CHAPTER 65 Sepsis and Meningitis

Systemic and local infections (lung, cutaneous, ocular, umbilical, kidney, bone-joint, and meningeal) are common in the newborn period. Infection may be acquired in utero through the transplacental or transcervical routes and during or after birth. Ascending infection through the cervix, with or without rupture of the amniotic fluid membranes, may result in amnionitis, funisitis (infection of the umbilical cord), congenital pneumonia, and sepsis. The bacteria responsible for ascending infection of the fetus are common bacterial organisms of the maternal genitourinary tract, such as group B streptococci, Escherichia coli, Haemophilus influenzae, and Klebsiella. Herpes simplex virus (HSV)-1 or more often HSV-2 also causes ascending infection that at times may be indistinguishable from bacterial sepsis. Syphilis and Listeria monocytogenes are acquired by transplacental infection.

Maternal humoral immunity may protect the fetus against some neonatal pathogens, such as group B streptococci and HSV. Nonetheless, various deficiencies of the neonatal antimicrobial defense mechanism probably are more important than maternal immune status as a contributing factor for neonatal infection, especially in the low birth weight infant. The incidence of sepsis is approximately 1:1500 in full-term infants and 1:250 in preterm infants. The sixfold-higher rate of sepsis in preterm infants compared with term infants relates to the more immature immunologic systems of preterm infants and to their prolonged periods of hospitalization, which increase risk of nosocomially acquired infectious diseases.

Preterm infants before 32 weeks of gestational age have not received the full complement of maternal antibodies (IgG), which cross the placenta by active transport predominantly in the latter half of the third trimester. In addition, although low birth weight infants may generate IgM antibodies, their own IgG response to infection is reduced. These infants also have deficiencies of the alternate and, to a smaller degree, the classic complement activation pathways, which results in diminished complement-mediated opsonization. Newborn infants also show a deficit in phagocytic migration to the site of infection (to the lung) and in the bone marrow reserve pool of leukocytes. In addition, in the presence of suboptimal activation of complement, neonatal neutrophils ingest and kill bacteria less effectively than adult neutrophils do. Neutrophils from sick infants seem to have an even greater deficit in bacterial killing capacity compared with phagocytic cells from normal neonates.

Defense mechanisms against viral pathogens also may be deficient in a newborn. Neonatal antibody-dependent, cell-mediated immunity by the natural killer lymphocytes is deficient in the absence of maternal antibodies and in the presence of reduced interferon production; reduced antibody levels occur in premature infants and in infants born during a primary viral infection of the mother, such as with enteroviruses, HSV-2, or cytomegalovirus. In addition, antibody-independent cytotoxicity may be reduced in lymphocytes of newborns.

Bacterial sepsis and meningitis often are linked closely in neonates. Despite this association, the incidence of meningitis relative to neonatal sepsis has been on a steady decline. The incidence of meningitis is approximately 1 in 20 cases of sepsis. The causative organisms isolated most frequently are the same as for neonatal sepsis: group B streptococci, E. coli, and L. monocytogenes. Gram-negative organisms, such as Klebsiella and Serratia marcescens, are more common in less developed countries, and coagulase-negative staphylococci need to be considered in very low birth weight infants. Male infants seem to be more susceptible to neonatal infection than female infants. Severely premature infants are at even greater risk secondary to less effective defense mechanisms and deficient transfer of antibodies from the mother to the fetus (which occurs mostly after 32 weeks' gestation). Neonates in the neonatal intensive care unit live in a hostile environment, with exposure to endotracheal tubes, central arterial and venous catheters, and blood draws all predisposing to bacteremia and meningitis. Genetic factors have been implicated in the ability of bacteria to cross the blood-brain barrier. This penetration has been noted for group B streptococci, E. coli, Listeria, Citrobacter, and Streptococcus pneumoniae.

Neonatal sepsis presents during three periods. Early-onset sepsis often begins in utero and usually is a result of infection caused by the bacteria in the mother’s genitourinary tract. Organisms related to this sepsis include group B streptococci, E. coli, Klebsiella, L. monocytogenes, and nontypeable H. influenzae. Most infected infants are premature and show nonspecific cardiorespiratory signs, such as grunting, tachypnea, and cyanosis at birth. Risk factors for early-onset sepsis include vaginal colonization with group B streptococci, prolonged rupture of the membranes (>24 hours), amnionitis, maternal fever or leukocytosis, fetal tachycardia, and preterm birth. African-American race and male sex are unexplained additional risk factors for neonatal sepsis.

Early-onset sepsis (birth to 7 days) is an overwhelming multiorgan system disease frequently manifested as respiratory failure, shock, meningitis (in 30% of cases), disseminated intravascular coagulation, acute tubular necrosis, and symmetrical peripheral gangrene. Early manifestations—grunting, poor feeding, pallor, apnea, lethargy, hypothermia, or an abnormal cry—may be nonspecific. Profound neutropenia, hypoxia, and hypotension may be refractory to treatment with broad-spectrum antibiotics, mechanical ventilation, and vasopressors such as dopamine and dobutamine. In the initial stages of early-onset septicemia in a preterm infant, it is often difficult to differentiate sepsis from respiratory distress syndrome. Because of this difficulty, premature infants with respiratory distress syndrome receive broad-spectrum antibiotics.

The clinical manifestations of sepsis are difficult to separate from the manifestations of meningitis in the neonate. Infants with early-onset sepsis should be evaluated by blood and cerebrospinal fluid (CSF) cultures, CSF Gram stain, cell count, and protein and glucose levels. Normal newborns generally have an elevated CSF protein content (100 to 150 mg/dL) and may have 25 to 30/mm³ white blood cells (mean, 9/mm³), which are 75% lymphocytes in the absence of infection. Some infants with neonatal meningitis caused by group B streptococci do not have an elevated CSF leukocyte count but are seen to have microorganisms in the CSF on Gram stain. In addition to culture, other methods of identifying the pathogenic bacteria are the determination of bacterial antigen in samples of blood, urine, or CSF. In cases of neonatal meningitis, the ratio of CSF glucose to blood glucose usually is less than 50%. The polymerase chain reaction test primarily is used to identify viral infections. Serial complete blood counts should be performed to identify neutropenia, an increased number of immature neutrophils (bands), and thrombocytopenia. C-reactive protein levels are often elevated in neonatal patients with bacterial sepsis.

A chest radiograph also should be obtained to determine the presence of pneumonia. In addition to the traditional neonatal pathogens, pneumonia in very low birth weight infants may be the result of acquisition of maternal genital mycoplasmal agent (e.g., Ureaplasma urealyticum or Mycoplasma hominis). Arterial blood gases should be monitored to detect hypoxemia and metabolic acidosis that may be caused by hypoxia, shock, or both. Blood pressure, urine output, and peripheral perfusion should be monitored to determine the need to treat septic shock with fluids and vasopressor agents.

The mainstay of treatment for sepsis and meningitis is antibiotic therapy. Antibiotics are used to suppress bacterial growth, allowing the infant’s defense mechanisms time to respond. In addition, support measures, such as assisted ventilation and cardiovascular support, are equally important to the management of the infant. A combination of ampicillin and an aminoglycoside (usually gentamicin) for 10 to 14 days is effective treatment against most organisms responsible for early-onset sepsis. The combination of ampicillin and cefotaxime also is proposed as an alternative method of treatment. If meningitis is present, the treatment should be extended to 21 days or 14 days after a negative result from a CSF culture. Persistently positive results from CSF cultures are common with neonatal meningitis caused by gram-negative organisms, even with appropriate antibiotic treatment, and may be present for 2 to 3 days after antibiotic therapy. If gram-negative meningitis is present, some authorities continue to treat with an effective penicillin derivative combined with an aminoglycoside, whereas most change to a third-generation cephalosporin. High-dose penicillin (250,000 to 450,000 U/kg/24 hr) is appropriate for group B streptococcal meningitis. Inhaled nitric oxide, extracorporeal membrane oxygenation (in term infants), or both, may improve the outcome of sepsis-related pulmonary hypertension. Intratracheal surfactant may reverse respiratory failure. Intrapartum penicillin empirical prophylaxis for group B streptococcal colonized mothers or mothers with risk factors (fever, preterm labor, previous infant with group B streptococci, and amnionitis) has reduced the rate of early-onset infection.

Late-onset sepsis (8 to 28 days) usually occurs in a healthy full-term infant who was discharged in good health from the normal newborn nursery. Clinical manifestations may include lethargy, poor feeding, hypotonia, apathy, seizures, bulging fontanelle, fever, and direct-reacting hyperbilirubinemia. In addition to bacteremia, hematogenous seeding may result in focal infections, such as meningitis (in 75% of cases), osteomyelitis (group B streptococci, Staphylococcus aureus), arthritis (gonococcus, S. aureus, Candida albicans, gram-negative bacteria), and urinary tract infection (gram-negative bacteria).

The evaluation of infants with late-onset sepsis is similar to that for infants with early-onset sepsis, with special attention given to a careful physical examination of the bones (infants with osteomyelitis may exhibit pseudoparalysis) and to the laboratory examination and culture of urine obtained by sterile suprapubic aspiration or urethral catheterization. Late-onset sepsis may be caused by the same pathogens as early-onset sepsis, but infants exhibiting sepsis late in the neonatal period also may have infections caused by the pathogens usually found in older infants (H. influenzae, S. pneumoniae, and Neisseria meningitidis). In addition, viral agents (HSV, cytomegalovirus, or enteroviruses) may manifest with a late-onset, sepsis-like picture.

Because of the increased rate of resistance of H. influenzae and pneumococcus to ampicillin, some centers begin treatment with ampicillin and a third-generation cephalosporin (and vancomycin if meningitis is present) when sepsis occurs in the last week of the first month of life. The treatment of late-onset neonatal sepsis and meningitis is the same as that for early-onset sepsis.

Nosocomially acquired sepsis (8 days to discharge) occurs predominantly in premature infants in the neonatal intensive care unit; many of these infants have been colonized with the multidrug-resistant bacteria indigenous to the neonatal intensive care unit. The risk of such serious bacterial infection is increased by frequent treatment with broad-spectrum antibiotics for sepsis and by the presence of central venous indwelling catheters, endotracheal tubes, umbilical vessel catheters, and electronic monitoring devices. Epidemics of bacterial (coagulase-negative staphylococci, fungi, enteric bacteria) or viral sepsis, bacterial or aseptic meningitis, staphylococcal bullous skin infections, cellulitis, pneumonia (bacterial or caused by adenovirus or respiratory syncytial virus), omphalitis (caused by S. aureus or gram-negative bacilli), and diarrhea (staphylococcal, enteroviral, or caused by rotavirus or enteropathogenic E. coli) are common in the neonatal intensive care unit and in the nursery for well infants.

The initial clinical manifestations of nosocomial infection in a premature infant may be subtle and include apnea and bradycardia, temperature instability, abdominal distention, and poor feeding. In the later stages, signs of infection are shock, disseminated intravascular coagulation, worsening respiratory status, and local reactions, such as omphalitis, eye discharge, diarrhea, and bullous impetigo.

The treatment of nosocomially acquired sepsis depends on the indigenous microbiologic flora of the particular hospital and the antibiotic sensitivities. Because S. aureus (occasionally methicillin-resistant), Staphylococcus epidermidis (methicillin-resistant), and gram-negative pathogens are common nosocomial bacterial agents in many nurseries, a combination of vancomycin or oxacillin/nafcillin (some use ampicillin) with an aminoglycoside (gentamicin or tobramycin) is appropriate. The dose and interval for administering all aminoglycosides, such as gentamicin, vary with postnatal age and birth weight. In addition, treatment with aminoglycosides for more than 3 days necessitates monitoring of the serum peak and trough concentrations to optimize therapy and to avoid ototoxicity and nephrotoxicity. Persistent signs of infection despite antibacterial treatment suggest candidal or viral sepsis.