Early-Onset Neonatal Sepsis Treatment Guidelines
First-Line Empiric Antibiotic Regimen
Ampicillin plus gentamicin is the standard first-line empiric therapy for all neonates with suspected or proven early-onset sepsis. 1, 2 This combination provides optimal coverage against the most common early-onset pathogens: Group B Streptococcus, E. coli, Listeria monocytogenes, and other Enterobacteriaceae. 1
Dosing for Ampicillin
Neonates ≤28 days of postnatal age with suspected sepsis or meningitis: 3
- Gestational age ≤34 weeks AND postnatal age ≤7 days: 100 mg/kg/day divided every 12 hours 3
- Gestational age ≤34 weeks AND postnatal age 8-28 days: 150 mg/kg/day divided every 12 hours 3
- Gestational age >34 weeks AND postnatal age ≤28 days: 150 mg/kg/day divided every 8 hours 3
For confirmed meningitis: Increase ampicillin to 150-200 mg/kg/day divided every 3-4 hours. 3, 1
Dosing for Gentamicin
Standard dosing: 3 mg/kg/day for neonates. 4 Gentamicin is indicated for serious gram-negative infections including neonatal sepsis caused by Pseudomonas aeruginosa, Proteus species, E. coli, Klebsiella-Enterobacter-Serratia species, and Staphylococcus species. 5
Alternative Regimen: Third-Generation Cephalosporins
Cefotaxime (NOT ceftriaxone) represents a reasonable alternative to gentamicin, particularly when gram-negative meningitis is suspected. 1, 4 Ceftriaxone is absolutely contraindicated in neonates due to risk of bilirubin displacement and kernicterus. 1
The combination of ampicillin plus cefotaxime may be considered when: 4
- Gram-negative meningitis is suspected or confirmed 1
- Local aminoglycoside resistance patterns are high 6
Critical Timing and Culture Management
Obtain blood cultures before initiating antibiotics, but never delay treatment waiting for results. 1, 2 Empiric antimicrobials must be administered within 1 hour of identifying severe sepsis. 4
Discontinue antibiotics at 48 hours if blood cultures are negative and the infant remains asymptomatic. 1, 7 Time to positivity (TTP) data demonstrates that pathogenic organisms grow within 48 hours in 100% of cases (mean TTP 17.7 hours for pathogens versus 80.5 hours for contaminants). 7 Prolonged empirical antibiotic therapy (≥5 days) in preterm infants is associated with increased risks of late-onset sepsis, necrotizing enterocolitis, and mortality. 2
For culture-confirmed sepsis: Continue treatment for 10-14 days for bacteremia without focal infection. 1, 6 Meningitis requires 14-21 days of therapy. 8
Risk-Stratified Management by Gestational Age
Preterm Infants <35 Weeks Gestation
All preterm infants <35 weeks with high-risk delivery characteristics require empiric antibiotics even after adequate intrapartum prophylaxis. 1 High-risk characteristics include: 4, 1
- Maternal chorioamnionitis
- Prolonged rupture of membranes >18 hours
- Inadequate GBS intrapartum prophylaxis
Blood culture and antibiotic treatment are mandatory for these high-risk preterm deliveries. 1 Lumbar puncture with CSF analysis should be performed if the infant is stable and early-onset GBS disease is highly suspected. 1
Term and Late Preterm Infants ≥35 Weeks Gestation
Three acceptable risk assessment strategies per AAP guidelines: 1
- Categorical risk assessment
- Multivariate risk assessment (Neonatal Early-Onset Sepsis Calculator)
- Clinical condition-based assessment
The Kaiser Permanente EOS Calculator can reduce unnecessary antibiotic exposure when applied appropriately, using a baseline EOS risk of 0.5 per 1,000 live births. 1 However, this tool should not override clinical judgment.
Mandatory treatment regardless of risk assessment method: 1
- All infants with clinical signs of sepsis
- Maternal fever ≥100.4°F (38°C)
Specific High-Risk Clinical Scenarios Requiring Immediate Treatment
All asymptomatic infants born to mothers with suspected chorioamnionitis must receive broad-spectrum antibiotics (ampicillin plus gentamicin). 1, 4 If chorioamnionitis is confirmed or suspected, the newborn requires full diagnostic evaluation and empiric therapy pending culture results, regardless of clinical condition at birth, duration of maternal antibiotic therapy, or gestational age. 4
All premature infants <37 weeks require broad-spectrum antibiotics if ANY of the following: 1, 4
- Maternal chorioamnionitis
- Prolonged rupture of membranes >18 hours
- Inadequate GBS intrapartum prophylaxis (defined as <4 hours of penicillin, ampicillin, or cefazolin before delivery) 8
Diagnostic Evaluation Requirements
When clinical signs suggest sepsis, perform a full diagnostic evaluation including lumbar puncture if the infant is stable. 1, 4 Blood cultures can be sterile in up to 15% of newborns with meningitis. 4 If lumbar puncture is initially deferred and empiric therapy continues beyond 48 hours due to clinical instability, CSF must be obtained for cell count, glucose, protein, and culture. 4
Common Pitfalls and How to Avoid Them
Pitfall #1: Continuing antibiotics beyond 48 hours despite negative cultures and clinical stability. 1, 7 This practice increases risks of late-onset sepsis, NEC, and mortality in preterm infants. 2 Solution: Implement strict 48-hour stopping rules for asymptomatic infants with negative cultures. 1, 7
Pitfall #2: Using ceftriaxone instead of cefotaxime in neonates. 1 Ceftriaxone displaces bilirubin and causes kernicterus. Solution: Always use cefotaxime as the third-generation cephalosporin if needed. 1
Pitfall #3: Failing to obtain CSF when meningitis is suspected. 1, 4 This results in inadequate dosing and duration. Solution: Perform lumbar puncture in stable infants with suspected sepsis, as meningitis requires higher ampicillin doses (150-200 mg/kg/day) and longer treatment courses (14-21 days). 1, 8
Pitfall #4: Inadequate coverage for Listeria monocytogenes. 1, 6 Third-generation cephalosporins lack activity against Listeria. Solution: Always include ampicillin in empiric regimens for early-onset sepsis. 1, 4
Pitfall #5: Prolonging therapy based on subjective clinical assessments or isolated CRP elevation. 9 Recent data shows that 35.9% of neonates with negative blood cultures receive prolonged therapy based on non-specific signs and arbitrary CRP interpretations. 9 Solution: Use objective criteria—if cultures are negative at 48 hours and the infant is clinically well, discontinue antibiotics. 1, 7
Antibiotic Resistance Considerations
Approximately 20% of GBS isolates are resistant to clindamycin, requiring susceptibility testing before use. 8 For penicillin-allergic mothers requiring intrapartum prophylaxis, cefazolin is preferred if low risk for anaphylaxis. 8
In settings with high aminoglycoside resistance, consider combining third-generation cephalosporins with ampicillin rather than gentamicin. 6 However, extensive cephalosporin use leads to more rapid emergence of resistant organisms compared to aminoglycosides. 6
Adjunctive Therapies in Severe Sepsis
For fluid-refractory shock, initiate inotropes (dopamine or epinephrine for cold shock; norepinephrine for warm shock) and consider hydrocortisone if at risk for absolute adrenal insufficiency. 4 Target hemoglobin >10 g/dL during resuscitation of low superior vena cava oxygen saturation shock (<70%). 4
Use lung-protective ventilation strategies in mechanically ventilated neonates with sepsis. 4 Control hyperglycemia with target <180 mg/dL, ensuring glucose infusion accompanies insulin therapy. 4