Late-Onset Neonatal Sepsis

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Original Author(s): Shivali Jain and Ranveer Sanghera
Last updated: 16th December 2023
Revisions: 10

Original Author(s): Shivali Jain and Ranveer Sanghera
Last updated: 16th December 2023
Revisions: 10

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Sepsis is defined as ‘a life-threatening organ dysfunction caused by a dysregulated host response to infection’ (1). NICE defines late-onset neonatal sepsis (LONS) as sepsis in infants between 72 hours and 28 days corrected gestational age (2). Although the time element of the definition for LONS varies in the literature (3), for the purpose of this article, we will use the NICE definition.



The NeonIN surveillance network found the incidence of LONS to be 3/1000 live births and 29/1000 neonatal admissions in 2010, however it should be noted that their definition of LONS was sepsis in infants above 48 hours of age (4).



Group B streptococci are a common cause of early and late onset neonatal sepsis. Other causative organisms to consider in late onset sepsis are (4):

  • Coagulase-negative Staphylococci (most common cause)
  • Enterobacteriaceae
  • Staphylococcus aureus (including Methicillin resistant)
  • Fungi (usually Candida albicans)


Gram-positive organisms (staphylococci) are usually introduced from the environment or the patient’s skin, whereas Gram-negative organisms are usually from the infant’s gut microbiome (5).


Risk Factors 

Risk factors for LONS include (2):

  • Prematurity
  • Mechanical ventilations
  • History of surgery
  • Presence of a central catheter
  • Presence or concern of an infection in another baby when from a multiple birth.


Clinical Features

Clinical features are often non-specific, and are similar to those of early-onset sepsis (2):


  • Parental concern for change in behaviour
  • Reduced responsiveness


  • Increased respiratory rate >60
  • Signs of respiratory distress
  • Grunting or apnoea


  • Tachycardia or bradycardia


  • Mottled or ashen skin
  • Non-blanching rash
  • Cyanosis


  • Abdominal distension
  • Temperature abnormality (lower than 36°C or higher than 38°C)
  • Seizures
  • Reduced feeding
  • Bulging fontanelle


Differential Diagnosis

Differential diagnoses of late-onset neonatal sepsis include (6):

  • Bowel obstruction

    • This can present as a failure to pass meconium (thick sticky dark-green stool), abdominal distension, reduced feeding, and bilious vomiting (7).
  • Necrotizing enterocolitis (NEC)

    • This is a medical and surgical emergency, most commonly occurring in preterm infants. It commonly presents as reduced feeding, abdominal distension and decreased bowel sounds. The baby may also have signs of sepsis (8).
  • Metabolic disease

    • A variety of metabolic diseases can present in the neonatal period. Clinical features include drowsiness, poor feeding, hypoglycaemia and seizures (9).
  • Cardiac

    • Congenital cardiac disease may present with lethargy, difficulty breathing, or poor feeding, which can mimic symptoms of LONS.



Ideally the following investigations should be performed prior to starting antibiotics, although they should not delay antibiotics being given within 1 hour of the decision to treat sepsis. These are (2):

  • Blood culture
  • CRP (useful to monitor serially to assess likelihood of infection and monitor response to treatment)
  • Urine microscopy and culture (clean catch or catheter only)
  • Lumbar puncture if safe to do so and there is a strong clinical suspicion of neonatal infection/meningitis

Lumbar puncture contraindications (10)

Absolute contraindications:

    • GCS < 8
    • Signs of raised intracranial pressure (Note: a bulging fontanelle alone, without other signs of raised intracranial pressure, is not a contraindication)

Relative contraindications:

      • Septic shock
      • Respiratory compromise (including apnoeas)
      • New focal neurology or seizures
      • INR > 1.5 or platelets < 50



The antibiotic regimes used to treat LONS vary depending upon the following factors due to their influence on the most likely bacterial cause:

  1. If the baby has never been discharged home after birth, flucloxacillin and gentamicin are most commonly used.
  2. If the baby was discharged home and then readmitted, ceftriaxone is recommended (caution must be taken if there is coexisting jaundice due to potential liver damage.)
  3. If there are clinical signs of meningitis, IV amoxicillin and cefotaxime are most commonly used.

Local antibiotic guidelines should always be followed and cases discussed with the microbiology team regarding  culture findings. A CRP should be repeated 18-24 hours after starting antibiotics, and antibiotics should be continued for at least 48 hours (2).


Antibiotics may be stopped if all the following criteria are met:

  • Initial clinical suspicion of infection was not strong
  • Baby is clinically well with no signs of infection
  • CRP level and trend are reassuring
  • Blood culture is negative

If the blood culture is positive and there are no signs of meningitis, then antibiotics should be continued to complete a 7-day course (2).

  • A shorter course can be considered if baby is well and no causative organism is identified/the causative organism is a common commensal such as coagulase negative staphylococcus. The decision to continue treatment with antibiotics should be reviewed every 24 hours.
  • A prolonged course can be considered if baby has not yet fully recovered or if the causative organism/site of infection requires a prolonged course.



LONS is a major cause of death in newborns, especially in preterm infants or those who develop fungal sepsis (5). However, newborns who recover from sepsis alone generally do not go on to develop long-term complications.

Newborns who develop LONS secondary to meningitis however, can suffer from significant sequelae, including hearing loss, seizures and cognitive impairment (12).



1. National Institute for Health and Clinical Excellence. Neonatal infection: antibiotics for prevention and treatment. NICE clinical guideline NG195. htt World Health Organization. Sepsis. April 2021.
2. National Institute for Health and Clinical Excellence. Neonatal infection: antibiotics for prevention and treatment. NICE clinical guideline NG195. April 2021.
3. Kaneshiro N. Neonatal sepsis.
4. Vergnano S, Menson E, Kennea N, Embleton N, Russell AB, Watts T, Robinson MJ, Collinson A, Heath PT. Neonatal infections in England: the NeonIN surveillance network. Arch Dis Child Fetal Neonatal Ed. 2011 Jan;96(1):F9-F14. doi: 10.1136/adc.2009.178798. Epub 2010 Sep 27. PMID: 20876594.
5. Tesini B. Neonatal Sepsis.
6. UTMB Neonatology Manual. Neonatal Sepsis and Other Infections.
7. University of Chicago. Neonatal Intestinal Obstruction.
8. University of Chicago. Necrotizing Enterocolitis.
9. Brimingham Women’s and Children’s Hospital. Metabolic disorders.
10. Royal Children’s Hospital Melbourne. Lumbar Puncture.
11. National Institute for Health and Clinical Excellence. Sepsis: recognition, diagnosis and early management. NICE clinical guideline NG51. September 2017.
12. National Institute for Health and Clinical Excellence. Meningitis – bacterial meningitis and meningococcal disease – Clinical Knowledge Summary.  July 2020.