Neonatal bacterial infections

Neonatal bacterial infections include neonatal sepsis, neonatal meningitis, neonatal urinary tract infection, neonatal pneumonia, neonatal conjunctivitis, and omphalitis. Neonatal bacterial infections are often classified as early-onset if they occur within 72 hours of life and late-onset if they occur between 73 hours and 28 days of life. The clinical manifestations of these infections are similar and often nonspecific (e.g., temperature instability, respiratory symptoms, poor feeding, irritability). The diagnostic approach and management differ according to clinical presentation, risk factors, and age. If untreated, systemic neonatal infections are associated with a high risk for complications and increased mortality. Screening for maternal Group B streptococcus (GBS) and GBS prophylaxis have drastically reduced rates of early-onset neonatal sepsis. Infection prevention and control in neonatal intensive care units (NICU) can help decrease the risk of late-onset neonatal sepsis.

This article discusses late-preterm neonates ≥ 35 weeks' gestation and full-term neonates. Congenital TORCH infections are described in a separate article.

Classification ^[1][2]

Neonatal bacterial infections are often classified based on the timing of disease onset. ^[3][4][5]

• Early-onset infection: disease onset within 72 hours of life
• Late-onset infection: disease onset between 73 hours (3 days) and 28 days of life

Types of neonatal bacterial infections

• Neonatal bacterial sepsis
• Neonatal bacterial meningitis
• Neonatal bacterial pneumonia
• Neonatal urinary tract infection
• Neonatal conjunctivitis
• Respiratory infections (e.g., pertussis)
• Neonatal osteomyelitis
• Skin and soft tissue infections
• Necrotizing enterocolitis
• Omphalitis

Neonates have an immature immune system and an increased risk for life-threatening infections. ^[2][5]

Clinical features of neonatal bacterial infection

Systemic features ^[6]

Systemic features of infection are often subtle and nonspecific.

• General: low Apgar score, irritability, excessive crying, lethargy
• Temperature instability: fever (temperature ≥ 38°C or 100.4°F) and/or hypothermia (temperature < 36°C or 96.8°F) ^[6]
• Cardiovascular: tachycardia: (pulse > 160/minute) or bradycardia (pulse < 100/minute), hypotension, cyanosis
• Respiratory: tachypnea (≥ 60/minute), hypoxia, expiratory grunting, nasal flaring, apnea, retractions
• Gastrointestinal: poor feeding, diarrhea, vomiting, abdominal distension, hepatosplenomegaly
• Skin: jaundice, cyanosis, pallor, petechiae, purpura, erythema (e.g., due to cellulitis, impetigo, abscess)

Localized features

Localized signs of infection depend on the underlying cause, e.g.:

• Neonatal pneumonia: adventitious breath sounds and respiratory symptoms
• Neonatal meningitis: seizures and/or bulging fontanelle
• Neonatal conjunctivitis: eye redness or discharge
• Osteomyelitis and/or septic arthritis: swelling or redness of joints or limbs
• Omphalitis: umbilical redness or discharge

Symptoms may be subtle and/or nonspecific in neonates even in severe infection. ^[2][6][7]

Differential diagnoses ^[8]

• Viral infections (e.g., neonatal herpes simplex virus infection)
• Fungal infections ^[9]
• Congenital heart disease
• Adrenal insufficiency (e.g., from congenital adrenal hyperplasia)
• Inborn errors of metabolism

Diagnostics and management differ based on the neonate's clinical appearance, risk factors, and age. ^[2]

Ill-appearing neonates ^[10][11]

• Perform an ABCDE survey.
• Initiate cardiovascular (e.g., IV fluids) and respiratory support as needed.
• Obtain diagnostics for neonatal bacterial sepsis.
• Start empiric antibiotics for neonatal sepsis.
• Add additional antimicrobials if there is concern for nonbacterial infection, e.g.:
  • Risk factors for neonatal HSV: Perform neonatal HSV testing and start acyclovir.
  • Risk factors for invasive candidiasis: Consult a specialist for consideration of amphotericin. ^[2]
• Admit to the NICU.
• Determine further management based on results of diagnostic testing. ^[1]
  • Identified infection
    • Provide source-specific treatment.
    • See respective sections for details.
  • No source identified and negative cultures at 36–48 hours ^[1]
    • Bacterial infection unlikely: Discontinue empiric antibiotic therapy.
    • Persistent symptoms: Consult a specialist for consideration of culture-negative sepsis or alternative diagnoses.

Do not delay neonatal resuscitation and empiric antibiotics to obtain diagnostic studies. ^[1]

Well-appearing neonates ^[1]

• Risk factors for early-onset sepsis
  • Consider using a risk factor assessment tool to guide management. ^[1]
  • Management typically includes ≥ 1 of the following: ^[6][12]
    • Enhanced clinical observation (e.g., serial physical examinations, vital signs every 4 hours) for 48 hours
    • Blood culture with or without CSF studies
    • Empiric antibiotics for neonatal bacterial sepsis
  • If empiric antimicrobials are recommended, start treatment and consult or transfer to the NICU.
• Isolated fever with no risk factors for early-onset sepsis or signs of infection
  • Management differs based on age.
  • See “Fever of unknown source in infants ≤ 60 days of age.”
• Signs of localized infection
  • Manage the specific condition (e.g., neonatal conjunctivitis, omphalitis).
  • Consider obtaining a blood culture if starting systemic antibiotics.
  • Obtain diagnostics for neonatal bacterial sepsis if systemic symptoms develop.

There is no consensus on the definition of neonatal bacterial sepsis, but it is commonly defined as an infection with a positive bacterial blood or CSF culture in a neonate ≤ 28 days of age. ^[1][2][3][8]

Classification

Clinical features ^[6]

• Clinical features are often nonspecific.
• See “Clinical features of neonatal bacterial infection.”

Diagnostics for neonatal bacterial sepsis ^[1][2][6]

• Testing in all patients
  • Blood culture (ideally of two different samples): pathogen identification confirms diagnosis ^[1][2]
  • CBC with differential
    • Leukopenia or leukocytosis
    • ↓ ANC
    • I/T ratio ≥ 0.2 ^[1][2]
    • Thrombocytopenia
  • Inflammatory markers (e.g., CRP, procalcitonin, IL-6, IL-8): typically elevated ^[1][6]
• Additional testing in selected patients
  • CSF analysis and culture
    • Obtain in all patients with critical illness or positive blood cultures.
    • Consider for all other patients if it does not delay management.
    • If available, a multiplex PCR meningitis panel can facilitate rapid identification of certain pathogens. ^[17]
  • Urinalysis and urine culture: in late-onset neonatal sepsis ^[1][6]
  • Blood PCR (if available): Consider for rapid pathogen detection. ^[11][12]
  • Cultures of localized sources of infection (e.g., conjunctiva, umbilicus)
  • Neonatal HSV testing: for patients with clinical features of or risk factors for neonatal HSV infection
  • CMP and blood gas: to assess for organ dysfunction in patients with suspected septic shock ^[10]
  • Chest x-ray: in patients with respiratory symptoms to assess for pneumonia ^[18][19]

In neonates ≤ 72 hours of age, urine culture is not recommended to evaluate for sepsis. ^[1]

Management ^[1][12]

• Perform an ABCDE survey.
• Start cardiovascular (e.g., IV fluids) and respiratory support as needed.
• Start empiric antibiotics for neonatal sepsis based on:
  • Neonate age (i.e., early-onset vs. late-onset sepsis)
  • Suspected source of infection
  • Risk factors (e.g., gestational age, comorbidities, risk factors for MRDO infection)
• Obtain daily blood cultures until there is no growth. ^[1]
• Perform CSF analysis and culture if not previously done. ^[6]
• Narrow antibiotics based on culture results and the source of infection.
• Consult infectious diseases for antibiotic-resistant and/or atypical pathogens.
• Determine duration of therapy based on causative organism and site of involvement. ^[1]

Continued empiric antibiotics may be indicated for symptomatic neonates with culture-negative sepsis. ^[1]

Prevention

See “Prevention of neonatal bacterial infection.”

The antibiotic therapy regimens below are recommended for neonates who were born ≥ 35 weeks' gestation with sepsis due to an unknown source. For well-appearing neonates with an isolated fever, see “Fever in infants ≤ 60 days of age” for empiric antibiotics. ^[1][2][12]

Early-onset bacterial sepsis

• No concern for meningitis
  • Ampicillin ^[12]
  • PLUS an aminoglycoside, e.g., gentamicin ^[12]
• Concern for meningitis
  • Ampicillin
  • PLUS an aminoglycoside, e.g., gentamicin ^[12][20]
  • PLUS a cephalosporin, e.g., cefotaxime OR carbapenem, e.g., meropenem (off-label) ^[2][12]

Late-onset bacterial sepsis

Provide coverage for both gram-negative and gram-positive pathogens. Tailor specific antibiotic choice based on risk factors and suspected source of infection. Suspected meningitis may require higher dosages.

• Gram-positive coverage
  • Vancomycin ^[12]
  • Ampicillin ^[12]
  • Nafcillin ^[2][12][15]
• Gram-negative coverage
  • Aminoglycoside, e.g., gentamicin ^[12]
  • Cephalosporin, e.g., cefotaxime ^[12]
  • Carbapenem, e.g., meropenem (off-label) ^[12]

Avoid ceftriaxone during the first 1–2 weeks of life due to the risk for kernicterus; other cephalosporins (e.g., cefotaxime, ceftazidime, or cefepime) are preferred. ^[6][21]

For patients with suspected intra-abdominal sources of sepsis (e.g., necrotizing enterocolitis, midgut volvulus), include anaerobic coverage (e.g., metronidazole, piperacillin/tazobactam). ^[11][12]

Etiology ^[12][17][22]

• Commonly: GBS, E. coli
• Less common: Klebsiella spp., Enterobacter spp., L. monocytogenes
• See also “Most common causative agents of bacterial meningitis by age group and underlying condition.”

Clinical features ^[4][8]

• Systemic clinical features of neonatal bacterial infection (often nonspecific)
• Altered mental status: lethargy; , irritability, seizures
• Signs of increased intracranial pressure (e.g., bulging fontanelle)
• High-pitched crying
• Hypotonia

Meningismus does not typically occur in neonates. ^[8]

Diagnostics for neonatal bacterial meningitis ^[4][17]

• Perform diagnostics for neonatal bacterial sepsis in all patients with suspected meningitis.
• Confirm diagnosis of meningitis through pathogen detection on CSF culture and/or PCR. ^[4][22][23]
• Consider neuroimaging in all neonates to assess for complications (e.g., brain abscess, brain injury) and predict neurodevelopmental outcomes. ^[24]
  • Cranial ultrasound ^[25]
  • MRI or CT brain

Clinical features of meningitis and sepsis are similar in neonates. Perform diagnostics for neonatal sepsis for all patients with suspected meningitis. ^[8]

Lumbar puncture is contraindicated in patients with clinical instability or criteria for imaging prior to LP. ^[2]

Management of neonatal bacterial meningitis ^[6][12][26]

Management of neonatal meningitis is typically performed in consultation with specialists (e.g., infectious diseases, intensive care, and/or neurology).

• Unstable patients: Provide immediate stabilization for meningitis.
• Start empiric antibiotics.
  • Treatment typically includes ampicillin plus gentamicin and/or cefotaxime.
  • See empiric antibiotics for neonatal sepsis for details.
• Narrow antibiotics based on cultures; see “Pathogen-specific therapy in meningitis.”
• Complete 14–21 days of antibiotics depending on the organism. ^[6]
• Consider repeat lumbar puncture to assess for CSF clearance.
• Ensure follow-up for long-term complications of neonatal meningitis, e.g.:
  • Audiology evaluation for hearing loss
  • Monitoring for developmental delay

There is insufficient evidence to support the use of glucocorticoids in neonates with meningitis. ^[12][27]

Complications ^[2]

• Brain abscess
• Ventriculitis
• Septic brain infarcts
• Hydrocephalus
• Subdural effusions

Etiology ^[5]

• Congenital pneumonia: vertical transmission from intrauterine TORCH infections
• Early-onset pneumonia
  • Pathogens
    • Similar to early-onset neonatal sepsis
    • See “Overview of neonatal bacterial sepsis” for details.
  • Risk factors
    • Same as risk factors for early-onset sepsis
    • Male sex
    • Low socioeconomic status
    • Galactosemia
• Late-onset pneumonia
  • Main pathogens
    • Similar to late onset neonatal sepsis
    • See “Overview of neonatal bacterial sepsis” for details.
  • Additional pathogens
    • Gram-negative bacilli: Enterobacter spp., Klebsiella spp., Proteus spp., Citrobacter spp., Acinetobacter spp., Stenotrophomonas maltophilia
    • Gram-positive cocci: Enterococcus spp.
    • See also “Etiology of pediatric CAP.”
  • Risk factors
    • Prematurity and/or low birth weight
    • Mechanical ventilation

Clinical features ^[5]

• Nonspecific clinical features of neonatal bacterial infection
• Tachypnea
• Signs of increased work of breathing
• Adventitious breath sounds (e.g., wheezes, rales, rhonchi)
• New onset of or increase in purulent sputum
• Hypoxia
• Cyanosis, especially central cyanosis ^[8]

Abnormal respiratory findings may also be seen in neonates with sepsis who do not have pneumonia. ^[5]

Diagnostics ^[5]

Perform diagnostics for neonatal bacterial sepsis in all patients with ill appearance or nonspecific clinical features of neonatal infection. Diagnosis of pneumonia is based on a combination of clinical, laboratory, and imaging findings.

• Clinical evaluation for signs of impaired oxygenation, i.e.:
  • Oxygen desaturation
  • Increased oxygen requirement
  • Increased ventilator support
• Chest x-ray ^[5][8]
  • Indicated in all patients to assess for CXR findings in pneumonia (e.g., consolidation, infiltrates)
  • Findings may be normal in early stages of infection.
• CBC findings include:
  • ≤ 4000 WBC/mm³
  • ≥ 15,000 WBC/mm³
  • ≥ 10% bands
• Sputum analysis
  • PCR of pharyngeal sputum (e.g., with RV PCR panel): to exclude viral causes of late-onset pneumonia
  • Tracheal sputum culture (if intubated): can show leukocytic infiltrate with a predominant organism ^[5][28]

Evaluate for congenital TORCH infections in neonates with pneumonia and other common findings in TORCH infections. ^[5]

Management ^[5]

For suspected congenital pneumonia, see “TORCH infection.”

• Perform an ABCDE survey.
• Start cardiovascular (e.g., IV fluids) and respiratory support as needed.
• Consider NICU admission based on level of acuity.
• Start empiric antibiotics based on newborn age, severity of illness, and suspected pathogen.
  • Antibiotics are the same as empiric antibiotics for neonatal sepsis.
  • Use a three-drug regimen for severely ill neonates.
• Narrow antibiotics based on suspected or proven pathogens.
• Complete at least 7–14 days of antibiotics. ^[5]
• Consider surfactant replacement therapy (e.g., in GBS pneumonia).

Prevention ^[5]

• Follow recommended prevention of neonatal bacterial infection.
• In ventilated patients, use strategies for the prevention of ventilator-associated infections.

Omphalitis is a bacterial infection of the umbilical cord stump. ^[29]

Etiology ^[29][30]

• S. aureus: MRSA is more common than MSSA.
• Group A Streptococcus and GBS
• Gram negative bacilli: E. coli, Klebsiella pneumoniae, Pseudomonas spp.
• Anaerobes (rare)
• Clostridium tetani: common cause of omphalitis and neonatal tetanus in low-income countries

Risk factors ^[29][30]

• Inadequate umbilical hygiene
• Low birth weight
• Prolonged rupture of membranes
• Maternal intrauterine infection
• Umbilical catheterization
• Unplanned home birth

Clinical features ^[29][31]

• Periumbilical redness, tenderness, swelling
• Purulent discharge, fluctuance
• Possible systemic symptoms (see “Clinical features of neonatal bacterial infection”)

Diagnosis ^[29][31]

Diagnosis is clinical. Consider diagnostic studies based on patient presentation.

• All patients
  • Obtain wound culture if possible. ^[31]
  • Consider urinalysis and urine culture.
  • Consider an ultrasound to evaluate for a urachal abnormality and abscess in patients with:
    • Umbilical drainage
    • Other clinical features of abscess
• Patients with fever or other systemic clinical features of neonatal bacterial infection: Obtain diagnostic studies for neonatal sepsis.
• Afebrile patients without systemic symptoms: Consider blood culture if ≤ 21 days of age. ^[29]

Blood and CSF cultures may not be necessary in well-appearing neonates > 21 days of age. ^[29]

Management ^[29][31]

• Febrile and/or ill-appearing: Start empiric antibiotics for neonatal sepsis.
• Afebrile and well-appearing: Start antibiotics to cover common pathogens (e.g., S. aureus and gram-negative organisms).
  • Strongly consider MRSA coverage based on local resistance patterns.
  • Agents are similar to those used for late-onset sepsis; see “Empiric antibiotics for neonatal sepsis” for details.
• Concern for necrotizing infection or abscess: Consult surgery for possible debridement and/or incision and drainage.

Differential diagnosis ^[31]

• Irritant dermatitis
• Umbilical granuloma

Complications ^[29][30]

Serious complications can occur due to direct access to the bloodstream and peritoneum.

• Neonatal sepsis
• Skin and soft tissue infections: periumbilical cellulitis, necrotizing fasciitis
• Intra-abdominal complications: peritonitis, intestinal necrosis, small bowel evisceration, abscess
• Portal vein thrombosis and/or umbilical vein thrombosis

Serious bacterial infections are a rare (< 1% of cases) complication of omphalitis in high-income countries. ^[29]

Prevention ^[30]

• Follow hand hygiene practices during labor and delivery.
• Use sterile technique when cutting the umbilical cord.
• Educate caregivers on neonatal umbilical hygiene: ^[32]
  • Dry cord care: The umbilical stump should be kept clean and loosely covered with a clean cloth or left exposed to the air to dry out.
  • If the stump becomes soiled (e.g., with stool), it should be cleaned with soap and sterile water.
• Topical antiseptics (e.g., chlorhexidine) are not recommended unless in a setting with:
  • Poor hygienic practices ^[32]
  • High rates of omphalitis

Prenatal prevention ^[1][6]

• Administer appropriate immunizations during pregnancy to provide passive immunization to the fetus.
• Provide prenatal GBS screening and prophylaxis.
• Identify and treat maternal infections during pregnancy (e.g., chorioamnionitis, UTI in pregnancy).
• See also “Prenatal care.”

Postnatal prevention ^[1][6]

• Assess all newborns for risk factors for early-onset sepsis and provide management for neonates at risk (see “Approach to suspected neonatal bacterial infection” for details).
• Use preventive strategies to avoid iatrogenic infections, e.g., ^[33]
  • Hand hygiene and sterile technique
  • Removal of invasive catheters as early as possible
• Administer routine neonatal ophthalmic antibiotic prophylaxis (see “Prevention of neonatal conjunctivitis”).
• Educate caregivers on proper umbilical cord hygiene.