
        "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Introducci&#243;n</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">La formaci&#243;n de biofilm se asocia con la virulencia y la resistencia al tratamiento de <span class="elsevierStyleItalic">Candida albicans</span> &#40;<span class="elsevierStyleItalic">C&#46; albicans&#41;</span> sin embargo&#44; son poco conocidas las caracter&#237;sticas de los aislamientos procedentes de pacientes con candidemias de brecha&#46; Evaluamos la actividad antif&#250;ngica de fluconazol&#44; anidulafungina&#44; anfotericina B desoxicolato &#40;dAMB&#41; y el complejo lip&#237;dico de la anfotericina B &#40;ABLC&#41; frente a biofilms de <span class="elsevierStyleItalic">C&#46; albicans</span> aisladas de pacientes con candidemia de brecha&#46;</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">M&#233;todos</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Se utilizaron cepas de <span class="elsevierStyleItalic">C&#46; albicans</span> aisladas de candidemias de brecha y de otras candidemias &#40;grupo control&#41;&#46; La sensibilidad de las c&#233;lulas planct&#243;nicas a la anfotericina B&#44; la anidulafungina y el fluconazol se determin&#243; mediante el m&#233;todo de microdiluci&#243;n en caldo&#46; En c&#233;lulas s&#233;siles&#44; la actividad antif&#250;ngica se evalu&#243; mediante la concentraci&#243;n min&#237;ma de erradicaci&#243;n de biofilm &#40;MBEC&#41;&#44; la actividad metab&#243;lica se estim&#243; mediante la reducci&#243;n de MTT y la biomasa mediante la retenci&#243;n de cristal violeta&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Las cepas en forma planct&#243;nica fueron sensibles a la anfotericina B&#44; anidulafungina y fluconazol&#44; con CMI de 1 mg&#47;L&#44; &#8804; 0&#44;03 y 2 mg&#47;L&#44; respectivamente&#59; sin embargo&#44; no se observ&#243; efecto antif&#250;ngico sobre los biofilms con fluconazol o anidulafungina&#46; Con dAMB y ABCL se observ&#243; una reducci&#243;n de la actividad metab&#243;lica y de la biomasa&#44; pero la erradicaci&#243;n solo se consigui&#243; con 16 mg&#47;L de dAMB&#46; Las cepas de <span class="elsevierStyleItalic">C&#46; albicans</span> que causan candidemia de brecha producen abundante biofilm y las opciones terap&#233;uticas disponibles no son activas <span class="elsevierStyleItalic">in vitro</span> frente a ellas&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclusi&#243;n</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Solo dAMB y ABCL exhibieron efecto antibiofilm frente a los aislamientos de <span class="elsevierStyleItalic">C&#46; albicans</span> s&#233;siles y planct&#243;nicos&#46;</p></span>"
        "secciones" => array:4 [
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            "identificador" => "abst0025"
            "titulo" => "Introducci&#243;n"
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          1 => array:2 [
            "identificador" => "abst0030"
            "titulo" => "M&#233;todos"
          ]
          2 => array:2 [
            "identificador" => "abst0035"
            "titulo" => "Resultados"
          ]
          3 => array:2 [
            "identificador" => "abst0040"
            "titulo" => "Conclusi&#243;n"
          ]
        ]
      ]
    ]
    "apendice" => array:1 [
      0 => array:1 [
        "seccion" => array:1 [
          0 => array:4 [
            "apendice" => "<p id="par0235" class="elsevierStylePara elsevierViewall">The following are the supplementary data to this article&#58;<elsevierMultimedia ident="upi0005"></elsevierMultimedia></p>"
            "etiqueta" => "Appendix A"
            "titulo" => "Supplementary data"
            "identificador" => "sec0120"
          ]
        ]
      ]
    ]
    "multimedia" => array:7 [
      0 => array:7 [
        "identificador" => "fig0005"
        "etiqueta" => "Fig&#46; 1"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr1.jpeg"
            "Alto" => 1659
            "Ancho" => 2928
            "Tamanyo" => 655123
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        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Images obtained through scanning electronic microscopy &#40;SEM&#41; of biofilms formed by <span class="elsevierStyleItalic">Candida albicans</span> isolated from breakthrough and non-breakthrough candidemia strains on polystyrene discs&#44; at a 1000&#215; magnification&#46; Images A&#58; strain 269&#44; B&#58; strain 307&#44; C&#58; strain 332&#44; and D&#58; strain 334&#44; all representing breakthrough strains obtained from a location closer to the edges of the polystyrene disk&#44; where the biofilm was denser and it is possible to observe the predominance of intertwined pseudohyphae and&#47;or blastoconids&#46; Images E&#58; strain 300&#44; F&#58; strain 328&#44; G&#58; strain 347&#44; and H&#58; strain 358&#44; all representing non-breakthrough candidemia&#46;</p>"
        ]
      ]
      1 => array:7 [
        "identificador" => "fig0010"
        "etiqueta" => "Fig&#46; 2"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr2.jpeg"
            "Alto" => 2281
            "Ancho" => 2514
            "Tamanyo" => 266539
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        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Minimal biofilm eradication concentration &#40;MBEC&#41; for fluconazole&#44; deoxycholate amphotericin B&#44; anidulafungin&#44; and amphotericin B lipid complex &#40;ABLC&#41; of <span class="elsevierStyleItalic">Candida albicans</span> isolates from blood culture in patients with breakthrough &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>4&#41; and non-breakthrough &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>4&#41; candidemia&#46; The <span class="elsevierStyleItalic">X</span> axis is the antifungal concentration &#40;mg&#47;L&#41;&#46; &#42; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05 in comparison with control&#46;</p>"
        ]
      ]
      2 => array:7 [
        "identificador" => "fig0015"
        "etiqueta" => "Fig&#46; 3"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr3.jpeg"
            "Alto" => 2312
            "Ancho" => 2933
            "Tamanyo" => 353139
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        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Candida albicans</span> biofilm cell viability using MTT method for fluconazole&#44; deoxycholate amphotericin B&#44; anidulafungin&#44; and amphotericin B lipid complex &#40;ABLC&#41; in breakthrough &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>4&#41; and non-breakthrough &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>4&#41; candidemia&#46; The box plot represents min&#44; max&#44; and interquartile range at 25&#37; and 75&#37;&#46; The values are expressed as percentage in relation to positive control &#40;PC&#41;&#46; The <span class="elsevierStyleItalic">X</span> axis is the antifungal concentration &#40;mg&#47;L&#41;&#46; &#42; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05 in comparison with control&#46;</p>"
        ]
      ]
      3 => array:7 [
        "identificador" => "fig0020"
        "etiqueta" => "Fig&#46; 4"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr4.jpeg"
            "Alto" => 2331
            "Ancho" => 2933
            "Tamanyo" => 337235
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        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Candida albicans</span> biomass after progressive concentrations of fluconazole&#44; deoxycholate amphotericin B&#44; anidulafungin&#44; and amphotericin B lipid complex &#40;ABLC&#41; in breakthrough &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>4&#41; and non-breakthrough &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>4&#41; candidemia&#46; The box plot represents min&#44; max&#44; and interquartile range at 25&#37; and 75&#37;&#46; The values are expressed as percentage in relation to positive control &#40;PC&#41;&#46; The <span class="elsevierStyleItalic">X</span> axis is the antifungal concentration &#40;mg&#47;L&#41;&#46; &#42; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05 in comparison with control&#46;</p>"
        ]
      ]
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        "identificador" => "tbl0005"
        "etiqueta" => "Table 1"
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            "identificador" => "at1"
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                  <table border="0" frame="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Group&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Strain ID&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">OD<span class="elsevierStyleInf">B</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Classification&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">269&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">0&#46;158&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">1&#46;770&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t">Strong biofilm producer&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">0&#46;158&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">2&#46;620&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Strong biofilm producer&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">332&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">0&#46;163&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Strong biofilm producer&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">334&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">0&#46;168&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t">3&#46;371&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Strong biofilm producer&nbsp;\t\t\t\t\t\t\n
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