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Study of microbiological laboratory techniques for the etiological diagnosis and guidance in the treatment of invasive candidiasis

Invasive candidiasis is an important medical problem with a high mortality (30-50%) associated with both the health status of patients who are usually people with immunodeficiencies, and with the virulence of the fungus. The fungal species Candida albicans causes half of these diseases. Other species such as Candida parapsilosis, Candida glabrata or Candida tropicalis are important etiological agents because of their increasing frequency and the potential resistance to the antifungal drugs used in the therapy of candidiasis. Candida auris is an emerging species of recent association with human disease with cross resistance to antifungal drugs and the ability to persist in the hospital environment [1]. The early diagnosis of invasive candidiasis is difficult: There are not specific biomarkers for diagnosis and identification by conventional and molecular methods of the species causing the infection is based in the culture of this fungus in suitable mycological media.

Aims: To become familiar with the microbiological laboratory techniques used for the etiological diagnosis of invasive candidiasis and to guide in the treatment of invasive fungal infections.

Methodology: The current project performs several phases related to the diagnosis and treatment of invasive candidiasis. In one of the phases, studying in vitro antifungal susceptibilities for supporting treatment of candidiasis, we have studied the activity of SCY-078, a new antifungal drug for treating infections caused by species of Candida resistant to conventional treatments, including Candida auris. This compound SCY-078 is a

new oral and intravenous drug for the treatment. We have evaluated the in vitro action of this drug SCY-078 and other antifungal drugs (azoles and echinocandins) against isolates of different Candida species isolated from blood cultures, such as Candida albicans, Candida parapsilosis, Candida tropicalis, Candida auris or Candida glabrata using the EUCAST method [2]. This method is the European protocol for studying the in vitro activity of antifungal drugs. EUCAST is a microdilution method for determining the Minimum Inhibitory Concentration (MIC) of the different antifungal agents and their usefulness for the treatment of invasive mycoses.

Conclusion: The main action of azoles is to inhibit lanosterol 14-α-demethylase coupled to cytochrome P-450. This action causes an alteration of fungal cell membranes increasing permeability and producing inhibition of cell growth and cell replication. Echinocandins inhibit 1,3-β-D-glucan synthetase, the enzymatic complex that forms β-D-glucan polymers in the cell wall of the fungus. The cell wall provides rigidity to the cell and its rupture causes the cell death. The compound CSY-078 is derived from enfumafungin (formerly MK-3118) and it is an inhibitor of the 1,3-β-D-glucan synthesis. This drug is the first in its class: triterpenic antifungal drugs. SCY-078 has demonstrated in vitro activity against many Candida species and against the multidrug-resistant pathogen Candida auris, which has been classified by the Centers for Disease Control and Prevention (CDC) as a Serious Threatens a global level for health In clinical development to treat candidemia and candidiasis [1,3,4]. During my stay, we have verified the excellent in vitro efficacy of the echinocandins caspofungin and micafungin and the new drug SCY-078 against many of the clinical isolates of Candida that were resistant to fluconazole. Moreover, SCY-078 was active against many Candida blood isolates with decreased susceptibility to caspofungin and micafungin.

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Ecotoxicological assessment of pharmaceuticals using computational toxicology approaches: QSTR and interspecies QTTR modelling
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Although pharmaceuticals have been released into the environment for decades with seemingly no or very little care, their environmental toxicity has been studied experimentally only to a limited extent until today. There are reports of measurable quantities of drug molecules and other bioactive metabolites in rivers and other surface water bodies (mg/L range), notably in China and India where bulk production occurs. It is virtually impossible to carry out experimental evaluation of the impact of pharmaceuticals on all relevant and exposed organisms – this is also both unethical, costly and slow.  However, computational tools such as Quantitative Structure-Activity Relationship (QSAR) can be used to fill the data gaps where limited number of experimental data is available. In the current study, we have developed Quantitative Structure-Toxicity Relationship (QSTR) models for toxicity of pharmaceuticals on three different organisms namely algae, daphnia and fish. In order to study relationships between structural features and toxicity responses we developed models by partial least squares regression approach using descriptors selected through a genetic algorithm approach. The novel developed models were subsequently extensively validated following OECD guidelines. An additional interspecies quantitative structure-toxicity-toxicity relationship (QSTTR) modelling was performed to check for the interrelationship of various pattern of response as we moved across the hierarchy of genetics in different taxonomical class. Various descriptor calculating software such as PaDEL-Descriptor, DRAGON and SiRMS were used to compute a wide array of 2D descriptors for capturing chemical information required to correlate the biological properties (toxicities) inherited in the chemical structure of the molecules. All the obtained models showed that with an increase in hydrophobic characteristics (in terms of Log P) toxicity also increases linearly while with an increase in hydrogen bond donating groups, toxicity decreases. An applicability domain study was carried out in order to define the scope of developed model and to highlight compounds falling outside the domain of the respective models. The obtained QSTTR models were finally utilized to fill the data gaps of 275 pharmaceuticals, by using as a template to predict toxicity of pharmaceuticals where experimental data were missing for at least one of the endpoints. Finally, the developed QSTR models were used to predict a large dataset of approximately 7000 drug like molecules in order to prioritize the existing drug like substances in accordance to their acute predicted aquatic toxicities.

Keywords: QSAR, QSTR, QSTTR, Ecotoxicity, Pharmaceuticals

References

  1. Ternes, Thomas A. "Occurrence of drugs in German sewage treatment plants and rivers." Water research32, no. 11 (1998): 3245-3260.
  2. Hirsch, Roman, Thomas Ternes, Klaus Haberer, and Karl-Ludwig Kratz. "Occurrence of antibiotics in the aquatic environment." Science of the Total Environment225, no. 1-2 (1999): 109-118.
  3. Sanderson, Hans, and Marianne Thomsen. "Comparative analysis of pharmaceuticals versus industrial chemicals acute aquatic toxicity classification according to the United Nations classification system for chemicals. Assessment of the (Q) SAR predictability of pharmaceuticals acute aquatic toxicity and their predominant acute toxic mode-of-action." Toxicology Letters187, no. 2 (2009): 84-93.
  4. Kar Supratik, Das Rudra Narayan, Roy Kunal, and Leszcznyski, Jerzy, Can Toxicity for Different Species be Correlated?: The Concept and Emerging Applications of Interspecies Quantitative Structure-Toxicity Relationship (i-QSTR) Modeling. Int J Quant Struct-Prop Relat 1, no. 2 (2016): 23-51, http://dx.doi.org/10.4018/IJQSPR.2016070102
  5. Das, Rudra Narayan, Kunal Roy, and Paul LA Popelier. "Interspecies quantitative structure–toxicity–toxicity (QSTTR) relationship modeling of ionic liquids. Toxicity of ionic liquids to V. fischeri, D. magna and S. vacuolatus." Ecotoxicology and Environmental Safety122 (2015): 497-520.
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MOL2NET: FROM MOLECULES TO NETWORKS (PROC. BOOK), 2018, Vol. 3, 679 pp.

Proceedings of the conference MOL2NET International Conference on Multidisciplinary Sciences (3rd edition), 2017. Year-Round conference series hosted by MDPI Sciforum, Basel, Switzerland. These conferences have more than 10 associated workshop series in universities of USA, Spain, China, Chile, Brazil, etc. These workshop series run in person and/or online. Some of these workshops are the SRI-08 St Thomas University (STU)- Miami Dade College (MDC), Miami, USA; WCUCW, West Coast University, Miami, USA; IWMEDIC UDC, Coruña, Spain, etc. The conference series also has general online only sections for online publication of online papers, research highligths of previous papers, letters, short revies, etc. The topics are multidisciplinary covering, but not limited to, Chemistry (All areas), Physics, Biology, Ecology, Statistics, Bioinformatics, Education, Nanotechnology, Materials, Computational, Complex Networks, and Social sciences, etc. This edition attracted >200 communications submitted by >400 authors. Thank you very much to all colleagues for your kind support.

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Estudio comparativo de la Candidiasis Invasiva en México y España

El género Cándida incluye más de 150 especies, de las cuales solo unas cuantas causan enfermedad en seres humanos. Estafadores Excepciones Raras, los Patogenos para Seres humanos hijo C. albicans , C. guilliermondii , C. krusei , C. parapsilosis , C. tropicalis , C. lusitaniae , C. dubliniensis y C . glabrata . De naturaleza ubicua, estos microorganismos se encuentran en objetos inanimados, alimentos, animales y comensales normales de los seres humanos. Habitante en el tubo digestivo, en el aparato reproductor femenino y en la piel. Con la introducción de antimicóticos,

La candidiasis invasiva (CI) es la enfermedad fúngica más común entre los pacientes hospitalizados en países en vía de desarrollo. Comprende tanto candidemia como candidiasis de tejidos profundos. Generalmente se ve como el tipo más común de la enfermedad y representa la mayoría de los casos incluidos en ensayos clínicos. La candidiasis profunda se presenta ya sea por diseminación hematógena o por inoculación directa de las diferentes especies de cándida a un sitio estéril, como la cavidad peritoneal. La mortalidad entre los pacientes con candidiasis invasiva alcanza un 40% y en neonatos y niños hasta un 15% (del Palacio, Villar & Alhambra, 2009), incluso cuando los pacientes reciben terapia antifúngica. Además,

La candidiasis invasiva es una de las tantas presentaciones que existen de las infecciones por Cándida. Candidiasis localizadas en diferentes órganos internos y la Candidiasis Diseminada (CD) ya sea aguda o crónica. Las principales rutas de invasión de la levadura son vía catéteres endovenosos y por penetración a través de la mucosa intestinal, esta última involucra a las especies que forman parte de la microbiota gastrointestinal. Como mencionamos antes, la candidemia en el hallazgo del hongo en muestras de hemocultivo, sin cambios inmunológicos en el huésped y en ausencia de compromiso visceral; Puede ser transitoria, por un hemocultivo positivo aislado, o persistente, por hemocultivos positivos repetitivos. En la mayoría de los casos, La desaparición de la función se obtiene retirando el catéter y el paciente no presentan los factores de inmunosupresión añadidos. La candidemia en inmunosuprimidos, en particular neutropénicos, siempre debe considerar como infección potencialmente grave, el riesgo de muerte elevada. Es más frecuente en pacientes con enfermedades hematológicas malignas (Biasoli, 2011).

La candidiasis profunda localizada es una infección focal que se produce en muchos casos por siembra hematógena. El compromiso visceral afecta a un único órgano citando como los más frecuentes: pulmones, riñones, sistema nervioso, hígado, etc. (Biasoli, 2011). En todos estos casos es necesario demostración de la presencia del hongo en tejidos comprometidos a través de estudios histopatológicos.

La candidiasis diseminada (CD) es una infección con múltiple localización visceral demostrable por biopsia o necropsia. Está habitualmente acompañado por una respuesta inmunológica del huésped (si esta es inmunocompetente). En la CD aguda los pacientes presentan fiebre persistente que no responde a antibioterapia, otros síntomas hijo mialgias, fallo renal, lesiones nodulares cutáneas, en algunos casos endoftalmitis, meningitis, abceso cerebral, miocarditis, neumonía y más tardíamente artritis séptica. En la CD crónica es casi exclusivamente observada en pacientes neutropénicos (Kullberg y Arendrup, 2015). Se manifiesta frecuentemente después de la recuperación de un trasplante de médula ósea cuando el paciente presenta una fiebre persistente que no responde a los antibióticos.

Existen diversos estudios donde la diabetes mellitus (DM), hemodiálisis, nutrición parenteral e inmunosuprimidos (VIH / SIDA), quimioterapia, corticoterapia tenía una prevalencia de CI del 78%, mientras que en los que no tenían esta combinación de (Palacio, Alhambra y Cuetara, 2010). Los pacientes pediátricos que tienen el riesgo de una CI son los neonatos con los factores de riesgo como la intubación, los catéteres intravasculares, el peso bajo al nacer (<1.500 gr) antibioterapia aunada a su inmadurez inmunológica. Por otra parte, la población infantil con riesgo también de una CI, los niños con enfermedades oncohematológicas, los receptores de transplantes (hígado 90%), los alimentos con nutrición parenteral total (NPT) y fallo renal (del Palacio, Villar & Alhambra, 2009).

Las especies no- albicans representan casi 50% de todos los casos de candidemia y de la candidosis de diseminación hematógena. La identificación de este cambio es de importancia clínica, porque varias especies difieren en susceptibilidad a los nuevos antimicóticos. En países desarrollados, donde se utilizan los tratamientos farmacológicos, el género Cándida se encuentra entre los patógenos más comunes (Longo, Fauci, Kasper & Hauser, 2012).

En Pacientes Pediátricos Mexicanos, las Infecciones causadas por C. albicans predominan en la Mayoría (64%), Seguido de C . tropicalis (26%), C . Glabrata (6%), C. parapsilosis (2%) y el resto el 2% (Martínez Garnica, Jiménez Jiménez, Ramírez Guerrero y López Martínez, 2015). En Pacientes Adultos Mexicanos, C. albicans Predomina En un 62%, C. glabrata En un 12%, C. tropicalis ES 7,5%, C . Parapsilosis 7,3%, C. krusei 2,7% y el resto <1% (del Palacio, Villar & Alhambra, 2009).

En la población pediátrica española la especie C. parapsilosis representa el 43% seguido de C. albicans con un 36%; El resto engloba principalmente C. glabrata, tropicalis y krusei.  (García-Rodríguez et al., 2013). En Pacientes Adultos españoles El Hongo Más frecuentemente Aislado en Sangre ES C . albicans (40-75%), Seguido de C . Glabrata ó C. parapsilosis (25%) según las áreas geográficas, C. tropicalis (10%) y con menor frecuencia C. krusei, C. lusitaniae y C. guillermondii (Gómez, García Vázquez, Hernández, Espinoza y Ruiz, 2010) .

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