Neonatal Sepsis


Article Author:
Esra Shermadou


Article Editor:
Georgios Mavrogeorgos


Editors In Chief:
Venkat Minnaganti
John Brusch
Janak Koirala


Managing Editors:
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Frank Smeeks
Kristina Soman-Faulkner
Benjamin Eovaldi
Radia Jamil
Sobhan Daneshfar
Pritesh Sheth
Hassam Zulfiqar
Steve Bhimji
John Shell
Matthew Varacallo
Ahmad Malik
Mark Pellegrini
James Hughes
Beata Beatty
Hajira Basit
Phillip Hynes
Kavin Sugumar


Updated:
10/27/2018 12:31:45 PM

Introduction

Neonatal sepsis continues to remain a leading cause of morbidity and mortality worldwide. Neonatal sepsis is divided into 2 groups based on the age of presentation: early-onset sepsis (EOS) and late-onset sepsis (LOS). EOS refers to sepsis in neonates at 72 hours or before 7 days of life (definitions based on different experts). LOS is defined as sepsis occurring at or after 72 hours or 7 days of life, again based on different experts.[1]

Etiology

EOS is generally caused by vertical transmission of pathogens from the female genitourinary system. These pathogens can ascend up the vagina, the cervix, and the uterus, and can also infect the amniotic fluid. Neonates can become infected in utero or during delivery as they pass through the vaginal canal. Typical bacterial pathogens for EOS include Group B streptococcus (GBS), Escherichia coli, coagulase-negative Staphylococcus, Haemophilus influenza, or Listeria monocytogenes. The incidence of GBS infection has decreased but has not been completely eradicated since the introduction of intrapartum antibiotic prophylaxis (IAP) in 1990 for colonized females. Other maternal factors that increase the risk of neonatal sepsis include chorioamnionitis, delivery before 37 weeks, and prolonged rupture of membranes greater than 18 hours.[2]

LOS usually occurs via horizontal transmission after delivery, such as from environmental factors or contact from healthcare workers or caregivers. LOS can also be caused by a late manifestation of vertically transmitted infection. Infants that require intravascular catheter insertion, or other invasive procedure that disrupts the mucosa, are at increased risk for developing LOS. Preterm neonates are at greater risk for this than term neonates, as they tend to require more invasive procedures than term neonates. Many bacterial and viral pathogens are associated with LOS but coagulase-negative staphylococcal species, especially Staphylococcus epidermidis, is the leading cause, responsible for greater than 50% of LOS cases in industrialized countries.[2]

Epidemiology

EOS rates have decreased in the United States with the introduction of IAP in colonized females. Rates of LOS have remained relatively the same. In the United States, cases of sepsis with positive blood cultures account for 2two of every 1000 births (UTD). Seven percent to 13% of all neonates are worked up for sepsis, but only 3% to 8% develop positive cultures. Due to the nonspecific neonatal presentation for sepsis and the high risk of mortality and morbidity without treatment, many asymptomatic neonates undergo a sepsis workup, if concerning factors are present.[2]

The incidence of sepsis is significantly higher in premature infants as well as those with very low birth weights (VLBW) of less than 1000 grams, compared to term infants and those with weight greater than 1000 grams at birth.[3] African American infants have an increased risk of GBS and LOS, likely secondary to the higher rate of GBS carrier rates in African American females. Among all races, males have a higher risk of sepsis and meningitis, especially with gram-negative enteric bacilli.[2]

Pathophysiology

The immature immune system of the neonate is a large contributing factor in the development of neonatal sepsis. Polymorphonuclear neutrophils, macrophages, and T lymphocytes are all important in fighting off infection. These cells, however, are not fully developed and are incapable of carrying out a complete inflammatory response in neonates. Furthermore, neonates have a limited number of immunoglobulins at birth and are unable to generate a large antigenic quantity during this time. Maternal-fetal immunoglobulin transfer occurs late in gestation, putting premature neonates at greater risk of being immunocompromised.[3]

History and Physical

Signs and symptoms of neonatal sepsis can range from nonspecific or vague symptoms to obvious shock. Physicians must, therefore, be aware of any factors that may increase an infant’s risk of developing sepsis. Nonspecific symptoms include irritability, lethargy, respiratory distress, hyperpyrexia, hypopraxia, hypotension, jaundice, tachycardia, poor perfusion, and poor feeding. Prematurity and very low birth weights are also important risk factors to consider. Maternal factors that put neonates at risk of sepsis include GBS status, the presence of chorioamnionitis, infant prematurity, or prolonged rupture of membranes.[2]

Evaluation

While positive cultures are typically considered the gold standard for the diagnosis of sepsis, studies have shown that most neonatal septic workups result in negative blood cultures. Furthermore, given the vague or nonspecific symptoms with which neonates present, blood cultures may not be immediately drawn. Blood cultures should be drawn from 2 different sites to rule out contamination. Cultures should also be drawn from the catheter site if one is in place. Lumbar puncture with cerebrospinal fluid (CSF) analysis and culture should also be evaluated when considering sepsis, as meningeal signs may not be present on the physical exam. Lumbar puncture should be repeated if the patient fails to improve on antibiotic treatment, if symptoms worsen or if positive blood cultures result. Urine culture should be obtained if LOS is suspected. Isolated infections of the urinary tract in those younger than 3 to 7 days is usually indicative of severe bacteriemia or congenital anomalies. New technology using polymerase chain reaction (PCR) is currently being studied as a diagnostic tool to identify sepsis and the causative organism faster than blood cultures.[2]

Complete blood count (CBC) with differential and C-reactive protein (CRP) are also important lab tests to obtain and are often collected on a serial basis. White blood cells (WBC) may be falsely elevated, especially after birth. Abnormal absolute neutrophil counts, especially neutropenia, and elevated immature to the total neutrophil ratio (I/T) are often strong indicators of neonatal sepsis. CRP is an acute phase reactant made in the liver and may not be immediately elevated due to initially slow production rate in the liver. Serial CRP levels may be helpful in guiding antibiotic therapy. Other inflammatory markers, including procalcitonin, haptoglobin, and cytokines can also be obtained to support the diagnosis or to monitor during treatment. Radiography of the chest may be performed to look for any pulmonary findings. CT or MRI of the head may be warranted if concerns for hydrocephalus, infarction, or abscess exist.[1]

Treatment / Management

Empiric treatment with antibiotics should be started as soon as sepsis is clinically suspected, even without confirmatory lab data. Typical treatment regimens include intravenous (IV) broad-spectrum penicillin and aminoglycosides to cover for the most common pathogens in neonates: GBS, E. coli, and L. monocytogenes. The combination of ampicillin and gentamicin is the most commonly used antibiotic regimen. With LOS, nosocomial coverage should be provided for the hospital-acquired pathogens such as coagulase-negative Staphylococcus, S. aureus, and Pseudomonas species. Third-generation cephalosporins provide adequate coverage for these pathogens. However, ceftriaxone should be avoided, as it can lead to hyperbilirubinemia. Antibiotic treatment should be tailored to treat the most likely organisms based on history, risk factors, and antimicrobial resistance in the area. Increasing antibiotic resistance is a concern for neonatal sepsis and treatment should always be de-escalated as soon as possible.[1]

Differential Diagnosis

Given the nonspecific signs of neonatal sepsis, a wide differential must be considered. Many disease processes can present with the same nonspecific symptoms in the newborn. Important diseases to consider include congenital heart failure, respiratory distress, necrotizing enterocolitis, congenital pneumonia or pulmonary hypoplasia, meningitis, meconium aspiration syndrome, and hemolytic disease of the newborn, to name a few.

Treatment Planning

The treatment regimen for neonatal sepsis varies based on various risk factors and conditions. The typical antibiotics used are discussed above, but the duration of therapy can vary based on the underlying etiology, isolated organisms, the presence of any neonatal complications, or other risk factors. Neonates with positive blood cultures typically respond to treatment within 24 to 48 hours and repeat cultures and studies are usually negative by 72 hours.[2] Despite standard recommendations to discontinue antibiotics once cultures are negative, many clinicians will continue therapy for 10 to 14 days based on the organism, or 21 days if meningitis was suspected.[2] Increasing the duration of antibiotics may be necessary for some situations. However, it does contribute to the increasing incidence of antibiotic resistance and puts the neonate at increased risk of complications including necrotizing enterocolitis or death.[4]

The treatment for suspect EOS with negative cultures is also variable. Cultures can be negative for a variety of reasons, including maternal antibiotic use, initiation of antibiotics prior to obtaining cultures or false negative tests. Determining adequate antibiotic therapy without any positive cultures can make the determining duration of therapy difficult, and an empiric 10-day treatment course is completed, as long as the neonate's symptoms have improved.[2]

Prognosis

Neonatal sepsis accounts for about 15% of all infant deaths in the United States, and 25% of infant mortality worldwide. Mortality rates are inversely proportional with gestational age, such that preterm or younger neonates have higher mortality rates than do term neonates. E. coli has also found to be associated with a higher mortality rate when compared with GBS. As noted above, the introduction of GBS intrapartum antibiotic prophylaxis has decreased mortality rates caused by GBS. The treatment of clinically suspected neonates with negative cultures has also significantly decreased mortality rates.[2]

Complications

In addition to the increased mortality rate associated with neonatal sepsis, the morbidity rate is also high. Risk factors associated with increased morbidity include very low birth weight, cardiac dysfunction, acute renal failure, metabolic acidosis, increased bleeding, neutropenia, and bleeding. VLBW infants have been found to have a higher risk of chronic lung disease, and extremely low birth weight (ELBW) infants are at a greater risk of neurodevelopmental risks, such as hearing and visual deficits, cerebral palsy, and impaired psychomotor and mental development.[5]

Consultations

Any pediatrician or hospitalist comfortable with managing sepsis in neonates can do so. Pediatric consults may be necessary at times, however. A pediatric surgical consult may be warranted if there is a concern for abscess, hydrocephalus, necrotizing enterocolitis, or for central line placement. A pediatric infectious disease specialist may be indicated if the infant is not responding to antibiotics, or if there is concern regarding adequate antimicrobial coverage. Pediatric pharmacists can be helpful in monitoring trough levels to avoid toxic antibiotic levels and to offer other medication options.

Deterrence and Patient Education

Educating the patient’s family about the disease process and keeping them updated throughout the treatment process is an important part of management. This is often an unexpected and scary situation for parents and caregivers. Doctors should be mindful of this and ensure that parents be informed of all of the tests that must be performed, the importance of each test, as well as the results. Any changes in antibiotics or the treatment plan must be communicated to the parents.

Upon hospital discharge, caregivers of all infants, including healthy newborns, should be educated to watch for signs of illness or sepsis. These may include fever, jaundice, increased lethargy, a decline in feeding habits, difficulty or increased breathing, and cyanosis of the fingertips and toes. Caregivers should be informed to call their doctors if their neonate experiences any of these symptoms, as they could be indicative of LOS.

Enhancing Healthcare Team Outcomes

Neonatal sepsis is a significant cause of mortality in this age group. Attempts to prevent the development or progression of sepsis in this age group requires that many members of the medical staff work together and communicate with each other for the best outcome for the neonate. Obstetric physicians are important in ensuring that screening for GBS and all other prenatal screening for infections is performed and properly treated during delivery. Nursery nurses are also important in preventing and managing neonatal sepsis as they can pick up and detect early signs of sepsis. Pediatricians, in-hospital and outpatient, also play a key role in detecting signs of sepsis through history and physical exam. In-hospital pediatricians are essential in managing the evolving treatment of neonatal sepsis and making adjustments as necessary. They are also important in reaching out to the proper consultants, such as pediatric surgeons, pharmacists, as needed.


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Neonatal Sepsis - Questions

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What is the most common cause of neonatal sepsis?



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A 2 day old neonate is found to have total bilirubin of 15 mg/dL with a conjugated bilirubin of 4 mg/dL. Which of the following diagnosis is likely in this patient?



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What are the most common bacteria implicated in neonatal sepsis in the US?



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Which of the following organisms commonly causes neonatal sepsis?



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A baby boy born 24 hours earlier develops a fever of 102 F and tachycardia. His mother states that he has become increasingly fussy the past several hours and appears jaundiced. A sepsis workup is performed, but blood cultures are negative. What should be done?



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An 18-year-old G1P0 at 33 weeks presents to the emergency department in labor. Spontaneous rupture of membranes occurred one hour before arrival. Which of the following puts the unborn fetus at increased risk of sepsis?



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What are the most common pathogens responsible for early-onset neonatal sepsis?



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A lumbar puncture performed on a neonate born at 34 weeks confirmed bacterial growth in cerebrospinal fluid (CSF) despite normal white count in the fluid. In addition to antibiotics, which of the following should also be performed?



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Neonatal Sepsis - References

References

Wynn JL, Defining neonatal sepsis. Current opinion in pediatrics. 2016 Apr     [PubMed]
Simonsen KA,Anderson-Berry AL,Delair SF,Davies HD, Early-onset neonatal sepsis. Clinical microbiology reviews. 2014 Jan     [PubMed]
Raymond SL,Stortz JA,Mira JC,Larson SD,Wynn JL,Moldawer LL, Immunological Defects in Neonatal Sepsis and Potential Therapeutic Approaches. Frontiers in pediatrics. 2017     [PubMed]
Wynn JL,Wong HR, Pathophysiology and treatment of septic shock in neonates. Clinics in perinatology. 2010 Jun     [PubMed]
Dong Y,Speer CP, Late-onset neonatal sepsis: recent developments. Archives of disease in childhood. Fetal and neonatal edition. 2015 May     [PubMed]

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