Late Onset ( after 72 hours ) Neonatal Sepsis on the Neonatal Unit

Publication: 22/01/2015  
Next review: 26/06/2026  
Clinical Guideline
ID: 3688 
Approved By: Improving Antimicrobial Prescribing Group 
Copyright© Leeds Teaching Hospitals NHS Trust 2023  


This Clinical Guideline is intended for use by healthcare professionals within Leeds unless otherwise stated.
For healthcare professionals in other trusts, please ensure that you consult relevant local and national guidance.

Late Onset (after 72 hours) Neonatal Sepsis on the Neonatal Unit

Late Onset ( after 72 hours ) Neonatal Sepsis on the Neonatal Unit

Late Onset (after 72 hours) Neonatal Sepsis on the Neonatal Unit

Approach to suspected LONS


Evidence level

Key points from History and examination

Apnoea, feeding intolerance, abdominal distension, increased respiratory support, lethargy, hypotonia
temperature instability
poor perfusion and jaundice



Blood cultures (Paired where indicated), urine culture, FBC, CRP, PCT, CXR +/- AXR, LP, ETT secretions & thorough multi-system examination including joints, skin, eyes etc.



1st Line - Benzylpenicillin and Gentamicin*
2nd line - Teicoplanin and Gentamicin
3rd line - Meropenem and Vancomycin$.
*Consideration should be given to timing and likely source of sepsis before choosing antibiotic
Amoxicillin, gentamicin and metronidazole are first line for abdominal surgical conditions
$ Should be carefully considered on discussion with senior colleague or reserved for failure of second line treatment

In babies with a birthweight less than 1500g or born before 30 weeks gestation, consideration should be given to starting nystatin prophylaxis for the duration of antibiotic treatment


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This guideline covers late onset sepsis (LONS) defined as sepsis occurring after 72 hours postnatal.
Neonatal LONS is a significant cause of morbidity and mortality in the newborn infant. It is caused by pathogens acquired in the postnatal environment. It is more commonly seen in preterm or low birth weight infants in neonatal care rather than term newborns. The most common organisms are coagulase-negative staphylococci (CoNS), Gram- negative bacilli (e.g. E.coli, Klebsiella spp.), Staph. Aureus and Candida spp.
Many factors other than low birth weight or prematurity predispose neonates to LONS. These include

  • comorbidities of prematurity,
  • handling by multiple health care professionals,
  • previous exposure to antibiotics and
  • invasive interventions (see figure 1).

These infections are often associated with vascular catheters in babies in NICU, and coagulase-negative staphylococci (CoNS) are the most commonly reported pathogens. However, CoNS are the most common blood culture contaminants in patients in NICUs and optimal skin antisepsis and catheter disinfection before obtaining blood cultures needs to be reinforced.

In addition, increased rates of complications are associated with late-onset sepsis. Length of stay in hospital is longer and mortality higher (18% vs 7%) than babies who do not develop sepsis. Gram-negative sepsis (36%) and fungal sepsis (32%) carry a higher mortality rate. Early diagnosis of late-onset sepsis contributes to improved neonatal prognosis, but the outcome remains far from satisfactory. This is why it is so important to make the diagnosis early and err on the side of caution when considering a diagnosis of LONS.

Figure 1: Factors contributing to increased risk of LONS in premature infants.
Adapted from: Neoreviews 2012;13;e94.
(PDA patent ductus arteriosus, NEC necrotizing enterocolitis, CLD chronic lung disease)

Early diagnosis of LONS is a major challenge as the clinical manifestations are not.  As a result there is significant over use of antibiotics in neonates. Antibiotics change newborn intestinal flora and bacterial resistance mechanisms and so common sense must prevail.
Positive blood culture is considered the gold standard in sepsis diagnosis.

New tests are reported within the literature and evidence suggests that the association of IL-6 with C-reactive protein (CRP) or procalcitonin (PCT) can improve diagnostic accuracy. PCT is more sensitive than CRP in differentiating between a bacterial and a viral cause for infection and should be used to help reduce the duration babies remain on IV antibiotics for.

Risk Factors for LONS

  • Immature immune responses
  • Poor skin integrity
  • Immature mucosal barriers to infection
  • Numerous entry portals for organisms via cannulae, endotracheal tubes etc

These factors result in frequent exposure to opportunistic organisms during a prolonged hospital stay.

The importance of excellent hand hygiene and aseptic technique is paramount to reducing the risk of LONS in these vulnerable babies and cannot be over emphasised. In addition all medical staff caring for neonates have a responsibility to frequently look at line sites and review daily whether lines including cannulas are necessary or can be removed. The visual infusion phlebitis (VIP) score is there to ensure the timely removal of lines before infection or chemical irritation ensues.

Please refer to the guidelines for Peripherally Inserted Central (PIC) Lines in Neonates: and the guideline on prevention of Candidia Infection in Neonates

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Clinical Diagnosis

Signs and Symptoms

  • Apnoea
  • Feeding intolerance
  • Abdominal distension,
  • Increased respiratory support
  • Lethargy
  • Hypotonia
  • Temperature instability
  • Poor perfusion
  • Jaundice

Differential diagnosis of LONS is wide. Please refer to the following guidelines as required:

If signs (hepatosplenomegally, thrombocytopenia, cataracts, congenital anomalies, intracranial calcificationsuggestive of congenital infection): ToRCH - Laboratory Investigation and Treatment of Suspected Congenital Infection with Cytomegalovirus, Toxoplasma or Rubella (ToRCH) in the Neonate

If Candida spp. have been isolated see: link
If a long line is in situ see: Long Line Sepsis - Neonatal
Conjunctivitis Neonatal (ophthalmia neonatorum)
If signs of abdominal sepsis see: Necrotising Enterocolitis in Neonates

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In the case of suspected LONS the infant should have the following investigations:

Blood cultures Urine microbiology
Respiratory secretions if ventilated or respiratory signs
Thorough multi-system examination
  • Blood cultures (please see standard operating procedure blood culture Sampling in
    if central access is present take central and peripheral cultures.
  • Paired line and peripheral blood cultures should be taken in suspected line infection.
  • Serial blood cultures are useful when CoNS have been isolated to help determine whether they are contaminants or not.
  • CRP repeat after 24h may be helpful in determining whether infection is a significant likelihood.
  • PCT should be sent with the initial septic screen and at 24 hours. PCT interpretation can be seen in the flow chart below and can be used to stop antibiotics at 24 hours where levels are low.
  • Urine for microbiological investigation, ideally by suprapubic aspirate (SPA); if this is not possible then catheter or clean catch is appropriate. Even with a SPA the positivity is low.
  • CXR +/- AXR if there are respiratory and or gastrointestinal disturbance/abdominal signs.
  • Lumbar puncture -
Clinical signs of meningitis Abnormal clotting
Signs of systemic bacteraemia Platelets less than 50
Positive blood culture (except CoNS) Clinically well
CRP > 50 Definite focus of infection outside the CNS e.g. NEC
  • Respiratory secretions for microbiological investigation (bacteriology and virology) especially if respiratory signs/symptoms or ventilated.
  • Examination: Infection may involve skin/soft tissue/surgical sites, lung, gastrointestinal tract, eyes, urinary tract, cardiovascular, central nervous or musculoskeletal system.

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Table 1: Antimicrobial recommendations




1st Line non-surgical only 

Benzylpenicillin and gentamicin

Careful consideration should be given to antibiotic choice with regard to baby’s age and likely source of infection: Most babies will have had 1st line antibiotics during first few days of admission.

1st Line -surgical

Amoxicillin, gentamicin and metronidazole

If sepsis is thought to be abdominal/surgical in origin

2nd line

Teicoplanin and Gentamicin

Each subsequent screen for sepsis will start babies on 2nd line Abx unless clear reasons are discussed and stated otherwise

3rd line

Meropenem and Vancomycin

Should be carefully considered on discussion with senior colleague or reserved for failure of second line treatment.

If commencing meropenem and vancomycin for GI related symptoms, e.g. NEC, metronidazole is not required.



May be added in, at any stage if symptoms considered intra-abdominal in origin.

A guideline on how to prescribe Gentamicin is available.

The NICE guideline recommends that in babies with a birthweight less than 1500g or born before 30 weeks gestation, nystatin prophylaxis should be given for the duration of antibiotic treatment. In practice, in Leeds, most babies in this group will be on nystatin as part of their routine treatment. For those that are not, it must be recognised that, to date, we have not had any invasive candida infection because of treatment for LONS. Therefore, whilst it should be considered, it is not part of our usual practice.

The 24hr PCT should guide antibiotic therapy; if levels are low as per the flow chart below then consider stopping antibiotics if clinically improving. If clinical features of sepsis or positive blood cultures discuss continuing treatment with a senior colleague and de-escalate antibiotics based on blood culture results.

There has been an increase in Staphylococcus capitis bacteremia observed across neonatal units over past couple of years. S. capitis is a Coagulase-negative Staphylococcus which rarely causes invasive disease outside of the neonatal period. These isolates have been shown to have methicillin resistance, vancomycin hetero-resistance and specific aminoglycoside resistance. Such babies would need source isolation and management of these infections should be discussed with Microbiology.
If there are concerns with regards to invasive candidiasis please refer to the following trust guideline for appropriate management

Due to the risk of adverse outcome all infants with confirmed LONS must be followed up in the neonatal outpatient clinic 6 weeks after discharge to monitor progress and development.

Procalcitonin (PCT) Decision Making Flow Chart

Non-infectious causes of a rise in PCT

1. Trauma & burns
2. Carcinoma (medullary, small cell lung)
3. Immunomodulation therapy or severe immunosuppression
4. Cardiogenic shock
5. Peritoneal dialysis
6. Cardiopulmonary bypass
7. Open chest or abdomen
8. Surgery within the first week of life
9. Major congenital abnormalities
10. Severe respiratory failure in the preterm infant
11. Physiological elevation in Neonates <48 hours of age [and premature babies for a longer period as per the algorithm below]

Procalcitonin (PCT) Interpretation

PCT Level


Decision Making

PCT 0.05ng/ml

No systemic inflammatory reaction.

Normal for healthy individuals.
No risk of progression to sepsis.

PCT <0.5ng/ml

Measurable but low systemic inflammatory reaction.

Sepsis unlikely.
Low risk of progression to severe sepsis.

PCT 0.5 – 2.0ng/ml

Moderate systemic inflammatory reaction.

Sepsis possible.
Moderate risk of progression to severe sepsis.
Continue antibiotics and repeat PCT in 24 hours.

PCT 2.0 –

Severe systemic inflammatory reaction.

Sepsis likely.
High risk of progression to severe sepsis.
Continue antibiotics and liaise with Microbiology.

PCT >10.0ng/ml

Severe systemic inflammatory response.

Almost exclusively due to severe bacterial infection.
High likelihood of severe sepsis or progressing to septic shock.

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Record: 3688

To improve the diagnosis and management of late onset sepsis in the newborn infant (LONS)

To provide evidence-based recommendations for:

  • diagnosis
  • appropriate investigation and
  • streamlined management of newborn late onset sepsis
Clinical condition:

Suspected infection in the newborn infant after 72 hours of age

Target patient group: Newborn infants under the care of the neonatal service
Target professional group(s): Secondary Care Doctors
Adapted from:

Evidence base


  1. Chu A, Hageman JR, Schreiber M et al.  Antimicrobial Therapy and Late Onset Sepsis. Neoreviews 2012;13;e94
  2. Gerdes JS. Clinicopathologic approach to the diagnosis of neonatal sepsis. Isr J Med Sci. 1994;30:430–441
  3. Kumar Y, Qunibi M, Neal TJ, Yoxall CW. Time to positivity of neonatal blood cultures. Arch Dis Child Fetal Neonatal Ed. 2001; 85:F182–F186
  4. Mehr S, Doyle LW. Cytokines as markers of bacterial sepsis in newborn infants: a review. Pediatr Infect Dis J. 2000;19:879–887
  5. Beceiro Mosquera J, Sivera Monzo CL, Oria de Rueda SalgueroO, Olivas Lopez de Soria O, Herbozo Nory C. Usefulness of a rapid serum interleukin-6 test combined with CRP to predict sepsis in newborns with suspicion of infection. An Pediatr (Barc). 2009;71:483–488
  6. Fanaroff AA, Korones SB, Wright LL, et al. Incidence, presenting features, risk factors and significance of late onset septicemia in very low birth weight infants. The National Institute of Child Health and Human Development Neonatal Research Network. Pediatric Infect Dis J. 1998;17:593–598
  7. Bentlin MR, Suppo de Souza Rugolo LM. Late-onset Sepsis: Epidemiology, Evaluation, and Outcome. NeoReviews 2010;11;e426-e435
  8. Stocker, et al. Procalcitonin-guided decision making for duration of antibiotic therapy in neonates with suspected early-onset sepsis: a multicentre, randomised controlled trial (NeoPIns). Lancet. 2017; 390(10097):871-881

Evidence levels:
A. Meta-analyses, randomised controlled trials/systematic reviews of RCTs
B. Robust experimental or observational studies
C. Expert consensus.
D. Leeds consensus. (where no national guidance exists or there is wide disagreement with a level C recommendation or where national guidance documents contradict each other)

Approved By

Improving Antimicrobial Prescribing Group

Document history

LHP version 2.0

Related information

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