Therapies against murine Candida guilliermondii infection, relationship between in vitro antifungal pharmacodynamics and outcome

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Gerardo González, Luis A. Ceceñas, Gloria M. González" "autores" => array:5 [ 0 => array:2 [ "nombre" => "Mariana" "apellidos" => "Elizondo-Zertuche" ] 1 => array:2 [ "nombre" => "Efrén" "apellidos" => "Robledo-Leal" ] 2 => array:2 [ "nombre" => "J. Gerardo" "apellidos" => "González" ] 3 => array:2 [ "nombre" => "Luis A." "apellidos" => "Ceceñas" ] 4 => array:2 [ "nombre" => "Gloria M." "apellidos" => "González" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1130140613000855?idApp=UINPBA00004N" "url" => "/11301406/0000003200000001/v2_201706020154/S1130140613000855/v2_201706020154/en/main.assets" ] "en" => array:19 [ "idiomaDefecto" => true "cabecera" => "Original article" "titulo" => "Therapies against murine Candida guilliermondii infection, relationship between in vitro antifungal pharmacodynamics and outcome" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "34" "paginaFinal" => "39" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Katihuska Paredes, Francisco Javier Pastor, Javier Capilla, Deanna A. Sutton, Emilio Mayayo, Annette W. Fothergill, Josep Guarro" "autores" => array:7 [ 0 => array:3 [ "nombre" => "Katihuska" "apellidos" => "Paredes" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] 1 => array:3 [ "nombre" => "Francisco Javier" "apellidos" => "Pastor" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] 2 => array:4 [ "nombre" => "Javier" "apellidos" => "Capilla" "email" => array:2 [ 0 => "javier.capilla@urv.cat" 1 => "kpiluq@yahoo.es" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] 3 => array:3 [ "nombre" => "Deanna A." 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"apellidos" => "Fothergill" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "c" "identificador" => "aff0015" ] ] ] 6 => array:3 [ "nombre" => "Josep" "apellidos" => "Guarro" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] ] "afiliaciones" => array:3 [ 0 => array:3 [ "entidad" => "Unitat de Microbiologia, Facultat de Medicina i Ciències de la Salut, IISPV, Universitat Rovira i Virgili, Reus, Tarragona, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Unitat de Anatomia Patològica, Facultat de Medicina i Ciències de la Salut, IISPV, Universitat Rovira i Virgili, Reus, Tarragona, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Fungus Testing Laboratory, University of Texas Health Science Center, San Antonio, TX, USA" "etiqueta" => "c" "identificador" => "aff0015" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Terapia antifúngica frente a la infección por Candida guilliermondii en ratones, correlación entre los parámetros farmacodinámicos in vitro y la eficacia in vivo" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0015" "etiqueta" => "Fig. 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 2075 "Ancho" => 2883 "Tamanyo" => 292202 ] ] "descripcion" => array:1 [ "en" => "Time-killing kinetics assays of FLC against four strains of C. guilliermondii. (■) 0.03μg/mL, (▴) 0.12μg/ml, (□) 0.5μg/ml, (●) 1μg/ml, (Δ) 2μg/ml, (▿)8μg/ml, (♦) 32μg/ml, (●) control. Dashed lines represent a CFU decrease of 3log10 units in growth compared with the initial inoculum (fungicidal activity), dotted lines indicate the quantification limit of the test." ] ] ] "textoCompleto" => "The fungus Candida guilliermondii is widely distributed in nature, including the human microbiota of the skin and mucosal surfaces.<a class="elsevierStyleCrossRef" href="#bib0110">22</a> Although this species shows a reduced virulence in comparison to other Candida species,<a class="elsevierStyleCrossRef" href="#bib0015">3</a> it is currently considered an emerging pathogen, with a major incidence in Latin America.<a class="elsevierStyleCrossRef" href="#bib0090">18</a>C. guilliermondii has been recognized as the etiologic agent of a wide variety of clinical infections, including disseminated ones mainly in immunocompromised patients,<a class="elsevierStyleCrossRef" href="#bib0110">22</a> and nosocomial outbreaks in surgical patients with intravascular devices.<a class="elsevierStyleCrossRef" href="#bib0065">13</a> Currently, the recommended treatment for invasive candidiasis in neutropenic patients includes caspofungin (CFG) or micafungin (MFG) as first-line therapies, liposomal amphotericin B (LAMB) and anidulafungin (AFG) being alternatives, while fluconazole (FLC) is recommended only when susceptibility to this drug is confirmed.<a class="elsevierStyleCrossRef" href="#bib0115">23</a> However, several studies have shown that C. guilliermondii has a decreased susceptibility to FLC<a class="elsevierStyleCrossRefs" href="#bib0040">8,15,19</a>, and therapeutic failures associated with isolates with high amphotericin B (AMB) minimal inhibitory concentrations (MICs) have been reported.<a class="elsevierStyleCrossRefs" href="#bib0045">9,12,24</a> Although nearly 90% of isolates shows echinocandins MICs equal or lower than clinical breakpoints (CBP) of susceptibility (2μg/ml),<a class="elsevierStyleCrossRef" href="#bib0085">17</a> similar to other species of Candida, such as C. parapsilosis, some isolates of C. guilliermondii show MICs considerably high.<a class="elsevierStyleCrossRefs" href="#bib0040">8,15</a> Available data concerning the AFG efficacy in invasive candidiasis are limited and the potential role of that drug in the clinical practice is poorly known.<a class="elsevierStyleCrossRef" href="#bib0115">23</a> In this context, animal studies can play an important role for a better understanding of the in vitro–in vivo correlation.<a class="elsevierStyleCrossRef" href="#bib0055">11</a> Therefore, our main objective was to evaluate the in vitro and in vivo activities of AFG against different isolates of C. guilliermondii, comparing the results with those of AMB and FLC.Materials and methodsFungal isolatesFour clinical isolates of C. guilliermondii (UTHSC 11-142, UTHSC 10-499, UTHSC 11-685 and UTHSC 10-3207) were used in the in vitro study and two of them (UTHSC 11-685 and UTHSC 11-142) were selected for the murine model on the basis of their different in vitro susceptibilities. The isolates were identified by sequencing the internal transcribed spacer (ITS) region and the D1–D2 domains of the rRNA, comparing the sequences with those of the type strain of this species.In vitro studiesThe in vitro susceptibility of the four strains to AMB, FLC and AFG was evaluated using a reference broth microdilution method,<a class="elsevierStyleCrossRef" href="#bib0030">6</a>Candida parapsilosis ATCC 22019 and Candida krusei ATCC 6258 being included as quality controls.Time-kill curves were developed for all the strains according to previous studies.<a class="elsevierStyleCrossRefs" href="#bib0025">5,20</a> In brief, a stock solution of each antifungal was prepared, AMB (Sigma–Aldrich Co., St. Louis, USA) and AFG (Pfizer Inc., Madrid, Spain) were dissolved in dimethyl sulfoxide and FLC (Pfizer Inc., Madrid, Spain) in distilled water. Further, drug dilutions were prepared in 9ml of standard RPMI 1640 medium to obtain concentrations of 0.03, 0.12, 0.5, 1, 2, 8 and 32μg/ml of each drug. The isolates were subcultured at 35°C for 24h on potato dextrose agar (PDA) plates. Cultures of C. guilliermondii were suspended in sterile saline and the resulting suspensions were adjusted at 5×106 colony forming units (CFU)/ml by haemocytometer counts and by serial plating onto PDA to confirm viability. Dilutions and controls (drug-free) were inoculated with 1ml of the fungal suspensions, resulting in a starting inoculum of 5×105CFU/ml, and incubated at 35°C. An aliquot of 100μl from each tube was collected at 0, 2, 4, 6, 8, 24, and 48h after inoculation and diluted in distilled water; 30 μl of them were cultured onto PDA plates and incubated at 35°C for 48h for CFU/ml determination. A CFU decrease of ≥99.9% or 3 log10 unit compared to starting inoculum was considered fungicidal, while a reduction of <99.9% or <3log10 unit, was considered fungistatic. The limit of detection was 50CFU/ml. All time-kill curve studies were performed in duplicate.In vivo studiesMale OF-1 mice (Charles River; Criffa SA, Barcelona, Spain) with a mean weight of 30g were used in the experiment. Mice were housed in standard boxes with free access to food and water. All animal procedures were supervised and approved by the Universitat Rovira i Virgili Animal Welfare and Ethics Committee.Mice were rendered neutropenic one day prior to infection by an intraperitoneal (i.p.) injection of 200mg/kg of cyclophosphamide (Genoxal; Laboratorios Funk SA, Barcelona, Spain) plus an intravenous (i.v.) injection of 5-fluorouracil (Fluorouracilo; Ferrer Farma SA, Barcelona, Spain) at 150mg/kg.<a class="elsevierStyleCrossRefs" href="#bib0050">10,14</a> The day of infection, mice were challenged i.v. with 1×108CFU/animal of each of the two strains of C. guilliermondii, UTHSC 11-685 and UTHSC 11-142, in 0.2ml of sterile saline into the lateral tail vein.<a class="elsevierStyleCrossRefs" href="#bib0015">3,4</a>Groups of eight animals were randomly established for each strain and drug. The groups were treated as follows: amphotericin B deoxycholate (AMBd) (Xalabarder Pharmacy, Barcelona, Spain) at doses of 0.8mg/kg i.v. once a day (QD); liposomal amphotericin B (LAMB) (Gilead Sciences S.A., Madrid, Spain) at 10mg/kg i.v., QD; FLC (Pfizer Inc., Madrid, Spain) at 25mg/kg orally (p.o.) by gavage, twice daily (BID); and AFG (Ecalta; Pfizer Ltd., Sandwich, Kent, United Kingdom) at 10mg/kg of body weight/dose i.p., QD. All treatments began 24h after challenge, and lasted for 7 days. Controls received no treatment. To prevent bacterial infections, all mice received 5mg/kg day ceftazidime subcutaneously from days 1 to 7 after infection. Mice were checked daily and were euthanized on day 8 post-infection by CO2 anoxia. The efficacy of each drug was evaluated by tissue burden reduction and histopathological studies. Kidneys were aseptically removed, and one of them was weighed and homogenized in 2ml of sterile saline. Serial 10-fold dilutions of the homogenates were plated onto PDA and incubated for 48h at 35°C for CFU/g calculation. For the histopathology study the remaining kidney was fixed with 10% buffered formalin, dehydrated, paraffin embedded, and sliced into 2μm sections, which were stained with hematoxylin–eosin (H-E) and periodic acid-Schiff (PAS) stain for examination by light microscopy.StatisticsColony counts from tissue were analyzed using the Mann–Whitney U-test, using Graph Pad Prism 4.0 for Windows (GraphPad Software, San Diego, CA, USA). When P values were below 0.05 the differences were considered statistically significant.ResultsIn vitro studiesMICs of AMB were 0.25–1μg/ml, 0.06–0.25μg/ml for AFG and 0.5–1μg/ml for FLC. Following the cut-offs of susceptibility for AMB, FLC and AFG against C. guilliermondii,<a class="elsevierStyleCrossRef" href="#bib0080">16</a> all isolates were susceptible to the three drugs. Quality control strains susceptibilities were within the accepted ranges.<a class="elsevierStyleCrossRef" href="#bib0030">6</a>The killing kinetics of AMB showed a fast fungicidal activity that increased with drug concentration. At concentrations equivalent to the MIC, that drug showed a fungicidal effect against three of the four isolates tested (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). This activity started immediately after inoculation at concentrations over 1μg/ml, the fungicidal endpoint being reached after 4h at 32μg/ml. AFG at concentrations above 0.5μg/ml showed fungicidal activity starting after 4h of incubation. The fungicidal endpoint was reached at 12–24h of incubation at 32μg/ml (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>). FLC showed fungistatic activity against all four isolates (<a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>).<elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="fig0010"></elsevierMultimedia><elsevierMultimedia ident="fig0015"></elsevierMultimedia>In vivo studiesLAMB at 10mg/kg was the only drug able to reduce the fungal load in kidneys of mice infected with each of the two strains, being the reduction significantly higher than that of the other therapies (P≤0.04). AMBd and FLC were only able to reduce the tissue burden in mice infected with the strain that showed the lowest MICs for these two drugs, i.e., 0.25μg/ml for AMB and 0.5μg/ml for FLC (P≤0.008). In the case of AFG the fungal load reduction was modest and lower than that for AMBd, and it significantly reduced the tissue burden in kidney only with respect to control group for strain UTHSC 11-685 (P=0.002) (<a class="elsevierStyleCrossRef" href="#fig0020">Fig. 4</a>).<elsevierMultimedia ident="fig0020"></elsevierMultimedia>The histological study showed focal infiltration of fungal cells in kidneys of untreated animals and in mice treated with AMBd, FLC or AFG. Kidneys of mice treated with LAMB showed only a mild fungal invasion. Signs of necrosis, inflammatory response or parenchyma alterations were nor observed in controls neither in treated animals (<a class="elsevierStyleCrossRef" href="#fig0025">Fig. 5</a>).<elsevierMultimedia ident="fig0025"></elsevierMultimedia>DiscussionThe in vitro studies did not reveal decreased susceptibility of C. guilliermondii isolates to FLC or AFG. In agreement with previous studies, time-kill curves of AMB showed a concentration-dependent fungicidal activity against all the isolates,<a class="elsevierStyleCrossRefs" href="#bib0020">4,5,7</a> and FLC showed a fungistatic effect regardless of the concentration tested.<a class="elsevierStyleCrossRef" href="#bib0035">7</a> It is known that AMBd exhibits a higher efficacy than its lipidic formulation, especially in kidney, when administered both at the same doses.<a class="elsevierStyleCrossRef" href="#bib0005">1</a> However, pharmacokinetic studies showed that after the administration of 0.75mg/kg of AMBd the Cmax of AMB attained in mice serum was 0.30μg/ml.<a class="elsevierStyleCrossRef" href="#bib0125">25</a> However, the AMB MIC of one of the two isolates tested is higher than this value; therefore, we used a high dose of LAMB in order to reach higher concentrations.<a class="elsevierStyleCrossRef" href="#bib0005">1</a> Indeed, the administration of LAMB at 10mg/kg was effective in reducing the fungal load of both strains. This fact correlated with killing curves, where AMB achieved its fungicidal activity against the two isolates tested in vivo, at concentrations of 1μg/ml. To our knowledge, this is the first study that tried to establish a relationship between the killing kinetics and the in vivo experimental efficacy of AFG and FLC against clinical isolates of C. guilliermondii. Only a previous study on echinocandins exists, particularly on caspofungin (CFG) in disseminated infection by C. guilliermondii. CFG at 1mg/kg was effective in reducing the kidney fungal load in mice infected with one strain of C. guilliermondii with a MIC of 8μg/ml, while time killing revealed that no fungicidal activity was achieved at concentrations of 64μg/ml.<a class="elsevierStyleCrossRef" href="#bib0020">4</a> Conversely, our study showed a concentration-dependent activity of AFG, which at 32μg/ml exerted a fungicidal activity, as previously reported,<a class="elsevierStyleCrossRef" href="#bib0085">17</a> at 24h and at 8μg/ml. Previous studies reported AFG concentrations in serum and kidney of approximately 13μg/ml after 7 days of treatment at doses of 10mg/kg.<a class="elsevierStyleCrossRef" href="#bib0105">21</a> Here, AFG was able to reduce only modestly the fungal burden in kidneys of neutropenic mice infected with one of the two strains tested, which does not seem to be related with the low AFG MICs difference between the two strains tested (1 dilution), suggesting that the response to AFG treatment is strain dependent. Similarly, FLC was also only able to reduce slightly the fungal burden in kidney of mice challenged with one of the two strains in spite of the dose administrated which reach serum concentrations above the MICs,<a class="elsevierStyleCrossRef" href="#bib0010">2</a> which was also not surprising due to its fungistatic activity.In conclusion, our study showed the higher activity and efficacy of LAMB against the two strains of C. guilliermondii, in contrast to the poor effect of FLC and AFG. However, further studies with more isolates of C. guilliermondii representing a wider range of AFG MICs should be carried out to assess if any relationship between MIC values and AFG efficacy exists.Conflict of interestNone to declare." "textoCompletoSecciones" => array:1 [ "secciones" => array:9 [ 0 => array:3 [ "identificador" => "xres848060" "titulo" => "Abstract" "secciones" => array:5 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Background" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Aims" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Methods" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Results" ] 4 => array:2 [ "identificador" => "abst0025" "titulo" => "Conclusions" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec843092" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres848061" "titulo" => "Resumen" "secciones" => array:5 [ 0 => array:2 [ "identificador" => "abst0030" "titulo" => "Antecedentes" ] 1 => array:2 [ "identificador" => "abst0035" "titulo" => "Objetivos" ] 2 => array:2 [ "identificador" => "abst0040" "titulo" => "Métodos" ] 3 => array:2 [ "identificador" => "abst0045" "titulo" => "Resultados" ] 4 => array:2 [ "identificador" => "abst0050" "titulo" => "Conclusiones" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec843093" "titulo" => "Palabras clave" ] 4 => array:3 [ "identificador" => "sec0005" "titulo" => "Materials and methods" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "sec0010" "titulo" => "Fungal isolates" ] 1 => array:2 [ "identificador" => "sec0015" "titulo" => "In vitro studies" ] 2 => array:2 [ "identificador" => "sec0020" "titulo" => "In vivo studies" ] 3 => array:2 [ "identificador" => "sec0025" "titulo" => "Statistics" ] ] ] 5 => array:3 [ "identificador" => "sec0030" "titulo" => "Results" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0035" "titulo" => "In vitro studies" ] 1 => array:2 [ "identificador" => "sec0040" "titulo" => "In vivo studies" ] ] ] 6 => array:2 [ "identificador" => "sec0045" "titulo" => "Discussion" ] 7 => array:2 [ "identificador" => "sec0050" "titulo" => "Conflict of interest" ] 8 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2013-07-11" "fechaAceptado" => "2013-10-11" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec843092" "palabras" => array:3 [ 0 => "Candida guilliermondii" 1 => "Animal model" 2 => "Fungal infection" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec843093" "palabras" => array:3 [ 0 => "Candida guilliermondii" 1 => "Modelo animal" 2 => "Infección fúngica" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:3 [ "titulo" => "Abstract" "resumen" => "BackgroundCandida guilliermondii has been recognized as an emerging pathogen showing a decreased susceptibility to fluconazole and considerably high echinocandin MICs. AimsEvaluate the in vitro activity of anidulafungin in comparison to amphotericin B and fluconazole against different isolates of C. guilliermondii, and their efficacy in an immunosuppressed murine model of disseminated infection. MethodsThe in vitro susceptibility of four strains against amphotericin B, fluconazole and anidulafungin was performed by using a reference broth microdilution method and time-kill curves. The in vivo efficacy was evaluated by determination of fungal load reduction in kidneys of infected animals receiving deoxycholate AMB at 0,8mg/kg i.v., liposomal amphotericin B at 10mg/kg i.v., fluconazole at 50mg/kg, or anidulafungin at 10mg/kg. ResultsAmphotericin B and anidulafungin showed fungicidal activity, while fluconazole was fungistatic for all the strains. In the murine model, liposomal amphotericin B at 10mg/kg/day was effective in reducing the tissue burden in kidneys of mice infected with any of the tested strains. However, amphotericin B, anidulafungin and fluconazole were only effective against those strains showing low MIC values. ConclusionsLiposomal amphotericin B showed the higher activity and efficacy against the two strains of C. guilliermondii, in contrast to the poor effect of fluconazole and anidulafungin. Further studies with more isolates of C. guilliermondii representing a wider range of MICs should be carried out to assess whether there is any relationship between MIC values and anidulafungin efficacy." "secciones" => array:5 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Background" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Aims" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Methods" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Results" ] 4 => array:2 [ "identificador" => "abst0025" "titulo" => "Conclusions" ] ] ] "es" => array:3 [ "titulo" => "Resumen" "resumen" => "AntecedentesCandida guilliermondii es un patógeno emergente, con reducida sensibilidad al fluconazol y a las equinocandinas. ObjetivosEvaluar la actividad in vitro de la anidulafungina, en comparación con la de la anfotericina B y el fluconazol, frente a C. guilliermondii y su eficacia en un modelo animal de infección diseminada. MétodosLa sensibilidad in vitro se valoró mediante microdilución en caldo y curvas de mortalidad. La eficacia in vivo se evaluó mediante la determinación de la carga fúngica en riñón de ratones inmunosuprimidos con infección diseminada por C. guilliermondii tratados con anfotericina B desoxicolato (0.8mg/kg i.v.), anfotericina B liposomal (10mg/kg i.v.), fluconazol (50mg/kg) o anidulafungina (10mg/kg). ResultadosLa anfotericina B y la anidulafungina mostraron actividad fungicida, mientras que el fluconazol fue fungistático frente a todas las cepas. En el modelo murino, la anfotericina B liposomal redujo para todas las cepas la carga fúngica en riñones, mientras que la anfotericina B desoxicolato, la anidulafungina y el fluconazol fueron efectivas solo en aquellos animales infectados con las cepas de menor valor de concentración mínima inhibitoria (CMI). ConclusionesLa anfotericina B liposomal mostró la mayor actividad y eficacia frente a C. guilliermondii, en contraste con el limitado efecto del fluconazol y de la anidulafungina. Se necesitan estudios que incluyan cepas con un rango más amplio de CMI que permitan determinar la relación entre la actividad in vitro y la eficacia de la anidulafungina." "secciones" => array:5 [ 0 => array:2 [ "identificador" => "abst0030" "titulo" => "Antecedentes" ] 1 => array:2 [ "identificador" => "abst0035" "titulo" => "Objetivos" ] 2 => array:2 [ "identificador" => "abst0040" "titulo" => "Métodos" ] 3 => array:2 [ "identificador" => "abst0045" "titulo" => "Resultados" ] 4 => array:2 [ "identificador" => "abst0050" "titulo" => "Conclusiones" ] ] ] ] "multimedia" => array:5 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 2200 "Ancho" => 3042 "Tamanyo" => 427167 ] ] "descripcion" => array:1 [ "en" => "Time-killing kinetics assays of AMB against four strains of C. guilliermondii. (■) 0.03μg/ml, (▴) 0.12μg/ml, (□) 0.5μg/ml, (○) 1μg/ml, (Δ) 2μg/ml, (▿) 8μg/ml, (♦) 32μg/ml, (●) control. Dashed lines represent a CFU decrease of 3log10 units in growth compared with the initial inoculum (fungicidal activity), dotted lines indicate the quantification limit of the test." ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 2081 "Ancho" => 2900 "Tamanyo" => 402197 ] ] "descripcion" => array:1 [ "en" => "Time-killing kinetics assays of AFG against four strains of C. guilliermondii. (■) 0.03μg/ml, (▴) 0.12μg/ml, (□) 0.5μg/ml, (○) 1μg/ml, (Δ) 2μg/ml, (▿) 8μg/ml, (♦) 32μg/ml, (●) control. Dashed lines represent a CFU decrease of 3 log10 units in growth compared with the initial inoculum (fungicidal activity), dotted lines indicate the quantification limit of the test." ] ] 2 => array:7 [ "identificador" => "fig0015" "etiqueta" => "Fig. 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 2075 "Ancho" => 2883 "Tamanyo" => 292202 ] ] "descripcion" => array:1 [ "en" => "Time-killing kinetics assays of FLC against four strains of C. guilliermondii. (■) 0.03μg/mL, (▴) 0.12μg/ml, (□) 0.5μg/ml, (●) 1μg/ml, (Δ) 2μg/ml, (▿)8μg/ml, (♦) 32μg/ml, (●) control. Dashed lines represent a CFU decrease of 3log10 units in growth compared with the initial inoculum (fungicidal activity), dotted lines indicate the quantification limit of the test." ] ] 3 => array:7 [ "identificador" => "fig0020" "etiqueta" => "Fig. 4" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr4.jpeg" "Alto" => 882 "Ancho" => 2172 "Tamanyo" => 107850 ] ] "descripcion" => array:1 [ "en" => "Effects of antifungal treatment on colony counts of C. guilliermondii in kidney of neutropenic mice, 8 days post infection. LAMB 10, liposomal amphotericin B at 10mg/kg QD; AMBd 0.8, amphotericin B deoxycholate at 0.8mg/kg QD; AFG 10, anidulafungin at 10mg/kg QD. aP<0.05 versus control; bP<0.05 versus AMBd 0.8, AFG 10 and FLC 50; cP<0.05 versus AFG 10 and FLC 50." ] ] 4 => array:7 [ "identificador" => "fig0025" "etiqueta" => "Fig. 5" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr5.jpeg" "Alto" => 1470 "Ancho" => 1900 "Tamanyo" => 365171 ] ] "descripcion" => array:1 [ "en" => "Presence of fungal infiltration (black arrow) in the kidney section of a control mouse infected with C. guilliermondii, at 8 days post infection (periodic acid Schiff staining, magnification 1000×). 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Original article

Therapies against murine Candida guilliermondii infection, relationship between in vitro antifungal pharmacodynamics and outcome

Terapia antifúngica frente a la infección por Candida guilliermondii en ratones, correlación entre los parámetros farmacodinámicos in vitro y la eficacia in vivo

Katihuska Paredesa, Francisco Javier Pastora, Javier Capillaa,

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javier.capilla@urv.cat
kpiluq@yahoo.es

Corresponding author.

, Deanna A. Suttonc, Emilio Mayayob, Annette W. Fothergillc, Josep Guarroa

a Unitat de Microbiologia, Facultat de Medicina i Ciències de la Salut, IISPV, Universitat Rovira i Virgili, Reus, Tarragona, Spain

b Unitat de Anatomia Patològica, Facultat de Medicina i Ciències de la Salut, IISPV, Universitat Rovira i Virgili, Reus, Tarragona, Spain

c Fungus Testing Laboratory, University of Texas Health Science Center, San Antonio, TX, USA

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        "titulo" => "Terapia antif&#250;ngica frente a la infecci&#243;n por <span class="elsevierStyleItalic">Candida guilliermondii</span> en ratones&#44; correlaci&#243;n entre los par&#225;metros farmacodin&#225;micos in vitro y la eficacia in vivo"
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          "en" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">Time-killing kinetics assays of FLC against four strains of <span class="elsevierStyleItalic">C&#46; guilliermondii</span>&#46; &#40;&#9632;&#41; 0&#46;03<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;mL&#44; &#40;&#9652;&#41; 0&#46;12<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;ml&#44; &#40;&#9633;&#41; 0&#46;5<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;ml&#44; &#40;&#9679;&#41; 1<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;ml&#44; &#40;&#916;&#41; 2<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;ml&#44; &#40;&#9663;&#41;8<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;ml&#44; &#40;&#9830;&#41; 32<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;ml&#44; &#40;&#9679;&#41; control&#46; Dashed lines represent a CFU decrease of 3<span class="elsevierStyleHsp" style=""></span>log<span class="elsevierStyleInf">10</span> units in growth compared with the initial inoculum &#40;fungicidal activity&#41;&#44; dotted lines indicate the quantification limit of the test&#46;</p>"
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    "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">The fungus <span class="elsevierStyleItalic">Candida guilliermondii</span> is widely distributed in nature&#44; including the human microbiota of the skin and mucosal surfaces&#46;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a> Although this species shows a reduced virulence in comparison to other <span class="elsevierStyleItalic">Candida</span> species&#44;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> it is currently considered an emerging pathogen&#44; with a major incidence in Latin America&#46;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a><span class="elsevierStyleItalic">C&#46; guilliermondii</span> has been recognized as the etiologic agent of a wide variety of clinical infections&#44; including disseminated ones mainly in immunocompromised patients&#44;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a> and nosocomial outbreaks in surgical patients with intravascular devices&#46;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> Currently&#44; the recommended treatment for invasive candidiasis in neutropenic patients includes caspofungin &#40;CFG&#41; or micafungin &#40;MFG&#41; as first-line therapies&#44; liposomal amphotericin B &#40;LAMB&#41; and anidulafungin &#40;AFG&#41; being alternatives&#44; while fluconazole &#40;FLC&#41; is recommended only when susceptibility to this drug is confirmed&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a> However&#44; several studies have shown that <span class="elsevierStyleItalic">C&#46; guilliermondii</span> has a decreased susceptibility to FLC<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">8&#44;15&#44;19</span></a>&#44; and therapeutic failures associated with isolates with high amphotericin B &#40;AMB&#41; minimal inhibitory concentrations &#40;MICs&#41; have been reported&#46;<a class="elsevierStyleCrossRefs" href="#bib0045"><span class="elsevierStyleSup">9&#44;12&#44;24</span></a> Although nearly 90&#37; of isolates shows echinocandins MICs equal or lower than clinical breakpoints &#40;CBP&#41; of susceptibility &#40;2<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;ml&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a> similar to other species of <span class="elsevierStyleItalic">Candida</span>&#44; such as <span class="elsevierStyleItalic">C&#46; parapsilosis</span>&#44; some isolates of <span class="elsevierStyleItalic">C&#46; guilliermondii</span> show MICs considerably high&#46;<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">8&#44;15</span></a> Available data concerning the AFG efficacy in invasive candidiasis are limited and the potential role of that drug in the clinical practice is poorly known&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a> In this context&#44; animal studies can play an important role for a better understanding of the in vitro&#8211;in vivo correlation&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> Therefore&#44; our main objective was to evaluate the in vitro and in vivo activities of AFG against different isolates of <span class="elsevierStyleItalic">C&#46; guilliermondii</span>&#44; comparing the results with those of AMB and FLC&#46;</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Materials and methods</span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Fungal isolates</span><p id="par0010" class="elsevierStylePara elsevierViewall">Four clinical isolates of <span class="elsevierStyleItalic">C&#46; guilliermondii</span> &#40;UTHSC 11-142&#44; UTHSC 10-499&#44; UTHSC 11-685 and UTHSC 10-3207&#41; were used in the in vitro study and two of them &#40;UTHSC 11-685 and UTHSC 11-142&#41; were selected for the murine model on the basis of their different in vitro susceptibilities&#46; The isolates were identified by sequencing the internal transcribed spacer &#40;ITS&#41; region and the D1&#8211;D2 domains of the rRNA&#44; comparing the sequences with those of the type strain of this species&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">In vitro studies</span><p id="par0015" class="elsevierStylePara elsevierViewall">The in vitro susceptibility of the four strains to AMB&#44; FLC and AFG was evaluated using a reference broth microdilution method&#44;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a><span class="elsevierStyleItalic">Candida parapsilosis</span> ATCC 22019 and <span class="elsevierStyleItalic">Candida krusei</span> ATCC 6258 being included as quality controls&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">Time-kill curves were developed for all the strains according to previous studies&#46;<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">5&#44;20</span></a> In brief&#44; a stock solution of each antifungal was prepared&#44; AMB &#40;Sigma&#8211;Aldrich Co&#46;&#44; St&#46; Louis&#44; USA&#41; and AFG &#40;Pfizer Inc&#46;&#44; Madrid&#44; Spain&#41; were dissolved in dimethyl sulfoxide and FLC &#40;Pfizer Inc&#46;&#44; Madrid&#44; Spain&#41; in distilled water&#46; Further&#44; drug dilutions were prepared in 9<span class="elsevierStyleHsp" style=""></span>ml of standard RPMI 1640 medium to obtain concentrations of 0&#46;03&#44; 0&#46;12&#44; 0&#46;5&#44; 1&#44; 2&#44; 8 and 32<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;ml of each drug&#46; The isolates were subcultured at 35<span class="elsevierStyleHsp" style=""></span>&#176;C for 24<span class="elsevierStyleHsp" style=""></span>h on potato dextrose agar &#40;PDA&#41; plates&#46; Cultures of <span class="elsevierStyleItalic">C&#46; guilliermondii</span> were suspended in sterile saline and the resulting suspensions were adjusted at 5<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleSup">6</span> colony forming units &#40;CFU&#41;&#47;ml by haemocytometer counts and by serial plating onto PDA to confirm viability&#46; Dilutions and controls &#40;drug-free&#41; were inoculated with 1<span class="elsevierStyleHsp" style=""></span>ml of the fungal suspensions&#44; resulting in a starting inoculum of 5<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleSup">5</span><span class="elsevierStyleHsp" style=""></span>CFU&#47;ml&#44; and incubated at 35<span class="elsevierStyleHsp" style=""></span>&#176;C&#46; An aliquot of 100<span class="elsevierStyleHsp" style=""></span>&#956;l from each tube was collected at 0&#44; 2&#44; 4&#44; 6&#44; 8&#44; 24&#44; and 48<span class="elsevierStyleHsp" style=""></span>h after inoculation and diluted in distilled water&#59; 30 &#956;l of them were cultured onto PDA plates and incubated at 35<span class="elsevierStyleHsp" style=""></span>&#176;C for 48<span class="elsevierStyleHsp" style=""></span>h for CFU&#47;ml determination&#46; A CFU decrease of &#8805;99&#46;9&#37; or 3 log<span class="elsevierStyleInf">10</span> unit compared to starting inoculum was considered fungicidal&#44; while a reduction of &#60;99&#46;9&#37; or &#60;3<span class="elsevierStyleHsp" style=""></span>log<span class="elsevierStyleInf">10</span> unit&#44; was considered fungistatic&#46; The limit of detection was 50<span class="elsevierStyleHsp" style=""></span>CFU&#47;ml&#46; All time-kill curve studies were performed in duplicate&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">In vivo studies</span><p id="par0025" class="elsevierStylePara elsevierViewall">Male OF-1 mice &#40;Charles River&#59; Criffa SA&#44; Barcelona&#44; Spain&#41; with a mean weight of 30<span class="elsevierStyleHsp" style=""></span>g were used in the experiment&#46; Mice were housed in standard boxes with free access to food and water&#46; All animal procedures were supervised and approved by the Universitat Rovira i Virgili Animal Welfare and Ethics Committee&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">Mice were rendered neutropenic one day prior to infection by an intraperitoneal &#40;i&#46;p&#46;&#41; injection of 200<span class="elsevierStyleHsp" style=""></span>mg&#47;kg of cyclophosphamide &#40;Genoxal&#59; Laboratorios Funk SA&#44; Barcelona&#44; Spain&#41; plus an intravenous &#40;i&#46;v&#46;&#41; injection of 5-fluorouracil &#40;Fluorouracilo&#59; Ferrer Farma SA&#44; Barcelona&#44; Spain&#41; at 150<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#46;<a class="elsevierStyleCrossRefs" href="#bib0050"><span class="elsevierStyleSup">10&#44;14</span></a> The day of infection&#44; mice were challenged i&#46;v&#46; with 1<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleSup">8</span><span class="elsevierStyleHsp" style=""></span>CFU&#47;animal of each of the two strains of <span class="elsevierStyleItalic">C&#46; guilliermondii</span>&#44; UTHSC 11-685 and UTHSC 11-142&#44; in 0&#46;2<span class="elsevierStyleHsp" style=""></span>ml of sterile saline into the lateral tail vein&#46;<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3&#44;4</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">Groups of eight animals were randomly established for each strain and drug&#46; The groups were treated as follows&#58; amphotericin B deoxycholate &#40;AMBd&#41; &#40;Xalabarder Pharmacy&#44; Barcelona&#44; Spain&#41; at doses of 0&#46;8<span class="elsevierStyleHsp" style=""></span>mg&#47;kg i&#46;v&#46; once a day &#40;QD&#41;&#59; liposomal amphotericin B &#40;LAMB&#41; &#40;Gilead Sciences S&#46;A&#46;&#44; Madrid&#44; Spain&#41; at 10<span class="elsevierStyleHsp" style=""></span>mg&#47;kg i&#46;v&#46;&#44; QD&#59; FLC &#40;Pfizer Inc&#46;&#44; Madrid&#44; Spain&#41; at 25<span class="elsevierStyleHsp" style=""></span>mg&#47;kg orally &#40;p&#46;o&#46;&#41; by gavage&#44; twice daily &#40;BID&#41;&#59; and AFG &#40;Ecalta&#59; Pfizer Ltd&#46;&#44; Sandwich&#44; Kent&#44; United Kingdom&#41; at 10<span class="elsevierStyleHsp" style=""></span>mg&#47;kg of body weight&#47;dose i&#46;p&#46;&#44; QD&#46; All treatments began 24<span class="elsevierStyleHsp" style=""></span>h after challenge&#44; and lasted for 7 days&#46; Controls received no treatment&#46; To prevent bacterial infections&#44; all mice received 5<span class="elsevierStyleHsp" style=""></span>mg&#47;kg day ceftazidime subcutaneously from days 1 to 7 after infection&#46; Mice were checked daily and were euthanized on day 8 post-infection by CO<span class="elsevierStyleInf">2</span> anoxia&#46; The efficacy of each drug was evaluated by tissue burden reduction and histopathological studies&#46; Kidneys were aseptically removed&#44; and one of them was weighed and homogenized in 2<span class="elsevierStyleHsp" style=""></span>ml of sterile saline&#46; Serial 10-fold dilutions of the homogenates were plated onto PDA and incubated for 48<span class="elsevierStyleHsp" style=""></span>h at 35<span class="elsevierStyleHsp" style=""></span>&#176;C for CFU&#47;g calculation&#46; For the histopathology study the remaining kidney was fixed with 10&#37; buffered formalin&#44; dehydrated&#44; paraffin embedded&#44; and sliced into 2<span class="elsevierStyleHsp" style=""></span>&#956;m sections&#44; which were stained with hematoxylin&#8211;eosin &#40;H-E&#41; and periodic acid-Schiff &#40;PAS&#41; stain for examination by light microscopy&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Statistics</span><p id="par0040" class="elsevierStylePara elsevierViewall">Colony counts from tissue were analyzed using the Mann&#8211;Whitney <span class="elsevierStyleItalic">U</span>-test&#44; using Graph Pad Prism 4&#46;0 for Windows &#40;GraphPad Software&#44; San Diego&#44; CA&#44; USA&#41;&#46; When <span class="elsevierStyleItalic">P</span> values were below 0&#46;05 the differences were considered statistically significant&#46;</p></span></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Results</span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">In vitro studies</span><p id="par0045" class="elsevierStylePara elsevierViewall">MICs of AMB were 0&#46;25&#8211;1<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;ml&#44; 0&#46;06&#8211;0&#46;25<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;ml for AFG and 0&#46;5&#8211;1<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;ml for FLC&#46; Following the cut-offs of susceptibility for AMB&#44; FLC and AFG against <span class="elsevierStyleItalic">C&#46; guilliermondii</span>&#44;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> all isolates were susceptible to the three drugs&#46; Quality control strains susceptibilities were within the accepted ranges&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">The killing kinetics of AMB showed a fast fungicidal activity that increased with drug concentration&#46; At concentrations equivalent to the MIC&#44; that drug showed a fungicidal effect against three of the four isolates tested &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; This activity started immediately after inoculation at concentrations over 1<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;ml&#44; the fungicidal endpoint being reached after 4<span class="elsevierStyleHsp" style=""></span>h at 32<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;ml&#46; AFG at concentrations above 0&#46;5<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;ml showed fungicidal activity starting after 4<span class="elsevierStyleHsp" style=""></span>h of incubation&#46; The fungicidal endpoint was reached at 12&#8211;24<span class="elsevierStyleHsp" style=""></span>h of incubation at 32<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;ml &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#46; FLC showed fungistatic activity against all four isolates &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>&#41;&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="fig0010"></elsevierMultimedia><elsevierMultimedia ident="fig0015"></elsevierMultimedia></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">In vivo studies</span><p id="par0055" class="elsevierStylePara elsevierViewall">LAMB at 10<span class="elsevierStyleHsp" style=""></span>mg&#47;kg was the only drug able to reduce the fungal load in kidneys of mice infected with each of the two strains&#44; being the reduction significantly higher than that of the other therapies &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#8804;<span class="elsevierStyleHsp" style=""></span>0&#46;04&#41;&#46; AMBd and FLC were only able to reduce the tissue burden in mice infected with the strain that showed the lowest MICs for these two drugs&#44; i&#46;e&#46;&#44; 0&#46;25<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;ml for AMB and 0&#46;5<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;ml for FLC &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#8804;<span class="elsevierStyleHsp" style=""></span>0&#46;008&#41;&#46; In the case of AFG the fungal load reduction was modest and lower than that for AMBd&#44; and it significantly reduced the tissue burden in kidney only with respect to control group for strain UTHSC 11-685 &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;002&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0020">Fig&#46; 4</a>&#41;&#46;</p><elsevierMultimedia ident="fig0020"></elsevierMultimedia><p id="par0060" class="elsevierStylePara elsevierViewall">The histological study showed focal infiltration of fungal cells in kidneys of untreated animals and in mice treated with AMBd&#44; FLC or AFG&#46; Kidneys of mice treated with LAMB showed only a mild fungal invasion&#46; Signs of necrosis&#44; inflammatory response or parenchyma alterations were nor observed in controls neither in treated animals &#40;<a class="elsevierStyleCrossRef" href="#fig0025">Fig&#46; 5</a>&#41;&#46;</p><elsevierMultimedia ident="fig0025"></elsevierMultimedia></span></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Discussion</span><p id="par0065" class="elsevierStylePara elsevierViewall">The in vitro studies did not reveal decreased susceptibility of <span class="elsevierStyleItalic">C&#46; guilliermondii</span> isolates to FLC or AFG&#46; In agreement with previous studies&#44; time-kill curves of AMB showed a concentration-dependent fungicidal activity against all the isolates&#44;<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4&#44;5&#44;7</span></a> and FLC showed a fungistatic effect regardless of the concentration tested&#46;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> It is known that AMBd exhibits a higher efficacy than its lipidic formulation&#44; especially in kidney&#44; when administered both at the same doses&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> However&#44; pharmacokinetic studies showed that after the administration of 0&#46;75<span class="elsevierStyleHsp" style=""></span>mg&#47;kg of AMBd the <span class="elsevierStyleItalic">C</span><span class="elsevierStyleInf">max</span> of AMB attained in mice serum was 0&#46;30<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;ml&#46;<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a> However&#44; the AMB MIC of one of the two isolates tested is higher than this value&#59; therefore&#44; we used a high dose of LAMB in order to reach higher concentrations&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> Indeed&#44; the administration of LAMB at 10<span class="elsevierStyleHsp" style=""></span>mg&#47;kg was effective in reducing the fungal load of both strains&#46; This fact correlated with killing curves&#44; where AMB achieved its fungicidal activity against the two isolates tested in vivo&#44; at concentrations of 1<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;ml&#46; To our knowledge&#44; this is the first study that tried to establish a relationship between the killing kinetics and the in vivo experimental efficacy of AFG and FLC against clinical isolates of <span class="elsevierStyleItalic">C&#46; guilliermondii</span>&#46; Only a previous study on echinocandins exists&#44; particularly on caspofungin &#40;CFG&#41; in disseminated infection by <span class="elsevierStyleItalic">C&#46; guilliermondii</span>&#46; CFG at 1<span class="elsevierStyleHsp" style=""></span>mg&#47;kg was effective in reducing the kidney fungal load in mice infected with one strain of <span class="elsevierStyleItalic">C&#46; guilliermondii</span> with a MIC of 8<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;ml&#44; while time killing revealed that no fungicidal activity was achieved at concentrations of 64<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;ml&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> Conversely&#44; our study showed a concentration-dependent activity of AFG&#44; which at 32<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;ml exerted a fungicidal activity&#44; as previously reported&#44;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a> at 24<span class="elsevierStyleHsp" style=""></span>h and at 8<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;ml&#46; Previous studies reported AFG concentrations in serum and kidney of approximately 13<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;ml after 7 days of treatment at doses of 10<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#46;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a> Here&#44; AFG was able to reduce only modestly the fungal burden in kidneys of neutropenic mice infected with one of the two strains tested&#44; which does not seem to be related with the low AFG MICs difference between the two strains tested &#40;1 dilution&#41;&#44; suggesting that the response to AFG treatment is strain dependent&#46; Similarly&#44; FLC was also only able to reduce slightly the fungal burden in kidney of mice challenged with one of the two strains in spite of the dose administrated which reach serum concentrations above the MICs&#44;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> which was also not surprising due to its fungistatic activity&#46;</p><p id="par0070" class="elsevierStylePara elsevierViewall">In conclusion&#44; our study showed the higher activity and efficacy of LAMB against the two strains of <span class="elsevierStyleItalic">C&#46; guilliermondii</span>&#44; in contrast to the poor effect of FLC and AFG&#46; However&#44; further studies with more isolates of <span class="elsevierStyleItalic">C&#46; guilliermondii</span> representing a wider range of AFG MICs should be carried out to assess if any relationship between MIC values and AFG efficacy exists&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Conflict of interest</span><p id="par0075" class="elsevierStylePara elsevierViewall">None to declare&#46;</p></span></span>"
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Background</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Candida guilliermondii</span> has been recognized as an emerging pathogen showing a decreased susceptibility to fluconazole and considerably high echinocandin MICs&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Aims</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Evaluate the in vitro activity of anidulafungin in comparison to amphotericin B and fluconazole against different isolates of <span class="elsevierStyleItalic">C&#46; guilliermondii</span>&#44; and their efficacy in an immunosuppressed murine model of disseminated infection&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Methods</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">The in vitro susceptibility of four strains against amphotericin B&#44; fluconazole and anidulafungin was performed by using a reference broth microdilution method and time-kill curves&#46; The in vivo efficacy was evaluated by determination of fungal load reduction in kidneys of infected animals receiving deoxycholate AMB at 0&#44;8<span class="elsevierStyleHsp" style=""></span>mg&#47;kg i&#46;v&#46;&#44; liposomal amphotericin B at 10<span class="elsevierStyleHsp" style=""></span>mg&#47;kg i&#46;v&#46;&#44; fluconazole at 50<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#44; or anidulafungin at 10<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Results</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Amphotericin B and anidulafungin showed fungicidal activity&#44; while fluconazole was fungistatic for all the strains&#46; In the murine model&#44; liposomal amphotericin B at 10<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;day was effective in reducing the tissue burden in kidneys of mice infected with any of the tested strains&#46; However&#44; amphotericin B&#44; anidulafungin and fluconazole were only effective against those strains showing low MIC values&#46;</p></span> <span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Conclusions</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Liposomal amphotericin B showed the higher activity and efficacy against the two strains of <span class="elsevierStyleItalic">C&#46; guilliermondii</span>&#44; in contrast to the poor effect of fluconazole and anidulafungin&#46; Further studies with more isolates of <span class="elsevierStyleItalic">C&#46; guilliermondii</span> representing a wider range of MICs should be carried out to assess whether there is any relationship between MIC values and anidulafungin efficacy&#46;</p></span>"
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        "resumen" => "<span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Antecedentes</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Candida guilliermondii</span> es un pat&#243;geno emergente&#44; con reducida sensibilidad al fluconazol y a las equinocandinas&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Objetivos</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Evaluar la actividad in vitro de la anidulafungina&#44; en comparaci&#243;n con la de la anfotericina B y el fluconazol&#44; frente a <span class="elsevierStyleItalic">C&#46; guilliermondii</span> y su eficacia en un modelo animal de infecci&#243;n diseminada&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">M&#233;todos</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">La sensibilidad in vitro se valor&#243; mediante microdiluci&#243;n en caldo y curvas de mortalidad&#46; La eficacia in vivo se evalu&#243; mediante la determinaci&#243;n de la carga f&#250;ngica en ri&#241;&#243;n de ratones inmunosuprimidos con infecci&#243;n diseminada por <span class="elsevierStyleItalic">C&#46; guilliermondii</span> tratados con anfotericina B desoxicolato &#40;0&#46;8<span class="elsevierStyleHsp" style=""></span>mg&#47;kg i&#46;v&#46;&#41;&#44; anfotericina B liposomal &#40;10<span class="elsevierStyleHsp" style=""></span>mg&#47;kg i&#46;v&#46;&#41;&#44; fluconazol &#40;50<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#41; o anidulafungina &#40;10<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#41;&#46;</p></span> <span id="abst0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Resultados</span><p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">La anfotericina B y la anidulafungina mostraron actividad fungicida&#44; mientras que el fluconazol fue fungist&#225;tico frente a todas las cepas&#46; En el modelo murino&#44; la anfotericina B liposomal redujo para todas las cepas la carga f&#250;ngica en ri&#241;ones&#44; mientras que la anfotericina B desoxicolato&#44; la anidulafungina y el fluconazol fueron efectivas solo en aquellos animales infectados con las cepas de menor valor de concentraci&#243;n m&#237;nima inhibitoria &#40;CMI&#41;&#46;</p></span> <span id="abst0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Conclusiones</span><p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">La anfotericina B liposomal mostr&#243; la mayor actividad y eficacia frente a <span class="elsevierStyleItalic">C&#46; guilliermondii</span>&#44; en contraste con el limitado efecto del fluconazol y de la anidulafungina&#46; Se necesitan estudios que incluyan cepas con un rango m&#225;s amplio de CMI que permitan determinar la relaci&#243;n entre la actividad in vitro y la eficacia de la anidulafungina&#46;</p></span>"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Pharmacokinetic&#8211;pharmacodynamic comparison of amphotericin B &#40;AMB&#41; and two lipid-associated AMB preparations&#44; liposomal AMB and AMB lipid complex&#44; in murine candidiasis models"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "D&#46; Andes"
                            1 => "N&#46; Safdar"
                            2 => "K&#46; Marchillo"
                            3 => "R&#46; Conklin"
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                      "doi" => "10.1128/AAC.50.2.674-684.2006"
                      "Revista" => array:6 [
                        "tituloSerie" => "Antimicrob Agents Chemother"
                        "fecha" => "2006"
                        "volumen" => "50"
                        "paginaInicial" => "674"
                        "paginaFinal" => "684"
                        "link" => array:1 [
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                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16436726"
                            "web" => "Medline"
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Article information

ISSN: 11301406
Original language: English

DOI:10.1016/j.riam.2013.10.008

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Year/Month	Html	Pdf	Total

2024 November	6	0	6
2024 October	175	14	189
2024 September	196	17	213
2024 August	162	14	176
2024 July	171	11	182
2024 June	144	7	151
2024 May	120	4	124
2024 April	144	9	153
2024 March	180	15	195
2024 February	167	2	169
2024 January	210	24	234
2023 December	151	6	157
2023 November	133	3	136
2023 October	202	7	209
2023 September	157	12	169
2023 August	143	14	157
2023 July	148	22	170
2023 June	146	3	149
2023 May	146	8	154
2023 April	87	17	104
2023 March	137	13	150
2023 February	73	8	81
2023 January	77	15	92
2022 December	62	10	72
2022 November	67	9	76
2022 October	43	14	57
2022 September	77	16	93
2022 August	91	18	109
2022 July	50	14	64
2022 June	53	9	62
2022 May	75	19	94
2022 April	51	19	70
2022 March	68	17	85
2022 February	52	8	60
2022 January	96	20	116
2021 December	74	27	101
2021 November	67	16	83
2021 October	91	21	112
2021 September	74	18	92
2021 August	60	20	80
2021 July	39	18	57
2021 June	37	13	50
2021 May	47	14	61
2021 April	123	12	135
2021 March	72	3	75
2021 February	73	18	91
2021 January	62	11	73
2020 December	67	12	79
2020 November	53	17	70
2020 October	35	18	53
2020 September	35	15	50
2020 August	58	18	76
2020 July	37	12	49
2020 June	49	11	60
2020 May	58	14	72
2020 April	37	7	44
2020 March	71	5	76
2020 February	62	2	64
2020 January	60	12	72
2019 December	50	8	58
2019 November	64	5	69
2019 October	81	9	90
2019 September	90	8	98
2019 August	65	2	67
2019 July	53	16	69
2019 June	63	32	95
2019 May	90	75	165
2019 April	117	40	157
2019 March	33	4	37
2019 February	28	6	34
2019 January	16	5	21
2018 December	21	5	26
2018 November	16	7	23
2018 October	32	30	62
2018 September	11	4	15
2018 August	11	4	15
2018 July	15	2	17
2018 June	20	2	22
2018 May	14	10	24
2018 April	6	2	8
2018 March	7	0	7
2018 February	96	4	100
2018 January	6	2	8
2017 December	11	2	13
2017 November	11	3	14
2017 October	14	1	15
2017 September	26	18	44
2017 August	17	6	23
2017 July	13	4	17
2017 June	14	18	32
2017 May	19	7	26
2017 April	7	7	14
2017 March	14	30	44
2017 February	12	2	14
2017 January	6	2	8
2016 December	17	4	21
2016 November	11	3	14
2016 October	33	19	52
2016 September	32	6	38
2016 August	29	4	33
2016 July	11	3	14
2016 June	29	7	36
2016 May	9	13	22
2016 April	5	2	7
2016 March	17	7	24
2016 February	10	6	16
2016 January	16	9	25
2015 April	0	4	4
2015 March	0	2	2
2015 February	1	2	3

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