Sepsis Neonatal

Sepsis neonatal Article Last Updated: Aug 18, 2006 Artículo Última actualización: Aug 18, 2006

AUTHOR AND EDITOR INFORMATION Autor y editor de la información Section 1 of 11 Sección 1 de 11 • • • • • • • • • • •

Authors and Editors Autores y Editores Introduction Introducción Clinical Clínica Differentials Diferencias Workup Workup Treatment Tratamiento Medication Medicación Follow-up Seguimiento Miscellaneous Miscellaneous Multimedia Multimedia References Referencias

Author: Ann L Anderson-Berry, MD, Assistant Professor of Pediatrics, Joint Division of Newborn Medicine, Creighton University, University of Nebraska Medical Center Autor: Ann Anderson L-Berry, MD, Profesor Adjunto de Pediatría, División Mixta del Recién Nacido de Medicina, Universidad de Creighton, Universidad de Nebraska Medical Center Ann L Anderson-Berry is a member of the following medical societies: American Academy of Pediatrics and Nebraska Medical Association Ann-L Anderson Berry es miembro de las siguientes sociedades médicas: Academia Americana de Pediatría y la Asociación Médica de Nebraska Coauthor(s): Linda L Bellig, MA, RN, NNP, Track Coordinator, Instructor, Neonatal Nurse Practitioner Program, Medical University of South Carolina College of Nursing; Bryan L Ohning, MD, PhD, Clinical Associate Professor of Pediatrics, Medical University of South Carolina; Medical Director, NICU and Neonatal Transport Team, Department of Neonatology, Greenville Children's Hospital Coautor (s): Linda L Bellig, MA, RN, NNP, Coordinador de pista, Instructor, enfermera de práctica neonatal Programa de Medicina de la Universidad de Carolina del Sur Escuela de Enfermería; Ohning Bryan L, MD, PhD, Profesor Clínico Asociado de Pediatría, Universidad de Medicina de Carolina del Sur; Director Médico, UCIN y Equipo de Transporte Neonatal del Departamento de Neonatología, Greenville Children's Hospital Editors: Scott S MacGilvray, MD , Associate Professor, Department of Pediatrics, East

Carolina University School of Medicine; Mary L Windle, PharmD , Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; David A Clark, MD , Chairman, Professor, Department of Pediatrics, Albany Medical College; Carol L Wagner, MD , Professor of Pediatrics, Medical University of South Carolina; Neil N Finer, MD, Professor, Department of Pediatrics, University of California at San Diego School of Medicine; Program Director, Division of Neonatology, University of California San Diego Medical Center Editores: S MacGilvray Scott, MD, Profesor Asociado, Departamento de Pediatría, East Carolina University School of Medicine; María L Windle, PharmD, Profesor Asistente Adjunto de la Universidad de Nebraska Medical Center College de Farmacia, Farmacia Editor, eMedicine.com, Inc; A David Clark, MD, Presidente, Profesor del Departamento de Pediatría, Albany Medical College; Carol L Wagner, MD, Profesor de Pediatría, Universidad Médica de Carolina del Sur; Neil N fina, MD, Profesor del Departamento de Pediatría, Universidad de California en San Diego School of Medicine; Programa Director de la División de Neonatología, Universidad de California San Diego Medical Center Author and Editor Disclosure Autor y editor de divulgación Synonyms and related keywords: neonatal sepsis, neonatal infection, early-onset neonatal sepsis, late-onset neonatal sepsis, early-onset sepsis syndrome, late-onset sepsis syndrome, neonatal bacteremia Sinónimos y palabras clave relacionadas: sepsis neonatal, infección neonatal, a principios de inicio sepsis neonatal, de aparición tardía sepsis neonatal, a principios de sepsis de aparición de síndrome de aparición tardía, síndrome de sepsis, bacteriemia neonatal

INTRODUCTION INTRODUCCIÓN Section 2 of 11 Sección 2 de 11 • • • • • • • • •

Authors and Editors Autores y Editores Introduction Introducción Clinical Clínica Differentials Diferencias Workup Workup Treatment Tratamiento Medication Medicación Follow-up Seguimiento Miscellaneous Miscellaneous

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Background Fondo Neonatal sepsis may be categorized as early or late onset. Sepsis neonatal puede ser categorizada como principios o de inicio tardío. Eighty-five percent of newborns with early-onset infection present within 24 hours, 5% present at 24-48 hours, and a smaller percentage of patients present between 48 hours and 6 days of life. Ochenta y cinco por ciento de los recién nacidos con inicio temprano de la infección presente en las 24 horas, 5% actual al 24-48 horas, y un menor porcentaje de pacientes presentan entre 48 horas y 6 días de vida. Onset is most rapid in premature neonates. El inicio es más rápido en los recién nacidos prematuros. Early-onset sepsis syndrome is associated with acquisition of microorganisms from the mother. A principios de sepsis de aparición de síndrome se asocia con la adquisición de los microorganismos de la madre. Transplacental infection or an ascending infection from the cervix may be caused by organisms that colonize in the mother's genitourinary tract, with acquisition of the microbe by passage through a colonized birth canal at delivery. Infección transplacentaria o una infección ascendente desde el cuello del útero puede ser causada por organismos que colonizan a la madre del tracto genitourinario, con la adquisición de los microbios de paso a través de un canal de nacimiento colonizados en el momento del parto. The microorganisms most commonly associated with early-onset infection include group B Streptococcus (GBS), Escherichia coli, Haemophilus influenzae, and Listeria monocytogenes. Los microorganismos más comúnmente asociados con la aparición temprana de la infección incluyen Streptococcus del grupo B (GBS), Escherichia coli, Haemophilus influenzae y Listeria monocytogenes. Late-onset sepsis syndrome occurs at 7-90 days of life and is acquired from the caregiving environment. De aparición tardía, síndrome de sepsis se produce en 7-90 días de vida y se adquiere desde el entorno de asistencia a otras personas. Organisms that have been implicated in causing late-onset sepsis syndrome include coagulase-negative staphylococci, Staphylococcus aureus, E coli, Klebsiella, Pseudomonas, Enterobacter, Candida, GBS, Serratia, Acinetobacter, and anaerobes. Los organismos que han estado implicados en el origen de aparición tardía, síndrome de sepsis incluyen coagulasanegativos estafilococos, Staphylococcus aureus, E coli, Klebsiella, Pseudomonas, Enterobacter, Candida, GBS, Serratia, Acinetobacter, y anaerobios. The infant's skin, respiratory tract, conjunctivae, gastrointestinal tract, and umbilicus may become colonized from the environment, leading to the possibility of late-onset sepsis from invasive microorganisms. La piel del bebé, las vías respiratorias, conjunctivae, tracto gastrointestinal, ombligo y puede llegar a ser colonizada desde el medio ambiente, dando lugar a la posibilidad de aparición tardía de la sepsis microorganismos invasores. Vectors for such colonization may include vascular or urinary catheters, other indwelling lines, or contact from caregivers with bacterial colonization. Los vectores de esas colonización

puede incluir vascular o catéteres urinarios, inhabitación otras líneas, o póngase en contacto con cuidadores de colonización bacteriana. Pneumonia is more common in early-onset sepsis, whereas meningitis and bacteremia are more common in late-onset sepsis. La neumonía es más común en los principios de sepsis de aparición, mientras que la meningitis y la bacteriemia son más comunes a finales de sepsis de aparición. Premature and ill infants have an increased susceptibility to sepsis and subtle nonspecific initial presentations; therefore, they require much vigilance so that sepsis can be identified and treated effectively. Prematuros y recién nacidos enfermos, tienen una mayor susceptibilidad a la sepsis y sutil presentaciones iniciales inespecíficos, por lo que requieren mucha vigilancia a fin de que la sepsis puede ser identificada y tratada con eficacia.

Pathophysiology Fisiopatología The infectious agents associated with neonatal sepsis have changed over the past 50 years. S aureus and E coli were the most common bacterial infectious hazards for neonates during the 1950s in the United States. Los agentes infecciosos asociados con la sepsis neonatal han cambiado en los últimos 50 años. S aureus y E coli son los más comunes de bacterias infecciosas riesgos para los recién nacidos durante la década de 1950 en los Estados Unidos. Over the ensuing decades, GBS replaced S aureus as the most common gram-positive organism that caused early-onset sepsis. Durante los decenios subsiguientes, GBS sustituirá S aureus como el más común gram-positivos organismo que causaron a principios de sepsis de aparición. During the 1990s, GBS and E coli continued to be associated with neonatal infection; however, coagulase-negative S aureus is now more frequently observed. Durante el decenio de 1990, GBS y E coli sigue siendo asociado a infección neonatal, sin embargo, coagulasa-negativos S aureus es ahora más frecuentemente observada. Additional organisms, such as L monocytogenes, Chlamydia pneumoniae, H influenzae, Enterobacter aerogenes , and species of Bacteroides and Clostridium have also been identified in neonatal sepsis. Organismos adicionales, tales como L. monocytogenes, Chlamydia pneumoniae, H influenzae, Enterobacter aerogenes, y las especies de Bacteroides y Clostridium también han sido identificados en la sepsis neonatal. Meningoencephalitis and neonatal sepsis syndrome can also be caused by infection with adenovirus, enterovirus, or coxsackievirus. Meningoencefalitis y sepsis neonatal, síndrome también puede ser causada por infección con adenovirus, enterovirus, o coxsackievirus. Additionally, sexually transmitted diseases and viral diseases, such as gonorrhea, syphilis, herpes simplex virus (HSV), cytomegalovirus (CMV), hepatitis, HIV, rubella, toxoplasmosis, Trichomonas vaginalis, and Candida species, have all been implicated in neonatal infection. Además, las enfermedades de transmisión sexual y las enfermedades víricas, tales como la gonorrea, sífilis, virus herpes simplex (HSV), citomegalovirus (CMV), hepatitis, VIH, rubéola, toxoplasmosis, Trichomonas vaginalis, Candida y especies, han sido implicados en infección neonatal. Bacterial organisms with increased antibiotic resistance have also emerged and have further complicated the management of neonatal sepsis. Bacteriana organismos con una mayor resistencia a los

antibióticos también han surgido y se han complicado aún más la gestión de la sepsis neonatal. The colonization patterns in nurseries and personnel are reflected in the organisms currently associated with nosocomial infection. Los patrones de colonización en los viveros y el personal se reflejan en los organismos que actualmente está asociada a infecciones nosocomiales. In today's neonatal intensive care units (NICUs), infants with lower birth weight and infants who are less mature have an increased susceptibility to these organisms. En la situación actual de cuidados intensivos neonatales unidades (NICUs), los bebés con menor peso al nacer y bebés que son menos maduros tienen una mayor susceptibilidad a estos organismos. Staphylococcus epidermidis , a coagulase-negative Staphylococcus , is increasingly seen as a cause of nosocomial or late-onset sepsis, especially in the premature infant, in whom it is considered the leading cause of late-onset infections. Staphylococcus epidermidis, un coagulasa-negativos Staphylococcus, es cada vez más como una causa de infección nosocomial o de aparición tardía sepsis, especialmente en el recién nacido prematuro, en los cuales se considera la principal causa de aparición tardía infecciones. Its prevalence is likely related to several intrinsic properties of the organism that allow it to readily adhere to the plastic mediums found in intravascular catheters and intraventricular shunts. Su prevalencia está probablemente relacionado con varias propiedades intrínsecas del organismo que le permiten adherirse fácilmente a los medios de plástico se encuentran en los catéteres intravasculares intraventricular y derivaciones. The bacterial capsule polysaccharide adheres well to the plastic polymers of the catheters. La cápsula de polisacáridos bacterianos se adhiere así a los polímeros de plástico de los catéteres. Also, proteins found in the organism (AtlE and SSP-1) enhance attachment to the surface of the catheter. Además, las proteínas se encuentran en el organismo (Atle y SSP-1) aumentar la adhesión a la superficie del catéter. The adherence creates a capsule between microbe and catheter, preventing C3 deposition and phagocytosis. La adhesión crea una cápsula entre el microbio y el catéter, evitando la deposición de C3 y fagocitosis. Biofilms are formed on indwelling catheters by the aggregation of organisms that have multiplied with the protection provided by the adherence to the catheter. Biopelículas se forman en los catéteres inhabitación de la agregación de los organismos que se han multiplicado con la protección proporcionada por la adhesión al catéter. Slimes are produced at the site from the extracellular material formed by the organism, which provides a barrier to the host defense, as well as antibiotic action, making coagulasenegative staphylococcal septicemia more difficult to treat. Slimes se producen en el lugar de la material extracelular formado por el organismo, que proporciona una barrera para la defensa de acogida, así como antibiótico de acción, haciendo coagulasa-negativos toxina septicemia más difícil de tratar. The toxins formed by this organism have also been associated with necrotizing enterocolitis. Las toxinas formado por este organismo también se han asociado con la enterocolitis necrotizante. In addition to being a cause of neonatal sepsis, the ubiquitous nature of coagulase-negative Staphylococcus as part of the normal skin flora makes it a frequent contaminant of blood and cerebrospinal fluid (CSF) cultures; therefore, a culture growing coagulase-negative Staphylococcus may represent a contaminated sample rather than true coagulase-negative staphylococcal septicemia. Además de ser una causa de sepsis neonatal, el carácter omnipresente de coagulasa-

negativos Staphylococcus como parte de la flora normal de la piel lo convierte en un contaminante frecuente de la sangre y líquido cefalorraquídeo (LCR) las culturas, por lo que una cultura cada vez más coagulasa-negativos Staphylococcus Mayo representan una muestra contaminados en lugar de verdaderas coagulasa-negativos toxina septicemia. In addition to the specific microbial factors mentioned above, a number of host factors predispose the newborn infant to sepsis. Además de los factores específicos microbiana se ha mencionado anteriormente, una serie de factores que predisponen a acoger al niño recién nacido a la sepsis. These factors are especially prominent in the premature infant and involve all levels of host defense, including cellular immunity, humoral immunity, and barrier function. Estos factores son especialmente importantes en el recién nacido prematuro e implicar a todos los niveles de defensa de acogida, incluidos la inmunidad celular, inmunidad humoral, y la función barrera. Cellular immunity Inmunidad celular The neonatal neutrophil or polymorphonuclear (PMN) cell, which is vital for effective killing of bacteria, is deficient in chemotaxis and killing capacity. El neonatal o neutrófilos polimorfonucleares (PMN) de células, que es vital para la eficacia de asesinato de bacterias, es deficiente en la quimiotaxis y la capacidad de matar. Decreased adherence to the endothelial lining of blood vessels reduces their ability to marginate and leave the intravascular space to migrate into the tissues. Disminución de la adhesión al revestimiento del endotelio de los vasos sanguíneos reduce su capacidad de marginate y dejar el espacio intravascular a emigrar en los tejidos. Once in the tissues, they may fail to degranulate in response to chemotactic factors. Una vez en los tejidos, pueden dejar de degranulate en respuesta a chemotactic factores. Also, neonatal PMNs are less deformable; therefore, they are less able to move through the extracellular matrix of tissues to reach the site of inflammation and infection. Por otra parte, neonatal PMNs son menos deformables y, en consecuencia, son menos capaces de moverse a través de la matriz extracelular de los tejidos para llegar al lugar de la inflamación e infección. The limited ability of neonatal PMNs for phagocytosis and killing of bacteria is further impaired when the infant is clinically ill. La limitada capacidad de PMNs neonatal para la fagocitosis y muerte de las bacterias se altera cuando el bebé está clínicamente enfermos. Lastly, neutrophil reserves are easily depleted because of the diminished response of the bone marrow, especially in the premature infant. Por último, los neutrófilos son fácilmente reservas agotadas a causa de la disminución de la respuesta de la médula ósea, especialmente en el recién nacido prematuro. Neonatal monocyte concentrations are at adult levels; however, macrophage chemotaxis is impaired and continues to exhibit decreased function into early childhood. Neonatal monocitos son las concentraciones en los niveles de adultos, sin embargo, los macrófagos se perjudica la quimiotaxis y sigue exposición disminuyó en función de la primera infancia. The absolute numbers of macrophages are decreased in the lungs and are likely decreased in the liver and spleen, as well. El número absoluto de los macrófagos se redujo en los pulmones y es probable disminución en el hígado y el bazo, también. The chemotactic and bacteriocidal activity and the antigen presentation by these cells are also

not fully competent at birth. El chemotactic y bacteriocidal actividad y la presentación de antígenos por estas células tampoco son plenamente competentes en el momento del nacimiento. Cytokine production by macrophages is decreased, which may be associated with a corresponding decrease in T-cell production. La producción de citocinas por los macrófagos se redujo, lo que puede estar asociado con una correspondiente disminución en las células T de producción. Although T cells are found in early gestation in fetal circulation and increase in number from birth to about age 6 months, these cells represent an immature population. Aunque las células T se encuentran en la gestación temprana en la circulación fetal y aumento del número desde el nacimiento hasta alrededor de edad de 6 meses, estas células representan una población inmadura. These naive cells do not proliferate as readily as adult T cells when activated and do not effectively produce the cytokines that assist with B-cell stimulation and differentiation and granulocyte/monocyte proliferation. Estos ingenuos células no proliferan como fácilmente como adultos cuando las células T activadas y no producir eficazmente el citoquinas que ayudan a las células B-estimulación y la diferenciación y de granulocitos / monocitos proliferación. A delay occurs in the formation of antigen specific memory function following primary infection, and the cytotoxic function of neonatal T cells is 50-100% as effective as adult T cells. Un retraso se produce en la formación de antígenos específicos de la función de la memoria después de la infección primaria, y la función citotóxica de las células T neonatal 50-100% es tan efectivo como las células T de adultos. At birth, neonates are deficient in memory T cells. Al nacer, los recién nacidos son deficientes en células T de memoria. As the neonate is exposed to antigenic stimuli, the number of these memory T cells increases. A medida que el recién nacido está expuesto a estímulos antigénicos, el número de estas células T de memoria se incrementa. Natural killer (NK) cells are found in small numbers in the peripheral blood of neonates. Natural killer (NK), las células se encuentran en pequeñas cantidades en la sangre periférica de los recién nacidos. These cells are also functionally immature in that they produce far lower levels of interferon-gamma upon primary stimulation than do adult NK cells. Estas células son también funcionalmente inmaduros en el sentido de que producen muy por debajo de los niveles de interferón-gamma primaria a la estimulación que los adultos, las células NK. This combination of findings may contribute to the severity of HSV infections in the neonatal period. Esta combinación de hallazgos pueden contribuir a la gravedad de las infecciones por HSV en el período neonatal. Humoral immunity Inmunidad humoral The fetus has some preformed immunoglobulin present, primarily acquired through nonspecific placental transfer from the mother. El feto tiene algunas preformados inmunoglobulina presente, principalmente adquiridos a través de la transferencia placentaria inespecífico de la madre. Most of this transfer occurs in late gestation, such that lower levels are found with increasing prematurity. La mayor parte de esta transferencia se produce a finales de la gestación, de tal forma que los niveles inferiores se encuentran con el aumento de la prematuridad. The neonate's ability to generate

immunoglobulin in response to antigenic stimulation is intact; however, the magnitude of the response is initially decreased, rapidly rising with increasing postnatal age. El recién nacido de la capacidad de generar inmunoglobulina en respuesta a la estimulación antigénica está intacta, sin embargo, la magnitud de la respuesta se redujo inicialmente, que aumentan rápidamente con el aumento de la edad postnatal. The neonate is also capable of synthesizing immunoglobulin M (IgM) in utero at 10 weeks' gestation; however, IgM levels are generally low at birth, unless the infant was exposed to an infectious agent during the pregnancy, thereby stimulating increased IgM production. El recién nacido también es capaz de sintetizar la inmunoglobulina M (IgM) en el útero a las 10 semanas de gestación, sin embargo, los niveles de IgM son generalmente bajos en el momento del nacimiento, a menos que el niño estuvo expuesto a un agente infeccioso durante el embarazo, estimulando así el aumento de la producción de IgM. Immunoglobulin G (IgG) and immunoglobulin E (IgE) may be synthesized in utero; however, only traces are found in cord blood at delivery, as most of the IgG is acquired from the mother during late gestation. Inmunoglobulina G (IgG) y la inmunoglobulina E (IgE) puede ser sintetizada en el útero, sin embargo, sólo los rastros se encuentran en la sangre del cordón umbilical durante el parto, ya que la mayoría de la IgG se adquiere de la madre durante la gestación tardía. The neonate may receive immunoglobulin A (IgA) from breastfeeding but does not secrete IgA until 2-5 weeks after birth. El recién nacido puede recibir la inmunoglobulina A (IgA) de la lactancia materna pero no secretan IgA hasta 2-5 semanas después del nacimiento. Response to bacterial polysaccharide antigen is diminished and remains so during the first 2 years of life. La respuesta a antígenos polisacáridos bacterianos ha disminuido y sigue siendo así durante los 2 primeros años de vida. Complement protein production can be detected as early as 6 weeks' gestation; however, the concentration of the various components of the complement system widely varies among individual neonates. Complementar la producción de proteínas puede ser detectado tan pronto como 6 semanas de gestación, sin embargo, la concentración de los diversos componentes del sistema del complemento varía ampliamente entre los recién nacidos. While some infants have had complement levels comparable with those in adults, deficiencies appear to be greater in the alternative pathway than in the classic pathway. Aunque algunos niños han tenido complementar los niveles comparables con las de los adultos, las deficiencias parecen ser mayores en la vía alterna que en el clásico itinerario. The terminal cytotoxic components of the complement cascade that leads to killing of organisms, especially gram-negative bacteria, are deficient. La terminal citotóxica componentes de la cascada del complemento que lleva a la muerte de los organismos, especialmente bacterias gram-negativas, son deficientes. This deficiency is more marked in preterm infants. Esta deficiencia es más marcada en los recién nacidos prematuros. Mature complement activity is not reached until infants are aged 6-10 months. Pareja complementar la actividad no se alcanza hasta los bebés tienen edades 610 meses. Neonatal sera have reduced opsonic efficiency against GBS, E coli , and S pneumoniae because of decreased levels of fibronectin, a serum protein that assists with neutrophil adherence and has opsonic properties. Suero neonatal han reducido la eficiencia opsonic contra GBS, E coli, S pneumoniae y debido a la disminución de los

niveles de fibronectina, una proteína de suero que ayuda con la adhesión de neutrófilos y ha opsonic propiedades. Barrier function Función de barrera The physical and chemical barriers to infection in the human body are present in the newborn but are functionally deficient. La física y química barreras a la infección en el cuerpo humano están presentes en el recién nacido, pero son funcionalmente deficientes. Skin and mucus membranes are broken down easily in the premature infant. La piel y membranas mucosas se desglosan fácilmente en el recién nacido prematuro. Neonates who are ill and/or premature are additionally at risk because of the invasive procedures that breach their physical barriers to infection. Los recién nacidos que están enfermos y / o prematuro son, además, en situación de riesgo debido a los procedimientos invasivos que el incumplimiento de sus barreras físicas a la infección. Because of the interdependence of the immune response, these individual deficiencies of the various components of immune activity in the neonate conspire to create a hazardous situation for the neonate exposed to infectious threats. Debido a la interdependencia de la respuesta inmune, cada una de estas deficiencias de los distintos componentes de la actividad inmune en el recién nacido conspirar para crear una situación peligrosa para el recién nacido expuesto a amenazas infecciosas.

Frequency Frecuencia United States Estados Unidos The incidence of culture-proven sepsis is approximately 2 per 1000 live births. La incidencia de la cultura de la sepsis probada es de aproximadamente 2 por cada 1000 nacidos vivos. Of the 7-13% of neonates who are evaluated for neonatal sepsis, only 38% have culture-proven sepsis. De los 7-13% de los recién nacidos que son evaluados para la sepsis neonatal, sólo el 3-8% han probado la cultura de la sepsis. The early signs of sepsis in the newborn are nonspecific; therefore, many newborns undergo diagnostic studies and the initiation of treatment before the presence of sepsis has been proven. Los primeros signos de sepsis en el recién nacido son inespecíficos, por lo que muchos recién nacidos se someten a estudios de diagnóstico y el inicio de tratamiento antes de la presencia de sepsis se ha demostrado. Additionally, because the American Academy of Pediatrics (AAP), American Academy of Obstetrics and Gynecology (AAOG), and Centers for Disease Control and Prevention (CDC) all have recommended sepsis screening and/or treatment for various risk factors related to GBS diseases, many asymptomatic neonates now require evaluation. Además, debido a que la Academia Americana de Pediatría (AAP), Academia Americana de Obstetricia y Ginecología (AAOG), y los Centros para el Control y Prevención de Enfermedades (CDC) han recomendado todas las sepsis detección y / o tratamiento de diversos factores de riesgo relacionados con enfermedades GBS, muchos recién nacidos asintomáticos ahora requieren evaluación. Because the mortality rate of untreated sepsis can be as high as 50%, most clinicians believe that the hazard of untreated sepsis is too great to wait for confirmation based on positive culture results; therefore, most clinicians initiate treatment

while awaiting culture results. Debido a que la tasa de mortalidad de la sepsis no tratada puede ser tan alta como 50%, la mayoría de los médicos creen que el riesgo de sepsis no tratada es demasiado grande para esperar la confirmación sobre la base de la cultura resultados positivos, por lo que la mayoría de los médicos iniciar el tratamiento a la espera de los resultados de la cultura.

Mortality/Morbidity Mortalidad / morbilidad The mortality rate in neonatal sepsis may be as high as 50% for infants who are not treated. La tasa de mortalidad en la sepsis neonatal puede ser tan alto como el 50% de los lactantes que no son tratados. Infection is a major cause of fatality during the first month of life, contributing to 13-15% of all neonatal deaths. La infección es una de las principales causas de mortalidad durante el primer mes de vida, contribuyendo al 13-15% de todas las muertes neonatales. Neonatal meningitis, a serious morbidity of neonatal sepsis, occurs in 2-4 cases per 10,000 live births and significantly contributes to the mortality rate in neonatal sepsis; it is responsible for 4% of all neonatal deaths. Neonatal meningitis, una grave morbilidad de la sepsis neonatal, se produce en 2-4 casos por cada 10000 nacidos vivos y contribuye significativamente a la tasa de mortalidad en la sepsis neonatal, es responsable de un 4% de todas las muertes neonatales. In the preterm infant, inflammatory mediators associated with neonatal sepsis may contribute to brain injury and poor neurodevelopmental outcomes. En los lactantes prematuros, los mediadores de la inflamación asociada a la sepsis neonatal puede contribuir a la lesión cerebral y los pobres resultados del neurodesarrollo.

Race Raza Black infants have an increased incidence of GBS disease and late-onset sepsis. Negro lactantes tienen una mayor incidencia de la enfermedad y GBS de aparición tardía sepsis. This is observed even after controlling for risk factors of low birth weight and decreased maternal age. Esto se observa incluso después de controlar factores de riesgo de bajo peso al nacer y la disminución de la edad materna.

Sex Sexo The incidence of bacterial sepsis and meningitis, especially for gram-negative enteric bacilli, is higher in males than in females. La incidencia de sepsis bacteriana y la meningitis, especialmente para los gram-negativos bacilos entéricos, es mayor en hombres que en mujeres.

Age Edad Premature infants have an increased incidence of sepsis. Recién nacidos prematuros tienen una mayor incidencia de sepsis. The incidence of sepsis is significantly higher in infants with very low birth weight (<1000 g), at 26 per 1000 live births, than in infants with a birth weight of 1000-2000 g, at 8-9 per 1000 live births. La incidencia de sepsis es significativamente mayor en los recién nacidos con muy bajo peso al nacer (<1000 g), a

26 por 1000 nacidos vivos, que en los lactantes con un peso al nacer de 1000-2000 g, a 89 por cada 1000 nacidos vivos. The risk for death or meningitis from sepsis is higher in infants with low birth weight than in full-term neonates. El riesgo de muerte o la meningitis de sepsis es mayor en lactantes con bajo peso al nacer que en pleno plazo de los recién nacidos.

CLINICAL CLÍNICA Section 3 of 11 Sección 3 de 11 • • • • • • • • • • •

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History Historia The most common risk factors associated with early-onset neonatal sepsis include maternal GBS colonization (especially if untreated during labor), premature rupture of membranes (PROM), preterm rupture of membranes, prolonged rupture of membranes, prematurity, maternal urinary tract infection, and chorioamnionitis. La mayoría de los factores de riesgo comunes asociados con la aparición temprana de la sepsis neonatal incluyen la colonización materna GBS (sobre todo si no reciben tratamiento durante el parto), rotura prematura de membranas (PROM), ruptura prematura de membranas, rotura prolongada de membranas, prematuridad, la maternidad infección del tracto urinario, y corioamnionitis. Risk factors also associated with early-onset neonatal sepsis include low Apgar score (<6 at 1 or 5 min), maternal fever greater than 38°C, maternal urinary tract infection, poor prenatal care, poor maternal nutrition, low socioeconomic status, recurrent abortion, maternal substance abuse, low birth weight, difficult delivery, birth asphyxia, meconium staining, and congenital anomalies. Los factores de riesgo también se asocia con inicio temprano de la sepsis neonatal incluyen puntuación de Apgar baja (<6 a 1 o 5 min),

fiebre materna superior a 38 ° C, la maternidad infección del tracto urinario, la mala atención prenatal, la mala nutrición materna, nivel socioeconómico bajo, periódicos el aborto, el abuso de sustancias materna, bajo peso al nacer, parto difícil, la asfixia, manchas de meconio, y las anomalías congénitas. Risk factors implicated in neonatal sepsis reflect the stress and illness of the fetus at delivery, as well as the hazardous uterine environment surrounding the fetus before delivery. Los factores de riesgo implicados en la sepsis neonatal reflejar el estrés y la enfermedad del feto durante el parto, así como el medio ambiente uterino peligrosos que rodean el feto antes del parto. Late onset sepsis is associated with the following risk factors: prematurity, central venous catheterization (duration of >10 d), nasal cannula continuous positive airway pressure use, H2 blocker/proton pump inhibitor use, and gastrointestinal tract pathology. Sepsis de aparición tardía se asocia con los siguientes factores de riesgo: prematuridad, cateterismo venoso central (duración de> 10 d), cánula nasal positiva continua en las vías respiratorias uso de presión, bloqueador H2 / inhibidor de la bomba de protones uso, y patología del tracto gastrointestinal. An awareness of the many risk factors associated with neonatal sepsis prepares the clinician for early identification and effective treatment, thereby reducing mortality and morbidity. La conciencia de los muchos factores de riesgo asociados con la sepsis neonatal se prepara para el clínico de diagnóstico precoz y un tratamiento eficaz, reduciendo así la mortalidad y la morbilidad. •

Maternal GBS status GBS condición materna • o

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The most common etiology of neonatal bacterial sepsis is GBS. La etiología más común de sepsis bacteriana neonatal es GBS. Nine serotypes exist, and each is related to the polysaccharide capsule of the organism. Nueve serotipos existen, y cada una está relacionada con la cápsula de polisacárido del organismo. Types I, II, and III are commonly associated with neonatal GBS infection. Los tipos I, II y III son comúnmente asociados con la infección por SGB neonatal. The type III strain has been shown to be most highly associated with CNS involvement in early-onset infection, whereas type V has been associated with early-onset disease without CNS involvement. El tipo III cepa ha demostrado ser más asociados con afectación del sistema nervioso central a principios de aparición de infección, mientras que el tipo V se ha asociado con la aparición temprana de la enfermedad sin afectación del sistema nervioso central. The GBS organism colonizes the maternal gastrointestinal tract and birth canal. El GBS organismo coloniza el tracto gastrointestinal materna y el nacimiento del canal. Approximately 30% of women have asymptomatic GBS colonization during pregnancy. Aproximadamente el 30% de las mujeres tienen colonización asintomática GBS durante el embarazo. GBS is responsible for approximately 50,000 maternal infections per year in women, but only 2 neonates per 1000 live births are infected. GBS es

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responsable de aproximadamente 50000 infecciones maternas por año en mujeres, pero sólo el 2 recién nacidos por cada 1000 nacidos vivos están infectados. Women with heavy GBS colonization and culture results that are chronically positive for GBS have the highest risk of perinatal transmission. Las mujeres con GBS pesados colonización y la cultura que los resultados son positivos para crónicamente GBS tienen el mayor riesgo de transmisión perinatal. Also, heavy colonization at 23-26 weeks of gestation is associated with prematurity and low birth weight. Por otra parte, la colonización pesados en 23-26 semanas de gestación se asocia con prematuridad y el bajo peso al nacer. Colonization at delivery is associated with neonatal infection. La colonización en el momento del parto se asocia con infección neonatal. Intrapartal chemoprophylaxis of women with positive culture results for GBS has been shown to decrease the transmission of the organism to the neonate during delivery. Intrapartal quimioprofilaxis de las mujeres con resultados positivos para la cultura GBS ha demostrado que disminuye la transmisión del organismo para el recién nacido durante el parto. PROM may occur in response to an untreated infection of the urinary tract or birth canal and is also associated with previous preterm delivery, uterine bleeding in pregnancy, and heavy cigarette smoking during pregnancy. PROM puede ocurrir en respuesta a una infección no tratada del tracto urinario o el nacimiento del canal y también está asociada con parto prematuro previo, sangrado uterino durante el embarazo, pesados y el hábito de fumar cigarrillos durante el embarazo. • o

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Rupture of membranes without other complications for more than 24 hours prior to delivery is associated with a 1% increase in the incidence of neonatal sepsis; however, when chorioamnionitis accompanies the rupture of membranes, the incidence of neonatal infection is quadrupled. Ruptura de membranas sin otras complicaciones durante más de 24 horas antes del parto se asocia con un aumento del 1% en la incidencia de sepsis neonatal, sin embargo, cuando corioamnionitis acompaña a la ruptura de membranas, la incidencia de infección neonatal se cuadruplicó. A recent multicenter study demonstrated that clinical chorioamnionitis and maternal colonization with GBS are the most important predictors of subsequent neonatal infection following PROM. Un reciente estudio multicéntrico demostró que corioamnionitis clínica materna y la colonización con SGB son los predictores más importantes de infección neonatal posterior siguientes PROM. When membranes have ruptured prematurely before 37 weeks' gestational age, a longer latent period precedes vaginal delivery, increasing the likelihood that the infant will be infected. Cuando las membranas se han roto prematuramente antes de las 37 semanas de edad gestacional, un largo período de latencia precede a parto vaginal, lo que aumenta la probabilidad de que el bebé se infecte. The relationship between duration of membrane rupture and neonatal infection is inversely related to gestational age. La relación entre la duración de ruptura de membrana y la

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infección neonatal es inversamente proporcional a la edad gestacional. Therefore, the more premature an infant, the longer the delay between rupture of membranes and delivery, and the higher the likelihood of neonatal sepsis. Por tanto, cuanto más prematuro un niño, cuanto más largo sea el plazo transcurrido entre la ruptura de membranas y parto, y cuanto más alto es el riesgo de sepsis neonatal. o A study by Seaward et al found that more than 6 vaginal digital examinations, which may occur as part of the evaluation for PROM, were associated with neonatal infection even when considered separately from the presence of chorioamnionitis. Un estudio realizado por Seaward et al encontró que más de 6 exámenes vaginales digital, lo que puede ocurrir como parte de la evaluación de PROM, se asociaron a infección neonatal aun cuando se considere por separado de la presencia de corioamnionitis. Prematurity: The relationship between preterm PROM and neonatal sepsis has already been described; however, other associations between prematurity and neonatal sepsis increase the risk for premature infants. Prematuro: La relación entre parto prematuro y PROM sepsis neonatal ya se ha descrito, sin embargo, otras asociaciones entre la prematuridad y sepsis neonatal aumentar el riesgo para los bebés prematuros. •

Preterm infants are more likely to require invasive procedures, such as umbilical catheterization and intubation. Los recién nacidos prematuros tienen más probabilidades de requerir procedimientos invasivos, como la cateterización umbilical y la intubación. o Prematurity is associated with infection from CMV, HSV, hepatitis B, toxoplasmosis, Mycobacterium tuberculosis , Campylobacter fetus , and Listeria species. La prematuridad está asociada con la infección de CMV, HSV, la hepatitis B, toxoplasmosis, Mycobacterium tuberculosis, Campylobacter fetus, y especies de Listeria. o Intrauterine growth retardation and low birth weight are also observed in CMV and toxoplasmosis infections. Retardo del crecimiento intrauterino y bajo peso al nacer también se observó en el CMV y las infecciones de toxoplasmosis. o Premature infants have less immunologic ability to resist and combat infection. Recién nacidos prematuros tienen menos capacidad inmunológica para resistir y combatir la infección. Chorioamnionitis: The relationship between chorioamnionitis and other risk variables is strong. Corioamnionitis: La relación entre corioamnionitis y otras variables de riesgo es fuerte. Suspect chorioamnionitis in the presence of fetal tachycardia, uterine tenderness, purulent amniotic fluid, elevated maternal WBC count, and unexplained maternal temperature above 100.4°F (38°C). Sospechoso corioamnionitis en la presencia de taquicardia fetal, uterina ternura, purulenta líquido amniótico, elevación de WBC contar materna, y sin explicación materna temperatura superior a 100,4 ° F (38 ° C). o

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Physical Física

The clinical signs of neonatal sepsis are nonspecific and are associated with characteristics of the causative organism and the body's response to the invasion. Los signos clínicos de sepsis neonatal son inespecíficos y se asocian con las características de la causa y la respuesta del organismo a la invasión. These nonspecific clinical signs of early sepsis syndrome are also associated with other neonatal diseases, such as respiratory distress syndrome (RDS), metabolic disorders, intracranial hemorrhage, and a traumatic delivery. Estos signos clínicos inespecíficos del síndrome de sepsis temprana también se asocian con otras enfermedades neonatales, tales como el síndrome de dificultad respiratoria (SDR), trastornos metabólicos, hemorragia intracraneal, y una traumática del parto. Given the nonspecific nature of these signs, providing treatment for suspected neonatal sepsis while excluding other disease processes is prudent. Dado el carácter inespecífico de los síntomas, el tratamiento para la sospecha de sepsis neonatal, mientras que con exclusión de otros procesos de enfermedad es prudente. •

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Congenital pneumonia and intrauterine infection: Inflammatory lesions are observed postmortem in the lungs of infants with congenital and intrauterine pneumonia. Neumonía congénita y la infección intrauterina: lesiones inflamatorias postmortem se observan en los pulmones de los lactantes con congénita intrauterina y la neumonía. This may not be caused by the action of the microorganisms themselves but may be caused by aspiration of amniotic fluid containing maternal leukocytes and cellular debris. Esto puede no ser causada por la acción de los microorganismos, pero sí puede ser causada por la aspiración de líquido amniótico que contiene leucocitos materna y restos celulares. Tachypnea, irregular respirations, moderate retracting, apnea, cyanosis, and grunting may be observed. Taquipnea, irregular respirations, retracción moderada, apnea, cianosis, y grunting puede observarse. Neonates with intrauterine pneumonia may also be critically ill at birth and require high levels of ventilatory support. Los recién nacidos con neumonía intrauterino también puede ser crítico en el momento del nacimiento y que requieren altos niveles de soporte ventilatorio. The chest radiograph may depict bilateral consolidation or pleural effusions. La radiografía de tórax se presentan como si fuesen bilaterales consolidación o derrame pleural. Congenital pneumonia and intrapartum infection: Neonates who are infected during the birth process may acquire pneumonia through aspiration of the microorganisms during the delivery process. Neumonía congénita y la infección intraparto: Los recién nacidos que se infectan durante el proceso de nacimiento pueden adquirir a través de la neumonía por aspiración de los microorganismos durante el proceso de entrega. The aspiration may lead to infection with pulmonary changes, infiltration, and destruction of bronchopulmonary tissue. La aspiración puede dar lugar a una infección pulmonar con cambios, la infiltración y destrucción de tejido broncopulmonar. This damage is partly due to the granulocytes' release of prostaglandins and leukotrienes. Este daño se debe en parte a los granulocitos "liberación de prostaglandinas y leucotrienos. Fibrinous exudation into the alveoli leads to inhibition of pulmonary surfactant function and respiratory failure with an RDS-like presentation. Fibrinous exudado en los alvéolos conduce a la inhibición de la función de surfactante pulmonar y la insuficiencia respiratoria con un RDS-como presentación. Vascular congestion,

hemorrhage, and necrosis may occur. La congestión vascular, hemorragia, necrosis y puede ocurrir lo contrario. •

Klebsiella species and S aureus are especially likely to generate severe lung damage, producing microabscesses and empyema. Klebsiella especies y S aureus son especialmente susceptibles de generar grave daño pulmonar, la producción de micro y empiema. o Early-onset GBS pneumonia has a particularly fulminant course, with significant mortality in the first 48 hours of life. A principios de inicio GBS tiene una neumonía fulminante curso en particular, con una mortalidad significativa en las primeras 48 horas de vida. o Infectious pneumonia is also characterized by pneumatoceles within the pulmonary tissue. Infecciosas neumonía se caracteriza también por pneumatoceles en el tejido pulmonar. Coughing, grunting, costal and sternal retractions, nasal flaring, tachypnea and/or irregular respiration, rales, decreased breath sounds, and cyanosis may be observed. Tos, grunting, costales y esternales retracciones, quema nasal, taquipnea y / o respiración irregular, rales, disminución de la respiración sonidos, cianosis y puede observarse. o Radiographic evaluation may demonstrate segmental or lobar atelectasis or a diffuse reticulogranular pattern, much like what is observed in RDS. Evaluación radiográfica puede demostrar segmentaria o lobar atelectasia o un patrón reticulogranular difuso, al igual que lo observado en SDR. o Pleural effusions may be observed in advanced disease. Derrame pleural puede observarse en la enfermedad en estado avanzado. Postnatal infection: Postnatally acquired pneumonia may occur at any age. Infección posnatal: después del neumonía adquirida puede ocurrir a cualquier edad. Because these infectious agents exist in the environment, the likely cause depends heavily on the infant's recent environment. Debido a que estos agentes infecciosos existentes en el medio ambiente, la causa más probable depende en gran medida en los últimos infantil del medio ambiente. If the infant has remained hospitalized in an NICU environment, especially with endotracheal intubation and mechanical ventilation, the organisms may include Staphylococcus or Pseudomonas species. Si el bebé ha permanecido hospitalizado en una UCIN medio ambiente, sobre todo con la intubación endotraqueal y ventilación mecánica, los organismos pueden incluir Pseudomonas o Staphylococcus especies. Additionally, these hospital-acquired organisms frequently demonstrate multiple antibiotic resistances. Además, estos hospitales adquirido con frecuencia los organismos demuestran múltiples resistencias a antibióticos. Therefore, the choice of antibiotic agents in such cases requires knowledge of the likely causative organisms and the local antibiotic-resistance patterns. Por lo tanto, la elección de agentes antibióticos en estos casos requiere el conocimiento de la probable causante y los organismos locales de resistencia a los antibióticos patrones. Cardiac signs: In overwhelming sepsis, an initial early phase characterized by pulmonary hypertension, decreased cardiac output, and hypoxemia may occur. o

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Signos cardíacos: En la sepsis abrumadora, una primera fase inicial se caracteriza por hipertensión pulmonar, disminución del gasto cardíaco, hipoxemia y puede ocurrir lo contrario. These cardiopulmonary disturbances may be due to the activity of granulocyte-derived biochemical mediators, such as hydroxyl radicals and thromboxane B2, an arachidonic acid metabolite. Estos disturbios cardiopulmonar puede deberse a la actividad de los granulocitos y derivados mediadores bioquímicos, como los radicales hidroxilo y de tromboxano B2, un metabolito ácido araquidónico. These biochemical agents have vasoconstrictive actions that result in pulmonary hypertension when released in pulmonary tissue. Estos agentes bioquímicos han vasoconstrictive acciones que se traducen en la hipertensión pulmonar cuando se libera en los tejidos pulmonares. A toxin derived from the polysaccharide capsule of type III Streptococcus has also been shown to cause pulmonary hypertension. Una toxina derivada de la cápsula de polisacáridos de Streptococcus tipo III también ha sido demostrado que causa hipertensión pulmonar. The early phase of pulmonary hypertension is followed by further progressive decreases in cardiac output with bradycardia and systemic hypotension. La fase inicial de la hipertensión pulmonar es seguido por una disminución progresiva del gasto cardíaco con bradicardia y la hipotensión sistémica. The infant manifests overt shock with pallor, poor capillary perfusion, and edema. El infantil se manifiesta abierto choque con la palidez, mala perfusión capilar, y edema. These late signs of shock are indicative of severe compromise and are highly associated with mortality. Estos fines de signos de shock son indicativos de una grave compromiso y están muy asociados con la mortalidad. Metabolic signs: Hypoglycemia, hyperglycemia, metabolic acidosis, and jaundice all are metabolic signs that commonly accompany neonatal sepsis syndrome. Señales metabólicas: hipoglucemia, hiperglucemia, acidosis metabólica, ictericia y metabólicos son todos signos que comúnmente acompañan el síndrome de sepsis neonatal. The infant has an increased glucose requirement because of sepsis. El infantil tiene un aumento de glucosa requisito debido a sepsis. The infant may also have impaired nutrition from a diminished energy intake. El bebé también puede tener problemas de nutrición de la disminución de la ingesta energética. Metabolic acidosis is due to a conversion to anaerobic metabolism with the production of lactic acid. La acidosis metabólica se debe a una conversión del metabolismo anaeróbico con la producción de ácido láctico. When infants are hypothermic or they are not kept in a neutral thermal environment, efforts to regulate body temperature can cause metabolic acidosis. Cuando los bebés son hipotermia o que no se mantienen en un ambiente térmico neutro, los esfuerzos para regular la temperatura corporal puede causar acidosis metabólica. Jaundice occurs in response to decreased hepatic glucuronidation caused by both hepatic dysfunction and increased erythrocyte destruction. La ictericia se produce en respuesta a una disminución de la glucuronidación hepática causada por ambos disfunción hepática y el aumento de eritrocitos destrucción. Neurologic signs: Meningitis is the common manifestation of infection of the CNS. Signos neurológicos: La meningitis es común la manifestación de la infección del SNC. It is primarily associated with GBS (36%), E coli (31%), and Listeria species (5-10%) infections, although other organisms such as S

pneumoniae, S aureus, Staphylococcus epidermis, H influenzae , and species of Pseudomonas, Klebsiella, Serratia, Enterobacter, and Proteus may cause meningitis. Se asocia principalmente con GBS (36%), E coli (31%), y especies de Listeria (5-10%), infecciones, aunque otros organismos tales como S pneumoniae, S aureus, Staphylococcus epidermis, H influenzae, y especies de Pseudomonas , Klebsiella, Serratia, Enterobacter, Proteus y puede causar meningitis. Acute and chronic histologic features are associated with specific organisms. Aguda y crónica características histológicas están asociadas con organismos específicos. • o

Ventriculitis  Ventriculitis is the initiating event, with inflammation of the ventricular surface. Ventriculitis es iniciar el evento, con inflamación de la superficie ventricular. Exudative material usually appears at the choroid plexus and is external to the plexus. Exudativa material generalmente aparece en el plexo coroideo y es ajena a la del plexo. Then, ependymitis occurs with disruption of the ventricular lining and projections of glial tufts into the ventricular lumen. A continuación, ependymitis ocurre con los trastornos de la mucosa del ventrículo y proyecciones de bucles gliales en el lumen ventricular. Glial bridges may develop by these tufts and cause obstruction, particularly at the aqueduct of Sylvius. Gliales pueden desarrollar puentes de estos bucles y causa la obstrucción, en particular en el acueducto de Sylvius.  The lateral ventricles may become multiloculated, which is similar to forming abscesses. Los ventrículos laterales pueden llegar a ser multiloculated, que es similar a la formación de abscesos. Multiloculated ventricles can isolate organisms in an area, making treatment more difficult. Multiloculated ventrículos pueden aislar los organismos en una zona, haciendo más difícil el tratamiento.  Meningitis is likely to arise at the choroid plexus and extend via the ventricles through aqueducts into the subarachnoid space to affect the cerebral and cerebellar surfaces. La meningitis es probable que surjan en el plexo coroideo y ampliar a través de los ventrículos a través de acueductos en el espacio subaracnoideo a afectar a la cerebral y cerebeloso superficies. The high glycogen content in the neonatal choroid plexus provides an excellent medium for the bacteria. El alto contenido de glucógeno en el plexo coroideo neonatal constituye un medio excelente para las bacterias. When meningitis develops from ventriculitis, it complicates effective treatment because achieving adequate antibiotic levels in the cerebral ventricles is difficult. Cuando la meningitis se desarrolla a partir de ventriculitis, se complica un tratamiento eficaz, porque el logro de adecuados niveles de antibióticos en los ventrículos cerebrales es difícil.

When present, ventricular obstruction causes additional problems. Cuando la actualidad, la obstrucción ventricular causa problemas adicionales. Arachnoiditis is the next phase and is the hallmark of meningitis. La aracnoiditis es la próxima etapa y es el sello distintivo de la meningitis. The arachnoid is infiltrated with inflammatory cells that produce an exudate that is thick over the base of the brain and more uniform over the rest of the brain. El aracnoideo es infiltrados de células inflamatorias que producen un exudado que es más gruesa la base del cerebro y más uniforme durante el resto del cerebro. Early in the infection, the exudate is primarily PMNs, bacteria, and macrophages. A principios de la infección, el exudado es ante todo PMNs, bacterias y los macrófagos. Exudate is prominent around the blood vessels and extends into the brain parenchyma. Exudado es prominente alrededor de los vasos sanguíneos y se extiende hasta el parénquima cerebral. In the second and third weeks of infection, the proportion of PMNs decreases; the dominant cells are histiocytes, macrophages, and some lymphocytes and plasma cells. En la segunda y tercera semanas de la infección, el porcentaje de PMNs disminuye, la dominante son las células histiocitos, macrófagos y algunos linfocitos y células plasmáticas. Exudate infiltration of cranial roots 3-8 occurs. Exudado infiltración de raíces craneal se produce 3-8. After this period, the exudate decreases. Después de este período, el exudado disminuye. Thick strands of collagen form, and arachnoid fibrosis occurs, which is responsible for obstruction. Líneas gruesas de colágeno, y aracnoideo fibrosis ocurre, que es responsable de la obstrucción. Hydrocephalus results. Hidrocefalia resultados. Early-onset GBS meningitis is characterized by much less arachnoiditis than late-onset GBS meningitis. A principios GBS de aparición de meningitis se caracteriza por mucho menos que aracnoiditis de aparición tardía GBS meningitis. Vasculitis extends the inflammation of the arachnoid and ventricles to the blood vessels surrounding the brain. Vasculitis se extiende la inflamación de la aracnoideo y ventrículos a los vasos sanguíneos que rodean el cerebro. Occlusion of the arteries rarely occurs; however, venous involvement is more severe. Oclusión de las arterias rara vez ocurre, sin embargo, afectación venosa es más severa. Phlebitis may be accompanied with thrombosis and complete occlusion. Flebitis puede ir acompañada con trombosis y oclusión completa. Multiple fibrin thrombi are especially associated with hemorrhagic infarction. Múltiples fibrina sobre todo de trombosis asociado con infarto hemorrágico. This vascular involvement is apparent within the first days of meningitis and becomes more prominent during the second and third weeks. Esta participación vascular es evidente en los primeros días de la meningitis y se hace más prominente durante la segunda y tercera semanas. Cerebral edema may occur during the acute state of meningitis. Edema cerebral puede ocurrir durante el estado agudo de meningitis. The edema may be severe enough to greatly diminish the ventricular lumen. El edema 

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puede ser lo suficientemente graves como para disminuir en gran medida el lumen ventricular. The cause is unknown, but it is likely related to vasculitis and the increased permeability of blood vessels. La causa es desconocida, pero es probable relacionados con vasculitis y la mayor permeabilidad de los vasos sanguíneos. It may also be related to cytotoxins of microbial origin. También puede estar relacionado con cytotoxins de origen microbiano. Herniation of edematous supratentorial structures does not generally occur in neonates because of the cranium's distensibility. Hernia de edematous supratentorial estructuras no suele ocurrir en los recién nacidos a causa del cráneo del distensibility. Infarction is a prominent and serious feature of neonatal meningitis. Infarto es un grave y característica de la meningitis neonatal. It occurs in 30% of infants who die. Ocurre en el 30% de los lactantes que mueren. Lesions occur because of multiple venous occlusions, which are frequently hemorrhagic. Las lesiones se producen a causa de múltiples oclusiones venosas, que son con frecuencia hemorrágico. The loci of infarcts are most often in the cerebral cortex and underlying white matter but may also be subependymal within the deep white matter. El loci de infartos son la mayoría de las veces en la corteza cerebral y sustancia blanca subyacente, pero también puede ser subependymal dentro de la materia blanca profunda. Neuronal loss occurs, especially in the cerebral cortex, and periventricular leukomalacia may subsequently appear in areas of neuronal cell death. Pérdida neuronal se produce, especialmente en la corteza cerebral, y periventricular leukomalacia podrá posteriormente aparecen en las zonas de muerte celular neuronal. Meningitis due to early-onset neonatal sepsis usually occurs within 24-48 hours and is dominated by nonneural signs. La meningitis debido a la temprana aparición de sepsis neonatal por lo general ocurre dentro de 2448 horas y está dominado por nonneural signos. Neurologic signs may include stupor and irritability. Signos neurológicos pueden incluir estupor e irritabilidad. Overt signs of meningitis occur in only 30% of cases. Signos de meningitis ocurren en sólo el 30% de los casos. Even cultureproven meningitis may not demonstrate white cell changes in the CSF. Incluso la cultura demostrado la meningitis no pueden demostrar cambios de células blancas en el MCA. Meningitis due to late-onset disease is more likely to demonstrate neurologic signs (80-90%). La meningitis debido a la tardía aparición de la enfermedad es más probable que demostrar signos neurológicos (80-90%). Impairment of consciousness (ie, stupor with or without irritability), coma, seizures, bulging anterior fontanel, extensor rigidity, focal cerebral signs, cranial nerve signs, and nuchal rigidity occur. In the neonate, many of these physical examination findings are subtle or nonapparent. The CSF findings in infectious neonatal meningitis are an elevated WBC count (predominately PMNs), an elevated protein level, a decreased CSF glucose concentration, and positive culture results. The decrease in CSF glucose concentration does not necessarily reflect serum hypoglycemia.

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Glucose concentration abnormalities are more severe in late-onset disease and with gram-negative organisms. The CSF WBC count is within the reference range in 29% of GBS meningitis infections; in gram-negative meningitis, it is within the reference range in only 4%. Reference range CSF protein and glucose concentrations are found in about 50% of patients with GBS meningitis; however, in gram-negative infections, reference range CSF protein and glucose concentrations are found in only 15-20%. o Temperature instability is observed with neonatal sepsis and meningitis, either in response to pyrogens secreted by the bacterial organisms or from sympathetic nervous system instability. The neonate is most likely to be hypothermic. The infant may also have decreased tone, lethargy, and poor feeding. Signs of neurologic hyperactivity are more likely when late-onset meningitis occurs. Hematologic signs • o

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The platelet count in the healthy newborn is rarely less than 100,000/µL in the first 10 days of life. Thrombocytopenia with counts less than 100,000 may occur in neonatal sepsis in response to the cellular products of the microorganisms. These cellular products cause platelet clumping and adherence leading to platelet destruction. Thrombocytopenia may be a presenting sign and can last as long as 3 weeks. Only 10-60% of infants with sepsis have thrombocytopenia. Because of the appearance of newly formed platelets, mean platelet volume (MPV) and platelet distribution width (PDW) are shown to be significantly higher in neonatal sepsis after 3 days. Because of the myriad of causes of thrombocytopenia and its late appearance in neonatal sepsis, the presence of thrombocytopenia does not aid the diagnosis of neonatal sepsis. Although WBC counts and ratios are more sensitive for determining sepsis than platelet counts, they remain very nonspecific and have low positive predictive value. Normal WBC counts may be observed in as many as 50% of cases of culture-proven sepsis. Infants who are not infected may also demonstrate abnormal WBC counts related to the stress of delivery or several other factors. A differential may be of use in diagnosing sepsis. Total neutrophil count (PMNs and immature forms) is slightly more sensitive in determining sepsis than total leukocyte count (percent lymphocyte + monocyte/PMNs + bands). Abnormal neutrophil counts, taken at the time of symptom onset, are only observed in two thirds of infants; therefore, the neutrophil count does not provide adequate confirmation of sepsis. Neutropenia is observed with maternal hypertension, severe perinatal asphyxia, and periventricular or intraventricular hemorrhage. Neutrophil ratios have been more useful in diagnosing or excluding neonatal sepsis; the immature-to-total (I/T) ratio is the most sensitive. All immature neutrophil forms are counted, and the maximum acceptable ratio for excluding sepsis during the first 24 hours is 0.16. In most newborns,

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the ratio falls to 0.12 within 60 hours of life. The sensitivity of the I/T ratio has ranged from 60-90%, and elevations may be observed with other physiological events, limiting the positive predictive value of these ratios; therefore, when diagnosing sepsis, the elevated I/T ratio should be used in combination with other signs. o Disseminated intravascular coagulation (DIC) can occur in infected infants. Predicting which infants will be affected at the onset of sepsis is difficult. Affected infants show abnormalities in prothrombin time (PT), partial thromboplastin time (PTT), and fibrinogen and D-dimer levels and may need blood products, including fresh frozen plasma (FFP) and cryoprecipitate, to replace coagulation factors consumed in association with DIC. If infants show signs consistent with impaired coagulation, including gastric blood, bleeding intravenous or laboratory puncture sites, or other bleeding, evaluating coagulation by checking these values is important. Gastrointestinal signs: The intestinal tract can be colonized by organisms in utero or at delivery by swallowing infected amniotic fluid. The immunologic defenses of the intestinal tract are not mature, especially in the preterm infant. Lymphocytes proliferate in the intestines in response to mitogen stimulation; however, this proliferation is not fully effective in responding to a microorganism because antibody response and cytokine formation is immature until approximately 46 weeks. Necrotizing enterocolitis has been associated with the presence of a number of species of bacteria in the immature intestine, and bacterial overgrowth of these organisms in the neonatal lumen is a component of the multifactorial pathophysiology of NEC.

DIFFERENTIALS Section 4 of 11 • • • • • • • • • • •

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Acidosis, Metabolic

Bowel Obstruction in the Newborn Coarctation of the Aorta Congenital Diaphragmatic Hernia Congenital Lung Malformations Congenital Pneumonia Heart Failure, Congestive Hemolytic Disease of Newborn Hemorrhagic Disease of Newborn Hypoglycemia La hipoglucemia Hypoplastic Left Heart Syndrome Meconium Aspiration Syndrome Meningitis, Bacterial Necrotizing Enterocolitis Osteomyelitis Pericarditis, Bacterial Pulmonary Atresia With Intact Ventricular Septum Pulmonary Hypertension, Persistent-Newborn Pulmonary Hypoplasia Pulmonary Sequestration Respiratory Distress Syndrome Single Ventricle Urinary Tract Infection

WORKUP Section 5 of 11 • • • • • • • • • • •

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Lab Studies •

Blood, CSF, and urine cultures •

Aerobic cultures are appropriate for most of the bacterial etiologies associated with neonatal sepsis; however, anaerobic cultures are indicated in neonates with abscess formation, processes with bowel involvement, massive hemolysis, and refractory pneumonia. o A Gram stain provides early identification of the gram-negative or grampositive status of the organism for preliminary identification. o Bacterial culture results should generally reveal the organism of infection within 36-48 hours; the subsequent initial identification of the organism occurs within 12-24 hours of the growth. Single-site blood cultures are effective in isolating bacteria in the neonate with sepsis. o Urine cultures are most appropriate when investigating late-onset sepsis. o Blood and CSF cultures are appropriate for early- and late-onset sepsis. o Because of the low incidence of meningitis in the newborn infant with negative culture results, clinicians may elect to culture the CSF of only those infants with documented or presumed sepsis. However, recent data in large numbers of patients show a 38% rate of culture-positive meningitis in neonates with negative blood culture results and suspected sepsis. A CBC count and differential may be ordered serially to determine changes associated with the infection, such as thrombocytopenia or neutropenia, or to monitor the development of a left shift or an elevated I/T ratio. Such serial monitoring of the CBC count may be useful in aiding the differentiation of sepsis syndrome from nonspecific abnormalities due to the stress of delivery. o

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• o

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The platelet count in the healthy newborn is rarely less than 100,000/µL in the first 10 days of life. Thrombocytopenia with counts less than 100,000 may occur in neonatal sepsis. MPV and PDW have been shown to be significantly elevated in infants with sepsis after 2-3 days of life. These measures may assist in determining the etiology of thrombocytopenia. WBC counts and ratios may be helpful in determining sepsis, although normal WBC counts may be observed in as many as 50% of cultureproven sepsis cases. WBC counts and ratios remain very nonspecific and have low positive predictive value. Infants who are not infected may also have abnormal WBC counts related to the stress of delivery. A differential may be of use in diagnosing sepsis; however, these counts are laboratory technician–dependent. Total neutrophil count (PMNs and immature forms) is slightly more sensitive in determining sepsis than total leukocyte count (percent lymphocyte + monocyte/PMNs + bands). Abnormal neutrophil counts at the time of symptom onset are only observed in two thirds of infants; therefore, neutrophil count does not provide adequate confirmation of sepsis. Neutropenia is also observed with maternal hypertension, severe perinatal asphyxia, and periventricular or intraventricular hemorrhage. Neutrophil ratios have been more useful in diagnosing neonatal sepsis; the I/T ratio is the most sensitive. All immature neutrophil forms are counted, and the maximum acceptable ratio for excluding sepsis in the first 24

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hours is 0.16. In most newborns, the ratio falls to 0.12 within 60 hours of life. The sensitivity of the I/T ratio has ranged from 60-90%, and elevations may be observed with other physiological events, limiting the positive predictive value of these ratios; therefore, when diagnosing sepsis, the elevated I/T ratio should be used in combination with other signs. The CSF findings in infectious neonatal meningitis are an elevated WBC count (predominately PMNs), an elevated protein level, a depressed glucose level, and positive culture results. The decrease in glucose is not reflective of serum hypoglycemia. The CSF abnormalities are more severe in late onset and with gram-negative organisms. The WBC count is within the reference range in 29% of GBS meningitis infections; in gram-negative meningitis, it is within the reference range in only 4%. Reference range protein and glucose concentrations are found in about 50% of patients with GBS meningitis; however, in gramnegative infections, reference range protein and glucose concentration are found in only 15-20%. C-reactive protein, an acute phase protein associated with tissue injury, is elevated at some point in 50-90% of infants with systemic bacterial infections. This is especially true of infections with abscesses or cellulitis of deep tissue. C-reactive protein usually rises within 24 hours of infection, peaks within 2-3 days, and remains elevated until the inflammation is resolved. The C-reactive protein level is not recommended as a sole indicator of neonatal sepsis, but it may be used as part of a sepsis workup or as a serial study during infection to determine response to antibiotics, duration of therapy, and/or relapse of infection. IgM concentration in serum may be helpful in determining the presence of an intrauterine infection, especially if the infection has been present over a period of time. Current evidence on the use of infection markers such as CD11b, CD64, interleukin-6, and interleukin-8 for evaluation of sepsis in neonates shows that they may be helpful as adjunctive markers. Serial measurements and use of combinations of tests may improve their value. However, at this time, these tests should not be used alone to determine the need for antibiotic therapy. In some cases, they may prove useful in determining when to stop antibiotic therapy.

Imaging Studies •

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Chest radiographs may depict segmental or lobar infiltrate but they more commonly reveal a diffuse, fine, reticulogranular pattern, much like what is observed in RDS. Pleural effusions may also be observed. A CT scan may be needed late in the course of complex neonatal meningitis to document obstructive hydrocephalus, the site where the obstruction is occurring, and the occurrence of major infarctions or abscesses. Signs of chronic disease, such as ventricular dilation, multicystic encephalomalacia, and atrophy, may also be demonstrated on CT scan. Head ultrasonograms in neonates with meningitis may show evidence of ventriculitis, abnormal parenchymal echogenicities, extracellular fluid, and

chronic changes. Serially, head ultrasonograms can demonstrate the progression of complications.

Procedures •

Lumbar puncture is warranted for early- and late-onset sepsis, although clinicians may be unsuccessful in obtaining sufficient or clear fluid for all the studies. Infants may be positioned on their side or sit with support. The insertion site should be between L3 and L4 in order to be below the lowest point of the spinal cord in infants. If positive culture results are demonstrated, a follow-up lumbar puncture is often performed within 24-36 hours after antibiotic therapy is initiated to document CSF sterility. If organisms are still present, modification of drug type or dosage may be required to adequately treat the meningitis. An additional lumbar puncture within 24-36 hours is necessary if organisms are still present.

TREATMENT Section 6 of 11 • • • • • • • • • • •

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Medical Care When neonatal sepsis is suspected, treatment should be initiated immediately because of the neonate's relative immunosuppression. Begin antibiotics as soon as diagnostic tests are performed. Additional therapies have been investigated for the treatment of neonatal sepsis; however, no substantial clinical trials have shown that these treatments are beneficial. These additional therapies include granulocyte transfusion, intravenous immune globulin (IVIG) replacement, exchange transfusion, and the use of recombinant cytokines.

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In the United States and Canada, the current approach to treat early-onset neonatal sepsis syndrome includes combined IV aminoglycoside and expanded-spectrum penicillin antibiotic therapy. This provides coverage for gram-positive organisms, especially GBS, and gram-negative bacteria, such as E coli . The specific antibiotics to be used are chosen on the basis of maternal history and prevalent trends of organism colonization and antibiotic susceptibility in individual nurseries. • o

o

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If an infection appears to be nosocomial, antibiotic coverage should be directed at organisms implicated in hospital-acquired infections, including S aureus, S epidermis, and Pseudomonas species. Most strains of S aureus produce beta-lactamase, which makes them resistant to penicillin G, ampicillin, carbenicillin, and ticarcillin. Vancomycin has been favored for this coverage; however, concern exists that overuse of this drug may lead to vancomycin-resistant organisms, thereby eliminating the best response to these resistant organisms. Cephalosporins are attractive in the treatment of nosocomial infection because of their lack of dose-related toxicity and adequate serum and CSF concentration; however, resistance by gramnegative organisms has occurred with their use. Use ceftriaxone with caution in infants with hyperbilirubinemia because it displaces bilirubin from serum albumin. Resistance and sensitivities for the organism isolated from cultures are used to select themosteffectivedrug. Aminoglycosides and vancomycin both have the potential to produce ototoxicity and nephrotoxicity and should therefore be used with caution. The serum drug level is assessed 48 hours after starting treatment to determine if levels are within the therapeutic range. The drug dosage or interval may need to be changed to optimize the drug serum levels. A serum level may also be warranted if the infant's clinical condition has not improved to ensure that a therapeutic level has been reached. In addition, renal function and hearing screening should be considered after completion of the therapeutic course to determine if any short- or longrange toxic effects of these drugs have occurred. If culture results are negative but the infant has significant risk or clinical signs for sepsis, the clinician must decide whether to provide continued treatment. Three days of negative culture results should provide confidence in the data; however, a small number of infants documented to have had sepsis by postmortem examination had negative culture results during their initial sepsis evaluation. Management is further complicated if the mother received antibiotic therapy before delivery, especially if she received the therapy within several hours of delivery. This may result in negative culture results in an infant who actually has bacteremia or sepsis. With this in mind, the need for continued therapy should be based not on a single test, but on a review of all diagnostic data, including culture results, maternal and intrapartal risk factors, CSF results, the CBC count and differential radiographs, and

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the clinical picture. Treatment for 7-10 days may be appropriate, even if the infant has negative culture results at 48 hours. o Infants with bacterial meningitis often require different dosages of antibiotics and longer courses of treatment. These infants may also require a different drug that has better penetration of the blood-brain barrier to achieve therapeutic drug concentrations in the CSF. Perform a follow-up lumbar puncture within 24-36 hours after antibiotic therapy has been initiated to determine if the CSF is sterile. If organisms are still present, modification of drug type or dosage is required to adequately treat the meningitis. Continue antibiotic treatment for 2 weeks after sterilization of the CSF or for a minimum of 2 weeks for gram-positive meningitis and 3 weeks for gram-negative meningitis, whichever period is longest. Chloramphenicol or trimethoprim-sulfamethoxazole has been shown to be effective in the treatment of highly resistant bacterial meningitis. Granulocyte transfusion has been shown to be suitable for infants with significant depletion of the storage neutrophil pool; however, the documentation of storage pool depletion requires a bone marrow aspiration, and the granulocyte transfusion must be administered quickly to be beneficial. The number of potential adverse effects, such as graft versus host reaction, transmission of CMV or hepatitis B, and pulmonary leukocyte sequestration, is considerable. Therefore, this therapy remains an experimental treatment. IVIG infusion has been studied as a possible therapy for neonatal sepsis to provide type-specific antibodies to improve opsonization and phagocytosis of bacterial organisms and to improve complement activation and chemotaxis of neonatal neutrophils; however, difficulties with IVIG therapy for neonatal sepsis exist. The effect has been transient, and adverse effects associated with the infusion of any blood product can occur. Dose-related problems with this therapy decrease its usefulness in neonatal populations. At present, the data do not support the routine use of IVIG in neonatal sepsis. Recombinant human cytokine administration to stimulate granulocyte progenitor cells has been studied as an adjunct to antibiotic therapy. These therapies have shown promise in animal models, especially for GBS sepsis, but require pretreatment or immediate treatment to demonstrate efficacy. The use of granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF) has been studied in clinical trials, but their use in clinical neonatology remains experimental. The infant with sepsis may require treatment aimed at the overwhelming systemic effects of the disease. Cardiopulmonary support and intravenous nutrition may be required during the acute phase of the illness until the infant's condition stabilizes. Monitoring of blood pressure, vital signs, hematocrit, platelets, and coagulation studies is vital.

Surgical Care If hydrocephalus associated with neonatal meningitis occurs, and progressive accumulation of CSF is present, placing a ventriculoperitoneal (VP) shunt may be

necessary to drain off the excess fluid. The immediate complications of shunt placement are overdrainage, equipment failure, disconnection, migration of catheter, or shunt infection. Abdominal obstruction, omental cysts, and perforation of the bladder, gall bladder, or bowel occur infrequently. The VP shunt may cause long-term neurologic complications, including slit-ventricle syndrome, seizures, neuro-ophthalmological problems, and craniosynostosis; however, the outcome for children with VP shunt placement is generally good with careful follow-up. If an abscess is present, surgical drainage may be necessary because intravenous antibiotic therapy cannot adequately penetrate an abscess and because antibiotic treatment alone is ineffective.

Consultations •

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Infectious disease consultation is useful, especially if the infant is not responding to treatment, is infected with an unusual organism, or has had a complicated clinical course. If neonatal meningitis is identified, consultation with a pediatric neurologist may be necessary for assistance with outpatient follow-up of neurologic sequelae. Inpatient consultation may be necessary if meningitis is complicated by seizures. Consultation with a pediatric pharmacologist may be helpful for advice on the most appropriate antibiotic or dosage to use should changes prove necessary because of inadequate or toxic drug levels obtained with therapeutic monitoring.

Diet The neonate may need to be given nothing by mouth (NPO) during the first days of treatment because of gastrointestinal symptoms, feeding intolerance, or poor feeding. Consider parenteral nutrition to ensure that the patient's intake of calories, protein, minerals, and electrolytes is adequate during this period. Feeding may be restarted via a nasogastric tube for the infant with serious compromise. For most infants, breast milk is the enteral diet recommended by the AAP.

Activity The infant with temperature instability needs thermoregulatory support with a radiant warmer or incubator. Once the infant is stable from a cardiopulmonary standpoint, parental contact is important.

MEDICATION Section 7 of 11 • • • • • • • • • • •

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Some of the antibiotics commonly used to treat neonatal sepsis syndrome are ampicillin, gentamicin, cefotaxime, vancomycin, metronidazole, erythromycin, and piperacillin. The choice of antibiotic agents should be based on the specific organisms associated with sepsis, sensitivities of the bacterial agent, and prevalent nosocomial infection trends in the nursery. Viral infections such as herpes and fungal infections can masquerade as bacterial infections. Drug Category: Antibiotics

Empiric antimicrobial therapy must be comprehensive and should cover all likely pathogens in the context of the clinical setting. Neonatal doses for antibiotics may be based on several variables (eg, postmenstrual age [PMA], postnatal age, weight). Ampicillin (Marcillin, Omnipen, Polycillin, Principen, Totacillin) A beta-lactam antibiotic that is bacteriocidal for susceptible organisms, such as GBS, Listeria , non–penicillinase-producing Description Staphylococcus , some strains of H influenzae , Descripción and meningococci. Recent publications indicate ampicillin (in combination with gentamicin) is the first-line therapy for suspected sepsis in the newborn. < 29 weeks PMA and 0-28 days: 50-100 mg/kg/dose IV/IM q12h < 29 weeks PMA and >28 days: 50-100 mg/kg/dose IV/IM q8h 30-36 weeks PMA and 0-14 days: 50-100 mg/kg/dose IV/IM q12h 30-36 weeks PMA and >14 days: 50-100 mg/kg/dose IV/IM q8h Pediatric Dose 37-44 weeks PMA and 0-7 days: 50-100 mg/kg/dose IV/IM q12h 37-44 weeks PMA and > 7 days: 50-100 mg/kg/dose IV/IM q8h > 45 weeks PMA: 50-100 mg/kg/dose IV/IM q6h Higher dosage may be used with meningitis and GBS Contraindications Documented hypersensitivity Aminoglycosides reduce effectiveness when coadministered; probenecid and disulfiram Interactions elevate levels; allopurinol decreases effects and has additive effects on ampicillin rash B - Usually safe but benefits must outweigh Pregnancy the risks. Adjust dose in renal failure; evaluate rash and Precautions differentiate from hypersensitivity reaction Drug Name

Drug Name Description Descripción

Gentamicin (Garamycin) An aminoglycoside that is bacteriocidal for susceptible gram-negative organisms, such as E coli and Pseudomonas, Proteus, and

Serratia species. Effective in combination with ampicillin for GBS and Enterococcus . Recent publications indicate gentamicin (in combination with ampicillin) is the first-line therapy for suspected sepsis in the newborn. < 29 weeks PMA and 0-7 days: 5 mg/kg/dose IV/IM q48h < 29 weeks PMA and 8-28 days: 4 mg/kg/dose IV/IM q36h < 29 weeks PMA and >29 days: 4 mg/kg/dose IV/IM q24h Pediatric Dose 30-34 weeks PMA and 0-7 days: 4.5 mg/kg/dose IV/IM q36h 30-34 weeks PMA and > 7 days: 4 mg/kg/dose IV/IM q24h > 35 weeks PMA: 4 mg/kg/dose IV/IM q24h IV dosage preferred; IM may be used if IV access is difficult Documented hypersensitivity; Contraindications a relative contraindication is severe renal disease Coadministration with other aminoglycosides, cephalosporins, penicillins, indomethacin, and amphotericin B may increase nephrotoxicity; because aminoglycosides enhance effects of neuromuscular blocking agents prolonged Interactions respiratory depression may occur; coadministration with loop diuretics may increase auditory toxicity of aminoglycosides; possible irreversible hearing loss of varying degrees may occur (monitor levels regularly) Pregnancy D - Unsafe in pregnancy Neonates with renal immaturity, renal disease, auditory impairment, vestibular impairment, hypocalcemia, or who are receiving ECMO; Precautions monitoring levels is important to avoid possible renal and auditory damage (normal peaks 5-12 mcg/mL, normal troughs 0.5-1 mcg/mL) Drug Name Description Descripción

Cefotaxime (Claforan) Third-generation cephalosporin with excellent in vitro activity against GBS and E coli and other gram-negative enteric bacilli. Has good serum and CSF concentrations. Concern exists

about the emergence of drug-resistant gramnegative bacteria at a more rapid rate than with traditional penicillin and aminoglycoside coverage. Ineffective against Listeria and enterococci. Use in combination with ampicillin. In most recent publications, this is not a first-line agent for neonatal sepsis because of its association with increased mortality. < 29 weeks PMA and 0-28 days: 50 mg/kg/dose IV/IM q12h < 29 weeks PMA and >28 days: 50 mg/kg/dose IV/IM q8h 30-36 weeks PMA and 0-14 days: 50 mg/kg/dose IV/IM q12h Pediatric Dose 30-36 weeks PMA and >14 days: 50 mg/kg/dose IV/IM q8h 37-44 weeks PMA and 0-7 days: 50 mg/kg/dose IV/IM q12h 37-44 weeks PMA and > 7 days: 50 mg/kg/dose IV/IM q8h > 45 weeks PMA: 50 mg/kg/dose IV/IM q6h Contraindications Documented hypersensitivity Probenecid decreases renal elimination of cefotaxime and prolongs therapeutic half-life; Interactions coadministration with furosemide and aminoglycosides may increase nephrotoxicity B - Usually safe but benefits must outweigh Pregnancy the risks. History of penicillin hypersensitivity, impaired Precautions renal function, or history of colitis Drug Name

Description Descripción

Pediatric Dose

Vancomycin (Lyphocin, Vancocin, Vancoled) Bacteriocidal agent against most aerobic and anaerobic gram-positive cocci and bacilli. Especially important in the treatment of MRSA. Recommended therapy when coagulase-negative staphylococcal sepsis is suspected. Therapy with rifampin, gentamicin, or cephalothin may be required with endocarditis or CSF shunt infection by coagulase-negative staphylococcus. < 29 weeks PMA and 0-14 days: 10-15 mg/kg/dose IV/IM q18h

< 29 weeks PMA and >14 days: 10-15 mg/kg/dose IV/IM q12h 30-36 weeks PMA and 0-14 days: 10-15 mg/kg/dose IV/IM q12h 30-36 weeks PMA and >14 days: 10-15 mg/kg/dose IV/IM q8h 37-44 weeks PMA and 0-7 days: 10-15 mg/kg/dose IV/IM q12h 37-44 weeks PMA and > 7 days: 10-15 mg/kg/dose IV/IM q8h > 45 weeks PMA: 10-15 mg/kg/dose IV/IM q6h Use higher dosing range in meningitis Documented hypersensitivity; hearing Contraindications impairment Concurrent ototoxic or nephrotoxic drugs (eg, aminoglycosides, loop diuretics); erythema, histaminelike flushing and anaphylactic reactions may occur when administered with Interactions anesthetic agents; effects in neuromuscular blockade may be enhanced when coadministered with nondepolarizing muscle relaxants C - Safety for use during pregnancy has not Pregnancy been established. Administer over 60 min to avoid possibility of histamine reaction, which is characterized by a Precautions rash; levels greater than therapeutic trough (510 mg/dL) may be associated with ototoxicity; caution in renal failure or neutropenia Drug Name Description Descripción Pediatric Dose

Metronidazole (Flagyl) Antimicrobial that has shown effectiveness against anaerobic infections, especially Bacteroides fragilis meningitis, ventriculitis, and endocarditis. Also useful in treatment of infections caused by T vaginalis . Loading dose: 15 mg/kg PO/IV Maintenance dose: < 29 weeks PMA and 0-28 days: 7.5 mg/kg/dose IV/PO q48h < 29 weeks PMA and >28 days: 7.5 mg/kg/dose IV/PO q24h 30-36 weeks PMA and 0-14 days: 7.5 mg/kg/dose IV/PO q24h

30-36 weeks PMA and >14 days: 7.5 mg/kg/dose IV/PO q12h 37-44 weeks PMA and 0-7 days: 7.5 mg/kg/dose IV/PO q24h 37-44 weeks PMA and > 7 days: 7.5 mg/kg/dose IV/PO q12h > 45 weeks PMA: 7.5 mg/kg/dose IV/PO q8h Documented hypersensitivity; first trimester of Contraindications pregnancy May increase levels of phenytoin; phenobarbital and rifampin may increase Interactions metabolism of metronidazole; when administered with food, a decrease and/or delay in reaching peak levels may occur B - Usually safe but benefits must outweigh Pregnancy the risks. Liver impairment, blood dyscrasias, CNS disease; inject with caution in patients Precautions receiving corticosteroids or patients predisposed to edema because the drug molecule contains sodium Drug Name

Erythromycin (E-Mycin, Erythrocin) Macrolide antimicrobial agent that is primarily bacteriostatic and is active against most gramDescription positive bacteria, such as Neisseria species, Descripción Mycoplasma pneumoniae, Ureaplasma urealyticum, and Chlamydia trachomatis . Not well concentrated in the CSF. <7 days and <2000 g: 5 mg/kg/dose PO/IV/IM q12h <7 days and >2000 g: 5 mg/kg/dose PO/IV/IM q8h Pediatric Dose > 7 days and <1200 g: 5 mg/kg PO/IV/IM q12h > 7 days and >1200 g: 10 mg/kg PO/IV/IM q8h Documented hypersensitivity; hepatic Contraindications impairment CYP1A2 and CYP3A4 inhibitor; coadministration may increase toxicity of Interactions theophylline, digoxin, carbamazepine, and cyclosporine; may potentiate anticoagulant effects of warfarin

Pregnancy

Precautions

B - Usually safe but benefits must outweigh the risks. Monitor parenteral administration closely because of associated tissue damage; caution in liver disease; estolate formulation may cause cholestatic jaundice; GI adverse effects are common (give doses pc); discontinue use if nausea, vomiting, malaise, abdominal colic, or fever occur

Drug Name

Piperacillin (Pipracil) An acylampicillin with excellent activity against Pseudomonas aeruginosa . Effective Description against Klebsiella pneumonia, Proteus Descripción mirabilis, B fragilis, S marcescens, and many strains of Enterobacter . Administer in combination with an aminoglycoside. <7 days and 1200-2000 g: 75 mg/kg IV/IM q12h <7 days and >2000 g: 75 mg/kg IV/IM q8h Pediatric Dose > 7 days and 1200-2000 g: 75 mg/kg IV/IM q8h > 7 days and >2000 g: 75 mg/kg/dose IV/IM q6h Contraindications Documented hypersensitivity Synergic and antagonistic interactions observed when combined with various cephalosporins; piperacillin at high Interactions concentrations may physically inactivate aminoglycosides; coadministration with aminoglycosides has synergistic effects B - Usually safe but benefits must outweigh Pregnancy the risks. Dosage modification required in patients with Precautions impaired renal function Drug Category: Antivirals A viral infection, such as HSV, may masquerade as bacterial sepsis. At the onset of the infection, treatment must be initiated promptly to effectively inhibit the replicating virus. Drug Name Description Descripción

Acyclovir (Zovirax) Used for treatment of mucosal, cutaneous, and systemic HSV-1 and HSV-2 infections.

20 mg/kg/dose q8h IV; may increase dosing interval in patients <34 weeks PMA or in patients with significant hepatic or renal Pediatric Dose failure Treatment duration for localized infections is 14 d; for disseminated disease or CNS infections, treat for 21 d Contraindications Documented hypersensitivity Concomitant use of probenecid or zidovudine Interactions prolongs half-life and increases CNS toxicity of acyclovir B - Usually safe but benefits must outweigh Pregnancy the risks. Renal disease, dehydration, underlying neurologic disease, patients with hypoxia and hepatic or electrolyte abnormalities Precautions Periodic monitoring of CBC count is indicated Follow renal and hepatic function Drug Name Description Descripción

Pediatric Dose

Zidovudine (Retrovir, ZDV, AZT) A thymidine analog that inhibits viral replication. Used to treat patients with HIV. < 29 weeks PMA and 0-28 days: 1.5 mg/kg/dose IV q12h or 2 mg/kg/dose PO q12h < 29 weeks PMA and >28 days: 1.5 mg/kg/dose IV q8h or 2 mg/kg/dose PO q8h 30-34 weeks PMA and 0-14 days: 1.5 mg/kg/dose IV q12h or 2 mg/kg/dose PO q12h

30-34 weeks PMA and >14 days: 1.5 mg/kg/dose IV q8h or 2 mg/kg/dose PO q8h > 35 weeks PMA: 1.5 mg/kg/dose IV q6h or 2 mg/kg/dose PO q6h Contraindications Documented hypersensitivity Acyclovir, ganciclovir, or coadministration with drugs that inhibit glucuronidation (eg, Interactions acetaminophen, cimetidine, indomethacin) may increase toxicity C - Safety for use during pregnancy has not Pregnancy been established. Precautions Do not administer IM; bone marrow

compromise or impaired renal function; rare severe lactic acidosis and hepatomegaly with steatosis, including fatal cases, reported Drug Category: Antifungals Fungal infections can masquerade as bacterial infections and/or may appear at the end of prolonged antibacterial therapy. Their mechanism of action may involve an alteration of RNA and DNA metabolism or an intracellular accumulation of peroxide that is toxic to the fungal cell. Drug Name

Fluconazole (Diflucan) Used to treat susceptible fungal infections, including oropharyngeal, esophageal, and vaginal candidiasis. Also used for systemic candidal infections and cryptococcal Description meningitis. Fungistatic activity. Synthetic oral Descripción antifungal (broad-spectrum bistriazole) that selectively inhibits fungal CYP450 and sterol C-14 alpha-demethylation, which prevents conversion of lanosterol to ergosterol, thereby disrupting cellular membranes. Systemic infections and meningitis: Loading dose: 12 mg/kg IV Maintenance dose: < 29 weeks PMA and 0-14 days: 6 mg/kg/dose IV q72h < 29 weeks PMA and >14 days: 6 mg/kg/dose IV q48h 30-36 weeks PMA and 0-14 days: 6 mg/kg/dose IV q48h 30-36 weeks PMA and >14 days: 6 Pediatric Dose mg/kg/dose IV q24h 37-44 weeks PMA and 0-7 days: 6 mg/kg/dose IV q48h 37-44 weeks PMA and > 7 days: 6 mg/kg/dose IV q24h > 45 weeks PMA: 6 mg/kg/dose IV q24h Prophylaxis for ELBW infants in the NICU: 3 mg/kg/dose IV 2 times/wk Thrush: 6 mg/kg PO on day 1, then 3 mg/kg/dose PO q24h Contraindications Documented hypersensitivity Interactions CYP2C19 and CYP3A4 inhibitor; levels may

Pregnancy Precautions

increase with hydrochlorothiazide; long-term coadministration of rifampin may decrease levels; may decrease phenytoin clearance; may increase concentrations of theophylline, tolbutamide, glyburide, and glipizide; may increase effects of anticoagulants; may increase cyclosporine concentrations C - Safety for use during pregnancy has not been established. Perform periodic liver function and renal function tests; dosage modification required in patients with impaired renal function

Drug Name

Amphotericin B (Amphocin, Fungizone) Used to treat severe systemic infections and meningitis caused by susceptible fungi, such as Candida and Aspergillus species, H capsulatum, and C neoformans . Polyene Description antibiotic produced by a strain of S nodosus; Descripción can be fungistatic or fungicidal. Binds to sterols, such as ergosterol, in fungal cell membrane, causing intracellular components to leak and subsequent fungal cell death. Pediatric Dose 0.5-1 mg/kg IV q24h infused over 2-6 h Contraindications Documented hypersensitivity Coadministration with other nephrotoxic drugs (eg, antineoplastic agents, aminoglycosides, vancomycin, cyclosporine) may enhance renal Interactions toxicity; antineoplastic agents may increase risk of bronchospasm and hypotension; corticosteroids, digitalis, and thiazides may potentiate hypokalemia B - Usually safe but benefits must outweigh Pregnancy the risks. Decrease dose with renal impairment; determine BUN and serum creatinine levels weekly; monitor serum potassium and magnesium closely; check electrolytes, CBC, Precautions liver function studies, input and output, BP, and temperature regularly; administer slowly because cardiovascular collapse reported after rapid injection Drug Name

Amphotericin B, liposomal (AmBisome)

Used to treat severe systemic infections and meningitis caused by susceptible fungi, such as Candida and Aspergillus species, H capsulatum, and C neoformans . Used in systemic fungal infections resistant to amphotericin B or in patients with renal or Description hepatic failure. Consists of amphotericin B Descripción within a single bilayer liposomal drug delivery system. Polyene antibiotic produced by a strain of S nodosus; can be fungistatic or fungicidal. Binds to sterols, such as ergosterol, in fungal cell membrane, causing intracellular components to leak and subsequent fungal cell death. Pediatric Dose 5-7 mg/kg/dose IV q24h infused over 2 h Contraindications Documented hypersensitivity Coadministration with other nephrotoxic drugs (eg, antineoplastic agents, aminoglycosides, vancomycin, cyclosporine) may enhance renal Interactions toxicity; antineoplastic agents may increase risk of bronchospasm and hypotension; corticosteroids, digitalis, and thiazides may potentiate hypokalemia B - Usually safe but benefits must outweigh Pregnancy the risks. Can lead to anemia, thrombocytopenia, Precautions hypokalemia, nausea/vomiting, fever, and chills

Further Outpatient Care •

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The primary care provider (PCP) should evaluate the infant within one week of discharge from the hospital. The infant can be evaluated for superinfection and bacterial colonization associated with antibiotic therapy, especially if the therapy was prolonged. The PCP should evaluate growth and determine if the feeding regimen and activity have returned to normal. If neonatal sepsis was associated with meningitis, prolonged hypoxia, extracorporeal membrane oxygenation (ECMO) therapy, or brain abscess formation, the infant should be observed for several years to assess their neurodevelopment and should receive appropriate early intervention services and therapies when appropriate.

Transfer

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The infant may require transfer to a level III perinatal center, especially if he or she requires cardiopulmonary support, parenteral nutrition, or prolonged intravenous access. Multidisciplinary services available at larger centers may be necessary when treating an acutely compromised neonate.

Deterrence/Prevention •

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The Committee on Infectious Diseases of the AAP recommends that obstetric care include a strategy to manage early-onset GBS disease. Treat women with GBS bacteriuria during pregnancy when it is diagnosed and at delivery. The committee also recommends that women who have previously given birth to an infant with invasive GBS disease receive antibiotic prophylaxis during labor and delivery. To minimize the risk of early-onset GBS disease, practitioners should obtain screening vaginal and rectal cultures at 35-37 weeks' gestation for all pregnant women unless they have had GBS bacteriuria in the current pregnancy or a previous child with invasive GBS disease. The implementation of a screening protocol has led to a significant decrease in the incidence of neonatal GBS disease (see Image 1 ). Intrapartum antibiotic prophylaxis is indicated for all of the following (see Image 2 ): • o o o

o

Previous infant with GBS disease GBS bacteriuria in the current pregnancy Positive GBS screening culture results during the current pregnancy (unless a planned cesarean delivery, in the absence of labor or amniotic membrane rupture, is performed) Unknown GBS status (culture not done, or results unknown) and any of the following: o

Delivery earlier than 37 weeks' gestation Amniotic membrane rupture at 18 hours or later Intrapartum temperature of 100.4°F or higher ( > 38°C) See Image 3 for recommended antibiotic prophylaxis regimens.   

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Complications •

Infants with meningitis may acquire hydrocephalus and/or periventricular leukomalacia. They may also have complications associated with the use of aminoglycosides, such as hearing loss and/or nephrotoxicity.

Prognosis •

With early diagnosis and treatment, infants are not likely to experience long-term health problems associated with neonatal sepsis; however, if early signs and/or

risk factors are missed, the mortality rate increases. Residual neurologic damage occurs in 15-30% of neonates with septic meningitis.

Patient Education •

For excellent patient education resources, visit eMedicine's Blood and Lymphatic System Center . Also, see eMedicine's patient education article Sepsis (Blood Infection) .

MISCELLANEOUS Section 9 of 11 • • • • • • • • • • •

Authors and Editors Introduction Introducción Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Miscellaneous Multimedia Multimedia References Referencias

Medical/Legal Pitfalls • •

Delay in diagnosis and initiation of proper treatment may result in morbidity and mortality. Failure to provide prophylaxis to women with GBS infection may create liability if the infant subsequently becomes ill.

Special Concerns •

The Joint Commission on Infant Hearing of the AAP recommends that infants who received aminoglycosides should have audiology screening before discharge. Screen these infants again at 3 months, but no later than 6 months, to determine whether damage has occurred.

MULTIMEDIA Section 10 of 11 • • • • • • • • • • •

Authors and Editors Introduction Introducción Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Miscellaneous Multimedia Multimedia References Referencias

Media file 1: Incidence of early- and late-onset invasive group B Streptococcus (GBS) disease