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(See also Sepsis and Septic Shock.)
Neonatal sepsis is invasive infection, usually bacterial, occurring during the neonatal period. Signs are multiple and include diminished spontaneous activity, less vigorous sucking, apnea, bradycardia, temperature instability, respiratory distress, vomiting, diarrhea, abdominal distention, jitteriness, seizures, and jaundice. Diagnosis is clinical and based on culture results. Treatment is initially with ampicillin plus either gentamicin or cefotaxime, narrowed to organism-specific drugs as soon as possible.
Neonatal sepsis occurs in 0.5 to 8.0/1000 births. The highest rates occur in low-birth-weight (LBW) infants, those with depressed respiratory function at birth, those with maternal perinatal risk factors, males, and those with congenital anomalies.
Etiology
Neonatal sepsis can be early onset (within 7 days of birth) or late onset (after 7 days).
Early onset:
Early-onset sepsis usually results from organisms acquired intrapartum. Most infants have symptoms within 6 h of birth, and almost all cases occur within 72 h.
Group B streptococcus (GBS) and gram-negative enteric organisms (predominantly Escherichia coli) account for most cases of early-onset sepsis. Vaginal or rectal cultures of women at term may show GBS colonization rates of up to 30%. At least 35% of their infants also become colonized. The density of infant colonization determines the risk of early-onset invasive disease, which is 40 times higher with heavy colonization. Although only 1/100 of infants colonized develop invasive disease due to GBS, > 50% of those present within the first 6 h of life. Nontypeable Haemophilus influenzae sepsis has been increasingly identified in neonates, especially premature neonates.
Other gram-negative enteric bacilli (eg, Klebsiella sp) and gram-positive organisms—Listeria monocytogenes, enterococci (eg, Enterococcus faecalis, Enterococcus faecium), group D streptococci (eg, Streptococcus bovis), α-hemolytic streptococci, and staphylococci—account for most other cases. Streptococcus pneumoniae, H. influenzae type b, and, less commonly, Neisseria meningitidis have been isolated. Asymptomatic gonorrhea occurs occasionally in pregnancy, so Neisseria gonorrhoeae may be a pathogen.
Late onset:
Late-onset sepsis is usually acquired from the environment (see Infections in Neonates: Neonatal Hospital-Acquired Infection). Staphylococci account for 30 to 60% of late-onset cases and are most frequently due to intravascular devices (particularly umbilical artery or vein catheters). E. coli is also becoming increasingly recognized as a significant cause of late-onset sepsis, especially in very LBW infants. Isolation of Enterobacter cloacae or E. sakazakii from blood or CSF suggests contaminated feedings. Contaminated respiratory equipment is suspected in outbreaks of hospital-acquired Pseudomonas aeruginosa pneumonia or sepsis. Although universal screening and intrapartum antibiotic prophylaxis for GBS have significantly decreased the rate of early-onset disease due to this organism, the rate of late-onset GBS sepsis has remained unchanged, which is consistent with the hypothesis that late-onset disease is usually acquired from the environment.
The role of anaerobes (particularly Bacteroides fragilis) in late-onset sepsis remains unclear, although deaths have been attributed to Bacteroides bacteremia. Anaerobes may account for some culture-negative cases in which autopsy findings indicate sepsis.
Candida sp are increasingly important causes of late-onset sepsis, occurring in 12 to 13% of very LBW infants.
Early and late onset:
Certain viral infections (eg, disseminated herpes simplex, enterovirus, adenovirus, respiratory syncytial virus) may manifest as early-onset or late-onset sepsis.
Pathophysiology
Early onset:
Certain maternal perinatal and obstetric factors increase risk, particularly of early-onset sepsis, such as the following:
Hematogenous and transplacental dissemination of maternal infection occurs in the transmission of certain viral (eg, rubella, cytomegalovirus), protozoal (eg, Toxoplasma gondii), and treponemal (eg, Treponema pallidum) pathogens. A few bacterial pathogens (eg, L. monocytogenes, Mycobacterium tuberculosis) may reach the fetus transplacentally, but most are acquired by the ascending route in utero or as the fetus passes through the colonized birth canal.
Though the intensity of maternal colonization is directly related to risk of invasive disease in the neonate, many mothers with low-density colonization give birth to infants with high-density colonization who are therefore at risk. Amniotic fluid contaminated with meconium or vernix caseosa promotes growth of GBS and E. coli. Hence, the few organisms in the vaginal vault are able to proliferate rapidly after PROM, possibly contributing to this paradox. Organisms usually reach the bloodstream by fetal aspiration or swallowing of contaminated amniotic fluid, leading to bacteremia. The ascending route of infection helps to explain such phenomena as the high incidence of PROM in neonatal infections, the significance of adnexal inflammation (amnionitis is more commonly associated with neonatal sepsis than is central placentitis), the increased risk of infection in the twin closer to the birth canal, and the bacteriologic characteristics of neonatal sepsis, which reflect the flora of the maternal vaginal vault.
Late onset:
The most important risk factor in late-onset sepsis is preterm delivery. Others include
Gram-positive organisms (eg, coagulase-negative staphylococci and Staphylococcus aureus) may be introduced from the environment or the patient's skin. Gram-negative enteric bacteria are usually derived from the patient's endogenous flora, which may have been altered by antecedent antibiotic therapy or populated by resistant organisms transferred from the hands of personnel (the major means of spread) or contaminated equipment. Therefore, situations that increase exposure to these bacteria (eg, crowding, inadequate nurse staffing or provider hand washing) result in higher rates of hospital-acquired infection. Risk factors for Candida sp sepsis include prolonged (> 10 days) use of central IV catheters, hyperalimentation, use of antecedent antibiotics, necrotizing enterocolitis or other abdominal pathology, and previous surgery.
Initial foci of infection can be in the urinary tract, paranasal sinuses, middle ear, lungs, or GI tract, and may later disseminate to meninges, kidneys, bones, joints, peritoneum, and skin.
Symptoms and Signs
Early signs are frequently nonspecific and subtle and do not distinguish among organisms (including viral). Particularly common early signs include
Fever is present in only 10 to 15% but, when sustained (eg, > 1 h), generally indicates infection. Other symptoms and signs include respiratory distress, neurologic findings (eg, seizures, jitteriness), jaundice (especially occurring within the first 24 h without Rh or ABO blood group incompatibility and with a higher than expected direct bilirubin concentration), vomiting, diarrhea, and abdominal distention. Anaerobic infection is often indicated by foul-smelling amniotic fluid at birth.
Specific signs of an infected organ may pinpoint the primary site or a metastatic site.
Early-onset GBS infection may manifest as a fulminating pneumonia. Often, obstetric complications (particularly prematurity, PROM, or chorioamnionitis) have occurred. In > 50% of neonates, GBS infection manifests within 6 h of birth; 45% have an Apgar score of < 5. Meningitis may also be present but is not common. In late-onset GBS infection (at 1 to 12 wk), meningitis is often present. Late-onset GBS infection is generally not associated with perinatal risk factors or demonstrable maternal cervical colonization and may be acquired postpartum.
Diagnosis
Early diagnosis is important and requires awareness of risk factors (particularly in LBW neonates) and a high index of suspicion when any neonate deviates from the norm in the first few weeks of life. Neonates with suspected sepsis, and those whose mother was thought to have chorioamnionitis, should have a CBC, differential with smear, platelet count, blood culture, urine culture, and lumbar puncture (LP), if clinically feasible, as soon as possible. Those with respiratory symptoms require chest x-ray. Diagnosis is confirmed by isolation of a pathogen in culture. Other tests may have abnormal results but are not necessarily diagnostic.
For preterm neonates who appear well but whose mother received inadequate intrapartum antibiotics for GBS, the American Academy of Pediatrics recommends a limited evaluation (CBC and blood culture with at least a 48-h observation).
CBC, differential, and smear:
The normal WBC count in neonates varies, but values < 4,000/μL or > 25,000/μL are abnormal. The absolute band count is not sensitive enough to predict sepsis, but a ratio of immature:total polymorphonuclear leukocytes of < 0.2 has a high negative predictive value. A precipitous fall in a known absolute eosinophil count and morphologic changes in neutrophils (eg, toxic granulation, Döhle bodies, intracytoplasmic vacuolization in noncitrated blood or ethylenediaminetetraacetic acid [EDTA]) suggest sepsis.
The platelet count may fall hours to days before the onset of clinical sepsis but more often remains elevated until a day or so after the neonate becomes ill. This fall is sometimes accompanied by other findings of DIC (eg, increased fibrin degradation products, decreased fibrinogen, prolonged INR).
Because of the large numbers of circulating bacteria, organisms can sometimes be seen in or associated with polymorphonuclear leukocytes by applying Gram stain, methylene blue, or acridine orange to the buffy coat.
Regardless of the results of the CBC or LP, in all neonates with suspected sepsis (eg, those who look sick or are febrile or hypothermic), antibiotics should be started after cultures (eg, blood, urine, and CSF [if possible]) are taken.
Lumbar puncture:
There is a risk of increasing hypoxia during an LP in already hypoxemic neonates. However, LP should be done in neonates with suspected sepsis as soon as they are able to tolerate the procedure (see also Infections in Neonates: Diagnosis under Neonatal Bacterial Meningitis). Supplemental O2 is given before and during LP to prevent hypoxia. Because GBS pneumonia manifesting in the first day of life can be confused with respiratory distress syndrome, LP is often done routinely in neonates suspected of having these diseases.
Blood cultures:
Umbilical vessels are frequently contaminated by organisms on the umbilical stump, especially after a number of hours, so blood cultures from umbilical lines may not be reliable. Therefore, blood for culture should be obtained by venipuncture, preferably at 2 peripheral sites, each meticulously prepared by applying an iodine-containing liquid, then applying 95% alcohol, and finally allowing the site to dry. Blood should be cultured for both aerobic and anaerobic organisms. If catheter-associated sepsis is suspected, a culture specimen should be obtained through the catheter as well as peripherally. In > 90% of positive bacterial blood cultures, growth occurs within 48 h of incubation. Because bacteremia in neonates is associated with a high density of organisms and delayed clearance, a small amount of blood (eg, ≥ 1 mL) is usually sufficient for detecting organisms. Data on capillary blood cultures are insufficient to recommend them.
Candida sp grow in blood cultures and on blood agar plates, but if other fungi are suspected, a fungal culture medium should be used. For species other than Candida, fungal blood cultures may require 4 to 5 days of incubation before becoming positive and may be negative even in obviously disseminated disease. Proof of colonization (in mouth or stool or on skin) may be helpful before culture results are available. If disseminated candidiasis is suspected, indirect ophthalmoscopy with dilation of the pupils is done to identify retinal candidal lesions. Renal ultrasonography is done to detect renal mycetoma.
Urinalysis and culture:
Urine should be obtained by catheterization or suprapubic aspiration, not by urine collection bags. Although only culture is diagnostic, a finding of ≥ 5 WBCs/high-power field in the spun urine or any organisms in a fresh unspun gram-stained sample is presumptive evidence of a UTI. Absence of pyuria does not rule out UTI.
Other tests for infection and inflammation:
Numerous tests are often abnormal in sepsis and have been evaluated as possible early markers. In general, however, sensitivities tend to be low until later in illness, and specificities are suboptimal.
Acute-phase reactants are proteins produced by the liver under the influence of IL-1 when inflammation is present. The most valuable of these is quantitative C-reactive protein. A concentration of 1 mg/dL (measured by nephelometry) has both a false-positive and a false-negative rate of about 10%. Elevated levels occur within a day, peak at 2 to 3 days, and fall to normal within 5 to 10 days in neonates who recover.
The ESR is often elevated in sepsis. The micro-ESR correlates well with the standard Wintrobe method but has the same high false-negative rate (especially early in the course and with DIC) and a slow return to normal, well beyond the time of clinical cure. IL-6 and other inflammatory cytokines are being investigated as markers for sepsis.
Prognosis
The fatality rate is 2 to 4 times higher in LBW infants than in full-term infants. The overall mortality rate of early-onset sepsis is 3 to 40% (that of early-onset GBS infection is 2 to 30%) and of late-onset sepsis is 2 to 20% (that of late-onset GBS is about 2%). More recent studies have shown lower mortality rates.
Neonates who are both septic and granulocytopenic are less likely to survive, particularly if their bone marrow neutrophil storage pool (NSP) is depleted to < 7% of total nucleated cells (mortality rate, 75%). Because NSP levels may not be readily available, the peripheral blood immature:total (I:T) neutrophil ratio can approximate bone marrow NSP levels. I:T ratios of > 0.80 correlate with NSP depletion and death; such a ratio may identify neonates who might benefit from granulocyte transfusion.
Treatment
Because sepsis may manifest with nonspecific clinical signs and its effects may be devastating, rapid empiric antibiotic therapy is recommended (see Bacteria and Antibacterial Drugs: Selection and Use of Antibiotics); drugs are later adjusted according to sensitivities and the site of infection. If bacterial cultures show no growth by 48 h (although some pathogens may require 72 h) and the neonate appears well, antibiotics are stopped.
General supportive measures, including respiratory and hemodynamic management, are combined with antibiotic treatment.
Antimicrobials:
In early-onset sepsis, initial therapy should include ampicillin or penicillin G plus an aminoglycoside. Cefotaxime may be added to or substituted for the aminoglycoside if meningitis is suspected. If foul-smelling amniotic fluid is present at birth, therapy for anaerobes (eg, clindamycin, metronidazole) should be added. Antibiotics may be changed as soon as an organism is identified.
Previously well infants admitted from the community with presumed late-onset sepsis should also receive therapy with ampicillin plus gentamicin or ampicillin plus cefotaxime. If gram-negative meningitis is suspected, ampicillin, cefotaxime, and an aminoglycoside may be used. In late-onset hospital-acquired sepsis, initial therapy should include vancomycin (active against methicillin-resistant S. aureus) plus an aminoglycoside. If P. aeruginosa is prevalent in the nursery, ceftazidime may be used instead of an aminoglycoside. For neonates previously treated with a full 7- to 14-day aminoglycoside course who need retreatment, a different aminoglycoside or a 3rd-generation cephalosporin should be considered.
If coagulase-negative staphylococci are suspected (eg, an indwelling catheter has been in place for > 72 h) or are isolated from blood or other normally sterile fluid and considered a pathogen, initial therapy for late-onset sepsis should include vancomycin. However, if the organism is sensitive to nafcillin, cefazolin or nafcillin should replace vancomycin. Removal of the presumptive source of the organism (usually an indwelling intravascular catheter) may be necessary to cure the infection because coagulase-negative staphylococci may be protected by a biofilm (a covering that encourages adherence of organisms to the catheter).
Because Candida may take 2 to 3 days to grow in blood culture, initiation of amphotericin B therapy and removal of the infected catheter without positive blood or CSF cultures may be life saving.
Other treatment:
Exchange transfusions have been used for severely ill (particularly hypotensive and metabolically acidotic) neonates. Their purported value is to increase levels of circulating immunoglobulins, decrease circulating endotoxin, increase Hb levels (with higher 2,3-diphosphoglycerate levels), and improve perfusion. However, no controlled prospective studies of their use have been conducted.
Fresh frozen plasma may help reverse the heat-stable and heat-labile opsonin deficiencies that occur in LBW neonates, but controlled studies of its use are unavailable, and transfusion-associated risks must be considered.
Granulocyte transfusions (see Transfusion Medicine: WBCs) have been used in septic and granulocytopenic neonates but have not convincingly improved outcome.
Recombinant colony-stimulating factors (granulocyte colony-stimulating factor [G-CSF] and granulocyte-macrophage colony-stimulating factor [GM-CSF]) have increased neutrophil number and function in neonates with presumed sepsis but do not seem to be of routine benefit in neonates with severe neutropenia; further study is required.
Prevention
IV immune globulin given at birth may prevent sepsis in certain high-risk LBW infants but does not help in established infection.
Because invasive disease due to GBS often manifests within the first 6 h of life, women who have previously given birth to an infant with GBS disease should receive intrapartum antibiotics, and women who have symptomatic or asymptomatic GBS bacteriuria during pregnancy should receive antibiotics at the time of diagnosis and intrapartum (see Fig. 1: Infections in Neonates: Indications for intrapartum antibiotic prophylaxis to prevent perinatal group B streptococcal disease. ).
Last full review/revision October 2009 by Mary T. Caserta, MD
Content last modified October 2009
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