Neonatal sepsis refers to an infection involving bloodstream in newborn infants less than 28 days old. It continues to remain a leading cause of morbidity and mortality among infants, especially in middle and lower-income countries . Neonatal sepsis is divided into 2 groups based on the time of presentation after birth: early-onset sepsis (EOS) and late-onset sepsis (LOS). EOS refers to sepsis in neonates at or before 72 hours of life, and LOS is defined as sepsis occurring at or after 72 hours of life. Although, some experts use 7 days as the cutoff date .
Early-onset sepsis(EOS) is generally caused by the transmission of pathogens from the female genitourinary system to the newborn or the fetus. These pathogens can ascend 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. 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 .
Late-onset sepsis (LOS) usually occurs via the transmission of pathogens from the environment after delivery, such as contact from healthcare workers or caregivers. LOS may 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 higher risk for sepsis/infection than term neonates, as they tend to require more invasive procedures than term neonates. Coagulase-negative staphylococcal species, especially Staphylococcus epidermidis, is the leading cause, responsible for greater than 50% of LOS cases in industrialized countries, although many bacterial and viral pathogens can be associated with LOS .
The epidemiology of neonatal sepsis has been changing with time . The incidence of EOS has decreased since the 1990s due to the introduction of universal screening of group B streptococcus (GBS) in pregnant women and intrapartum antibiotic prophylaxis (IAP) . However, rates of LOS have remained relatively the same. Escherichia coli now accounts for more cases of EOS compared to GBS . In the United States, the incidence of EOS with positive blood cultures is estimated to be 0.77 to 1 per 1,000 live births . 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. Although approximately 7% to 13% of all neonates are worked up for sepsis, only 3% to 8% develop positive cultures . The incidence of sepsis is significantly higher in premature infants, as well as those with very low birth weight (<1000 grams). 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. Males have a higher risk of sepsis and meningitis, especially with gram-negative enteric bacilli .
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 .
Signs and symptoms of neonatal sepsis can range from nonspecific or vague symptoms to hemodynamic collapse. Early symptoms may include irritability, lethargy, or poor feeding. Others may quickly develop respiratory distress, fever, hypothermia or hypotension with poor perfusion and shock. Sometimes the diagnosis may only be suspected on the basis of laboratory findings, which may reveal hyperglycemia or hypoglycemia, acidosis, or hyperbilirubinemia. A high index of suspicion is, therefore, necessary for timely diagnosis. Physicians must, therefore, be aware of any factors that may increase an infant’s risk of developing sepsis. Prematurity and very low birth weights are also important risk factors to consider. Maternal factors that put neonates at risk of early-onset sepsis include GBS status, the presence of chorioamnionitis, infant prematurity, or prolonged rupture of membranes . For late-onset infection, consider whether the patient has indwelling foreign bodies such as a central venous catheter or endotracheal tube, is dependent on parenteral nutrition, or receives proton-pump inhibitor or histamine-2 blocking therapy.
The physical exam may reveal nonspecific signs of sepsis.
Bacteremia may be present in a neonate with apparently normal clinical examination, thus laboratory testing plays an important role in diagnosis. In a neonate with suspected sepsis, blood culture should be immediately drawn. It is recommended to draw at least 1ml of blood as low-level bacteremia may not be detected with smaller aliquotes and is common in neonatal sepsis . Cultures should also be drawn from the catheter site if one is in place. Urine cultures are usually not recommended for evaluation of EOS but should be performed for evaluation of LOS . Lumbar puncture with cerebrospinal fluid (CSF) analysis and culture should be evaluated in any infant with positive blood culture or when clinical or metabolic abnormalities strongly suggest bacterial 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. 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 .
CSF analysis may reveal:
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. These indices are poor at identifying neonatal sepsis but are better used for ruling it out . Neutropenia has better specificity than neutrophilia as a marker of neonatal sepsis . Elevated immature to total neutrophil (I/T)ratio of more than 0.27 has a very high negative predictive accuracy (99%) but an inadequate positive predictive value (25%) as it may be elevated in up to 50% of uninfected infants . These counts may be falsely elevated, especially after birth. It is better to perform CBC 6 to 12 hours after birth as an alteration in these neutrophil indices usually requires an established inflammatory response .
CRP levels start rising within 6 to 8 hours during an infectious episode in neonates and peak at about 24 hours . Persistently normal CRP levels provide strong evidence against bacterial sepsis and antimicrobial agents can be safely discontinued. 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 .
Empiric treatment with antibiotics should be started as soon as sepsis is clinically suspected, even without confirmatory lab data. In general, antimicrobial resistance patterns of common bacteria in the neonatal intensive care unit should guide the initial choice of antibiotics. 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. It is recommended to start these patients on a combination of vancomycin and an aminoglycoside . A Third-generation cephalosporin should be given if Gram-negative meningitis is suspected . It provides adequate penetration via blood-brain barrier and coverage for these pathogens. However, ceftriaxone should be avoided, as it can lead to hyperbilirubinemia. Increasing antibiotic resistance is a concern for neonatal sepsis and treatment should always be de-escalated as soon as possible .
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.
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 . 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 . 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 .
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 .
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.
Preterm infants with sepsis may gone to develop impaired neurodevelopment. In addition others may have vision impairment. Those infants pretreated with aminoglycosides may also develop ototoxicity and nephrotoxicity.
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 . Administration of broad-spectrum antibiotics also predisposes to fungal infections, including invasive candidiasis and meningitis. However, preterm infants recovered from EOS have not been shown to have increased risk for development of LOS .
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.
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.
Neonatal sepsis is a significant cause of mortality in this age group. There are many causes of neonatal sepsis and the disorder is best managed by an interprofessional team. 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.
While clinicians play a key role in diagnosis and treatment, the monitoring of the infant is done by the pediatric or neonatal nurses. These infants need more than just medical care; their nutrition status has to be improved, the psychological growth has to be continued and the overall body growth has to be monitored. Managing such infants is complex because even a simple thing like intravenous access can be a major challenge. The pharmacist has to ensure that all the medications are appropriate for the age group and they are safe. In addition, nursing and feeding the infant are also issues that need to be managed by the dietitian and the mother.
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.
Despite optimal treatment, neonatal sepsis continues to have high mortality rates and poor outcomes. While the rates of mortality have started to decline, the recovery for most infants is prolonged and some infants are left with residual deficits in mental and physical development.
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