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Neonatal sepsis may be categorized as early or late onset. 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 within 48-72 hours. Onset is most rapid in premature neonates. Early onset sepsis syndrome is associated with acquisition of microorganisms from the mother. 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. The microorganisms most commonly associated with early-onset infection include group B Streptococcus (GBS), Escherichia coli , coagulasenegative Staphylococcus, Haemophilus influenzae , and Listeria monocytogenes .1 Trends in the epidemiology of early onset sepsis show a decreasing incidence of GBS sepsis.2 This article primarily focuses on bacterial infection and sepsis. Please see relevant eMedicine chapters for discussion of congenital infection, fungal infection, and viral infection of the newborn. Late-onset sepsis syndrome occurs at 4-90 days of life and is acquired from the caregiving environment. 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. Trends in late-onset sepsis show an increase in coagulase-negative Streptococcal sepsis; most of these isolates are susceptible to first-generation cephalosporins.2 The infant's skin, respiratory tract, conjunctivae, GI tract, and umbilicus may become colonized from the environment, leading to the possibility of late-onset sepsis from invasive microorganisms. Vectors for such colonization may include vascular or urinary catheters, other indwelling lines, or contact from caregivers with bacterial colonization. Pneumonia is more common in early onset sepsis, whereas meningitis and bacteremia are more common in late-onset sepsis. 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 effectively identified and treated.
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. Over the ensuing decades, GBS replaced S aureus as the most common gram-positive organism that caused early-onset sepsis. During the 1990s, GBS and E coli continued to be associated with neonatal infection; however, coagulase-negative Staphylococcus epidermidis is now more frequently observed. 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. Meningoencephalitis and neonatal sepsis syndrome can also be caused by infection with adenovirus, enterovirus, or coxsackievirus. Additionally, sexually transmitted diseases (eg, gonorrhea, syphilis, herpes simplex virus [HSV], cytomegalovirus [CMV], hepatitis, human immunodeficiency virus [HIV], rubella, toxoplasmosis, Trichomonas vaginalis, Candida species) have all been implicated in neonatal infection. Bacterial organisms with increased antibiotic resistance have also emerged and have further complicated the
and barrier function. especially in the premature infant. including cellular immunity. 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. Also. therefore. humoral immunity. they are less able to move through the extracellular matrix of tissues to reach the site of inflammation and infection. Staphylococcus epidermidis. is deficient in chemotaxis and killing capacity. In addition to being a cause of neonatal sepsis. Cellular immunity The neonatal neutrophil or polymorphonuclear (PMN) cell. colony counts. numerous host factors predispose the newborn infant to sepsis. these cells represent an immature population. Slimes are produced at the site from the extracellular material formed by the organism. in whom it is considered the leading cause of late-onset infections. Although T cells are found in early gestation in fetal circulation and increase in number from birth to about age 6 months. Cytokine production by macrophages is decreased. as well as antibiotic action. however. neutrophil reserves are easily depleted because of the diminished response of the bone marrow. The chemotactic and bacteriocidal activity and the antigen presentation by these cells are also not fully competent at birth. Also. they may fail to degranulate in response to chemotactic factors. a culture growing coagulase-negative Staphylococcus may represent a contaminated sample rather than true coagulase-negative staphylococcal septicemia. Neonatal monocyte concentrations are at adult levels. The bacterial capsule polysaccharide adheres well to the plastic polymers of the catheters. macrophage chemotaxis is impaired and continues to exhibit decreased function into early childhood. Biofilms are formed on indwelling catheters by the aggregation of organisms that have multiplied with the protection provided by the adherence to the catheter. In addition to the specific microbial factors mentioned above. and presence of polymorphonuclear (PMN) cells on gram stain of the submitted specimen often help to differentiate true infection and positive culture from a false-positive or contaminated specimen. making coagulase-negative staphylococcal septicemia more difficult to treat. In neonatal ICUs (NICUs). proteins found in the organism (AtlE and SSP-1) enhance attachment to the surface of the catheter. The clinical setting. which may be associated with a corresponding decrease in T-cell production. Once in the tissues. especially in the premature infant. The colonization patterns in nurseries and personnel are reflected in the organisms currently associated with nosocomial infection. The toxins formed by this organism have also been associated with necrotizing enterocolitis. is increasingly seen as a cause of nosocomial or late-onset sepsis. The absolute numbers of macrophages are decreased in the lungs and are likely decreased in the liver and spleen. as well. a coagulase-negative Staphylococcus. which provides a barrier to the host defense. These naive cells do not proliferate as readily as adult . preventing C3 deposition and phagocytosis.management of neonatal sepsis. The adherence creates a capsule between microbe and catheter. therefore. which is vital for effective killing of bacteria. neonatal PMNs are less deformable. infants with lower birth weight and infants who are less mature have an increased susceptibility to these organisms. These factors are especially prominent in the premature infant and involve all levels of host defense. Lastly. 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. The limited ability of neonatal PMNs for phagocytosis and killing of bacteria is further impaired when the infant is clinically ill. Decreased adherence to the endothelial lining of blood vessels reduces their ability to marginate and leave the intravascular space to migrate into the tissues.
Complement protein production can be detected as early as 6 weeks' gestation. E coli. Barrier function The physical and chemical barriers to infection in the human body are present in the newborn but are functionally deficient. the number of these memory T cells increases. Although some infants have had complement levels comparable with those in adults. Skin and mucus membranes are broken down easily in the premature infant. 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. The neonate's ability to generate immunoglobulin in response to antigenic stimulation is intact. These cells are also functionally immature in that they produce far lower levels of interferon-gamma upon primary stimulation than do adult NK cells. Frequency United States The incidence of culture-proven sepsis is approximately 2 per 1000 live births. Natural killer (NK) cells are found in small numbers in the peripheral blood of neonates. Humoral immunity The fetus has some preformed immunoglobulin present. The early signs of sepsis in the . This deficiency is more marked in preterm infants. Because of the interdependence of the immune response. Neonatal sera have reduced opsonic efficiency against GBS. primarily acquired through nonspecific placental transfer from the mother. only 3-8% have culture-proven sepsis. Most of this transfer occurs in late gestation. and S pneumoniae because of decreased levels of fibronectin. rapidly rising with increasing postnatal age. unless the infant was exposed to an infectious agent during the pregnancy. the magnitude of the response is initially decreased. especially gram-negative bacteria. The neonate may receive immunoglobulin A (IgA) from breastfeeding but does not secrete IgA until 2-5 weeks after birth. Mature complement activity is not reached until infants are aged 6-10 months. This combination of findings may contribute to the severity of HSV infections in the neonatal period. deficiencies appear to be greater in the alternative pathway than in the classic pathway. The terminal cytotoxic components of the complement cascade that leads to killing of organisms. however. The neonate is also capable of synthesizing immunoglobulin M (IgM) in utero at 10 weeks' gestation. As the neonate is exposed to antigenic stimuli. the concentration of the various components of the complement system widely varies among individual neonates. are deficient. however.T cells when activated and do not effectively produce the cytokines that assist with B-cell stimulation and differentiation and granulocyte/monocyte proliferation. Most of the IgG is acquired from the mother during late gestation. such that lower levels are found with increasing prematurity. Neonates who are ill and/or premature are additionally at risk because of the invasive procedures that breach their physical barriers to infection. Of the 7-13% of neonates who are evaluated for neonatal sepsis. Immunoglobulin G (IgG) and immunoglobulin E (IgE) may be synthesized in utero. a serum protein that assists with neutrophil adherence and has opsonic properties. however. At birth. IgM levels are generally low at birth. A delay occurs in the formation of antigen specific memory function following primary infection. Response to bacterial polysaccharide antigen is diminished and remains so during the first 2 years of life. neonates are deficient in memory T cells. and the cytotoxic function of neonatal T cells is 50-100% as effective as adult T cells. thereby stimulating increased IgM production.
many newborns undergo diagnostic studies and the initiation of treatment before the presence of sepsis has been proven. occurs in 2-4 cases per 10. poor prenatal care. many asymptomatic neonates now undergo evaluation. poor maternal nutrition. Age Premature infants have an increased incidence of sepsis. maternal urinary tract infection. especially for gram-negative enteric bacilli. meconium staining. and Centers for Disease Control and Prevention (CDC)4 all have recommended sepsis screening and/or treatment for various risk factors related to GBS diseases. Additionally. The incidence of sepsis is significantly higher in infants with very low birth weight (<1000 g). . premature rupture of membranes (PROM). Infection is a major cause of fatality during the first month of life. Mortality/Morbidity The mortality rate in neonatal sepsis may be as high as 50% for infants who are not treated. inflammatory mediators associated with neonatal sepsis may contribute to brain injury and poor neurodevelopmental outcomes. low socioeconomic status. prematurity. and chorioamnionitis. maternal fever greater than 38°C. contributing to 13-15% of all neonatal deaths. is higher in males than in females. at 26 per 1000 live births. Race Black infants have an increased incidence of GBS disease and late-onset sepsis.000 live births and significantly contributes to the mortality rate in neonatal sepsis. Because the mortality rate of untreated sepsis can be as high as 50%. The risk for death or meningitis from sepsis is higher in infants with low birth weight than in full-term neonates History The most common risk factors associated with early onset neonatal sepsis include maternal group B Streptococcus (GBS) colonization (especially if untreated during labor).5 Risk factors implicated in neonatal sepsis reflect the stress and illness of the fetus at delivery. This is observed even after controlling for risk factors of low birth weight and decreased maternal age. birth asphyxia. maternal substance abuse. In the preterm infant. than in infants with a birth weight of 1000-2000 g. because the American Academy of Pediatrics (AAP). therefore. prolonged rupture of membranes. as well as the hazardous uterine environment surrounding the fetus before delivery. therefore. Neonatal meningitis.3 American Academy of Obstetrics and Gynecology (AAOG). at 8-9 per 1000 live births. most clinicians believe that the hazard of untreated sepsis is too great to wait for confirmation based on positive culture results. a serious morbidity of neonatal sepsis. preterm rupture of membranes. Sex The incidence of bacterial sepsis and meningitis. difficult delivery. maternal urinary tract infection. low birth weight. Other factors associated with or predisposing to early onset neonatal sepsis include low Apgar score (<6 at 1 or 5 min). recurrent abortion. most clinicians initiate treatment while awaiting culture results.newborn are nonspecific. it is responsible for 4% of all neonatal deaths. and congenital anomalies.
o Prematurity is associated with infection from cytomegalovirus (CMV). . and gastrointestinal tract pathology. Also. and the higher the likelihood of neonatal sepsis. however. GBS is responsible for approximately 50. when chorioamnionitis accompanies the rupture of membranes. • • • Maternal GBS status o The most common etiology of neonatal bacterial sepsis is GBS. hepatitis B. which may occur as part of the evaluation for PROM.Late onset sepsis is associated with the following risk factors: prematurity. but only 2 neonates per 1000 live births are infected. were associated with neonatal infection even when considered separately from the presence of chorioamnionitis. The type III strain has been shown to be most highly associated with CNS involvement in early-onset infection. Therefore. and heavy cigarette smoking during pregnancy. An awareness of the many risk factors associated with neonatal sepsis prepares the clinician for early identification and effective treatment. whereas types I and V have been associated with early-onset disease without CNS involvement. The relationship between duration of membrane rupture and neonatal infection is inversely related to gestational age. 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. Colonization at delivery is associated with neonatal infection. o The GBS organism colonizes the maternal GI tract and birth canal. H2 blocker/proton pump inhibitor use. o A recent multicenter study demonstrated that clinical chorioamnionitis and maternal colonization with GBS are the most important predictors of subsequent neonatal infection following PROM. the longer the delay between rupture of membranes and delivery. nasal cannula or continuous positive airway pressure (CPAP) use. o A study by Seaward et al found that more than 6 vaginal digital examinations. and Listeria species. Types I. thereby reducing mortality and morbidity. central venous catheterization (duration of >10 d). herpes simplex virus (HSV). Women with heavy GBS colonization and culture results that are chronically positive for GBS have the highest risk of perinatal transmission. Approximately 30% of women have asymptomatic GBS colonization during pregnancy. and each is related to the polysaccharide capsule of the organism. Campylobacter fetus. uterine bleeding in pregnancy.6 Prematurity: The relationship between preterm PROM and neonatal sepsis has already been described. the more premature an infant.000 maternal infections per year in women. heavy colonization at 23-26 weeks of gestation is associated with prematurity and low birth weight.6 o When membranes have ruptured prematurely before 37 weeks' gestation. the incidence of neonatal infection is quadrupled. other associations between prematurity and neonatal sepsis increase the risk for premature infants. however. toxoplasmosis. o 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. and III are commonly associated with neonatal GBS infection. II. Mycobacterium tuberculosis. Nine serotypes exist. PROM may occur in response to an untreated urinary tract infection or birth canal and is also associated with previous preterm delivery. o Preterm infants are more likely to require invasive procedures. such as umbilical catheterization and intubation. increasing the likelihood that the infant will be infected. a longer latent period precedes vaginal delivery.
o Physical 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. elevated maternal WBC count. o Pleural effusions may be observed in advanced disease.4°F (38°C). decreased breath sounds. These nonspecific clinical signs of early sepsis syndrome are also associated with other neonatal diseases. nasal flaring. infiltration. and destruction of bronchopulmonary tissue. Suspect chorioamnionitis in the presence of fetal tachycardia. grunting. This leads to infection with common organisms such as coagulase-negative staphylococci an organism usually not associated with severe sepsis. o Early onset GBS pneumonia has a particularly fulminant course. and a traumatic delivery. auscultation. Vascular congestion. Given the nonspecific nature of these signs. intracranial hemorrhage. Tachypnea. hemorrhage. with significant mortality in the first 48 hours of life. o Klebsiella species and S aureus are especially likely to generate severe lung damage. and grunting may be observed. and unexplained maternal temperature above 100. such as respiratory distress syndrome (RDS). Neonates with intrauterine pneumonia may also be critically ill at birth and require high levels of ventilatory support. 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. Fibrinous exudation into the alveoli leads to inhibition of pulmonary surfactant function and respiratory failure with an RDS-like presentation.7 • • • Congenital pneumonia and intrauterine infection: Inflammatory lesions are observed postmortem in the lungs of infants with congenital and intrauterine pneumonia. cyanosis. apnea. tachypnea and/or irregular respiration. and necrosis may occur. irregular respirations. costal and sternal retractions. Changes in findings from one examination to the next provides important information about the presence and evolution of sepsis. Because these infectious agents exist in the environment. o Infectious pneumonia is also characterized by pneumatoceles within the pulmonary tissue. uterine tenderness. Coughing. This damage is partly due to the granulocytes' release of prostaglandins and leukotrienes. o Radiographic evaluation may demonstrate segmental or lobar atelectasis or a diffuse reticulogranular pattern. purulent amniotic fluid. much like what is observed in RDS. Chorioamnionitis: The relationship between chorioamnionitis and other risk variables is strong. Postnatal infection: Postnatally acquired pneumonia may occur at any age. o Premature infants have less immunologic ability to resist and combat infection. the likely cause depends heavily on the infant's recent environment. The aspiration may lead to infection with pulmonary changes. A systematic physical assessment of the infant is best performed in series and should include observation. rales. and palpation in that order to obtain the most information from the examination. producing microabscesses and empyema. The chest radiograph may depict bilateral consolidation or pleural effusions. and cyanosis may be observed. moderate retracting. providing treatment for suspected neonatal sepsis while excluding other disease processes is prudent. metabolic disorders. 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.• Intrauterine growth retardation and low birth weight are also observed in CMV and toxoplasmosis infections. If .
The lateral ventricles may become multiloculated. efforts to regulate body temperature can cause metabolic acidosis. o Ventriculitis Ventriculitis is the initiating event. Hypoglycemia accompanied by hypotension may be secondary to an inadequate response from the adrenal gland and may be associated with a low cortisol level. 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. and jaundice all are metabolic signs that commonly accompany neonatal sepsis syndrome. H influenzae. making treatment more difficult. hyperglycemia. and Listeria species (5-10%) infections. particularly at the aqueduct of Sylvius. an initial early phase characterized by pulmonary hypertension. When present. and Proteus may cause meningitis. A toxin derived from the polysaccharide capsule of type III Streptococcus has also been shown to cause pulmonary hypertension. the choice of antibiotic agents in such cases requires knowledge of the likely causative organisms and the local antibiotic-resistance patterns. Acute and chronic histologic features are associated with specific organisms. Cardiac signs: In overwhelming sepsis. Serratia. Metabolic signs: Hypoglycemia. poor capillary perfusion. with inflammation of the ventricular surface. These cardiopulmonary disturbances may be due to the activity of granulocyte-derived biochemical mediators. These biochemical agents have vasoconstrictive actions that result in pulmonary hypertension when released in pulmonary tissue. and edema. Early in the infection. Enterobacter. When meningitis develops from ventriculitis. The infant has an increased glucose requirement because of sepsis. an arachidonic acid metabolite. and hypoxemia may occur. Neurologic signs: Meningitis is the common manifestation of infection of the CNS. such as hydroxyl radicals and thromboxane B2. These late signs of shock are indicative of severe compromise and are highly associated with mortality. The early phase of pulmonary hypertension is followed by further progressive decreases in cardiac output with bradycardia and systemic hypotension. and species of Pseudomonas. although other organisms such as S pneumoniae. Klebsiella.• • • the infant has remained hospitalized in an NICU environment. metabolic acidosis. Glial bridges may develop by these tufts and cause obstruction. Additionally. The high glycogen content in the neonatal choroid plexus provides an excellent medium for the bacteria. When infants are hypothermic or they are not kept in a neutral thermal environment. especially with endotracheal intubation and mechanical ventilation. ependymitis occurs with disruption of the ventricular lining and projections of glial tufts into the ventricular lumen. Multiloculated ventricles can isolate organisms in an area. o Arachnoiditis: This is the next phase and is the hallmark of meningitis. which is similar to forming abscesses. these hospital-acquired organisms frequently demonstrate multiple antibiotic resistances. Therefore. Jaundice occurs in response to decreased hepatic glucuronidation caused by both hepatic dysfunction and increased erythrocyte destruction. 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. Exudative material usually appears at the choroid plexus and is external to the plexus. decreased cardiac output. Then. S aureus. it complicates effective treatment because achieving adequate antibiotic levels in the cerebral ventricles is difficult. the exudate is . Staphylococcus epidermis. It is primarily associated with GBS (36%). ventricular obstruction causes additional problems. Metabolic acidosis is due to a conversion to anaerobic metabolism with the production of lactic acid. The infant manifests overt shock with pallor. the organisms may include Staphylococcus or Pseudomonas species. E coli (31%). The infant may also have impaired nutrition from a diminished energy intake.
Occlusion of the arteries rarely occurs. Laboratory findings Meningitis due to early onset neonatal sepsis usually occurs within 24-48 hours and is dominated by nonneural signs. Lesions occur because of multiple venous occlusions. Cerebral edema: This may occur during the acute state of meningitis. and positive culture results. and some lymphocytes and plasma cells. cranial nerve signs. bulging anterior fontanel. however. It may also be related to cytotoxins of microbial origin. reference range CSF protein and glucose concentrations are found in only 15-20%. coma. Neuronal loss occurs. This vascular involvement is apparent within the first days of meningitis and becomes more prominent during the second and third weeks. Multiple fibrin thrombi are especially associated with hemorrhagic infarction. Impairment of consciousness (ie. 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. a decreased CSF glucose concentration. Temperature instability is observed with neonatal sepsis and meningitis. venous involvement is more severe. stupor with or without irritability). bacteria. which is responsible for obstruction. many of these physical examination findings are subtle or nonapparent. Thick strands of collagen form. focal cerebral signs. it is within the reference range in only 4%. Even culture-proven meningitis may not demonstrate white cell changes in the CSF. Vasculitis: This extends the inflammation of the arachnoid and ventricles to the blood vessels surrounding the brain. Reference range CSF protein and glucose concentrations are found in about 50% of patients with GBS meningitis. Exudate is prominent around the blood vessels and extends into the brain parenchyma. Early onset GBS meningitis is characterized by much less arachnoiditis than late-onset GBS meningitis. Herniation of edematous supratentorial structures does not generally occur in neonates because of the cranium's distensibility. either in response to pyrogens secreted by the bacterial organisms or from sympathetic . but it is likely related to vasculitis and the increased permeability of blood vessels. The CSF findings in infectious neonatal meningitis are an elevated WBC count (predominately PMNs). and nuchal rigidity occur. the exudate decreases. After this period. macrophages. Infarction: This is a prominent and serious feature of neonatal meningitis. and macrophages. in gram-negative meningitis. the dominant cells are histiocytes. In the neonate. The CSF WBC count is within the reference range in 29% of GBS meningitis infections. in gram-negative infections. extensor rigidity. In the second and third weeks of infection. Neurologic signs may include stupor and irritability. Meningitis due to late-onset disease is more likely to demonstrate neurologic signs (80-90%). however.o o o o primarily polymorphonuclear (PMN) cells. It occurs in 30% of infants who die. Hydrocephalus results. an elevated protein level. Exudate infiltration of cranial roots 38 occurs. especially in the cerebral cortex. and periventricular leukomalacia may subsequently appear in areas of neuronal cell death. and arachnoid fibrosis occurs. The cause is unknown. The edema may be severe enough to greatly diminish the ventricular lumen. the proportion of PMNs decreases. Phlebitis may be accompanied with thrombosis and complete occlusion. seizures. The decrease in CSF glucose concentration does not necessarily reflect serum hypoglycemia. Glucose concentration abnormalities are more severe in late-onset disease and with gramnegative organisms. Overt signs of meningitis occur in only 30% of cases. which are frequently hemorrhagic.
000 may occur in neonatal sepsis in response to the cellular products of the microorganisms. and poor feeding. the neutrophil count does not provide adequate confirmation of sepsis. The immunologic defenses of the intestinal tract are not mature. Necrotizing enterocolitis (NEC) has been associated with the presence of a number of species of bacteria in the immature intestine. including gastric blood. this proliferation is not fully effective in responding to a microorganism because antibody response and cytokine formation is immature until approximately 46 weeks. Because of the appearance of newly formed platelets. and the maximum acceptable ratio for excluding sepsis during the first 24 hours is 0. If infants show signs consistent with impaired coagulation. to replace coagulation factors consumed in association with DIC. bleeding from intravenous or laboratory puncture sites. Normal WBC counts may be initially observed in as many as 50% of cases of culture-proven sepsis. Thrombocytopenia may be a presenting sign and can last as long as 3 weeks. the elevated I/T ratio should be used in combination with other signs. 10-60% of infants with sepsis have thrombocytopenia. Total neutrophil count (PMNs and immature forms) is slightly more sensitive in determining sepsis than total leukocyte count (percent lymphocyte + monocyte/PMNs + bands). the ratio falls to 0. nonseptic newborns. Signs of neurologic hyperactivity are more likely when late-onset meningitis occurs. o Neutrophil ratios have been more useful in diagnosing or excluding neonatal sepsis. mean platelet volume (MPV) and platelet distribution width (PDW) are shown to be significantly higher in neonatal sepsis after 3 days.16. lethargy. the immature-to-total (I/T) ratio is the most sensitive. Because of the myriad of causes of thrombocytopenia and its late appearance in neonatal sepsis. are only observed in two thirds of infants. therefore. Infants who are not infected may also demonstrate abnormal WBC counts related to the stress of delivery or several other factors. limiting the positive predictive value of these ratios. Predicting which infants will be affected at the onset of sepsis is difficult. evaluating coagulation by checking these values is important. All immature neutrophil forms are counted. The neonate is most likely to be hypothermic. or other bleeding.12 within 60 hours of life. the presence of thrombocytopenia does not aid the diagnosis of neonatal sepsis. o Disseminated intravascular coagulation (DIC) can occur in infected infants. partial thromboplastin time (PTT). and periventricular or intraventricular hemorrhage. Abnormal neutrophil counts. and elevations may be observed with other physiological events. severe perinatal asphyxia. when diagnosing sepsis.• • nervous system instability. taken at the time of symptom onset. maternal hypertension. These cellular products cause platelet clumping and adherence leading to platelet destruction. In most healthy. and fibrinogen and D-dimer levels and may need blood products. including fresh frozen plasma (FFP) and cryoprecipitate. Neutropenia is observed in sepsis. Thrombocytopenia with counts less than 100. however. therefore. The infant may also have decreased tone. The sensitivity of the I/T ratio has ranged from 60-90%. especially in the preterm infant. Affected infants show abnormalities in prothrombin time (PT). Lymphocytes proliferate in the intestines in response to mitogen stimulation. and bacterial overgrowth of these organisms in the neonatal lumen is a component of the multifactorial pathophysiology of NEC. Hematologic signs o The platelet count in the healthy newborn is rarely less than 100. GI signs: The intestinal tract can be colonized by organisms in utero or at delivery by swallowing infected amniotic fluid. . they remain very nonspecific and have low positive predictive value.000/µL in the first 10 days of life. A differential may be of use in diagnosing sepsis. o Although WBC counts and ratios are more sensitive for determining sepsis than platelet counts.
or long-range toxic effects of these drugs have occurred. thereby eliminating the best response to these resistant organisms. Resistance and sensitivities for the organism isolated from cultures are used to select the most effective drug. This may result in negative culture results in an infant who actually has bacteremia or sepsis. exchange transfusion. • In the United States and Canada. but on a review of all . however. especially group B Streptococcus (GBS). The drug dosage or interval may need to be adjusted to optimize the drug serum levels. S epidermis. intravenous immune globulin (IVIG) replacement.Treatment Medical Care When neonatal sepsis is suspected. 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. Oxacillin therapy is preferred by some clinicians because of this. This provides coverage for gram-positive organisms. the clinician must decide whether to provide continued treatment. Additional therapies have been investigated for the treatment of neonatal sepsis. antibiotic coverage should be directed at organisms implicated in hospital-acquired infections. renal function and hearing screening should be considered after completion of the therapeutic course to determine if any short. especially if she received the therapy within several hours of delivery. a small number of infants documented to have had sepsis by postmortem examination had negative culture results during their initial sepsis evaluation. including S aureus. o If culture results are negative but the infant has significant risk or clinical signs for sepsis. These additional therapies include granulocyte transfusion. Two to three days of negative culture results should provide confidence in the data. Begin antibiotics as soon as diagnostic tests are performed. and ticarcillin. the current approach to treat early onset neonatal sepsis syndrome includes combined intravenous (IV) aminoglycoside and expanded-spectrum penicillin antibiotic therapy. treatment should be initiated immediately because of the neonate's relative immunosuppression. resistance by gram-negative organisms has occurred with their use. o Aminoglycosides and vancomycin both have the potential to produce ototoxicity and nephrotoxicity and should therefore be used with caution. however. no substantial clinical trials have shown that these treatments are beneficial. and Pseudomonas species. Most strains of S aureus produce beta-lactamase. o Cephalosporins are attractive in the treatment of nosocomial infection because of their lack of dose-related toxicity and adequate serum and cerebrospinal fluid (CSF) concentration. 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. o Management is further complicated if the mother received antibiotic therapy before delivery. carbenicillin. The serum drug level is assessed around the third dose or at 48 hours after starting treatment to determine if levels are within the therapeutic range. the need for continued therapy should be based not on a single test. and gram-negative bacteria. such as E coli. and the use of recombinant cytokines. ampicillin. o If an infection appears to be nosocomial. concern exists that overuse of this drug may lead to vancomycin-resistant organisms. Ceftriaxone displaces bilirubin from serum albumin and should be used with caution in infants with significant hyperbilirubinemia. Vancomycin has been favored for this coverage. With this in mind. however. In addition. however. which makes them resistant to penicillin G.
even if culture results remain negative at 48-72 hours. A follow-up lumbar puncture within 24-36 hours after antibiotic therapy has been initiated to determine if the CSF is sterile is recommended. Dose-related problems with this therapy decrease its usefulness in neonatal populations. Granulocyte transfusion has been shown to be suitable for infants with significant depletion of the storage neutrophil pool. especially for GBS sepsis. and pulmonary leukocyte sequestration. the documentation of storage pool depletion requires a bone marrow aspiration. The number of potential adverse effects. Chloramphenicol or trimethoprim-sulfamethoxazole has been shown to be effective in the treatment of highly resistant bacterial meningitis. CSF results. At present. vital signs. Treatment for 7-10 days may be appropriate. maternal and intrapartal risk factors. Surgical Care If an abscess is present. Therefore. Monitoring of blood pressure. modification of drug type or dosage is required to adequately treat the meningitis. Cardiopulmonary support and intravenous nutrition may be required during the acute phase of the illness until the infant's condition stabilizes. platelets. If organisms are still present. These therapies have shown promise in animal models. the data do not support the routine use of IVIG in neonatal sepsis. and the granulocyte transfusion must be administered quickly to be beneficial. and coagulation studies is vital. and clinical progress. Trimethoprimsulfamethoxazole should not be used if hyperbilirubinemia and kernicterus are of concern in the newborn. C-reactive protein (CRP) trends. Continue antibiotic treatment for 2 weeks after sterilization of the CSF or for a minimum of 2 weeks for grampositive meningitis and 3 weeks for gram-negative meningitis. including culture results. The need for blood product transfusion including packed RBCs (PRBCs). 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. and fresh frozen plasma (FFP) is not uncommon. however. o Meningitis complicated by seizures or persistent positive cultures may require extended IV antimicrobial therapy. such as graft versus host reaction. the CBC count and differential. Recombinant human cytokine administration to stimulate granulocyte progenitor cells has been studied as an adjunct to antibiotic therapy.• • • • diagnostic data. this therapy remains an experimental treatment. The effect has been transient. These infants may also require an antimicrobial that has better penetration of the blood-brain barrier to achieve therapeutic drug concentrations in the CSF. is considerable. hematocrit. . radiographs. but their use in clinical neonatology remains experimental. difficulties with IVIG therapy for neonatal sepsis exist. however. Surgical consultation for central line placement may be necessary in infants who require prolonged IV antimicrobial therapy for sepsis. The infant with sepsis may require treatment aimed at the overwhelming systemic effects of the disease. transmission of cytomegalovirus (CMV) or hepatitis B. but require pretreatment or immediate treatment to demonstrate efficacy. o Infants with bacterial meningitis often require different dosages of antibiotics and longer courses of treatment. clinically available IVIG solutions do not contain type-specific antibody and adverse effects associated with the infusion of any blood product can occur. if peripheral IV access can not be maintained. The use of granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF) has been studied in clinical trials. surgical drainage may be necessary because intravenous antibiotic therapy cannot adequately penetrate an abscess and because antibiotic treatment alone is ineffective. platelets.
Feeding may be restarted via a nasogastric tube for the infant with serious compromise. Antibiotics . and piperacillin. The VP shunt may cause long-term neurologic complications. minerals. and electrolytes is adequate during this period. consultation with a pediatric neurologist may be necessary for assistance with outpatient follow-up of neurological sequelae. disconnection. parental contact is important. or has had a complicated clinical course. however. or bowel are uncommon. Consultations Infectious disease consultation is useful. and perforation of the bladder. Pediatric surgical consultation may be necessary if sepsis is complicated by abscess. Medication Some of the antibiotics commonly used to treat neonatal sepsis syndrome include ampicillin. sensitivities of the bacterial agent. Abdominal obstruction. or shunt infection. vancomycin. Consider parenteral nutrition to ensure that the patient's intake of calories. if the differential diagnosis includes necrotizing enterocolitis (NEC). including slit-ventricle syndrome. cefotaxime. breast milk is the enteral diet recommended by the AAP. omental cysts. is infected with an unusual organism. feeding intolerance. Activity The infant with temperature instability needs thermoregulatory support with a radiant warmer or incubator. seizures. a ventriculoperitoneal (VP) shunt may be necessary to drain off the excess fluid. especially if the infant is not responding to treatment.If hydrocephalus associated with neonatal meningitis occurs. 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. migration of catheter. • • • If neonatal meningitis is identified. erythromycin. and prevalent nosocomial infection trends in the nursery. or poor feeding. the outcome for children with VP shunt placement is generally good with careful follow-up. Inpatient consultation may be necessary if meningitis is complicated by seizures. and progressive accumulation of CSF is present. gentamicin. The immediate complications of shunt placement are overdrainage. Diet The neonate may need to be given nothing by mouth (NPO) during the first days of treatment because of gastrointestinal symptoms. For most infants. and craniosynostosis. neuro-ophthalmological problems. or if central line placement is required. The choice of antibiotic agents should be based on the specific organisms associated with sepsis. gallbladder. Once the infant is stable from a cardiopulmonary standpoint. protein. equipment failure. metronidazole. Viral infections such as herpes and fungal infections can masquerade as bacterial infections.
Recent publications indicate ampicillin (in combination with gentamicin) is the first-line therapy for suspected sepsis in the newborn. such as GBS. Recent publications indicate gentamicin (in combination with ampicillin) is the first-line therapy for suspected sepsis in the newborn. . weight). this is not a first-line agent for neonatal sepsis because of its association with increased mortality. some strains of H influenzae. Ineffective against Listeria and enterococci. Neonatal doses for antibiotics may be based on several variables (eg. postnatal age. Ampicillin A beta-lactam antibiotic that is bacteriocidal for susceptible organisms. Pediatric ≤ 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 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 • DosingInteractionsContraindicationsPrecautionsDosingInteractionsContraindicationsPrecautionsDosingInteractionsContraindicati onsPrecautions Gentamicin An aminoglycoside that is bacteriocidal for susceptible gram-negative organisms. Listeria.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. Proteus. Pediatric ≤ 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 30-34 weeks PMA and 0-7 days: 4. In most recent publications. and Serratia species. Concern exists about the emergence of drug-resistant gram-negative bacteria at a more rapid rate than with traditional penicillin and aminoglycoside coverage.Empiric antimicrobial therapy must be comprehensive and should cover all likely pathogens in the context of the clinical setting. postmenstrual age [PMA]. non– penicillinase-producing Staphylococcus. Has good serum and CSF concentrations. such as E coli and Pseudomonas. IM may be used if IV access is difficult • DosingInteractionsContraindicationsPrecautionsDosingInteractionsContraindicationsPrecautionsDosingInteractionsContraindicati onsPrecautions Cefotaxime (Claforan) Third-generation cephalosporin with excellent in vitro activity against GBS and E coli and other gram-negative enteric bacilli. Effective in combination with ampicillin for GBS and Enterococcus. Use in combination with ampicillin. and meningococci.
gentamicin.5 mg/kg/dose IV/PO q8h Oxacillin (Bactocill) .5 mg/kg/dose IV/PO q48h ≤ 29 weeks PMA and >28 days: 7. ventriculitis.5 mg/kg/dose IV/PO q24h 30-36 weeks PMA and 0-14 days: 7. Pediatric Loading dose: 15 mg/kg PO/IV Maintenance dose: ≤ 29 weeks PMA and 0-28 days: 7. Especially important in the treatment of MRSA. Pediatric ≤ 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 Metronidazole (Flagyl) Antimicrobial that has shown effectiveness against anaerobic infections.5 mg/kg/dose IV/PO q24h 30-36 weeks PMA and >14 days: 7. or cephalothin may be required with endocarditis or CSF shunt infection by coagulase-negative staphylococcus.5 mg/kg/dose IV/PO q12h ≥ 45 weeks PMA: 7. Recommended therapy when coagulase-negative staphylococcal sepsis is suspected. Also useful in treatment of infections caused by T vaginalis.5 mg/kg/dose IV/PO q12h 37-44 weeks PMA and 0-7 days: 7. especially Bacteroides fragilis meningitis.5 mg/kg/dose IV/PO q24h 37-44 weeks PMA and >7 days: 7. and endocarditis.Pediatric ≤ 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 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 Vancomycin (Vancocin) Bacteriocidal agent against most aerobic and anaerobic gram-positive cocci and bacilli. Therapy with rifampin.
treatment must be initiated promptly to effectively inhibit the replicating virus. Used in the treatment of infections caused by penicillinase-producing staphylococci. Administer in combination with an aminoglycoside. S marcescens. Pediatric 25-50 mg/kg dose IV Postmenstural age/Postnatal days/Dose interval <29 weeks and 0-28 days: q12h <29 weeks and >28 days: q8h 30-36 weeks and 0-14 days: q12h 30-36 weeks and >14 days: q8h 37-44 weeks and 0-7 days: q12h 37-44 weeks and >7 days: q8h >45 weeks (all postnatal ages): q6h Piperacillin An acylampicillin with excellent activity against Pseudomonas aeruginosa. Effective against Klebsiella pneumonia. Pediatric <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 ≥ 7 days and <1200 g: 5 mg/kg PO/IV/IM q12h ≥ 7 days and ≥ 1200 g: 10 mg/kg PO/IV/IM q8h Antivirals A viral infection. B fragilis. such as HSV. At the onset of the infection. Acyclovir (Zovirax) . and Chlamydia trachomatis. May be used to initiate therapy when a staphylococcal infection is suspected. such as Neisseria species. Ureaplasma urealyticum. may masquerade as bacterial sepsis.Bactericidal antibiotic that inhibits cell wall synthesis. Pediatric <7 days and 1200-2000 g: 75 mg/kg IV/IM q12h <7 days and >2000 g: 75 mg/kg IV/IM q8h ≥ 7 days and 1200-2000 g: 75 mg/kg IV/IM q8h ≥ 7 days and >2000 g: 75 mg/kg/dose IV/IM q6h Erythromycin base (Erythrocin) Macrolide antimicrobial agent that is primarily bacteriostatic and is active against most gram-positive bacteria. Proteus mirabilis. Not well concentrated in the CSF. Mycoplasma pneumoniae. and many strains of Enterobacter.
Used to treat patients with HIV. and vaginal candidiasis.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 q12h or 2 mg/kg/dose PO q12h 30-34 weeks PMA and >14 days: 1. 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. Synthetic oral antifungal (broad-spectrum bistriazole) that selectively inhibits fungal CYP450 and sterol C-14 alpha-demethylation. Fluconazole (Diflucan) Used to treat susceptible fungal infections. thereby disrupting cellular membranes. Pediatric 20 mg/kg/dose IV q8h.5 mg/kg/dose IV q6h or 2 mg/kg/dose PO q6h • DosingInteractionsContraindicationsPrecautionsDosingInteractionsContraindicationsPrecautionsDosingInteractionsContraindicati onsPrecautionsAntifungals Fungal infections can masquerade as bacterial infections and/or may appear at the end of prolonged antibacterial therapy. including oropharyngeal. Also used for systemic candidal infections and cryptococcal meningitis.5 mg/kg/dose IV q8h or 2 mg/kg/dose PO q8h 30-34 weeks PMA and 0-14 days: 1. esophageal. ZDV. and systemic HSV-1 and HSV-2 infections. which prevents conversion of lanosterol to ergosterol. cutaneous. Fungistatic activity.Used for treatment of mucosal. Pediatric 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 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 . AZT) A thymidine analog that inhibits viral replication. for disseminated disease or CNS infections.5 mg/kg/dose IV q8h or 2 mg/kg/dose PO q8h ≥ 35 weeks PMA: 1. may increase dosage interval in patients <34 weeks PMA or in patients with significant hepatic or renal failure Treatment duration for localized infections is 14 d. Pediatric ≤ 29 weeks PMA and 0-28 days: 1. treat for 21 d • DosingInteractionsContraindicationsPrecautionsDosingInteractionsContraindicationsPrecautionsDosingInteractionsContraindicati onsPrecautions Zidovudine (Retrovir.
Consists of amphotericin B within a single bilayer liposomal drug delivery system. and C neoformans. causing intracellular components to leak and subsequent fungal cell death. Polyene antibiotic produced by a strain of S nodosus. Binds to sterols. Fungizone) Used to treat severe systemic infections and meningitis caused by susceptible fungi. can be fungistatic or fungicidal. Liposomal product may be considered for systemic fungal infections resistant to amphotericin B or in patients with renal or hepatic failure. H capsulatum.Prophylaxis for ELBW infants in the NICU: 3 mg/kg/dose IV 2 times/wk Thrush: 6 mg/kg PO on day 1. • • • • Dosing Interactions Contraindications Precautions Adult Pediatric Conventional: 0.5-1 mg/kg IV q24h infused over 2-6 h Liposomal: 3-5 mg/kg/dose IV q24h infused over 2 h . in fungal cell membrane. then 3 mg/kg/dose PO q24h • DosingInteractionsContraindicationsPrecautionsDosingInteractionsContraindicationsPrecautionsDosingInteractionsContraindicati onsPrecautions Amphotericin B (AmBisome. such as ergosterol. such as Candida and Aspergillus species.
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