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Quimioprofilaxis de la gripe
Influenza chemoprophylaxis
T. Pumarolaa, MA. Marcosa, MT. Jiménez de Antaa
a Servicio de Microbiología. Institut Clínic d'Infeccions i Immunologia (ICII). Hospital Clínic. Barcelona. España.
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    "textoCompleto" => "<p class="elsevierStylePara">La prevenci&#243;n de la infecci&#243;n por los virus de la gripe debe basarse en la vacunaci&#243;n anual antes del inicio de los brotes epid&#233;micos&#44; ya que ha demostrado ser la medida m&#225;s eficaz en la reducci&#243;n del impacto de la gripe<span class="elsevierStyleSup">1-3</span>&#46; La utilizaci&#243;n de los f&#225;rmacos antigripales en la quimioprofilaxis debe entenderse como una actuaci&#243;n complementaria a la vacunaci&#243;n&#44; que puede ser de gran eficacia&#44; pero que no deber&#237;a substituirla&#46; En la actualidad se encuentran comercializadas dos familias de f&#225;rmacos antigripales&#58; los inhibidores de la prote&#237;na M2 y los inhibidores de la neuraminidasa<span class="elsevierStyleSup">4-6</span>&#46;</p><p class="elsevierStylePara">Los inhibidores de la prote&#237;na M2 o adamantanos &#40;amantadina y rimantadina&#41;&#44; desarrollados en la d&#233;cada de los a&#241;os sesenta&#44; son aminas primarias tric&#237;clicas que inhiben la decapsidaci&#243;n viral al neutralizar la acci&#243;n del canal i&#243;nico M2 en la acidificaci&#243;n del interior de la part&#237;cula viral<span class="elsevierStyleSup">7</span>&#46; Han demostrado ser f&#225;rmacos activos frente a los subtipos H1N1&#44; H2N2 y H3N2 del virus de la gripe A humana y tambi&#233;n frente a subtipos aviares&#44; lo que sugiere la posible susceptibilidad de las futuras cepas pand&#233;micas&#46; Son f&#225;rmacos de administraci&#243;n oral y han demostrado ser eficaces en el tratamiento de la infecci&#243;n aguda por el virus de la gripe A<span class="elsevierStyleSup">8</span> cuando se administran durante las primeras 24 h del inicio del cuadro cl&#237;nico&#44; reduciendo la sintomatolog&#237;a en 1-2 d&#237;as&#46; A dosis terap&#233;uticas no poseen efecto sobre el virus de la gripe B u otros virus respiratorios&#46; La amantadina<span class="elsevierStyleSup">9</span> posee una buena absorci&#243;n&#44; y alcanza concentraciones en mucosa nasal de aproximadamente la mitad de las plasm&#225;ticas&#46; El 90&#37; de la amantadina se excreta sin modificar por la orina por filtraci&#243;n glomerular y secreci&#243;n tubular&#46; Las concentraciones de rimantadina<span class="elsevierStyleSup">10</span> en mucosa nasal son superiores &#40;1&#44;5 veces m&#225;s&#41; a las plasm&#225;ticas&#46; El 75&#37; del f&#225;rmaco es metabolizado en el h&#237;gado y los diferentes estudios demuestran que es mejor tolerada que la amantadina a dosis equivalentes&#46; La amantadina y la rimantadina pueden ser causa de efectos secundarios ligeros de tipo gastrointestinal y sobre el sistema nervioso central &#40;SNC&#41;&#44; que cesan tras la retirada del f&#225;rmaco&#46; Asimismo&#44; se han descrito efectos secundarios graves sobre el SNC &#40;cambio de comportamiento&#44; delirio&#44; alucinaciones&#44; etc&#46;&#41;&#44; asociados con elevadas concentraciones de amantadina en plasma en pacientes con insuficiencia renal&#44; alteraciones del SNC o edad avanzada&#44; por lo que debe administrarse con precauci&#243;n y ajustando las dosis en estas situaciones<span class="elsevierStyleSup">6</span>&#46; Debido a la actividad anticolin&#233;rgica de la amantadina&#44; &#233;sta no debe administrarse con antihistam&#237;nicos o anticolin&#233;rgicos&#44; ya que aumentar&#237;a la incidencia de efectos secundarios de estas caracter&#237;sticas&#46;</p><p class="elsevierStylePara">Uno de los principales inconvenientes del tratamiento con amantadina y rimantadina es la r&#225;pida selecci&#243;n de cepas con resistencia cruzada a ambos f&#225;rmacos a los 2-3 d&#237;as de iniciado el tratamiento<span class="elsevierStyleSup">11-13</span> en&#44; aproximadamente&#44; un tercio de los pacientes<span class="elsevierStyleSup">11-14</span>&#46; Las variantes resistentes no presentan disminuciones de su eficacia biol&#243;gica&#44; y han demostrado su capacidad de transmisi&#243;n&#44; especialmente en los brotes en comunidades cerradas&#44; siendo causa del fracaso de la quimioprofilaxis en estas situaciones<span class="elsevierStyleSup">15-17</span>&#46; Sin embargo&#44; el cribado de cepas epid&#233;micas del virus de la gripe tan s&#243;lo ha detectado de forma espor&#225;dica cepas resistentes a los adamantanos<span class="elsevierStyleSup">11&#44;18&#44;19</span>&#44; incluso en pa&#237;ses que utilizan la amantadina regularmente en el tratamiento de la gripe&#44; como es el caso de Jap&#243;n desde 1998<span class="elsevierStyleSup">20-22</span>&#46;</p><p class="elsevierStylePara">La neuraminidasa es una glucoprote&#237;na presente en la envoltura de los virus de la gripe que participa&#44; gracias a su actividad sialidasa&#44; en la liberaci&#243;n de las nuevas part&#237;culas v&#237;ricas de la c&#233;lula diana&#44; al impedir la agregaci&#243;n de &#233;stas a los receptores de &#225;cido si&#225;lico de la superficie celular&#44; adem&#225;s de facilitar la difusi&#243;n de los viriones a trav&#233;s de la mucina del eptitelio respiratorio<span class="elsevierStyleSup">7</span>&#46; En la actualidad existen dos f&#225;rmacos inhibidores de la neuraminidasa aprobados para uso cl&#237;nico&#44; el zanamivir y el oseltamivir<span class="elsevierStyleSup">5</span>&#46; Han demostrado ser eficaces frente a una gran variedad de subtipos del virus de la gripe A&#44; tanto humanos como aviares&#44; y frente al virus de la gripe B&#46; Son eficaces en el tratamiento de la infecci&#243;n aguda por los virus de la gripe A y B&#44; cuando se administran durante las primeras 24-48 h del inicio del cuadro cl&#237;nico&#44; reduciendo la sintomatolog&#237;a en aproximadamente 2 d&#237;as&#46; El zanamivir<span class="elsevierStyleSup">23</span> es un f&#225;rmaco bien tolerado que se administra por inhalaci&#243;n oral&#44; deposit&#225;ndose un 14&#37; del polvo inhalado en los bronquios y los pulmones y el 78&#37; en la orofaringe&#46; Aproximadamente un 10&#37; se absorbe de forma sist&#233;mica y se elimina sin modificarse por orina&#46; El f&#225;rmaco no absorbido se elimina por heces&#46; Se han descrito casos espor&#225;dicos de disminuci&#243;n de la funci&#243;n respiratoria y de broncospasmo en pacientes con asma o enfermedad pulmonar obstructiva cr&#243;nica tras la administraci&#243;n de zanamivir&#46; El oseltamivir<span class="elsevierStyleSup">24</span> se administra por v&#237;a oral como prof&#225;rmaco siendo metabolizado en el h&#237;gado a oseltamivir carboxilato&#44; su forma activa&#44; por esterasas hep&#225;ticas y se elimina por orina&#46; Los principales efectos secundarios de oseltamivir son n&#225;useas y v&#243;mitos&#44; que mejoran tras su toma con las comidas y que no suelen ser causa de retirada del tratamiento&#46;</p><p class="elsevierStylePara">La selecci&#243;n de cepas resistentes a zanamivir y oseltamivir se ha demostrado <span class="elsevierStyleItalic">in vitro</span><span class="elsevierStyleSup">13&#44;25-31</span>&#46; Las mutaciones de resistencia se generan en regiones altamente conservadas de la neuraminidasa y son causa de una disminuci&#243;n importante de la eficacia biol&#243;gica viral&#44; lo que probablemente comprometer&#237;a su capacidad de transmisi&#243;n<span class="elsevierStyleSup">13</span>&#46; Sin embargo&#44; y a pesar de que el n&#250;mero de aislamientos tras el tratamiento con inhibidores de la neuraminidasa es escaso&#44; tan s&#243;lo se han descrito casos puntuales de selecci&#243;n de variantes resistentes <span class="elsevierStyleItalic">in vivo</span><span class="elsevierStyleSup">32-36</span>&#46;</p><p class="elsevierStylePara">La amantadina y la rimantadina han demostrado una eficacia de pr&#225;cticamente el 90&#37; en la prevenci&#243;n de la infecci&#243;n por el virus de la gripe A<span class="elsevierStyleSup">8&#44;10&#44;37</span>&#46; Cuando se utilizan como quimioprofil&#225;cticos previenen la enfermedad&#44; pero no evitan la infecci&#243;n subcl&#237;nica y el consecuente desarrollo de respuesta inmunitaria protectora al virus circulante&#46; La amantadina y la rimantadina no interfieren en la repuesta inmunitaria humoral a la vacunaci&#243;n<span class="elsevierStyleSup">8</span>&#46; Diversos estudios han demostrado la eficacia de los inhibidores de la prote&#237;na M2 en el control de los brotes de gripe en comunidades cerradas&#44; geri&#225;tricos y en el &#225;mbito familiar<span class="elsevierStyleSup">8&#44;38-41</span>&#46;</p><p class="elsevierStylePara">Los estudios realizados en la comunidad en adultos sanos han demostrado una eficacia de los inhibidores de la neuraminidasa en la quimioprofilaxis del 85&#37;<span class="elsevierStyleSup">42&#44;44</span>&#46; La experiencia con estos f&#225;rmacos en la profilaxis de la gripe en pacientes con enfermedades cr&#243;nicas es limitada en relaci&#243;n con los inhibidores de la prote&#237;na M2<span class="elsevierStyleSup">45-48</span>&#46; Un estudio de administraci&#243;n prolongada de oseltaminir durante 6 semanas demostr&#243; una reducci&#243;n del 92&#37; de los casos de enfermedad en una comunidad de personas de edad avanzada<span class="elsevierStyleSup">49</span>&#46; La utilizaci&#243;n de zanamivir ha demostrado que no altera la respuesta inmunitaria a la vacunaci&#243;n<span class="elsevierStyleSup">50</span>&#46;</p><p class="elsevierStylePara">Ninguno de los cuatro antigripales comercializados ha demostrado ser eficaz en la quimioprofilaxis de la gripe en los pacientes con inmunodepresi&#243;n grave&#46;</p><p class="elsevierStylePara">En la actualidad no existen datos suficientes que determinen cu&#225;l deber&#237;a ser la duraci&#243;n de la quimioprofilaxis para obtener un m&#225;ximo beneficio&#46; Deben considerarse factores como el coste&#44; la adhesi&#243;n y los posibles efectos secundarios&#46; La m&#225;xima eficacia se conseguir&#237;a a trav&#233;s de la administraci&#243;n diaria a lo largo de la duraci&#243;n del brote epid&#233;mico&#46; Sin embargo&#44; en un estudio de coste- efectividad realizado se considera que la quimioprofilaxis tan s&#243;lo ser&#237;a necesaria durante el pico de m&#225;xima actividad gripal<span class="elsevierStyleSup">51</span>&#46; Las dosis recomendadas en la quimioprofilaxis de la gripe se hallan detalladas en la tabla 1<span class="elsevierStyleSup">6</span>&#46;</p><p class="elsevierStylePara"><img src="72v03nSupl.1-13040220tab01.gif"></img></p><p class="elsevierStylePara">La quimioprofilaxis est&#225; indicada<span class="elsevierStyleSup">6</span> para la protecci&#243;n durante la respuesta a la vacunaci&#243;n tard&#237;a en sujetos de alto riesgo&#59; en los brotes de gripe en instituciones cerradas&#59; en los sujetos en contacto con personas de alto riesgo&#59; en los pacientes inmunodeprimidos y en aquellas situaciones en las que la vacunaci&#243;n est&#233; contraindicada&#46;</p><p class="elsevierStylePara">El desarrollo de anticuerpos tras la vacunaci&#243;n suele tardar aproximadamente 2 semanas&#46; Cuando la vacuna se administra una vez iniciada la actividad gripal&#44; estar&#237;a indicada la quimioprofilaxis en los sujetos de alto riesgo durante el tiempo necesario para alcanzar un buen valor de anticuerpos protectores&#46; Los ni&#241;os menores de 9 a&#241;os que se vacunan por primera vez deber&#237;an recibir quimioprofilaxis durante 6 semanas&#44; 4 semanas despu&#233;s de la primera dosis de vacuna y 2 semanas adicionales despu&#233;s de la segunda&#46;</p><p class="elsevierStylePara">Ante la confirmaci&#243;n o sospecha de un brote epid&#233;mico de gripe en una instituci&#243;n cerrada&#44; especialmente en los geri&#225;tricos&#44; la quimioprofilaxis debe instaurarse r&#225;pidamente a todos los residentes para evitar la difusi&#243;n del virus&#44; independientemente de su estado vacunal&#44; durante por lo menos 2 semanas o bien hasta una semana despu&#233;s de la presentaci&#243;n del &#250;ltimo caso&#46; Adicionalmente para evitar la posible transmisi&#243;n de virus resistentes&#44; deben adoptarse todas aquellas medidas necesarias para evitar o reducir el contacto de los pacientes en tratamiento con el resto de personas&#44; incluyendo aquellas con quimioprofilaxis<span class="elsevierStyleSup">15-17</span>&#46;</p><p class="elsevierStylePara">Para disminuir la transmisi&#243;n del virus a las personas de alto riesgo durante los brotes epid&#233;micos en la comunidad o en instituciones cerradas&#44; puede considerarse la quimioprofilaxis&#44; durante el pico de actividad gripal&#44; en todas aquellas personas con contacto frecuente con sujetos de alto riesgo&#44; sin olvidar que la medida m&#225;s eficaz es la vacunaci&#243;n&#46; Sin embargo&#44; en las situaciones en que las caracter&#237;sticas del virus circulante hagan perder eficacia a la vacunaci&#243;n&#44; la quimioprofilaxis deber&#237;a considerarse independientemente del estado vacunal&#46;</p><p class="elsevierStylePara">La quimioprofilaxis puede considerarse en los sujetos inmunodeprimidos&#44; a los que se supone una baja respuesta a la vacunaci&#243;n&#46; En el &#225;mbito de la infecci&#243;n por el VIH&#44; se desconocen las interacciones de los antigripales con el resto de f&#225;rmacos utilizados en el manejo cl&#237;nico de estos pacientes&#46;</p><p class="elsevierStylePara">No se han realizado estudios sobre la seguridad de los antigripales durante el embarazo&#46; Existen dos publicaciones de utilizaci&#243;n de amantadina en dos casos graves de gripe durante el tercer trimestre del embarazo<span class="elsevierStyleSup">52&#44;53</span>&#46; En el modelo animal&#44; los adamantanos han demostrado ser teratog&#233;nicos a dosis elevadas<span class="elsevierStyleSup">54&#44;55</span>&#46; As&#237;&#44; su utilizaci&#243;n se hallar&#237;a justificada en las situaciones en las que los beneficios superen ampliamente los riesgos sobre el feto&#46;</p><p class="elsevierStylePara">En caso de una nueva pandemia&#44; y debido a la m&#225;s que probable ausencia de una vacuna eficaz durante las primeras fases&#44; los f&#225;rmacos antigripales ser&#225;n de gran utilidad tanto para el tratamiento como para la quimioprofilaxis durante la primera ola pand&#233;mica&#46; En la actualidad&#44; los diferentes pa&#237;ses&#44; a trav&#233;s de sus autoridades sanitarias&#44; est&#225;n concretando las condiciones de utilizaci&#243;n&#44; a trav&#233;s de sus planes de preparaci&#243;n frente a una nueva pandemia de gripe&#46; En &#233;stos debe darse respuesta a&#58; f&#225;rmacos&#44; pautas de tratamiento y quimioprofilaxis&#44; disponibilidad&#44; almacenamiento preventivo de grandes cantidades de estos f&#225;rmacos o sus precursores&#44; grupos de poblaci&#243;n prioritarios&#44; monitorizaci&#243;n de la selecci&#243;n de variantes resistentes&#44; y control y seguimiento de los efectos adversos&#46;</p><p class="elsevierStylePara">Por &#250;ltimo&#44; es importante destacar que para la instauraci&#243;n de una correcta quimioprofilaxis&#44; y en su caso tratamiento&#44; es necesario establecer una adecuada vigilancia epidemiol&#243;gica y un diagn&#243;stico r&#225;pido y eficaz&#46; No hay que olvidar que no todos los antigripales poseen el mismo espectro de actividad frente a los virus de la gripe A y B&#44; y que &#233;stos no son activos frente a otros virus causantes de infecci&#243;n respiratoria aguda&#46;</p>"
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ISSN: 15769887
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