Lecture 05. BACTERIAL INFECTIONS IN NEWBORNS
Neonatal sepsis
Neonatal Sepsis is a clinical syndrome of systemic illness accompanied by bacteremia occurring in the first month of live.
The incidence of neonatal bacterial sepsis varies from 1 to 4/1,000 live births in developed countries, with considerable fluctuation over time and with geographic variation. Studies suggest that term male infants have a higher incidence of sepsis than term females. This sex difference is less clear in preterm LBW infants. Attack rates of neonatal sepsis increase significantly in LBW infants in the presence of maternal chorioamnionitis, congenital immune defects, mutations of genes involved in the innate immune system, asplenia, galactosemia (E. coli), and malformations leading to high inocula of bacteria (obstructive uropathy).
Neonatal sepsis can be early onset (within 7 days of birth) or late onset (after 7 days).
Etiologic agents for early-onset sepsis (0 to 4 days of age)
– Group B streptococci (GBS)
– Escherichia coli 60% to 70% of infections
– Listeria
– Klebsiella
– Enterococcus
– Staphylococcus aureus
– Streptococcus pneumoniae
– group A streptococci
Etiologic agents for late-onset sepsis ( > 5 days of age)
– Staphylococcus Aureus
– GBS
– E. Coli
– Klebsiella
– Pseudomonas
– Serratia
– Staph.epidermidis
– Haemophilus influenzae
– Herpes simplex virus
– Enteroviruses
In very low-birthweight infants:
– Candida
– Coagulase-negative staphylococci
Symptoms and Signs
Early signs are frequently nonspecific and subtle and do not distinguish among organisms (including viral). Particularly common early signs include:
– Diminished spontaneous activity
– Less vigorous sucking
– Apnea
– Bradycardia
– Temperature instability (hypothermia or hyperthermia)
Fever is present in only 10 to 15% but, when sustained (> 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.
– Most neonates with early-onset GBS (and many with L. monocytogenes) infection present with respiratory distress that is difficult to distinguish from respiratory distress syndrome.
– 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, encephalitis, 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 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
CBC, differential, and smear: The normal WBC count ieonates 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 ieutrophils (eg, toxic granulation, Döhle bodies, intracytoplasmic vacuolization ioncitrated blood) 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 ( 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 (those who look sick or are febrile or hypothermic), antibiotics should be started after cultures ( blood, urine, and CSF) are taken.
Lumbar puncture: There is a risk of increasing hypoxia during an LP in already hypoxemic neonates. However, LP should be done ieonates with suspected sepsis as soon as they are able to tolerate the procedure. 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 ieonates 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 ieonates is associated with a high density of organisms and delayed clearance, a small amount of blood (≥ 1 mL) is usually sufficient for detecting organisms. Data on capillary blood cultures are insufficient to recommend them.
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.
Treatment
Because sepsis may manifest with nonspecific clinical signs and its effects may be devastating, rapid empiric antibiotic therapy is recommended; 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 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 aminoglycoside may be used.
In late-onset hospital-acquired sepsis, initial therapy should include vancomycin (active against methicillin-resistant S. aureus) plus 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.
Supportive therapy
– Respiratory (oxygen and ventilation as necessary);
– Cardiovascular (support blood pressure with volume expanders and/or pressors);
– Hematologic (treat DIC);
– CNS (treat seizures with Phenobarbital);
– Metabolic (treat hypoglycemia/hyperglycemia and metabolic acidosis).
Bacterial meningitis
Etiology of neonatal meningitis
The most common bacterial causes of neonatal meningitis are GBS, E. coli, and L. monocytogenes. S. pneumoniae, other streptococci, non-typable Haemophilus influenzae, both coagulase-positive and coagulase-negative staphylococci, Klebsiella, Enterobacter, Pseudomonas, T. pallidum, and Mycobacterium tuberculosis may also produce meningitis.
Early-onset group B streptococcal meningitis occurs during the first 7 days of life, a consequence of maternal colonization and the absence of protective antibody in the neonate; it often is associated with obstetric complications. The disease is seen most often in premature or low birth weight babies. Pathogens are acquired before or during the birth process.
Late-onset meningitis is defined as disease occurring after 7 days of life. Etiologic agents include perinatally acquired and nosocomial pathogens. S agalactiae (group B streptococci) are classified into 5 distinct serotypes: Ia, Ib, Ic, II, and III. Although these serotypes occur with almost equal frequency in the early onset of disease, serotype III causes 90% of late-onset disease.
Use of respiratory equipment in the nursery increases the risk of infection caused by Serratia marcescens, Pseudomonas aeruginosa, and Proteus species. Invasive devices predispose infants to the infections caused by Staphylococcus epidermidis and Pseudomonas, Citrobacter, and Bacteroides species.
Symptoms and Signs
Frequently, only those findings typical of neonatal sepsis (eg, temperature instability, respiratory distress, jaundice, apnea) are manifest. CNS (central nervous system) signs, such as, lethargy, seizures (particularly focal), vomiting, irritability more specifically suggest neonatal bacterial meningitis. So-called paradoxical irritability, in which cuddling and consoling by a parent irritates rather than comforts the neonate, is more specific for the diagnosis. A bulging or full fontanelle occurs in about 25% and nuchal rigidity in only 15%. The younger the patient, the less common are these findings. Cranial nerve abnormalities (particularly those involving the 3rd, 6th, and 7th nerves) may also be present.
Meningitis due to GBS may occur in the first week of life, accompanying early-onset neonatal sepsis and frequently manifesting initially as a systemic illness with prominent respiratory signs. Usually, however, GBS meningitis occurs after this period (most commonly in the first 3 mo of life) as an isolated illness characterized by absence of antecedent obstetric or perinatal complications and the presence of more specific signs of meningitis (eg, fever, lethargy, seizures).
Ventriculitis frequently accompanies neonatal bacterial meningitis, particularly when caused by gram-negative enteric bacilli. Organisms that cause meningitis together with severe vasculitis, particularly C. diversus and Enterobacter sakazakii, are likely to cause cysts and abscesses. Pseudomonas aeruginosa, E. coli K1, and Serratia sp also may cause brain abscesses. An early clinical sign of brain abscess is increased intracranial pressure (ICP), commonly manifested by vomiting, a bulging fontanelle, and sometimes enlarging head size. Deterioration in an otherwise stable neonate with meningitis suggests progressive increased ICP caused by abscess or hydrocephalus, or rupture of an abscess into the ventricular system.
Early onset
Symptoms appearing in the first 48 hours of life are referable primarily to systemic illness rather than to meningitis. Such symptoms include temperature instability, episodes of apnea or bradycardia, hypotension, feeding difficulty, hepatic dysfunction, and irritability alternating with lethargy.Respiratory symptoms can become prominent within hours of birth in group B streptococcal (GBS) infection; however, the symptom complex also is seen with infection by E coli or Listeria species.
Late onset
Late-onset bacterial meningitis (ie, symptom onset after 48 hours of life) is more likely to be associated with neurological symptoms. Most commonly seen are stupor and irritability, which Volpe describes in more than 75% of affected neonates. Between 25% and 50% of neonates will exhibit the following neurological signs:
– Seizures
– Bulging anterior fontanel
– Extensor posturing or opisthotonos
– Focal cerebral signs including gaze deviation and hemiparesis
– Cranial nerve palsies
–
Diagnosis
• Gram-stained smear can be helpful in making a more rapid definitive diagnosis and identifying the initial classification of the causative agent.
• Cerebrospinal glucose levels must be compared with serum glucose levels. Normal CSF values are one half to two thirds of serum values.
• CSF protein is usually elevated, although normal values for infants, especially preemies, may be much higher than in later life, and the test may be confounded by the presence of blood in the specimen.
• CSF pleocytosis is variable. Normal values range from 8-32 white blood cells in various studies, some of which may be polymorphonuclear cells. Pleocytosis may also be an irritant reaction to CNS hemorrhage.
• Rapid antigen tests are available for several organisms and should be done on spinal fluid.
• Ventricular tap, with culture and examination fluid, is indicated in patients not responding to treatment.
Radiologic studies
• Cranial ultrasound examination has been useful in the diagnosis of ventriculitis.
• Computed tomography (CT) scan of the head may be indicated to rule out abscess, subdural effusion, or an area of thrombosis, hemorrhage, or infarction.
Treatment
Empiric ampicillin plus gentamicin, cefotaxime, or both, followed by culture-specific drugs
Empiric antibiotic therapy: Initial empiric treatment depends on patient age and is still debated. Most experts recommend ampicillin plus aminoglycoside, a 3rd-generation cephalosporin (eg, cefotaxime), or both. Ampicillin is active against organisms such as GBS, enterococci, and Listeria. Gentamicin provides synergy and added efficacy against these organisms and adequate gram-negative coverage. Cephalosporins provide adequate gram-negative coverage but do not provide synergy with ampicillin for gram-positive organisms and may allow for some resistant organisms.
Hospitalized neonates who previously received antibiotics (eg, for early-onset sepsis) may have resistant organisms; fungal disease may also be considered in a septic-appearing neonate after prolonged hospitalization. Ill neonates with hospital-acquired infection should initially receive vancomycin plus aminoglycoside with or without a 3rd-generation cephalosporin. Antibiotics are adjusted when results of CSF culture and sensitivities are known. The results of the Gram stain should not change antibiotic therapy.
Organism-specific antibiotic therapy: The recommended initial treatment for GBS meningitis ieonates < 1 wk of age is penicillin G 100,000 to 150,000 units/kg IV q 8 h or ampicillin 100 mg/kg IV q 8 h, plus gentamicin 4 mg/kg IV once/day if the infant is 32 to 35 wk gestational age or 5 mg/kg IV once/day if the infant is > 35 wk gestational age. If clinical improvement occurs or sterilization of CSF is documented, gentamicin can be stopped.
For enterococci or L. monocytogenes, treatment is generally ampicillin plus gentamicin.
In gram-negative bacillary meningitis, treatment is difficult. The traditional regimen of ampicillin plus aminoglycoside results in a 15 to 20% mortality rate, with a high rate of sequelae in survivors. A 3rd-generation cephalosporin (eg, cefotaxime) should be strongly considered ieonates with proven gram-negative meningitis (or sepsis) or those convincingly septic. If antibiotic resistance is a concern, both an aminoglycoside and a 3rd-generation cephalosporin may be used until sensitivities are known. However, except for initial empiric therapy, 3rd-generation cephalosporins are generally not used routinely, because certain gram-negative organisms are induced to produce β-lactamase, resulting in rapid development of resistance.
Parenteral therapy for gram-positive meningitis is given for a minimum of 14 days, and for complicated gram-positive or gram-negative meningitis, a minimum of 21 days.
Neonatal Necrotizing Enterocolitis
NEC is the most common life-threatening emergency of the gastrointestinal tract in the newborn period. The disease is characterized by various degrees of mucosal or transmural necrosis of the intestine. The cause of NEC remains unclear but is most likely multifactorial. The incidence of NEC is 1-5% of infants ieonatal intensive care units. Because very small, ill preterm infants are particularly susceptible to NEC, a rising incidence may reflect improved survival of this high-risk group of patients.
Infants with NEC have a variety of signs and symptoms and may have an insidious or sudden onset. The onset of NEC is usually in the 2nd or 3rd week of life but can be as late as 3 mo in VLBW infants. Age of onset is inversely related to gestational age. The 1st signs of impending disease may be nonspecific, including lethargy and temperature instability, or related to gastrointestinal pathology, such as abdominal distention and gastric retention. Obvious bloody stools are seen in 25% of patients. Because of nonspecific signs, sepsis may be suspected before NEC. The spectrum of illness is broad, ranging from mild disease with only guaiac-positive stools to severe illness with bowel perforation, peritonitis, systemic inflammatory response syndrome, shock, and death. Progression may be rapid, but it is unusual for the disease to progress from mild to severe after 72 hr.
Signs and symptoms of necrotizing enterocolitis
Gastrointestinal
– Abdominal distention
– Abdominal tenderness
– Feeding intolerance
– Delayed gastric emptying
– Vomiting
– Occult/gross blood in stool
– Change in stool pattern/diarrhea
– Abdominal mass
– Erythema of abdominal wall
Systemic
– Lethargy
– Apnea/respiratory distress
– Temperature instability
– Acidosis (metabolic and/or respiratory
– Glucose instability
– Poor perfusion/shock
– Disseminated intravascular coagulopathy
– Positive results of blood cultures
Diagnosis
Plain abdominal radiographs are essential to make a diagnosis of NEC. The finding of pneumatosis intestinalis (air in the bowel wall) confirms the clinical suspicion of NEC and is diagnostic; 50-75% of patients have pneumatosis when treatment is started . Portal venous gas is a sign of severe disease, and pneumoperitoneum indicates a perforation.
Hepatic ultrasonography may detect portal venous gas despite normal abdominal roentgenograms.
Rapid initiation of therapy is required for suspected as well as proven cases of NEC. There is no definitive treatment for established NEC, so, therapy is directed at giving supportive care and preventing further injury with cessation of feeding, nasogastric decompression, and administration of intravenous fluids.
Careful attention to respiratory status, coagulation profile, and acid-base and electrolyte balances are important.
Once blood has been drawn for culture, systemic antibiotics (with broad coverage based on the antibiotic sensitivity patterns of the gram-positive, gram-negative, and anaerobic organisms in the particular NICU) should be started immediately. If present, umbilical catheters should be removed, but good intravenous access is maintained.
Ventilation should be assisted in the presence of apnea or if abdominal distention is contributing to hypoxia and hypercapnia. Intravascular volume replacement with crystalloid or blood products, cardiovascular support with fluid boluses and/or inotropes, and correction of hematologic, metabolic, and electrolyte abnormalities are essential to stabilize the infant with NEC.
The patient’s course should be monitored closely by means of frequent physical assessments; sequential anteroposterior and cross-table lateral or lateral decubitus abdominal radiographs to detect intestinal perforation; and serial determinations of hematologic, electrolyte, and acid-base status. Gown and glove isolation and grouping of infants at similar increased risks into cohorts separate from other infants should be instituted to contain an epidemic.
A surgeon should be consulted early in the course of treatment. Indications for surgery include evidence of perforation on abdominal roentgenograms (pneumoperitoneum) or positive result of abdominal paracentesis (stool or organism on Gram stain preparation from peritoneal fluid). Failure of medical management, a single fixed bowel loop on radiographs, abdominal wall erythema, and a palpable mass are relative indications for exploratory laparotomy. Ideally, surgery should be performed after intestinal necrosis develops but before perforation and peritonitis occur.
In unstable premature infants with perforated NEC, peritoneal drainage can be cautiously considered as an alternative to exploratory laparotomy, although the best surgical approach in these infants remains unresolved.
REFERENCES
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2. Daniel Bernstein, Steven P. Shelov. Pediatrics for medical students. –
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