Efecto Antimicrobiano de una Solución Comercial de Ácido Hipocloroso Contra Microorganismos Implicados en Infecciones Asociadas a la Atención de la Salud
Digital
- Autores:
-
Rueda-Jaimes, María Paula
Uribe-Sánchez, Valentina
- Tipo de recurso:
- Trabajo de grado de pregrado
- Fecha de publicación:
- 2023
- Institución:
- Universidad de Santander
- Repositorio:
- Repositorio Universidad de Santander
- Idioma:
- spa
- OAI Identifier:
- oai:repositorio.udes.edu.co:001/10465
- Palabra clave:
- Ácido Hipocloroso
Fibroblastos
Antimicrobiano
Citotoxicidad
Hypochlorous Acid
Fibroblasts
Antimicrobial
Cytotoxicity
- Rights
- openAccess
- License
- http://purl.org/coar/access_right/c_abf2
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Efecto Antimicrobiano de una Solución Comercial de Ácido Hipocloroso Contra Microorganismos Implicados en Infecciones Asociadas a la Atención de la Salud |
| dc.title.translated.none.fl_str_mv |
Antimicrobial Effect of a Commercial Hypochlorous Acid Solution Against Microorganisms Implicated in Healthcare-Associated Infections |
| title |
Efecto Antimicrobiano de una Solución Comercial de Ácido Hipocloroso Contra Microorganismos Implicados en Infecciones Asociadas a la Atención de la Salud |
| spellingShingle |
Efecto Antimicrobiano de una Solución Comercial de Ácido Hipocloroso Contra Microorganismos Implicados en Infecciones Asociadas a la Atención de la Salud Ácido Hipocloroso Fibroblastos Antimicrobiano Citotoxicidad Hypochlorous Acid Fibroblasts Antimicrobial Cytotoxicity |
| title_short |
Efecto Antimicrobiano de una Solución Comercial de Ácido Hipocloroso Contra Microorganismos Implicados en Infecciones Asociadas a la Atención de la Salud |
| title_full |
Efecto Antimicrobiano de una Solución Comercial de Ácido Hipocloroso Contra Microorganismos Implicados en Infecciones Asociadas a la Atención de la Salud |
| title_fullStr |
Efecto Antimicrobiano de una Solución Comercial de Ácido Hipocloroso Contra Microorganismos Implicados en Infecciones Asociadas a la Atención de la Salud |
| title_full_unstemmed |
Efecto Antimicrobiano de una Solución Comercial de Ácido Hipocloroso Contra Microorganismos Implicados en Infecciones Asociadas a la Atención de la Salud |
| title_sort |
Efecto Antimicrobiano de una Solución Comercial de Ácido Hipocloroso Contra Microorganismos Implicados en Infecciones Asociadas a la Atención de la Salud |
| dc.creator.fl_str_mv |
Rueda-Jaimes, María Paula Uribe-Sánchez, Valentina |
| dc.contributor.advisor.none.fl_str_mv |
Leal-Pinto, Sandra Milena Roa-Cordero, Martha Viviana Vargas-Caicedo, José David |
| dc.contributor.author.none.fl_str_mv |
Rueda-Jaimes, María Paula Uribe-Sánchez, Valentina |
| dc.contributor.jury.none.fl_str_mv |
Pardo-Casas, Marithza Portilla-Rodríguez, Jenniffer Amalia |
| dc.subject.proposal.spa.fl_str_mv |
Ácido Hipocloroso Fibroblastos Antimicrobiano Citotoxicidad |
| topic |
Ácido Hipocloroso Fibroblastos Antimicrobiano Citotoxicidad Hypochlorous Acid Fibroblasts Antimicrobial Cytotoxicity |
| dc.subject.proposal.eng.fl_str_mv |
Hypochlorous Acid Fibroblasts Antimicrobial Cytotoxicity |
| description |
Digital |
| publishDate |
2023 |
| dc.date.issued.none.fl_str_mv |
2023-12-04 |
| dc.date.accessioned.none.fl_str_mv |
2024-05-30T16:28:17Z |
| dc.date.available.none.fl_str_mv |
2024-05-30T16:28:17Z 2025-03-31 |
| dc.type.none.fl_str_mv |
Trabajo de grado - Pregrado |
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http://purl.org/coar/resource_type/c_7a1f |
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Universidad de Santander |
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T 17.23 R822e |
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Repositorio Digital Universidad de Santander |
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https://repositorio.udes.edu.co |
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https://repositorio.udes.edu.co/handle/001/10465 |
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Universidad de Santander T 17.23 R822e Repositorio Digital Universidad de Santander |
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https://repositorio.udes.edu.co https://repositorio.udes.edu.co/handle/001/10465 |
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spa |
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spa |
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Kopsidas I, Collins M, Zaoutis T. Healthcare-associated Infections—Can We Do Better? Pediatric Infectious Disease Journal. 2021 Aug 10;40(8):e305–9. Sreeramoju P. Recent advances in understanding the epidemiology of healthcare-associated infections. F1000Res. 2019 Jan 25;8:106 Bore E, Hébraud M, Chafsey I, Chambon C, Skjæret C, Moen B, et al. Adapted tolerance to benzalkonium chloride in Escherichia coli K-12 studied by transcriptome and proteome analyses. Microbiology (N Y). 2007 Apr 1;153(4):935–46. Lafaurie GI, Calderón JL, Zaror C, Millán LV, Castillo DM. Ácido Hipocloroso: una Nueva Alternativa como Agente Antimicrobiano y para la Proliferación Celular para Uso en Odontología. International journal of odontostomatology. 2015 Dec;9(3):475–81. Aranke M, Moheimani R, Phuphanich M, Kaye AD, Ngo AL, Viswanath O, et al. Disinfectants in Interventional Practices. Curr Pain Headache Rep. 2021 Apr 11;25(4):21. Liu JY, Dickter JK. Nosocomial Infections. Gastrointest Endosc Clin N Am. 2020 Oct;30(4):637–52. Quijada H. Comportamiento epidemiológico de los brotes de Infecciones Asociadas a la Atención en Salud (IAAS), Colombia, 2021 a 2022. https://www.ins.gov.co/Paginas/Inicio.aspx; 2023 Ocampo Moreira PO, Ortega Reyes VÁ, Alvarado Avila VA, Campuzano Rizzo BL. Etiología de las infecciones de sitio quirúrgico. Una revisión bibliográfica. RECIAMUC. 2023 Jan 6;7(1):233–40. Barahona N, Rodriguez M, De Moya Y. Importancia de la vigilancia epidemiológica en el control de las infecciones asociadas a la atención en saluD. Biociencias. 2019 Apr 24;14(1):65–81. Rutala WA, Weber DJ. Disinfection and Sterilization in Health Care Facilities. Infect Dis Clin North Am. 2021 Sep;35(3):575–607. Rather MA, Gupta K, Mandal M. Microbial biofilm: formation, architecture, antibiotic resistance, and control strategies. Brazilian Journal of Microbiology. 2021 Dec 23;52(4):170118. Leal MA, Freitas-Vilela AA de. Costs of healthcare-associated infections in an Intensive Care Unit. Rev Bras Enferm. 2021;74(1). Ortiz-Mayorga JL, Pineda-Rodríguez IG, Dennis RJ, Porras A. Costos atribuidos a las infecciones asociadas con la atención en salud en un hospital de Colombia, 2011-2015. Biomédica. 2019 Mar 31;39(1):102–12. Rojas Castillo JC, Ruiz AM, Moreno López CL, Silva Soler MA, Páez Gutiérrez CC. Parkinson genetico: Reporte de un caso clínico y revisión de la literatura. Acta Neurológica Colombiana. 2021 oct 22;37(3):133–8. Clarke K, Hall CL, Wiley Z, Tejedor SC, Kim JS, Reif L, et al. Catheter-Associated Urinary Tract Infections in Adults: Diagnosis, Treatment, and Prevention. J Hosp Med. 2020 Sep 1;15(9):552–6. Gonçalves SCM, Carmo TIG do. Implicações das Infeções Associadas aos Cuidados de Saúde na Gestão em Saúde. Enfermería: Cuidados Humanizados. 2022 Apr 4;11(1):e2746. Venkatesan N, Perfumar G, Doble M. Bacterial resistance in biofilm-associated bacteria. Future Microbiol. 2015 nov;10(11):1743–50. Bardi T, Pintado V, Gomez-Rojo M, Escudero-Sanchez R, Azzam Lopez A, Diez-Remesal Y, et al. Nosocomial infections associated to COVID-19 in the intensive care unit: clinical characteristics and outcome. European Journal of Clinical Microbiology & Infectious Diseases. 2021 Mar 3;40(3):495–502. Salud RD. Resolución Nº 008430 de 1993. Cali, Colombia. 1993. Mc Carlie S, Boucher CE, Bragg RR. Molecular basis of bacterial disinfectant resistance. Drug Resistance Updates. 2020 Jan; 48:100672. Morante J, Quispe AM, Ymaña B, Moya-Salazar J, Luque N, Soza G, et al. Tolerance to disinfectants (chlorhexidine and isopropanol) and its association with antibiotic resistance in clinically-related Klebsiella pneumoniae isolates. Pathog Glob Health. 2021 Jan 2;115(1):53–60. Block MS, Rowan BG. Hypochlorous Acid: A Review. Journal of Oral and Maxillofacial Surgery. 2020 Sep;78(9):1461–6. Hatanaka N, Yasugi M, Sato T, Mukamoto M, Yamasaki S. Hypochlorous acid solution is a potent antiviral agent against SARS‐CoV‐2. J Appl Microbiol. 2022 feb 17;132(2):1496–502. Palau M, Muñoz E, Lujan E, Larrosa N, Gomis X, Márquez E, et al. In Vitro and In Vivo Antimicrobial Activity of Hypochlorous Acid against Drug-Resistant and Biofilm-Producing Strains. Microbiol Spectr. 2022 Oct 26;10(5). Ashby L V., Springer R, Hampton MB, Kettle AJ, Winterbourn CC. Evaluating the bactericidal action of hypochlorous acid in culture media. Free Radic Biol Med. 2020 Nov; 159:119–24. Mahdizadeh S, Sawford K, van Andel M, Browning GF. Efficacy of citric acid and sodium hypochlorite as disinfectants against Mycoplasma bovis. Vet Microbiol. 2020 Apr; 243:108630. Aherne O, Ortiz R, Fazli MM, Davies JR. Effects of stabilized hypochlorous acid on oral biofilm bacteria. BMC Oral Health. 2022 Sep 20;22(1):415. Zmuda HM, Mohamed A, Raval YS, Call DR, Schuetz AN, Patel R, et al. Hypochlorous acid-generating electrochemical scaffold eliminates Candida albicans biofilms. J Appl Microbiol. 2020 Oct 1;129(4):776–86. Burian EA, Sabah L, Kirketerp-Møller K, Gundersen G, Ågren MS. Effect of Stabilized Hypochlorous Acid on Re-epithelialization and Bacterial Bioburden in Acute Wounds: A Randomized Controlled Trial in Healthy Volunteers. Acta Derm Venereol. 2022 May 31;102:adv00727. Hatanaka N, Yasugi M, Sato T, Mukamoto M, Yamasaki S. Hypochlorous acid solution is a potent antiviral agent against SARS‐CoV‐2. J Appl Microbiol. 2022 Feb 17;132(2):1496–502. Fam A, Finger PT, Tomar AS, Garg G, Chin KJ. Hypochlorous acid antiseptic washout improves patient comfort after intravitreal injection: A patient reported outcomes study. Indian J Ophthalmol. 2020 nov;68(11):2439–44. Puro V, Coppola N, Frasca A, Gentile I, Luzzaro F, Peghetti A, et al. Pillars for prevention and control of healthcare-associated infections: an Italian expert opinion statement. Antimicrob Resist Infect Control. 2022 Jun 20;11(1):87. O’Toole RF. The interface between COVID-19 and bacterial healthcare-associated infections. Clinical Microbiology and Infection. 2021 Dec;27(12):1772–6. Boev C, Kiss E. Hospital-Acquired Infections. Crit Care Nurs Clin North Am. 2017 Mar;29(1):51–65. Instituto Nacional de Salud. Semana epidemiológica 24 11 al 17 de junio de 2023. Bogotá; 2023 jun. Serna Trejos JS, Bermúdez Moyano SG, Estacio Diaz JD, Agudelo Giraldo E. Comportamiento epidemiológico de las infecciones asociadas a procedimientos médico-quirúrgicos en Colombia. Medicina Clínica y Social. 2023 May 5;7(2):125–7. Flores-Mireles A, Hreha TN, Hunstad DA. Pathophysiology, Treatment, and Prevention of Catheter-Associated Urinary Tract Infection. Top Spinal Cord Inj Rehabil. 2019 Jun;25(3):228–40 Melzer M, Welch C. Outcomes in UK patients with hospital-acquired bacteraemia and the risk of catheter-associated urinary tract infections. Postgrad Med J. 2013 Jun 1;89(1052):329–34. Melzer M, Welch C. Outcomes in UK patients with hospital-acquired bacteraemia and the risk of catheter-associated urinary tract infections. Postgrad Med J. 2013 Jun 1;89(1052):329–34. Rubi H, Mudey G, Kunjalwar R. Catheter-Associated Urinary Tract Infection (CAUTI). Cureus. 2022 Oct;14(10):e30385. Chuang L, Tambyah PA. Catheter-associated urinary tract infection. Journal of Infection and Chemotherapy. 2021 Oct;27(10):1400–6. Rajaramon S, Shanmugam K, Dandela R, Solomon AP. Emerging evidence-based innovative approaches to control catheter-associated urinary tract infection: a review. Front Cell Infect Microbiol. 2023 Jul 25;13. Flores-Mireles A, Hreha TN, Hunstad DA. Pathophysiology, Treatment, and Prevention of Catheter-Associated Urinary Tract Infection. Top Spinal Cord Inj Rehabil. 2019 Jun;25(3):228–40. Kanti SPY, Csóka I, Jójárt-Laczkovich O, Adalbert L. Recent Advances in Antimicrobial Coatings and Material Modification Strategies for Preventing Urinary Catheter-Associated Complications. Biomedicines. 2022 Oct 14;10(10). Papazian L, Klompas M, Luyt CE. Ventilator-associated pneumonia in adults: a narrative review. Intensive Care Med. 2020 May 10;46(5):888–906. Maes M, Higginson E, Pereira-Dias J, Curran MD, Parmar S, Khokhar F, et al. Ventilator-associated pneumonia in critically ill patients with COVID-19. Crit Care. 2021 Dec 11;25(1):25. Cisneros E, Campos R, Jorge G. Neumonía nosocomial por Pseudomonas aeruginosa. artículo de revisión. Vallecoccia MS, Dominedò C, Cutuli SL, Martin-Loeches I, Torres A, De Pascale G. Is ventilated hospital-acquired pneumonia a worse entity than ventilator-associated pneumonia? European Respiratory Review. 2020 Sep 30;29(157):200023. Timsit JF, Ruppé E, Barbier F, Tabah A, Bassetti M. Bloodstream infections in critically ill patients: an expert statement. Intensive Care Med. 2020 Feb 11;46(2):266–84. García Palomo JD, Agüero Balbín J, Parra Blanco JA, Santos Benito MF. Enfermedades infecciosas. Concepto. Clasificación. Aspectos generales y específicos de las infecciones. Criterios de sospecha de enfermedad infecciosa. Pruebas diagnósticas complementarias. Criterios de indicación. Medicine - Programa de Formación Médica Continuada Acreditado. 2010 feb;10(49):3251–64. Lafuente Cabrero E, Terradas Robledo R, Civit Cuñado A, García Sardelli D, Hidalgo López C, Giro Formatger D, et al. Risk factors of catheter- associated bloodstream infection: Systematic review and meta-analysis. PLoS One. 2023 Mar 23;18(3):e0282290. Moriyama K, Ando T, Kotani M, Tokumine J, Nakazawa H, Motoyasu A, et al. Risk factors associated with increased incidences of catheter-related bloodstream infection. Medicine. 2022 Oct 21;101(42):e31160. Selby LM, Rupp ME, Cawcutt KA. Prevention of Central-Line Associated Bloodstream Infections: 2021 Update. Infect Dis Clin North Am. 2021 Dec;35(4):841–56. 54. Rodríguez Nájera GF, Camacho Barquero FA, Umaña Bermúdez CA. Factores de riesgo y prevención de infecciones del sitio quirúrgico. Revista Medica Sinergia. 2020 Apr 1;5(4):e444. Bath M, Davies J, Suresh R, Machesney M. Surgical site infections: a scoping review on current intraoperative prevention measures. The Annals of The Royal College of Surgeons of England. 2022 Sep;104(8):571–6. Orcasitas D, Ospino C, Mendoza M, Bermúdez A, Quintero M: Infecciones del sitio operatorio en Colombia: una revisión exhaustiva de la literatura 2007-2017. [Artículo de revisión]. [Barranquilla]: Universidad Del Norte; 2018. Landaverde E. Determinación de bacterias con mayor prevalencia en las infecciones de sitio quirúrgico y la resistencia a los antibióticos. [México]: Universidad Abierta y a Distancia de México; 2019. Vega P, Veloz D. Perfil microbiológico de infección de sitio quirúrgico en el servicio de Cirugía General en el Hospital Abel Gilbert Pontón en los años 2014 al 2017 [Thesis]. [Mexico]: Universidad de Guayaquil; Molina I, Bejarano M, García O. Infección del sitio operatorio en un hospital nivel II. Montoya M, Carrascal D. Infección del sitio operatorio en pacientes del servicio de cirugía en el hospital general de Medellín. Artículo de investigación. Kolasiński W. Surgical site infections- review of current knowledge, methods of prevention. Polish Journal of Surgery. 2018 nov 6;90(5):1–7. Velázquez-Acosta C, Cornejo-Juárez P, Volkow-Fernández P. Cepas E-ESKAPE multidrogorresistentes aisladas en hemocultivos de pacientes con cáncer. Salud Publica Mex. 2018 Mar 23;60(2, mar-abr):151. Robinson J. HF, Guamán-Rivera SA, Correa-Salgado M de L, Carrión-Salazar BE, Mecías-Herrera NL. Resistencia Antibiótica de Microorganismos del grupo ESKAPE y la Relevancia de las Prácticas de Uso Prudente de Antibióticos (PROA). Código Científico Revista de Investigación. 2023 Sep 29;4(E2):240–54. Arias CA, Murray BE. The rise of the Enterococcus: beyond vancomycin resistance. Nat Rev Microbiol. 2012 Apr 16;10(4):266–78. Cheung GYC, Bae JS, Otto M. Pathogenicity and virulence of Staphylococcus aureus. Virulence. 2021 Dec 31;12(1):547–69. Tang M, Kong X, Hao J, Liu J. Epidemiological Characteristics and Formation Mechanisms of Multidrug-Resistant Hypervirulent Klebsiella pneumoniae. Front Microbiol. 2020 Nov 20;11. Lee CR, Lee JH, Park M, Park KS, Bae IK, Kim YB, et al. Biology of Acinetobacter baumannii: Pathogenesis, Antibiotic Resistance Mechanisms, and Prospective Treatment Options. Front Cell Infect Microbiol. 2017 Mar 13;7. Davin-Regli A, Lavigne JP, Pagès JM. Enterobacter spp.: Update on Taxonomy, Clinical Aspects, and Emerging Antimicrobial Resistance. Clin Microbiol Rev. 2019 Sep 18;32(4). Chávez-Jacobo VM. La batalla contra las superbacterias: No más antimicrobianos, no hay ESKAPE. TIP Revista Especializada en Ciencias Químico-Biológicas. 2020 Feb 19;23. Loyola-Cruz MÁ, Gonzalez-Avila LU, Martínez-Trejo A, Saldaña-Padilla A, Hernández-Cortez C, Bello-López JM, et al. ESKAPE and Beyond: The Burden of Coinfections in the COVID-19 Pandemic. Pathogens. 2023 May 22;12(5):743. Bolívar A, Torres M, Sánchez Y. Biofilms de Pseudomonas aeruginosa como mecanismosde resistencia y tolerancia a antibióticos. 2020 Jul 12; Lin Y, Chen J, Zhou X, Li Y. Inhibition of Streptococcus mutans biofilm formation by strategies targeting the metabolism of exopolysaccharides. Crit Rev Microbiol. 2021 Sep 3;47(5):667–77. Singh S, Singh SK, Chowdhury I, Singh R. Understanding the Mechanism of Bacterial Biofilms Resistance to Antimicrobial Agents. Open Microbiol J. 2017 Apr 28;11(1):53–62. Arciola CR, Campoccia D, Speziale P, Montanaro L, Costerton JW. Biofilm formation in Staphylococcus implant infections. A review of molecular mechanisms and implications for biofilm-resistant materials. Biomaterials. 2012 sep ; 33(26):5967–82. Naze F, Jouen E, Randriamahazo RT, Simac C, Laurent P, Blériot A, et al. Pseudomonas aeruginosa Outbreak Linked to Mineral Water Bottles in a Neonatal Intensive Care Unit: Fast Typing by Use of High-Resolution Melting Analysis of a Variable-Number Tandem-Repeat Locus. J Clin Microbiol. 2010 Sep;48(9):3146–52. Oluyombo O, Penfold CN, Diggle SP. Competition in Biofilms between Cystic Fibrosis Isolates of Pseudomonas aeruginosa Is Shaped by R-Pyocins. mBio. 2019 Feb 26;10(1). Pang Z, Raudonis R, Glick BR, Lin TJ, Cheng Z. Antibiotic resistance in Pseudomonas aeruginosa: mechanisms and alternative therapeutic strategies. Biotechnol Adv. 2019 Jan;37(1):177–92. Jiménez Pearson MA, Galas M, Corso A, Hormazábal JC, Duarte Valderrama C, Salgado Marcano N, et al. Consenso latinoamericano para definir, categorizar y notificar patógenos multirresistentes, con resistencia extendida o panresistentes. Revista Panamericana de Salud Pública. 2019;1–8. Lemiech-Mirowska E, Kiersnowska Z, Michałkiewicz M, Depta A, Marczak M. Nosocomial infections as one of the most important problems of healthcare system. Annals of Agricultural and Environmental Medicine. 2021 Sep 16;28(3):361–6. Peters A, Schmid MN, Parneix P, Lebowitz D, de Kraker M, Sauser J, et al. Impact of environmental hygiene interventions on healthcare-associated infections and patient colonization: a systematic review. Antimicrob Resist Infect Control. 2022 Dec 19;11(1):38 Pankey GA, Sabath LD. Clinical Relevance of Bacteriostatic versus Bactericidal Mechanisms of Action in the Treatment of Gram‐Positive Bacterial Infections. Clinical Infectious Diseases. 2004 Mar 15;38(6):864–70. Park GW, Boston DM, Kase JA, Sampson MN, Sobsey MD. Evaluation of Liquid- and Fog-Based Application of Sterilox Hypochlorous Acid Solution for Surface Inactivation of Human Norovirus. Appl Environ Microbiol. 2007 jul 15;73(14):4463–8. Arrieta J. Estrategias terapéuticas para la eliminación y control del biofilm bacteriano en la ulcera de pie diabético. Artículo de revisión. Severino C. Eficiencia germicida y coeficiente de dilución del Ácido Hipocloroso in vitro frente a cepas bacterianas potencialmente frecuentes en la Industria Alimentaria. [Santiago]: Universidad de Chile; 2023. Sánchez Ruiz FH, Furuya Meguro AT, Arroniz Padilla S, Gómez Moreno A, Gómez L. Comparación de la acción bactericida de hipoclorito de sodio y microcyn 60. Revista Odontológica Mexicana. 2009 Aug 26;13(1). Antimicrobial activities of Ankaferd Bloodstopper, Hypochlorous Acid and Chlorhexidine against specific organisms. Turk J Med Sci. 2021; Robson MC, Payne WG, Ko F, Mentis M, Donati G, Shafii SM, et al. Hypochlorous Acid as a Potential Wound Care Agent: Part II. Stabilized Hypochlorous Acid: Its Role in Decreasing Tissue Bacterial Bioburden and Overcoming the Inhibition of Infection on Wound Healing. J Burns Wounds. 2007 Apr 11;6:e6. Kletzer J, Raval YS, Mohamed A, Mandrekar JN, Greenwood-Quaintance KE, Beyenal H, et al. In Vitro Activity of a Hypochlorous Acid-Generating Electrochemical Bandage against Yeast Biofilms. Antimicrob Agents Chemother. 2023 Jan 24;67(1). Severing AL, Rembe JD, Koester V, Stuermer EK. Safety and efficacy profiles of different commercial sodium hypochlorite/hypochlorous acid solutions (NaClO/HClO): antimicrobial efficacy, cytotoxic impact and physicochemical parameters in vitro. Journal of Antimicrobial Chemotherapy. 2019 Feb 1;74(2):365–72. Whiteman M, Hooper DC, Scott GS, Koprowski H, Halliwell B. Inhibition of hypochlorous acid-induced cellular toxicity by nitrite. Proceedings of the National Academy of Sciences. 2002 Sep 17;99(19):12061–6. |
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Leal-Pinto, Sandra Milena4e3a70e9-8291-4730-b87d-80362d2f6d61-1Roa-Cordero, Martha Vivianae84c56b3-2007-43cb-a9be-2e2de068fdf2600Vargas-Caicedo, José Davidf49abdc3-8133-4683-9430-ed2a740e57bc-1Rueda-Jaimes, María Paula3fa640a1-784b-403b-8b02-af7bdbfb2de2-1Uribe-Sánchez, Valentina133fc170-c9cd-45a1-9cf2-d5a76a986b85-1Pardo-Casas, Marithzaf5027580-8266-45bb-93e5-9772d1daa437-1Portilla-Rodríguez, Jenniffer Amalia21ee5f05-f641-4c13-9cef-c2f072c8c82e-12024-05-30T16:28:17Z2025-03-312024-05-30T16:28:17Z2023-12-04DigitalIntroducción: Las Infecciones Asociadas a la Atención en Salud (IAAS) y la resistencia antimicrobiana son problemas de salud pública a nivel global debido a su alta morbimortalidad en pacientes hospitalizados y críticamente enfermos. Estas infecciones afectan aproximadamente al 7-10% de los pacientes hospitalizados en todo el mundo, provocando más de 140,000 muertes al año. En Colombia, se observó un aumento del 9.7% en el número de casos en 2022, entornos hospitalarios o dispositivos médicos. Es prioritario encontrar alternativas de desinfección intrahospitalaria. El ácido hipocloroso, producido por el sistema inmunológico, tiene desafíos de estabilidad que podrían solucionarse con formulaciones sintéticas. Objetivo: Evaluar efecto antimicrobiano y citotóxico de una solución comercial de ácido hipocloroso contra microorganismos implicados en IAAS. Metodología: La actividad antimicrobiana fue evaluada por el método microdilución establecido por el CLSI, guía M07-A11 para bacterias y M27-A4 para levaduras. Klebsiella pneumonie 700603, Escherichia coli 10536, Staphylococcus aureus 11632, Pseudomonas aeruginosa 27853, C. albicans 90028 y C. tropicalis 29066 adquiridas de ATCC, fueron expuestas a diferentes diluciones de Citrilac 24 horas para determinar la concentración mínima inhibitoria (CMI) y concentración mínima fungicida o bactericida. El efecto citotóxico fue determinado sobre monocapas de fibroblastos NIH3T3 usando el ensayo colorimétrico con sal de tetrazolio. Resultados: Citrilac inhibió el crecimiento planctónico de los microorganismos evaluados con CMI basados en la concentración de ácido hipocloroso en la solución C. albicans 0,0550%, C. tropicalis 0,0275%, S. aureus 0,0034%, E. coli 0,0034%, K. pneumoniae 0,0069%, P. aeruginosa 0,0138%. Adicionalmente, CC50 de 0,009% sobre fibroblastos fue determinada. Conclusión: Este estudio constituye una base experimental demostrando el efecto antimicrobiano de la solución comercial de ácido hipocloroso (CitrilacⓇ) contra microorganismos implicados en IAAS, así mismo, demuestra la selectividad sobre células de mamífero, en concentraciones bajas del principio activo.Introduction: Healthcare-Associated Infections (HAIs) and antimicrobial resistance represent a serious global public health issue due to their high morbidity and mortality rates in hospitalized and critically ill patients. These infections affect approximately 7-10% of hospitalized patients worldwide and result in over 140,000 deaths per year. In Colombia, there was a 9.7% increase in reported cases in 2022 compared to previous years. These adverse events are caused by opportunistic microorganisms that are part of the human microbiome or acquired exogenously from the hospital environment or through the use of medical devices. In this context, the search for intrahospital disinfection alternatives that can help mitigate these infections should be a priority. Hypochlorous acid is a natural molecule produced by the cells of the immune system, but its low stability poses challenges. The use of synthetic formulations could represent an effective solution to improve its stability. Objective: To evaluate the antimicrobial and cytotoxic effect of a commercial solution of hypochlorous acid against microorganisms involved in HAIs. Methodology: The antimicrobial activity was evaluated using the microdilution method established by the Clinical and Laboratory Standards Institute (CLSI), guidelines M07-A11 for bacteria and M27-A4 for yeast. Klebsiella pneumoniae 700603, Escherichia coli 10536, Staphylococcus aureus 11632, Pseudomonas aeruginosa 27853, C. albicans 90028, and C. tropicalis 29066 obtained from ATCC were exposed to different dilutions of CitrilacⓇ for 24 hours to determine the minimum inhibitory concentration (MIC) and minimum fungicidal or bactericidal concentration. The cytotoxic effect was determined on NIH3T3 fibroblast monolayers using a colorimetric assay with tetrazolium salt. Results: CitrilacⓇ inhibited the planktonic growth of the evaluated microorganisms with MIC values based on the concentration of hypochlorous acid in the solution: C. albicans 0.0550%, C. tropicalis 0.0275%, S. aureus 0.0034%, E. coli 0.0034%, K. pneumoniae 0.0069%, P. aeruginosa 0.0138%. Additionally, a CC50 of 0.009% on fibroblasts was determined. Conclusion: This study provides experimental evidence of the antimicrobial effect of the commercial hypochlorous acid solution (CitrilacⓇ) against microorganisms involved in HAIs. It also demonstrates selectivity for mammalian cells at low concentrations of hypochlorous acid (active ingredient).PregradoBacteriólogo(a) y Laboratorista ClínicoIntroducción 16 Objetivos 18 Objetivo General 18 Objetivos Específicos 18 Planteamiento del Problema 19 Justificación 22 Metodología 25 Tipo de Estudio 25 Unidad de Observación 25 Unidad de Análisis 25 Hipótesis 25 Material Biológico y Condiciones de Cultivo 25 Compuestos Evaluados y Medicamentos de Referencia 26 Determinación de la Concentración Inhibitoria Mínima 27 Evaluación In Vitro de la Citotoxicidad 28 Análisis de Resultados 28 Aspectos Éticos 29 Marco Referencial 30 Estado del Arte 30 Marco Teórico 34 Infecciones Asociadas a la Atención en Salud: Generalidades y Epidemiologia Global 34 Tipos de IAAS 35 Infección del Torrente Sanguíneo Asociada al uso de Catéter 43 Infecciones de Sitio Quirúrgico 46 Prevalencia de Microrganismos Multidrogorresistentes del Grupo SKAPE en IAAS 48 Antimicrobianos y su Papel en las IAAS 51 Mecanismos de Resistencia Mediados por Biofilm 52 Resultados 60 Discusión 63 Conclusiones 67 Referencias Bibliográficas 6878 papplication/pdfapplication/mswordUniversidad de SantanderT 17.23 R822eRepositorio Digital Universidad de Santanderhttps://repositorio.udes.edu.cohttps://repositorio.udes.edu.co/handle/001/10465spaUniversidad de SantanderBucaramangaFacultad de Ciencias Médicas y de la SaludBucaramanga, ColombiaBacteriología y Laboratorio ClínicoKopsidas I, Collins M, Zaoutis T. 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Estrategias terapéuticas para la eliminación y control del biofilm bacteriano en la ulcera de pie diabético. Artículo de revisión.Severino C. Eficiencia germicida y coeficiente de dilución del Ácido Hipocloroso in vitro frente a cepas bacterianas potencialmente frecuentes en la Industria Alimentaria. [Santiago]: Universidad de Chile; 2023.Sánchez Ruiz FH, Furuya Meguro AT, Arroniz Padilla S, Gómez Moreno A, Gómez L. Comparación de la acción bactericida de hipoclorito de sodio y microcyn 60. Revista Odontológica Mexicana. 2009 Aug 26;13(1).Antimicrobial activities of Ankaferd Bloodstopper, Hypochlorous Acid and Chlorhexidine against specific organisms. Turk J Med Sci. 2021;Robson MC, Payne WG, Ko F, Mentis M, Donati G, Shafii SM, et al. Hypochlorous Acid as a Potential Wound Care Agent: Part II. Stabilized Hypochlorous Acid: Its Role in Decreasing Tissue Bacterial Bioburden and Overcoming the Inhibition of Infection on Wound Healing. J Burns Wounds. 2007 Apr 11;6:e6.Kletzer J, Raval YS, Mohamed A, Mandrekar JN, Greenwood-Quaintance KE, Beyenal H, et al. In Vitro Activity of a Hypochlorous Acid-Generating Electrochemical Bandage against Yeast Biofilms. Antimicrob Agents Chemother. 2023 Jan 24;67(1).Severing AL, Rembe JD, Koester V, Stuermer EK. Safety and efficacy profiles of different commercial sodium hypochlorite/hypochlorous acid solutions (NaClO/HClO): antimicrobial efficacy, cytotoxic impact and physicochemical parameters in vitro. Journal of Antimicrobial Chemotherapy. 2019 Feb 1;74(2):365–72.Whiteman M, Hooper DC, Scott GS, Koprowski H, Halliwell B. Inhibition of hypochlorous acid-induced cellular toxicity by nitrite. Proceedings of the National Academy of Sciences. 2002 Sep 17;99(19):12061–6.Derechos Reservados - Universidad de Santander, 2023. 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GF1dG9yKSBwYXJhIGVqZXJjZXIgZXN0b3MgZGVyZWNob3Mgc29icmUgbGEgT2JyYSB0YWwgeSBjb21vIHNlIGluZGljYSBhIGNvbnRpbnVhY2nDs246PC9wPgogICAgPG9sIHR5cGU9ImEiPgogICAgICA8bGk+UmVwcm9kdWNpciBsYSBPYnJhLCBpbmNvcnBvcmFyIGxhIE9icmEgZW4gdW5hIG8gbcOhcyBPYnJhcyBDb2xlY3RpdmFzLCB5IHJlcHJvZHVjaXIgbGEgT2JyYSBpbmNvcnBvcmFkYSBlbiBsYXMgT2JyYXMgQ29sZWN0aXZhcy48L2xpPgogICAgICA8bGk+RGlzdHJpYnVpciBjb3BpYXMgbyBmb25vZ3JhbWFzIGRlIGxhcyBPYnJhcywgZXhoaWJpcmxhcyBww7pibGljYW1lbnRlLCBlamVjdXRhcmxhcyBww7pibGljYW1lbnRlIHkvbyBwb25lcmxhcyBhIGRpc3Bvc2ljacOzbiBww7pibGljYSwgaW5jbHV5w6luZG9sYXMgY29tbyBpbmNvcnBvcmFkYXMgZW4gT2JyYXMgQ29sZWN0aXZhcywgc2Vnw7puIGNvcnJlc3BvbmRhLjwvbGk+CiAgICAgIDxsaT5EaXN0cmlidWlyIGNvcGlhcyBkZSBsYXMgT2JyYXMgRGVyaXZhZGFzIHF1ZSBzZSBnZW5lcmVuLCBleGhpYmlybGFzIHDDumJsaWNhbWVudGUsIGVqZWN1dGFybGFzIHDDumJsaWNhbWVudGUgeS9vIHBvbmVybGFzIGEgZGlzcG9zaWNpw7NuIHDDumJsaWNhLjwvbGk+CiAgICA8L29sPgogICAgPHA+TG9zIGRlcmVjaG9zIG1lbmNpb25hZG9zIGFudGVyaW9ybWVudGUgcHVlZGVuIHNlciBlamVyY2lkb3MgZW4gdG9kb3MgbG9zIG1lZGlvcyB5IGZvcm1hdG9zLCBhY3R1YWxtZW50ZSBjb25vY2lkb3MgbyBxdWUgc2UgaW52ZW50ZW4gZW4gZWwgZnV0dXJvLiBMb3MgZGVyZWNob3MgYW50ZXMgbWVuY2lvbmFkb3MgaW5jbHV5ZW4gZWwgZGVyZWNobyBhIHJlYWxpemFyIGRpY2hhcyBtb2RpZmljYWNpb25lcyBlbiBsYSBtZWRpZGEgcXVlIHNlYW4gdMOpY25pY2FtZW50ZSBuZWNlc2FyaWFzIHBhcmEgZWplcmNlciBsb3MgZGVyZWNob3MgZW4gb3RybyBtZWRpbyBvIGZvcm1hdG9zLCBwZXJvIGRlIG90cmEgbWFuZXJhIHVzdGVkIG5vIGVzdMOhIGF1dG9yaXphZG8gcGFyYSByZWFsaXphciBvYnJhcyBkZXJpdmFkYXMuIFRvZG9zIGxvcyBkZXJlY2hvcyBubyBvdG9yZ2Fkb3MgZXhwcmVzYW1lbnRlIHBvciBlbCBMaWNlbmNpYW50ZSBxdWVkYW4gcG9yIGVzdGUgbWVkaW8gcmVzZXJ2YWRvcywgaW5jbHV5ZW5kbyBwZXJvIHNpbiBsaW1pdGFyc2UgYSBhcXVlbGxvcyBxdWUgc2UgbWVuY2lvbmFuIGVuIGxhcyBzZWNjaW9uZXMgNChkKSB5IDQoZSkuPC9wPgogIDwvbGk+CiAgPGJyLz4KICA8bGk+CiAgICBSZXN0cmljY2lvbmVzLgogICAgPHA+TGEgbGljZW5jaWEgb3RvcmdhZGEgZW4gbGEgYW50ZXJpb3IgU2VjY2nDs24gMyBlc3TDoSBleHByZXNhbWVudGUgc3VqZXRhIHkgbGltaXRhZGEgcG9yIGxhcyBzaWd1aWVudGVzIHJlc3RyaWNjaW9uZXM6PC9wPgogICAgPG9sIHR5cGU9ImEiPgogICAgICA8bGk+VXN0ZWQgcHVlZGUgZGlzdHJpYnVpciwgZXhoaWJpciBww7pibGljYW1lbnRlLCBlamVjdXRhciBww7pibGljYW1lbnRlLCBvIHBvbmVyIGEgZGlzcG9zaWNpw7NuIHDDumJsaWNhIGxhIE9icmEgc8OzbG8gYmFqbyBsYXMgY29uZGljaW9uZXMgZGUgZXN0YSBMaWNlbmNpYSwgeSBVc3RlZCBkZWJlIGluY2x1aXIgdW5hIGNvcGlhIGRlIGVzdGEgbGljZW5jaWEgbyBkZWwgSWRlbnRpZmljYWRvciBVbml2ZXJzYWwgZGUgUmVjdXJzb3MgZGUgbGEgbWlzbWEgY29uIGNhZGEgY29waWEgZGUgbGEgT2JyYSBxdWUgZGlzdHJpYnV5YSwgZXhoaWJhIHDDumJsaWNhbWVudGUsIGVqZWN1dGUgcMO6YmxpY2FtZW50ZSBvIHBvbmdhIGEgZGlzcG9zaWNpw7NuIHDDumJsaWNhLiBObyBlcyBwb3NpYmxlIG9mcmVjZXIgbyBpbXBvbmVyIG5pbmd1bmEgY29uZGljacOzbiBzb2JyZSBsYSBPYnJhIHF1ZSBhbHRlcmUgbyBsaW1pdGUgbGFzIGNvbmRpY2lvbmVzIGRlIGVzdGEgTGljZW5jaWEgbyBlbCBlamVyY2ljaW8gZGUgbG9zIGRlcmVjaG9zIGRlIGxvcyBkZXN0aW5hdGFyaW9zIG90b3JnYWRvcyBlbiBlc3RlIGRvY3VtZW50by4gTm8gZXMgcG9zaWJsZSBzdWJsaWNlbmNpYXIgbGEgT2JyYS4gVXN0ZWQgZGViZSBtYW50ZW5lciBpbnRhY3RvcyB0b2RvcyBsb3MgYXZpc29zIHF1ZSBoYWdhbiByZWZlcmVuY2lhIGEgZXN0YSBMaWNlbmNpYSB5IGEgbGEgY2zDoXVzdWxhIGRlIGxpbWl0YWNpw7NuIGRlIGdhcmFudMOtYXMuIFVzdGVkIG5vIHB1ZWRlIGRpc3RyaWJ1aXIsIGV4aGliaXIgcMO6YmxpY2FtZW50ZSwgZWplY3V0YXIgcMO6YmxpY2FtZW50ZSwgbyBwb25lciBhIGRpc3Bvc2ljacOzbiBww7pibGljYSBsYSBPYnJhIGNvbiBhbGd1bmEgbWVkaWRhIHRlY25vbMOzZ2ljYSBxdWUgY29udHJvbGUgZWwgYWNjZXNvIG8gbGEgdXRpbGl6YWNpw7NuIGRlIGVsbGEgZGUgdW5hIGZvcm1hIHF1ZSBzZWEgaW5jb25zaXN0ZW50ZSBjb24gbGFzIGNvbmRpY2lvbmVzIGRlIGVzdGEgTGljZW5jaWEuIExvIGFudGVyaW9yIHNlIGFwbGljYSBhIGxhIE9icmEgaW5jb3Jwb3JhZGEgYSB1bmEgT2JyYSBDb2xlY3RpdmEsIHBlcm8gZXN0byBubyBleGlnZSBxdWUgbGEgT2JyYSBDb2xlY3RpdmEgYXBhcnRlIGRlIGxhIG9icmEgbWlzbWEgcXVlZGUgc3VqZXRhIGEgbGFzIGNvbmRpY2lvbmVzIGRlIGVzdGEgTGljZW5jaWEuIFNpIFVzdGVkIGNyZWEgdW5hIE9icmEgQ29sZWN0aXZhLCBwcmV2aW8gYXZpc28gZGUgY3VhbHF1aWVyIExpY2VuY2lhbnRlIGRlYmUsIGVuIGxhIG1lZGlkYSBkZSBsbyBwb3NpYmxlLCBlbGltaW5hciBkZSBsYSBPYnJhIENvbGVjdGl2YSBjdWFscXVpZXIgcmVmZXJlbmNpYSBhIGRpY2hvIExpY2VuY2lhbnRlIG8gYWwgQXV0b3IgT3JpZ2luYWwsIHNlZ8O6biBsbyBzb2xpY2l0YWRvIHBvciBlbCBMaWNlbmNpYW50ZSB5IGNvbmZvcm1lIGxvIGV4aWdlIGxhIGNsw6F1c3VsYSA0KGMpLjwvbGk+CiAgICAgIDxsaT5Vc3RlZCBubyBwdWVkZSBlamVyY2VyIG5pbmd1bm8gZGUgbG9zIGRlcmVjaG9zIHF1ZSBsZSBoYW4gc2lkbyBvdG9yZ2Fkb3MgZW4gbGEgU2VjY2nDs24gMyBwcmVjZWRlbnRlIGRlIG1vZG8gcXVlIGVzdMOpbiBwcmluY2lwYWxtZW50ZSBkZXN0aW5hZG9zIG8gZGlyZWN0YW1lbnRlIGRpcmlnaWRvcyBhIGNvbnNlZ3VpciB1biBwcm92ZWNobyBjb21lcmNpYWwgbyB1bmEgY29tcGVuc2FjacOzbiBtb25ldGFyaWEgcHJpdmFkYS4gRWwgaW50ZXJjYW1iaW8gZGUgbGEgT2JyYSBwb3Igb3RyYXMgb2JyYXMgcHJvdGVnaWRhcyBwb3IgZGVyZWNob3MgZGUgYXV0b3IsIHlhIHNlYSBhIHRyYXbDqXMgZGUgdW4gc2lzdGVtYSBwYXJhIGNvbXBhcnRpciBhcmNoaXZvcyBkaWdpdGFsZXMgKGRpZ2l0YWwgZmlsZS1zaGFyaW5nKSBvIGRlIGN1YWxxdWllciBvdHJhIG1hbmVyYSBubyBzZXLDoSBjb25zaWRlcmFkbyBjb21vIGVzdGFyIGRlc3RpbmFkbyBwcmluY2lwYWxtZW50ZSBvIGRpcmlnaWRvIGRpcmVjdGFtZW50ZSBhIGNvbnNlZ3VpciB1biBwcm92ZWNobyBjb21lcmNpYWwgbyB1bmEgY29tcGVuc2FjacOzbiBtb25ldGFyaWEgcHJpdmFkYSwgc2llbXByZSBxdWUgbm8gc2UgcmVhbGljZSB1biBwYWdvIG1lZGlhbnRlIHVuYSBjb21wZW5zYWNpw7NuIG1vbmV0YXJpYSBlbiByZWxhY2nDs24gY29uIGVsIGludGVyY2FtYmlvIGRlIG9icmFzIHByb3RlZ2lkYXMgcG9yIGVsIGRlcmVjaG8gZGUgYXV0b3IuPC9saT4KICAgICAgPGxpPlNpIHVzdGVkIGRpc3RyaWJ1eWUsIGV4aGliZSBww7pibGljYW1lbnRlLCBlamVjdXRhIHDDumJsaWNhbWVudGUgbyBlamVjdXRhIHDDumJsaWNhbWVudGUgZW4gZm9ybWEgZGlnaXRhbCBsYSBPYnJhIG8gY3VhbHF1aWVyIE9icmEgRGVyaXZhZGEgdSBPYnJhIENvbGVjdGl2YSwgVXN0ZWQgZGViZSBtYW50ZW5lciBpbnRhY3RhIHRvZGEgbGEgaW5mb3JtYWNpw7NuIGRlIGRlcmVjaG8gZGUgYXV0b3IgZGUgbGEgT2JyYSB5IHByb3BvcmNpb25hciwgZGUgZm9ybWEgcmF6b25hYmxlIHNlZ8O6biBlbCBtZWRpbyBvIG1hbmVyYSBxdWUgVXN0ZWQgZXN0w6kgdXRpbGl6YW5kbzogKGkpIGVsIG5vbWJyZSBkZWwgQXV0b3IgT3JpZ2luYWwgc2kgZXN0w6EgcHJvdmlzdG8gKG8gc2V1ZMOzbmltbywgc2kgZnVlcmUgYXBsaWNhYmxlKSwgeS9vIChpaSkgZWwgbm9tYnJlIGRlIGxhIHBhcnRlIG8gbGFzIHBhcnRlcyBxdWUgZWwgQXV0b3IgT3JpZ2luYWwgeS9vIGVsIExpY2VuY2lhbnRlIGh1YmllcmVuIGRlc2lnbmFkbyBwYXJhIGxhIGF0cmlidWNpw7NuICh2LmcuLCB1biBpbnN0aXR1dG8gcGF0cm9jaW5hZG9yLCBlZGl0b3JpYWwsIHB1YmxpY2FjacOzbikgZW4gbGEgaW5mb3JtYWNpw7NuIGRlIGxvcyBkZXJlY2hvcyBkZSBhdXRvciBkZWwgTGljZW5jaWFudGUsIHTDqXJtaW5vcyBkZSBzZXJ2aWNpb3MgbyBkZSBvdHJhcyBmb3JtYXMgcmF6b25hYmxlczsgZWwgdMOtdHVsbyBkZSBsYSBPYnJhIHNpIGVzdMOhIHByb3Zpc3RvOyBlbiBsYSBtZWRpZGEgZGUgbG8gcmF6b25hYmxlbWVudGUgZmFjdGlibGUgeSwgc2kgZXN0w6EgcHJvdmlzdG8sIGVsIElkZW50aWZpY2Fkb3IgVW5pZm9ybWUgZGUgUmVjdXJzb3MgKFVuaWZvcm0gUmVzb3VyY2UgSWRlbnRpZmllcikgcXVlIGVsIExpY2VuY2lhbnRlIGVzcGVjaWZpY2EgcGFyYSBzZXIgYXNvY2lhZG8gY29uIGxhIE9icmEsIHNhbHZvIHF1ZSB0YWwgVVJJIG5vIHNlIHJlZmllcmEgYSBsYSBub3RhIHNvYnJlIGxvcyBkZXJlY2hvcyBkZSBhdXRvciBvIGEgbGEgaW5mb3JtYWNpw7NuIHNvYnJlIGVsIGxpY2VuY2lhbWllbnRvIGRlIGxhIE9icmE7IHkgZW4gZWwgY2FzbyBkZSB1bmEgT2JyYSBEZXJpdmFkYSwgYXRyaWJ1aXIgZWwgY3LDqWRpdG8gaWRlbnRpZmljYW5kbyBlbCB1c28gZGUgbGEgT2JyYSBlbiBsYSBPYnJhIERlcml2YWRhICh2LmcuLCAiVHJhZHVjY2nDs24gRnJhbmNlc2EgZGUgbGEgT2JyYSBkZWwgQXV0b3IgT3JpZ2luYWwsIiBvICJHdWnDs24gQ2luZW1hdG9ncsOhZmljbyBiYXNhZG8gZW4gbGEgT2JyYSBvcmlnaW5hbCBkZWwgQXV0b3IgT3JpZ2luYWwiKS4gVGFsIGNyw6lkaXRvIHB1ZWRlIHNlciBpbXBsZW1lbnRhZG8gZGUgY3VhbHF1aWVyIGZvcm1hIHJhem9uYWJsZTsgZW4gZWwgY2Fzbywgc2luIGVtYmFyZ28sIGRlIE9icmFzIERlcml2YWRhcyB1IE9icmFzIENvbGVjdGl2YXMsIHRhbCBjcsOpZGl0byBhcGFyZWNlcsOhLCBjb21vIG3DrW5pbW8sIGRvbmRlIGFwYXJlY2UgZWwgY3LDqWRpdG8gZGUgY3VhbHF1aWVyIG90cm8gYXV0b3IgY29tcGFyYWJsZSB5IGRlIHVuYSBtYW5lcmEsIGFsIG1lbm9zLCB0YW4gZGVzdGFjYWRhIGNvbW8gZWwgY3LDqWRpdG8gZGUgb3RybyBhdXRvciBjb21wYXJhYmxlLjwvbGk+CiAgICAgIDxsaT4KICAgICAgICBQYXJhIGV2aXRhciB0b2RhIGNvbmZ1c2nDs24sIGVsIExpY2VuY2lhbnRlIGFjbGFyYSBxdWUsIGN1YW5kbyBsYSBvYnJhIGVzIHVuYSBjb21wb3NpY2nDs24gbXVzaWNhbDoKICAgICAgICA8b2wgdHlwZT0iaSI+CiAgICAgICAgICA8bGk+UmVnYWzDrWFzIHBvciBpbnRlcnByZXRhY2nDs24geSBlamVjdWNpw7NuIGJham8gbGljZW5jaWFzIGdlbmVyYWxlcy4gRWwgTGljZW5jaWFudGUgc2UgcmVzZXJ2YSBlbCBkZXJlY2hvIGV4Y2x1c2l2byBkZSBhdXRvcml6YXIgbGEgZWplY3VjacOzbiBww7pibGljYSBvIGxhIGVqZWN1Y2nDs24gcMO6YmxpY2EgZGlnaXRhbCBkZSBsYSBvYnJhIHkgZGUgcmVjb2xlY3Rhciwgc2VhIGluZGl2aWR1YWxtZW50ZSBvIGEgdHJhdsOpcyBkZSB1bmEgc29jaWVkYWQgZGUgZ2VzdGnDs24gY29sZWN0aXZhIGRlIGRlcmVjaG9zIGRlIGF1dG9yIHkgZGVyZWNob3MgY29uZXhvcyAocG9yIGVqZW1wbG8sIFNBWUNPKSwgbGFzIHJlZ2Fsw61hcyBwb3IgbGEgZWplY3VjacOzbiBww7pibGljYSBvIHBvciBsYSBlamVjdWNpw7NuIHDDumJsaWNhIGRpZ2l0YWwgZGUgbGEgb2JyYSAocG9yIGVqZW1wbG8gV2ViY2FzdCkgbGljZW5jaWFkYSBiYWpvIGxpY2VuY2lhcyBnZW5lcmFsZXMsIHNpIGxhIGludGVycHJldGFjacOzbiBvIGVqZWN1Y2nDs24gZGUgbGEgb2JyYSBlc3TDoSBwcmltb3JkaWFsbWVudGUgb3JpZW50YWRhIHBvciBvIGRpcmlnaWRhIGEgbGEgb2J0ZW5jacOzbiBkZSB1bmEgdmVudGFqYSBjb21lcmNpYWwgbyB1bmEgY29tcGVuc2FjacOzbiBtb25ldGFyaWEgcHJpdmFkYS48L2xpPgogICAgICAgICAgPGxpPlJlZ2Fsw61hcyBwb3IgRm9ub2dyYW1hcy4gRWwgTGljZW5jaWFudGUgc2UgcmVzZXJ2YSBlbCBkZXJlY2hvIGV4Y2x1c2l2byBkZSByZWNvbGVjdGFyLCBpbmRpdmlkdWFsbWVudGUgbyBhIHRyYXbDqXMgZGUgdW5hIHNvY2llZGFkIGRlIGdlc3Rpw7NuIGNvbGVjdGl2YSBkZSBkZXJlY2hvcyBkZSBhdXRvciB5IGRlcmVjaG9zIGNvbmV4b3MgKHBvciBlamVtcGxvLCBsb3MgY29uc2FncmFkb3MgcG9yIGxhIFNBWUNPKSwgdW5hIGFnZW5jaWEgZGUgZGVyZWNob3MgbXVzaWNhbGVzIG8gYWxnw7puIGFnZW50ZSBkZXNpZ25hZG8sIGxhcyByZWdhbMOtYXMgcG9yIGN1YWxxdWllciBmb25vZ3JhbWEgcXVlIFVzdGVkIGNyZWUgYSBwYXJ0aXIgZGUgbGEgb2JyYSAo4oCcdmVyc2nDs24gY292ZXLigJ0pIHkgZGlzdHJpYnV5YSwgZW4gbG9zIHTDqXJtaW5vcyBkZWwgcsOpZ2ltZW4gZGUgZGVyZWNob3MgZGUgYXV0b3IsIHNpIGxhIGNyZWFjacOzbiBvIGRpc3RyaWJ1Y2nDs24gZGUgZXNhIHZlcnNpw7NuIGNvdmVyIGVzdMOhIHByaW1vcmRpYWxtZW50ZSBkZXN0aW5hZGEgbyBkaXJpZ2lkYSBhIG9idGVuZXIgdW5hIHZlbnRhamEgY29tZXJjaWFsIG8gdW5hIGNvbXBlbnNhY2nDs24gbW9uZXRhcmlhIHByaXZhZGEuPC9saT4KICAgICAgICA8L29sPgogICAgICA8L2xpPgogICAgICA8bGk+R2VzdGnDs24gZGUgRGVyZWNob3MgZGUgQXV0b3Igc29icmUgSW50ZXJwcmV0YWNpb25lcyB5IEVqZWN1Y2lvbmVzIERpZ2l0YWxlcyAoV2ViQ2FzdGluZykuIFBhcmEgZXZpdGFyIHRvZGEgY29uZnVzacOzbiwgZWwgTGljZW5jaWFudGUgYWNsYXJhIHF1ZSwgY3VhbmRvIGxhIG9icmEgc2VhIHVuIGZvbm9ncmFtYSwgZWwgTGljZW5jaWFudGUgc2UgcmVzZXJ2YSBlbCBkZXJlY2hvIGV4Y2x1c2l2byBkZSBhdXRvcml6YXIgbGEgZWplY3VjacOzbiBww7pibGljYSBkaWdpdGFsIGRlIGxhIG9icmEgKHBvciBlamVtcGxvLCB3ZWJjYXN0KSB5IGRlIHJlY29sZWN0YXIsIGluZGl2aWR1YWxtZW50ZSBvIGEgdHJhdsOpcyBkZSB1bmEgc29jaWVkYWQgZGUgZ2VzdGnDs24gY29sZWN0aXZhIGRlIGRlcmVjaG9zIGRlIGF1dG9yIHkgZGVyZWNob3MgY29uZXhvcyAocG9yIGVqZW1wbG8sIEFDSU5QUk8pLCBsYXMgcmVnYWzDrWFzIHBvciBsYSBlamVjdWNpw7NuIHDDumJsaWNhIGRpZ2l0YWwgZGUgbGEgb2JyYSAocG9yIGVqZW1wbG8sIHdlYmNhc3QpLCBzdWpldGEgYSBsYXMgZGlzcG9zaWNpb25lcyBhcGxpY2FibGVzIGRlbCByw6lnaW1lbiBkZSBEZXJlY2hvIGRlIEF1dG9yLCBzaSBlc3RhIGVqZWN1Y2nDs24gcMO6YmxpY2EgZGlnaXRhbCBlc3TDoSBwcmltb3JkaWFsbWVudGUgZGlyaWdpZGEgYSBvYnRlbmVyIHVuYSB2ZW50YWphIGNvbWVyY2lhbCBvIHVuYSBjb21wZW5zYWNpw7NuIG1vbmV0YXJpYSBwcml2YWRhLjwvbGk+CiAgICA8L29sPgogIDwvbGk+CiAgPGJyLz4KICA8bGk+CiAgICBSZXByZXNlbnRhY2lvbmVzLCBHYXJhbnTDrWFzIHkgTGltaXRhY2lvbmVzIGRlIFJlc3BvbnNhYmlsaWRhZC4KICAgIDxwPkEgTUVOT1MgUVVFIExBUyBQQVJURVMgTE8gQUNPUkRBUkFOIERFIE9UUkEgRk9STUEgUE9SIEVTQ1JJVE8sIEVMIExJQ0VOQ0lBTlRFIE9GUkVDRSBMQSBPQlJBIChFTiBFTCBFU1RBRE8gRU4gRUwgUVVFIFNFIEVOQ1VFTlRSQSkg4oCcVEFMIENVQUzigJ0sIFNJTiBCUklOREFSIEdBUkFOVMONQVMgREUgQ0xBU0UgQUxHVU5BIFJFU1BFQ1RPIERFIExBIE9CUkEsIFlBIFNFQSBFWFBSRVNBLCBJTVBMw41DSVRBLCBMRUdBTCBPIENVQUxRVUlFUkEgT1RSQSwgSU5DTFVZRU5ETywgU0lOIExJTUlUQVJTRSBBIEVMTEFTLCBHQVJBTlTDjUFTIERFIFRJVFVMQVJJREFELCBDT01FUkNJQUJJTElEQUQsIEFEQVBUQUJJTElEQUQgTyBBREVDVUFDScOTTiBBIFBST1DDk1NJVE8gREVURVJNSU5BRE8sIEFVU0VOQ0lBIERFIElORlJBQ0NJw5NOLCBERSBBVVNFTkNJQSBERSBERUZFQ1RPUyBMQVRFTlRFUyBPIERFIE9UUk8gVElQTywgTyBMQSBQUkVTRU5DSUEgTyBBVVNFTkNJQSBERSBFUlJPUkVTLCBTRUFOIE8gTk8gREVTQ1VCUklCTEVTIChQVUVEQU4gTyBOTyBTRVIgRVNUT1MgREVTQ1VCSUVSVE9TKS4gQUxHVU5BUyBKVVJJU0RJQ0NJT05FUyBOTyBQRVJNSVRFTiBMQSBFWENMVVNJw5NOIERFIEdBUkFOVMONQVMgSU1QTMONQ0lUQVMsIEVOIENVWU8gQ0FTTyBFU1RBIEVYQ0xVU0nDk04gUFVFREUgTk8gQVBMSUNBUlNFIEEgVVNURUQuPC9wPgogIDwvbGk+CiAgPGJyLz4KICA8bGk+CiAgICBMaW1pdGFjacOzbiBkZSByZXNwb25zYWJpbGlkYWQuCiAgICA8cD5BIE1FTk9TIFFVRSBMTyBFWElKQSBFWFBSRVNBTUVOVEUgTEEgTEVZIEFQTElDQUJMRSwgRUwgTElDRU5DSUFOVEUgTk8gU0VSw4EgUkVTUE9OU0FCTEUgQU5URSBVU1RFRCBQT1IgREHDkU8gQUxHVU5PLCBTRUEgUE9SIFJFU1BPTlNBQklMSURBRCBFWFRSQUNPTlRSQUNUVUFMLCBQUkVDT05UUkFDVFVBTCBPIENPTlRSQUNUVUFMLCBPQkpFVElWQSBPIFNVQkpFVElWQSwgU0UgVFJBVEUgREUgREHDkU9TIE1PUkFMRVMgTyBQQVRSSU1PTklBTEVTLCBESVJFQ1RPUyBPIElORElSRUNUT1MsIFBSRVZJU1RPUyBPIElNUFJFVklTVE9TIFBST0RVQ0lET1MgUE9SIEVMIFVTTyBERSBFU1RBIExJQ0VOQ0lBIE8gREUgTEEgT0JSQSwgQVVOIENVQU5ETyBFTCBMSUNFTkNJQU5URSBIQVlBIFNJRE8gQURWRVJUSURPIERFIExBIFBPU0lCSUxJREFEIERFIERJQ0hPUyBEQcORT1MuIEFMR1VOQVMgTEVZRVMgTk8gUEVSTUlURU4gTEEgRVhDTFVTScOTTiBERSBDSUVSVEEgUkVTUE9OU0FCSUxJREFELCBFTiBDVVlPIENBU08gRVNUQSBFWENMVVNJw5NOIFBVRURFIE5PIEFQTElDQVJTRSBBIFVTVEVELjwvcD4KICA8L2xpPgogIDxici8+CiAgPGxpPgogICAgVMOpcm1pbm8uCiAgICA8b2wgdHlwZT0iYSI+CiAgICAgIDxsaT5Fc3RhIExpY2VuY2lhIHkgbG9zIGRlcmVjaG9zIG90b3JnYWRvcyBlbiB2aXJ0dWQgZGUgZWxsYSB0ZXJtaW5hcsOhbiBhdXRvbcOhdGljYW1lbnRlIHNpIFVzdGVkIGluZnJpbmdlIGFsZ3VuYSBjb25kaWNpw7NuIGVzdGFibGVjaWRhIGVuIGVsbGEuIFNpbiBlbWJhcmdvLCBsb3MgaW5kaXZpZHVvcyBvIGVudGlkYWRlcyBxdWUgaGFuIHJlY2liaWRvIE9icmFzIERlcml2YWRhcyBvIENvbGVjdGl2YXMgZGUgVXN0ZWQgZGUgY29uZm9ybWlkYWQgY29uIGVzdGEgTGljZW5jaWEsIG5vIHZlcsOhbiB0ZXJtaW5hZGFzIHN1cyBsaWNlbmNpYXMsIHNpZW1wcmUgcXVlIGVzdG9zIGluZGl2aWR1b3MgbyBlbnRpZGFkZXMgc2lnYW4gY3VtcGxpZW5kbyDDrW50ZWdyYW1lbnRlIGxhcyBjb25kaWNpb25lcyBkZSBlc3RhcyBsaWNlbmNpYXMuIExhcyBTZWNjaW9uZXMgMSwgMiwgNSwgNiwgNywgeSA4IHN1YnNpc3RpcsOhbiBhIGN1YWxxdWllciB0ZXJtaW5hY2nDs24gZGUgZXN0YSBMaWNlbmNpYS48L2xpPgogICAgICA8bGk+U3VqZXRhIGEgbGFzIGNvbmRpY2lvbmVzIHkgdMOpcm1pbm9zIGFudGVyaW9yZXMsIGxhIGxpY2VuY2lhIG90b3JnYWRhIGFxdcOtIGVzIHBlcnBldHVhIChkdXJhbnRlIGVsIHBlcsOtb2RvIGRlIHZpZ2VuY2lhIGRlIGxvcyBkZXJlY2hvcyBkZSBhdXRvciBkZSBsYSBvYnJhKS4gTm8gb2JzdGFudGUgbG8gYW50ZXJpb3IsIGVsIExpY2VuY2lhbnRlIHNlIHJlc2VydmEgZWwgZGVyZWNobyBhIHB1YmxpY2FyIHkvbyBlc3RyZW5hciBsYSBPYnJhIGJham8gY29uZGljaW9uZXMgZGUgbGljZW5jaWEgZGlmZXJlbnRlcyBvIGEgZGVqYXIgZGUgZGlzdHJpYnVpcmxhIGVuIGxvcyB0w6lybWlub3MgZGUgZXN0YSBMaWNlbmNpYSBlbiBjdWFscXVpZXIgbW9tZW50bzsgZW4gZWwgZW50ZW5kaWRvLCBzaW4gZW1iYXJnbywgcXVlIGVzYSBlbGVjY2nDs24gbm8gc2Vydmlyw6EgcGFyYSByZXZvY2FyIGVzdGEgbGljZW5jaWEgbyBxdWUgZGViYSBzZXIgb3RvcmdhZGEgLCBiYWpvIGxvcyB0w6lybWlub3MgZGUgZXN0YSBsaWNlbmNpYSksIHkgZXN0YSBsaWNlbmNpYSBjb250aW51YXLDoSBlbiBwbGVubyB2aWdvciB5IGVmZWN0byBhIG1lbm9zIHF1ZSBzZWEgdGVybWluYWRhIGNvbW8gc2UgZXhwcmVzYSBhdHLDoXMuIExhIExpY2VuY2lhIHJldm9jYWRhIGNvbnRpbnVhcsOhIHNpZW5kbyBwbGVuYW1lbnRlIHZpZ2VudGUgeSBlZmVjdGl2YSBzaSBubyBzZSBsZSBkYSB0w6lybWlubyBlbiBsYXMgY29uZGljaW9uZXMgaW5kaWNhZGFzIGFudGVyaW9ybWVudGUuPC9saT4KICAgIDwvb2w+CiAgPC9saT4KICA8YnIvPgogIDxsaT4KICAgIFZhcmlvcy4KICAgIDxvbCB0eXBlPSJhIj4KICAgICAgPGxpPkNhZGEgdmV6IHF1ZSBVc3RlZCBkaXN0cmlidXlhIG8gcG9uZ2EgYSBkaXNwb3NpY2nDs24gcMO6YmxpY2EgbGEgT2JyYSBvIHVuYSBPYnJhIENvbGVjdGl2YSwgZWwgTGljZW5jaWFudGUgb2ZyZWNlcsOhIGFsIGRlc3RpbmF0YXJpbyB1bmEgbGljZW5jaWEgZW4gbG9zIG1pc21vcyB0w6lybWlub3MgeSBjb25kaWNpb25lcyBxdWUgbGEgbGljZW5jaWEgb3RvcmdhZGEgYSBVc3RlZCBiYWpvIGVzdGEgTGljZW5jaWEuPC9saT4KICAgICAgPGxpPlNpIGFsZ3VuYSBkaXNwb3NpY2nDs24gZGUgZXN0YSBMaWNlbmNpYSByZXN1bHRhIGludmFsaWRhZGEgbyBubyBleGlnaWJsZSwgc2Vnw7puIGxhIGxlZ2lzbGFjacOzbiB2aWdlbnRlLCBlc3RvIG5vIGFmZWN0YXLDoSBuaSBsYSB2YWxpZGV6IG5pIGxhIGFwbGljYWJpbGlkYWQgZGVsIHJlc3RvIGRlIGNvbmRpY2lvbmVzIGRlIGVzdGEgTGljZW5jaWEgeSwgc2luIGFjY2nDs24gYWRpY2lvbmFsIHBvciBwYXJ0ZSBkZSBsb3Mgc3VqZXRvcyBkZSBlc3RlIGFjdWVyZG8sIGFxdcOpbGxhIHNlIGVudGVuZGVyw6EgcmVmb3JtYWRhIGxvIG3DrW5pbW8gbmVjZXNhcmlvIHBhcmEgaGFjZXIgcXVlIGRpY2hhIGRpc3Bvc2ljacOzbiBzZWEgdsOhbGlkYSB5IGV4aWdpYmxlLjwvbGk+CiAgICAgIDxsaT5OaW5nw7puIHTDqXJtaW5vIG8gZGlzcG9zaWNpw7NuIGRlIGVzdGEgTGljZW5jaWEgc2UgZXN0aW1hcsOhIHJlbnVuY2lhZGEgeSBuaW5ndW5hIHZpb2xhY2nDs24gZGUgZWxsYSBzZXLDoSBjb25zZW50aWRhIGEgbWVub3MgcXVlIGVzYSByZW51bmNpYSBvIGNvbnNlbnRpbWllbnRvIHNlYSBvdG9yZ2FkbyBwb3IgZXNjcml0byB5IGZpcm1hZG8gcG9yIGxhIHBhcnRlIHF1ZSByZW51bmNpZSBvIGNvbnNpZW50YS48L2xpPgogICAgICA8bGk+RXN0YSBMaWNlbmNpYSByZWZsZWphIGVsIGFjdWVyZG8gcGxlbm8gZW50cmUgbGFzIHBhcnRlcyByZXNwZWN0byBhIGxhIE9icmEgYXF1w60gbGljZW5jaWFkYS4gTm8gaGF5IGFycmVnbG9zLCBhY3VlcmRvcyBvIGRlY2xhcmFjaW9uZXMgcmVzcGVjdG8gYSBsYSBPYnJhIHF1ZSBubyBlc3TDqW4gZXNwZWNpZmljYWRvcyBlbiBlc3RlIGRvY3VtZW50by4gRWwgTGljZW5jaWFudGUgbm8gc2UgdmVyw6EgbGltaXRhZG8gcG9yIG5pbmd1bmEgZGlzcG9zaWNpw7NuIGFkaWNpb25hbCBxdWUgcHVlZGEgc3VyZ2lyIGVuIGFsZ3VuYSBjb211bmljYWNpw7NuIGVtYW5hZGEgZGUgVXN0ZWQuIEVzdGEgTGljZW5jaWEgbm8gcHVlZGUgc2VyIG1vZGlmaWNhZGEgc2luIGVsIGNvbnNlbnRpbWllbnRvIG11dHVvIHBvciBlc2NyaXRvIGRlbCBMaWNlbmNpYW50ZSB5IFVzdGVkLjwvbGk+CiAgICA8L29sPgogIDwvbGk+CiAgPGJyLz4KPC9vbD4K 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