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(See also Sepsis and Septic Shock.)
Neonatal
sepsis is invasive bacterial infection occurring in the 1st 90 days
of life. 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, with extensive laboratory
testing. 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, and those with maternal perinatal risk factors. The risk is greater in males (2:1) and in neonates with congenital anomalies.
A neonate may be predisposed to sepsis by obstetric complications, eg, premature rupture of membranes (PROM) occurring ≥ 18 h before birth or maternal bleeding (placenta previa, abruptio placentae), toxemia, precipitous delivery, or maternal infection (particularly of the urinary tract or endometrium, most commonly manifested as maternal fever shortly before or during parturition).
Etiology
Early-onset sepsis (ie, within 7 days of birth) usually results from organisms acquired intrapartum. In > 50% of cases, early-onset sepsis appears within 6 h of birth, and most cases occur within 72 h. Late-onset sepsis (after 7 days) is often acquired from the environment (see Infections in Neonates: Neonatal Hospital-Acquired Infection).
Group B streptococcus (GBS) and gram-negative enteric organisms (predominantly Escherichia coli) account for 70% 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 for invasive disease, which is 40 times higher with heavy colonization. Although only 1/100 of those colonized develop invasive disease due to GBS, > 50% of those present within the 1st 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, E. 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 in 5 to 10% of pregnancies, so N. gonorrhoeae may be a pathogen.
Staphylococci account for 30 to 50% of late-onset cases and are most frequently due to intravascular devices (particularly umbilical artery or vein catheters). 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.
The role of anaerobes (particularly Bacteroides
fragilis) 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.
Certain viral infections (eg, disseminated herpes simplex, enterovirus, adenovirus, respiratory syncytial virus) may manifest as early- or late-onset sepsis.
Pathophysiology
The most important risk factor in late-onset sepsis is prolonged use of intravascular catheters. Others include associated illnesses (which may, however, be only a marker for the use of invasive procedures), exposure to antibiotics (which selects resistant bacterial strains), prolonged hospitalization, and contaminated equipment or IV or enteral solutions. Gram-positive organisms (eg, coagulase-negative staphylococci and Staphylococcus aureus) may be introduced from the environment. 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, nurse:patient ratios > 1:1, inadequate 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, and previous surgery.
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) agents. 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 for 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.
Initial foci of infection can be in the paranasal sinuses, middle ear, lungs, or GI tract, and may later disseminate to meninges, kidneys, bones, joints, peritoneum, and skin. Pneumonia is the most common invasive bacterial infection after primary sepsis.
Symptoms and Signs
Early signs are frequently nonspecific and subtle and do not distinguish among organisms (including viral). Diminished spontaneous activity, less vigorous sucking, apnea, bradycardia, and temperature instability (hypo- or hyperthermia) are particularly common. Fever is present in only 10 to 50% 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 1st 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 or a metastatic site. Most neonates with early-onset GBS (and many with L. monocytogenes) infection present with respiratory distress that is difficult to distinguish from hyaline membrane disease. Periumbilical erythema, discharge, or bleeding without a hemorrhagic diathesis suggests omphalitis (infection prevents obliteration of the umbilical vessels). Coma, seizures, opisthotonos, or a bulging fontanelle suggests meningitis or brain abscess. Decreased spontaneous movement of an extremity and swelling, warmth, erythema, or tenderness over a joint indicates osteomyelitis or pyogenic arthritis. Unexplained abdominal distention may indicate peritonitis or necrotizing enterocolitis (particularly when accompanied by bloody diarrhea and fecal leukocytes). Cutaneous vesicles, mouth ulcers, and hepatosplenomegaly (particularly with disseminated intravascular coagulation [DIC]) can identify disseminated herpes simplex.
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 is frequently absent. 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 1st 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, 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 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 PMNs of < 0.2 has a very high negative predictive value. A precipitous fall in a known absolute eosinophil count and morphologic changes in neutrophils (eg, toxic granulation, Döhle bodies, and 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 manifests illness. 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 PMNs by applying Gram stain, methylene blue , or acridine orange to the buffy coat.
Lumbar
puncture (LP):
There is a risk of increasing hypoxia during an LP in an already hypoxemic neonate. Therefore, routine LP is not mandatory if the suspicion for sepsis is low. However, LP should be performed in a neonate with suspected sepsis as soon as he is able to tolerate the procedure (see also Infections in Neonates: Diagnosis under Neonatal Meningitis). Supplemental O2 is administered before and during LP to prevent hypoxia. Because GBS pneumonia manifesting in the 1st day of life can be confused with hyaline membrane disease, LP is often performed 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. (Bacteroides fragilis requires special culture conditions, so the laboratory should be notified if this organism is a concern.) If catheter-associated sepsis is suspected, a culture should be obtained through the catheter as well as peripherally. In > 90% of positive bacterial blood cultures, growth occurs within 48 h of incubation; 50% of positive blood cultures contain > 50 colony-forming units (CFU)/mL. Because this bacteremia is high-density, 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 grows 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 ultrasound is performed 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 specifities are suboptimal.
Counterimmunoelectrophoresis and latex agglutination tests detect antigen in body fluids (eg, CSF, concentrated urine); they can be used when antibiotic pretreatment renders culture results unreliable. They may also detect capsular polysaccharide antigen of GBS, E.
coli K1, N. meningitidis type B, S. pneumoniae
, and H. influenzae type b.
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 than in full-term infants. The overall mortality rate of early-onset sepsis is 15 to 40% (that of early-onset GBS infection is 2 to 30%) and of late-onset sepsis is 10 to 20% (that of late-onset GBS is about 2%).
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%). Since 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 patients 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 Antibacterial Drugs); 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.
Antibiotics:
In early-onset sepsis, initial therapy should include ampicillin or penicillin G plus an aminoglycoside. Cefotaxime may be substituted for the aminoglycoside. 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 . In late-onset hospital-acquired sepsis, initial therapy should include vancomycin plus an aminoglycoside. If P. aeruginosa is prevalent in the nursery, ceftazidime may be used instead of an aminoglycoside. Neonates previously treated with a full 7- to 14-day aminoglycoside course who need retreatment should receive a different aminoglycoside or a 3rd-generation cephalosporin.
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 , that drug 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 glycocalix (covering slime 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: Blood Products) 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 appear 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 1st 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. ).
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Fig. 1
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Indications for intrapartum antibiotic prophylaxis to prevent perinatal group B streptococcal disease.
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(Adapted from Schrag S, Gorwitz R, Fultz-Butts K, Schuchat A: Prevention of perinatal group B streptococcal disease. Morbidity and Mortality Weekly Report 51(RR-11): 1–22, 2002.)
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Last full review/revision November 2005
Content last modified November 2005
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