A.General Comments Bacterial Infections Most Frequently Are Acquired Via the Birth Canal

Neonatal Sepsis

A.General comments Bacterial infections most frequently are acquired via the birth canal or nosocomially. The infection almost always is bacteremic (often with seeding of the meanings by way of the blood) and associated with systemic symptoms – a condition referred as neonatal sepsis. Neonatal sepsis, sepsis neonatorum, and neonatal septicemia are terms that have been used to describe the systemic response to infection in the newborn infant. There is little agreement on the proper use of the term, i.e., whether it should be restricted to bacterial infections, positive cultures, or severity of illness. The concept of sepsis as a syndrome caused by metabolic and hеmodynamic consequences of infection is logical and important. In the future, the definition of sepsis in the newborn infant and child will become more precise. At this time, criteria for neonatal sepsis should include documentation of infection in a newborn infant with a serious systemic illness in which noninfectious explanations for the abnormal pathophysiological state are excluded or unlikely. Serious systemic illness in the newborn infant may be caused by perinatal asphyxia, respiratory tract, cardiac, metabolic, neurological or hematological diseases. Sepsis occurs in a small proportion of all neonatal infections. Bacteria and Candida are the usual etiologic agents, but viruses and, rarely, protozoa may also cause sepsis. Blood cultures may be negative, increasing the difficulty in establishing infection etiologically. Finally, infection with or without sepsis may be present concurrently with a noninfectious illness in the newborn infant, child, or adult.

1. Incidence. Neonatal sepsis is common in premature infants. About 1% - 4 % of these infants have at least one episode of sepsis during their hospitalization. Sepsis in term infants is rare, occurring in less than 1%. The incidence of neonatal sepsis varies according to definition from 1 –4/1000 live births in developed countries with considerable fluctuation over time and geographic location. Neonatal bacterial sepsis is associated with 10% to 40% mortality and significant morbidity, especially neurological sequel of meningitis. Hospital – to – hospital variability in incidence may be related to rates of prematurity, prenatal care, conduct of labor and environmental conditions in nurseries. Neonatal sepsis may divide into: early onset; late onset; nosocomial. Table 10 classifies the important patterns of neonatal infection by the main features.

Attack rates of neonatal sepsis increase significantly in low-birth-weight infants and in the presence of maternal (obstetric) risk factors. Infants <1 month old have immunologic deficient and are predisposed to serious infections.

1. Predisposing factors.

Premature rupture of membranes (>24 hours), premature labor, maternal fever, UTI, foul lochia, chorioamnionitis, IV catheters (in infant), intrapartum asphyxia,

intrauterine monitoring (pressure catheter or scalp electrode).

Host risk factors include male sex, developmental or congenital immune defects, galactosemia (Esherichia coli), administration of intramuscular iron, congenital anomalies ( urinary tract, asplenia, myelomeningocele, sinus tracts), omphalitis, and twinning ( especially the second twin of an infected twin). Prematurity is a risk factor for early-onset sepsis.

Table 12 Pattern of neonatal infection

D.Etiology Bacteria, viruses, fungi, and rarely protozoa may produce neonatal sepsis:

1. Early infection (0 to 4 days of age).

Group B streptococci (GBS) and Escherichia coli 60% to 70% of infections. Also Listeria , Klebsiella, Enterococcus, Staphylococcus aureus (uncommon), Streptococcus pneumoniae, group A streptococci.

1. Late infection (>5 days of age).

Staph. aureus, GBS, E. coli, Klebsiella, Pseudomonas, Serratia, Staph. epidermidis, Haemophilus influenzae, herpes simplex virus (HSV), enteroviruses. In very low-birthweight infants, Candida and coagulase-negative staphylococci (CONS) are the most common pathogens in late-onset sepsis.

Figure 16 Modes of transmission of infections from mother to fetus of infant

Maternal Circulation

PlacentaAmniotic FluidVaginal Secretion

Fetal CirculationAspiration IngestionWound

LungGI TractFetal monitors,vascular

access, umbilicus, surgery,

necrotizing enterocolitis.

D. Pathogenesis. Rarely, inhalation of infected amniotic fluid may produce pneumonia and sepsis in utero, manifested by fetal distress or neonatal asphyxia. Exposure to pathogenesis at delivery and in the nursery or community is the mechanism of infection after birth. The physiologic manifestations of the inflammatory response are mediated by a variety of inflammatory cytokines, principally TNF, interleukin-1 (IL-1), and IL-6, and by-products of activation of the complement and coagulation systems. Studies in the newborn are limited, but it appears that some cytokine production may be diminished, which is consistent with an impaired inflammatory response. However, elevated levels of IL-6, TNF, and platelet-activating factor have been reported in newborn infants with neonatal sepsis and necrotizing enterocolitis. IL-6 appears to be the cytokine most often elevated in neonatal sepsis.

F. Signs and symptoms. Presentation may be subtle; thus any febrile neonate (temperature >38° C) must have a septic work-up. Fever may be absent; so watch for symptoms below.

1.The presentation may include irritability, vomiting, poor feeding, poor temperature control, lethargy, apneas spells, and hypoglycemia.

2.May progress to respiratory distress, poor perfusion, abdominal distension, jaundice, bleeding, petechiae, or seizures.

1. Bulging fontanel is a very late sign of neonatal meningitis and Brudzinski’s sign or Kernig’s sign is rarely found.

1. Clinical manifestations. Infection is considered in the differential diagnosis of many physical signs in the newborn infant. All of these may have noninfectious explanations. When there is multisystem involvement or when the cardiorespiratory signs are consistent with severe illness, sepsis should be considered. The initial presentation may be limited to only one system, such as apnea, tachypnea with retractions, or tachycardia, but a full clinical and laboratory evaluation will usually reveal other abnormalities. Infants with suspected sepsis should be evaluation for multiorgan system disease. Metabolic acidosis is common. Hypoxemia and carbon dioxide retention may be associated with adult and congenital respiratory distress syndrome (RDS) or pneumonia.

The baby who was sucking normally becomes lethargic and unresponsive. He stops sucking at breast. He has a vacant stare and looks ill. Temperature is usually elevated but may be normal or even below normal. The baby loses weight. The liver and spleen may become enlarged. Episodes of apnea may be the only manifestations of sepsis in the preterm babies. Diarrhea, vomiting, abdominal distension and jaundice are other cardinal manifestations. Marked pallor, ashen gray color, cold extremities with absent peripheral pulsations and fall in blood pressure indicate a state of shock, precipitated by the infection.

Many newborn infants with infections don’t have serious systemic physiologic abnormalities. Many infants with pneumonia and infants with stage II NEC do not have sepsis. In contrast, stage III NEC is usually accompanied by the systemic manifestations of sepsis, and urinary tract infections (UTIs) secondary to obstructive uropathy may have hematological and hepatic abnormalities consistent with sepsis. Each infant should be re-evaluated over time to determine physiologic changes secondary to infection have reached a moderate to severe level of severity that is consistent with sepsis. Late manifestations of sepsis include signs of cerebral edema and/or thromboses, respiratory failure as a result of acquired respiratory distress syndrome (ARDS). Pulmonary hypertension, cardiac failure, renal failure, liver disease with hyperbilirubinemia and elevated enzymes, prolonged prothrombin time (PT) and partial thromboplastin time (PTT), septic shock, adrenal hemorrhage with adrenal insufficiency, bone marrow failure ( thrombocytopenia, neutropenia, anemia), and disseminated intravascular coagulation (DIC).

1. Laboratory findings The laboratory evaluation for neonatal sepsis should include:

1. Complete blood count (neutropenia or an elevated ratio of immature to total neutrophils thrombocytopenia are suggest sepsis) and repeat in 5 hours, ESR and C-reactive protein

2. A lumbar puncture (LP) (LP for cell count, protein, glucose, and culture. Consider sending CSF for viral studies).

1. Cultures of blood, urine, and any other site as indicated. Latex agglutination test for pneumococcus, E. coli, H. influenzae, group B streptococci, and meningococcus in blood, urine, and CSF is done even though the usefulness is questionable. Negative latex agglutination tests do not rule out infection, but positive results may help guide therapy.
2. Chest radiograph
3. Gastric aspirate (at the time of delivery) for neutrophil count, Gram stain, and culture.
4. Gram stain and culture of a tracheal aspirate, if the infant is intubated.

Associated laboratory findings. Hypocalcaemia, hypoglycemia, hyponatremia, prolonged PT and PTT and DIC.

Documentation of infection is the first diagnostic criterion that must be met. It is important to note that infants with bacterial sepsis may have negative blood cultures so that other approaches to identification of infection should be taken. Test to demonstrate an inflammatory response include erythrocyte sedimentation rate, C-reactive protein, haptoglobin, fibrinogen, nitroblue tetrazolium dye, and leukocyte alkaline phosphatase. In general, these tests have limited sensitivity and are not helpful. Only the total WBC count with differential and the ratio of immature to total neutrophils provide immediately predictive information compared with age standards. Neutropenia is more common than neutrophili in severe neonatal sepsis, but it also occurs in association with maternal hypertension, neonatal sensitization, periventricular hemorrhage, seizures, surgery, and possibly hemolysis. An immature neutrophil-total neutrophil ratio 0,16 or greater suggests bacterial infection.

Criteria for the magnitude of physiologic change in newborn infants with sepsis are not currently defined but should be consistent with the systemic effects of endogenous mediators on one or more organ systems. For example, the effect of sepsis from pneumonia on respiratory function should exceed the local damage in the lung. Thus, a work up for sepsis should include the laboratory studies:

1. Evidence for infection. Culture from a normally sterile site (blood, CSF, other).Demonstration of a microorganism in tissue or fluid. Antigen detection (urine, CSF). Maternal or neonatal serology (syphilis, toxoplasmosis). Autopsy.
2. Evidence for inflammation. Leukocytosis, increased immature/ total neutrophil count ratio. Acute-phase reactants: CRP, ESR. . Cytokines, IL-6. Pleocytosis in CSF, sunovial, or pleural fluid. Disseminated intravascular coagulation: fibrin split products.
3. Evidence for Multiorgan System Disease. Metabolic acidosis: pH, pCO2. Pulmonary function: , pO2 , pCO2. Renal function: BUN, creatinine. Hepatic injury/function: bilirubin, SGPT,SGOT, ammonia, PT, PTT. Bone marrow function: neutropenia, anemia, thrombocytopenia. , pCO2

Treatment.

Treatment of neonatal sepsis may be divided into antimicrobal therapy for the suspected or known pathogen and supportive care.

1. Should be tailored to age of onset, clinical setting, and initial findings.

2. There should be NO DELAY in antibiotic therapy. Begin empiric therapy after cultures are obtained or before cultures if any delay is anticipated. There are isolates of Streptococcus pneumoniae that are resistant to penicillin and cephalosporins.

3. As of 1997, the AmericanAcademy of Pediatrics recommends adding vancomycin with or without rifampincin to these regimens when meningitis or pneumococcal sepsis is suspected until sensitivities are known. Never use rifampincin alone since resistance can rapidly develop.

1. Empiric early (0 to 4 days old). Ampicillin 50 mg/kg/day (100 mg/kg/day in meningitis) divided 12 hours IV and gentamicin 5 mg/kg/day divided 12 hours IV. Or cefotaxime 50mg/kg q 12 h + ampicillin as above (preferred by some authors). Ceftriaxone is an alternative to cefotaxime.
2. Empiric late (5 days old). Depends on cause (for example methicillin-resistant Staph. aureus outbreak requires vancomycin). General guidelines include ampicillin 100 to 200 mg/kg/day divided Q6h plus cefotaxime 150 mg/kg/day IV Q8h), or ampicillin-gentamicin as above usually adequate. Ceftriaxone 100 mg/kg/day IV Q12h is an alternative to cefotaxime.

Dose and interval for administration of antibiotics commonly used in newborns vary with the birth weight and postnatal age (see Table 13).

1. Repeat cultures in 24 to 48 hours. In meningitis, repeat LP every day until clear.
2. Other. Fluids, electrolytes, and glucose should be monitored carefully with correction of hypovolemia, hyponatremia, and hypoglycemia and limitation of fluids if there is inappropriate antidiuretic hormone secretion. Shock, hypoxia, and metabolic acidosis should be identified and managed with inotropic agents, fluid resuscitation, and mechanical ventilation. Adequate oxygenation of tissues should be maintained because support of ventilation is frequently necessary for respiratory failure caused by congenital pneumonia, persistent fetal circulation, or adult RDS (shock lung). Refractory hypoxia and shock may require extracorporeal membrane oxygenation, which has reduced mortality rates in full-term infants with septic shock and persistent fetal circulation. Hyperbilirubinemia should be considered for infants who cannot sustain enteral feedings.

Table 13 Doses of antibiotics for the newborn
DIC may complicate neonatal septicemia. Platelet counts, hemoglobin, PT, PTT, and fibrin split products should be monitored. DIC may be treated by management of the primary sepsis, but if bleeding occurs, DIC may be treated with fresh frozen plasma, platelet transfusions, or whole blood. Because neutrophil storage pool depletion has been associated with a poor prognosis, a number of clinical trials of polymorphonuclear replacement therapy have been conducted, with variable. Results: sepsis that is unresponsive to antibiotics with persistent neutropenia may be an indication for granulocyte transfusion. The use of granulocyte-macrophage colony-stimulating factor (GM-CSF) is under investigation. Treatment with intravenous immunoglobulins (IVIG) containing specific antibiotics is currently under clinical investigation. Currently, granulocyte colony-stimulating factor (G-CSF), and IVIG are experimental therapies of undetermined value. It is important to remember that nonbacterial infectious agents can produce the syndrome of neonatal sepsis. Herpes simplex infection requires specific treatment, as no systemic Candida infection. Such agents should be considered in all patients who have negative cultures but whose condition continues to deteriorate despite supportive care and the use of broad-spectrum antibiotics.

INTRAUTERINE INFECTIONS

According to literature more than 10% children were infected intrauterine. Most infection agents are viruses in antenatal period. In intranatal period both viruses and bacteria can cause infections. Clinical manifestation takes place in 5-50% children. Severity and clinical signs of intrauterine infections depend on the phase of embrio- or fetogeneses more than onthe property of infection agent. If the infection develops at the early stage of pregnancy, severe defects of fetus (embriopathy) are formed. That leads to miscarriage. If infection occurs after 8-12 weeks of gestation embrio/fetopathy may be compatible with survival. But there is some changes which lead to miscarriage or severe disease or lethal outcome. If infection develops after II or III trimester of pregnancy, the signs of generalized infection or pathology of organs (hepatitis, myocarditis, meningoencephalitis, meningitis, horioretinitis) may be present. The most typical symptoms of intrauterine infections which can manifest in early neonatal period are summarised in table 14.

Table14 NONSPECIFIC SIGNS OF INTRAUTERINE INFECTIONS IN NEWBORN

General / Cardiovascular System
Fever, hypothermia
"Not doing well"
Poor feeding
Scleroema
Gastrointestinal System
Abdominal distention
Vomiting
Diarrhea
Hepatomegaly
Respiratory System
Apnea, dyspnea
Tachypnea, retraction
Flaring, grunting, cry / Pallor, mottling, cold,
clammy skin
Tachycardia
Hypotension
Bradycardia
Central Nervous System
Irritability, lethargy
Tremors, seizures
Hyporeflexia, hypotonia
Abnormal Moro reflex
Irregular respirations
Full fontanel
High-pitched cry
Cyanosis
Renal System
OliguriaSplenomegaly
Petechiae, purpura Bleeding / Hematologic System
Jaundice
Pallor

Taking into consideration the totality of all clinical signs in intrauterine infection of various etiology the term "TORCH-syndrome”is used.

„T” stands for toxoplasmosis

„O” stands for „other” includes-siphylis, listeriosis, viral hepatitis, variocelar and other

„R” stands for „rubella”;

„C” stands for cytomegalovirus;

„H” stands for herpes.

Lately a tendency to increased mixed infection has been observed.

In some cases (more frequently at the intrauterine infection) classic TORCH-syndrome is absent at first days of a child’s life, but symptoms of infection develop during observations of a newborn. The early diagnosis promotes separation of the baby to the higher risk group.

Definition of higher risk group of intrauterine infection

Besides children, who actually have intrauterine infection, the newborn is considered to belong to the risk group, if the mothers have:

-pathology of obstetric-gynecological history (miscarriages, stillborn, newborns with defects, children, that died in early age.)

-pathology of the pregnancy and delivery (miscarriage, placenta previa, oligohydramnion, membranes rupture.)

-diseases of the urogenital system (erosion of cervix uterus, endocervicitis, colpitis, salpingoophoritis, urine infection)

-infection diseases during pregnancy accompanied by rash, jaundice, hepatosplenomegaly, lymphadenopathy, hyperthermia, ARVI

-immunodeficiency (AIDS)

-blood transfusions

-state after transplantation, immunosuppressive therapy

Intrauterine infection may be suspected if the newborn has the following clinical, laboratory or instrumental signs:

-growth retardation (intrauterine hypotrophy)

-congenital defects (including congenital heart disease) or stigmata

-nonimmune hydrops of fetus

-micro- or hydrocephaly

-skin exanthemas

-fever on the first day of life

-neurological damages and seizures during some days after birth

-interstitial pneumonia, myocarditis or carditis

-keratoconjuctivitis

-cataracts and glaucoma

- „inflammatory” changes in the blood count (thrombocytopenia, anemia, increase of erythrocyte sedimentation rate, leucopenia, lymphocytosis, monocytosis and erythroblastosis) during the first days of life

-changes of neurosonography (cysts, diffuse or periventricular brain calcification).

Revealing of two or more sings permits to relate a newborn to thehigher risk group of intrauterine infection.