• Summary
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• Background
• Clinical Diagnosis
• Investigation
• Treatment

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

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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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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 (please see standard operating procedure blood culture Sampling in
  Neonates) 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 -

• 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

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

Prognosis
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

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