Neonatal Sepsis

Early-onset neonatal sepsis usually results from organisms acquired intrapartum. Most infants have symptoms within 6 hours of birth.

Most cases are caused by group B streptococcus Streptococcal Infections Streptococci are gram-positive aerobic organisms that cause many disorders, including pharyngitis, pneumonia, wound and skin infections, sepsis, and endocarditis. Symptoms vary with the organ... read more (GBS) and gram-negative enteric organisms (predominantly Escherichia coli Escherichia coli Infections The gram-negative bacterium Escherichia coli is the most numerous aerobic commensal inhabitant of the large intestine. Certain strains cause diarrhea, and all can cause infection when... read more ). Vaginal or rectal cultures of women at term may show GBS colonization rates of up to 35%. 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 hours of life. Nontypeable Haemophilus influenzae sepsis has also been identified in neonates, especially premature neonates.

Other cases tend to be caused by gram-negative enteric bacilli (eg, Klebsiella Klebsiella, Enterobacter, and Serratia Infections The gram-negative bacteria Klebsiella, Enterobacter, and Serratia are closely related normal intestinal flora that rarely cause disease in normal hosts. Diagnosis is by... read more species) and certain gram-positive organisms (Listeria monocytogenes Listeriosis Listeriosis is bacteremia, meningitis, cerebritis, dermatitis, an oculoglandular syndrome, intrauterine and neonatal infections, or rarely endocarditis caused by Listeria species. Symptoms... read more , enterococci Enterococcal Infections Enterococci are gram-positive, facultative anaerobic organisms. Enterococcus faecalis and E. faecium cause a variety of infections, including endocarditis, urinary tract infections... read more [eg, Enterococcus faecalis, E. faecium], group D streptococci Streptococcal Infections Streptococci are gram-positive aerobic organisms that cause many disorders, including pharyngitis, pneumonia, wound and skin infections, sepsis, and endocarditis. Symptoms vary with the organ... read more [eg, Streptococcus bovis], alpha-hemolytic streptococci Streptococcal Infections Streptococci are gram-positive aerobic organisms that cause many disorders, including pharyngitis, pneumonia, wound and skin infections, sepsis, and endocarditis. Symptoms vary with the organ... read more , and staphylococci Staphylococcal Infections Staphylococci are gram-positive aerobic organisms. Staphylococcus aureus is the most pathogenic; it typically causes skin infections and sometimes pneumonia, endocarditis, and osteomyelitis... read more ). Also, S. pneumoniae Pneumococcal Infections Streptococcus pneumoniae (pneumococci) are gram-positive, alpha-hemolytic, aerobic, encapsulated diplococci. Pneumococcal infection is a major cause of otitis media, pneumonia, sepsis... read more , H. influenzae type b Haemophilus Infections The gram-negative bacteria Haemophilus species cause numerous mild and serious infections, including bacteremia, meningitis, pneumonia, sinusitis, otitis media, cellulitis, and epiglottitis... read more , and, less commonly, Neisseria meningitidis Meningococcal Diseases Meningococci (Neisseria meningitidis) are gram-negative diplococci that cause meningitis and meningococcemia. Symptoms, usually severe, include headache, nausea, vomiting, photophobia... read more have been isolated. Asymptomatic gonorrhea occurs occasionally in pregnancy, so N. gonorrhoeae Gonorrhea Gonorrhea is caused by the bacterium Neisseria gonorrhoeae. It typically infects epithelia of the urethra, cervix, rectum, pharynx, or conjunctivae, causing irritation or pain and purulent... read more may rarely be a pathogen.

Late-onset neonatal sepsis is usually acquired from the environment ( see Neonatal Hospital-Acquired Infection Neonatal Hospital-Acquired Infection Some infections are acquired after admission to the nursery rather than from the mother in utero or intrapartum. For some infections (eg, group B streptococci, herpes simplex virus [HSV]) it... read more ). Staphylococci Staphylococcal Infections Staphylococci are gram-positive aerobic organisms. Staphylococcus aureus is the most pathogenic; it typically causes skin infections and sometimes pneumonia, endocarditis, and osteomyelitis... read more account for 30 to 60% of late-onset cases and are most frequently due to intravascular devices (particularly central vascular catheters). E. coli Escherichia coli Infections The gram-negative bacterium Escherichia coli is the most numerous aerobic commensal inhabitant of the large intestine. Certain strains cause diarrhea, and all can cause infection when... read more is also becoming increasingly recognized as a significant cause of late-onset sepsis, especially in extremely LBW infants. Isolation of Enterobacter cloacae Klebsiella, Enterobacter, and Serratia Infections The gram-negative bacteria Klebsiella, Enterobacter, and Serratia are closely related normal intestinal flora that rarely cause disease in normal hosts. Diagnosis is by... read more or Cronobacter sakazakii (formerly Enterobacter sakazakii) from blood or cerebrospinal fluid may be due to 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 group B streptococcus 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 Overview of Anaerobic Bacteria Bacteria can be classified by their need and tolerance for oxygen: Facultative: Grow aerobically or anaerobically in the presence or absence of oxygen Microaerophilic: Require a low oxygen concentration... read more (particularly Bacteroides fragilis) in late-onset sepsis remains unclear, although deaths have been attributed to Bacteroides bacteremia.

Candida Candidiasis Candidiasis is infection by Candida species (most often C. albicans), manifested by mucocutaneous lesions, fungemia, and sometimes focal infection of multiple sites. Symptoms depend... read more species are increasingly important causes of late-onset sepsis, occurring in 12 to 18% of extremely LBW infants.

Certain viral infections (eg, disseminated herpes simplex Neonatal Herpes Simplex Virus (HSV) Infection Neonatal herpes simplex virus infection is usually transmitted during delivery. A typical sign is vesicular eruption, which may be accompanied by or progress to disseminated disease. Diagnosis... read more , enterovirus Overview of Enterovirus Infections Enteroviruses, along with rhinoviruses (see Common Cold) and human parechoviruses, are a genus of picornaviruses (pico, or small, RNA viruses). All enteroviruses are antigenically heterogeneous... read more , adenovirus Adenovirus Infections Infection with one of the many adenoviruses may be asymptomatic or result in specific syndromes, including mild respiratory infections, keratoconjunctivitis, gastroenteritis, cystitis, and primary... read more , respiratory syncytial virus Respiratory Syncytial Virus (RSV) and Human Metapneumovirus Infections Respiratory syncytial virus and human metapneumovirus infections cause seasonal lower respiratory tract disease, particularly in infants and young children. Disease may be asymptomatic, mild... read more ) may manifest as early-onset or late-onset sepsis.

Certain maternal perinatal and obstetric factors increase risk, particularly of early-onset neonatal sepsis, such as the following:

Hematogenous and transplacental dissemination of maternal infection occurs in the transmission of certain viral (eg, rubella Congenital Rubella Congenital rubella is a viral infection acquired from the mother during pregnancy. Signs are multiple congenital anomalies that can result in fetal death. Diagnosis is by serology and viral... read more , cytomegalovirus Congenital and Perinatal Cytomegalovirus Infection (CMV) Cytomegalovirus infection may be acquired prenatally or perinatally and is the most common congenital viral infection. Signs at birth, if present, are intrauterine growth restriction, prematurity... read more ), protozoal (eg, Toxoplasma gondii Toxoplasmosis Toxoplasmosis is infection with Toxoplasma gondii. Symptoms range from none to benign lymphadenopathy, a mononucleosis-like illness, to life-threatening central nervous system (CNS) disease... read more ), and treponemal (eg, Treponema pallidum Congenital Syphilis Congenital syphilis is a multisystem infection caused by Treponema pallidum and transmitted to the fetus via the placenta. Early signs are characteristic skin lesions, lymphadenopathy... read more ) pathogens. A few bacterial pathogens (eg, L. monocytogenes Listeriosis Listeriosis is bacteremia, meningitis, cerebritis, dermatitis, an oculoglandular syndrome, intrauterine and neonatal infections, or rarely endocarditis caused by Listeria species. Symptoms... read more , Mycobacterium tuberculosis Tuberculosis (TB) Tuberculosis is a chronic, progressive mycobacterial infection, often with an asymptomatic latent period following initial infection. Tuberculosis most commonly affects the lungs. Symptoms include... read more ) 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 group B streptococcus 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 early-onset neonatal sepsis, which reflect the flora of the maternal vaginal vault.

The most important risk factor in late-onset sepsis is

Other risk factors 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, inconsistent provider handwashing) result in higher rates of hospital-acquired infection.

Risk factors for candidal sepsis include prolonged (> 10 days) use of central IV catheters, hyperalimentation, use of antecedent antibiotics (especially 3rd-generation cephalosporins), and abdominal pathology.

Initial foci of infection can be in the urinary tract, paranasal sinuses, middle ear, lungs, or gastrointestinal tract and may later disseminate to meninges, kidneys, bones, joints, peritoneum, and skin.

The total white blood cell count and absolute band count in neonates are poor predictors of early-onset sepsis. However, an elevated ratio of immature:total polymorphonuclear leukocytes of > 0.16 is sensitive, and values below this cutoff have a high negative predictive value. However, specificity is poor; up to 50% of term neonates have an elevated ratio. Values obtained after 6 hours of life are more likely to be abnormal and clinically useful than those obtained immediately after birth.

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 international normalized ratio [INR]). Given the timing of these changes, the platelet count is not typically helpful in evaluating a neonate for sepsis.

Because of 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 immediately after cultures (eg, blood and CSF [if possible]) are taken.

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 Diagnosis Diagnosis under Neonatal Bacterial Meningitis). Supplemental oxygen 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 Respiratory Distress Syndrome in Neonates Respiratory distress syndrome is caused by pulmonary surfactant deficiency in the lungs of neonates, most commonly in those born at < 37 weeks gestation. Risk increases with degree of prematurity... read more , LP is often done routinely in neonates suspected of having these diseases.

Umbilical vessels are frequently contaminated by organisms on the umbilical stump, especially after a number of hours, so blood cultures from umbilical venous lines may not be reliable. Therefore, blood for culture should be obtained by venipuncture, preferably at 2 peripheral sites. Although the optimal skin preparation to do before obtaining blood cultures in neonates is not defined, clinicians can apply an iodine-containing liquid and allow the site to dry. Alternatively, blood obtained soon after placement of an umbilical arterial catheter may also be used for culture if necessary.

Blood should be cultured for both aerobic and anaerobic organisms. However, the minimum amount of blood per blood culture bottle is 1.0 mL; if < 2 mL is obtained, it should all be placed in a single aerobic blood culture bottle. 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 hours of incubation. Data on capillary blood cultures are insufficient to recommend them.

Candida species 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. Neonates with candidemia should undergo LP to identify candidal meningitis. Indirect ophthalmoscopy with dilation of the pupils is done to identify retinal candidal lesions. Renal ultrasonography is done to detect renal mycetoma.

Urine testing is needed only for evaluation of late-onset sepsis. Urine should be obtained by catheterization or suprapubic aspiration, not by urine collection bags. Although only culture is diagnostic, a finding of ≥ 5 white blood cells/high-power field in the spun urine or any organisms in a fresh unspun gram-stained sample is presumptive evidence of a urinary tract infection (UTI). Absence of pyuria does not rule out UTI.

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. Biomarkers are not considered useful for determining when to initiate antibiotics for neonatal sepsis because of their poor positive predictive value, but they may have an adjunctive role in determining when it may be acceptable to stop antibiotics if cultures remain negative in suspected early-onset sepsis.

Acute-phase reactants are proteins produced by the liver under the influence of IL-1 when inflammation is present. The most studied of these is quantitative C-reactive protein. A concentration of ≥ 1 mg/dL (9.52 nmol/L) (measured by nephelometry) is generally considered abnormal. Elevated levels occur within 6 to 8 hours of developing sepsis and peak at 1 day. The sensitivity of C-reactive protein measurements is higher if measured after 6 to 8 hours of life. Two normal values obtained between 8 hours and 24 hours after birth and then 24 hours later have a negative predictive value of 99.7%.

Procalcitonin is being investigated as an acute-phase reactant marker for neonatal sepsis. Although procalcitonin appears more sensitive than C-reactive protein, it is less specific (1 Diagnosis references Neonatal sepsis is invasive infection, usually bacterial, occurring during the neonatal period. Signs are multiple, nonspecific, and include diminished spontaneous activity, less vigorous sucking... read more ). A combination of biomarkers that includes procalcitonin and C-reactive protein may prove to be more useful for determining antibiotic duration (2 Diagnosis references Neonatal sepsis is invasive infection, usually bacterial, occurring during the neonatal period. Signs are multiple, nonspecific, and include diminished spontaneous activity, less vigorous sucking... read more ).

See table: Recommended Dosages of Selected Parenteral Antibiotics for Neonates Recommended Dosages of Selected Parenteral Antibiotics for Neonates .

In early-onset sepsis, initial therapy should include ampicillin plus an aminoglycoside (see table Recommended Dosages of Select Aminoglycosides for Neonates Recommended Dosages of Select Aminoglycosides for Neonates ). Cefotaxime may be added to or substituted for the aminoglycoside if meningitis caused by a gram-negative organism is suspected. Antibiotics may be changed as soon as an organism is identified.

In late-onset sepsis, 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; see table Vancomycin Dosage for Neonates ) plus an aminoglycoside. If P. aeruginosa is prevalent in the nursery, ceftazidime, cefepime, or piperacillin/tazobactam may be used in addition to, or instead of, an aminoglycoside depending on local susceptibilities.

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 hours) 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, empiric initiation of amphotericin B deoxycholate therapy and removal of the infected catheter before cultures confirm yeast infection may be lifesaving.

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 hemoglobin 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 White blood cells (WBCs) White blood cells (WBCs) Whole blood can provide improved oxygen-carrying capacity, volume expansion, and replacement of clotting factors and was previously recommended for rapid massive blood loss. However, because... read more ) 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.

All pregnant women should be screened for GBS colonization late in gestation using both vaginal and rectal culture.

Women with a positive GBS screen should be given intrapartum antibiotic prophylaxis unless they are undergoing cesarean delivery before labor starts and before membrane rupture.

Women with a negative GBS screen should receive intrapartum antibiotics if they previously gave birth to an infant with GBS disease.

Women whose GBS status is unknown (eg, because they were not tested or results are unavailable) should receive intrapartum antibiotics if ≥ 1 of the following factors are present:

Women who had a positive GBS screen in one pregnancy have a 50% probability of having GBS colonization in a subsequent pregnancy (4 Prevention references Neonatal sepsis is invasive infection, usually bacterial, occurring during the neonatal period. Signs are multiple, nonspecific, and include diminished spontaneous activity, less vigorous sucking... read more ).

Antibiotics typically used include penicillin, ampicillin, or cefazolin and should be given IV for ≥ 4 hours before delivery. Selection should take into account local GBS antimicrobial resistance patterns.