• Infection >72 hr after birth
• When acquired in hospital – most commonly Gram-positive organisms. Coagulase-negative staphylococci (CoNS) account for approximately 50% of all late onset infections
• Gram-negative bacteria accounts for 20–40% and these are increasingly resistant to gentamicin (Klebsiella>Serratia>Enterobacter>Pseudomonas>E.coli and Acinetobacter)

Risk factors

• Prematurity
• Low-birth-weight
• Mechanical ventilation
• History of surgery
• Presence of central catheter
• Parenteral nutrition
• Delayed introduction of enteral feeds is associated with higher infection rates
• Increased risk of sepsis after gut surgery especially if enteral feeds slow to establish e.g. post-gastroschisis or necrotising enterocolitis (NEC) with stoma
• Think about infection in the other babies when one baby from a multiple birth has infection

• Bare below elbow
  • no jewellery except wedding band
• Strict hand washing and alcohol hand rubs
• Follow WHO 5 moments of hand hygiene recommendations
• Meticulous regimen for changing IV fluid administration sets and 3-way taps
• Initiate enteral feeds with maternal breast milk within 6 hr of birth

• Can be vague and non-specific

Signs

Behaviour

• Parent or care-giver concern for change in behaviour
• Appears ill to healthcare professional
• Does not wake, or if roused does not stay awake
• Weak high-pitched or continuous cry

Respiratory

• Raised respiratory rate: ≥60 breaths/min
• Grunting and other signs of increased work of breathing
• Apnoea
• Oxygen saturation of <90% in air or increased oxygen requirement over baseline

• Persistent tachycardia: heart rate ≥160 beats/min
• Persistent bradycardia: heart rate <100 beats/min

Skin

• Mottled or ashen appearance
• Cyanosis of skin, lips or tongue
• Non-blanching rash

GI

• Alteration in feeding pattern
• Distension and tenderness
• Reduced or absent bowel sounds
• Blood in stool

Other

• Temperature <36°C or ≥38°C, unexplained by environmental factors
• Reluctance to move joint or limb (suggestive of osteomyelitis or septic arthritis)
• Septic spots in eyes, umbilicus, nails or skin
• Bulging fontanelle suggesting raised intracranial pressure (rarely detectable in babies with neonatal meningitis)
• Seizures
• Petechiae 

• Perform before starting antibiotics

Swabs or ETT secretions for culture

• Swab any suspicious lesion (e.g. skin, umbilicus or nails)
• Refer to recent swabs or ETT secretion cultures to guide antibiotic therapy 

Blood cultures

• From a peripheral vein, using a closed system, non-touch, aseptic technique 
• If blood collected from cannula hub risk of culturing CoNS skin contaminants 

Full blood count

• A neutrophil count <2 or >15 x 10⁹/L (supportive but not diagnostic, and marginally more sensitive than a total white cell count)
• Platelet count of <100 x 10⁹/L
• Toxic granulation in neutrophils [or if measured, an immature:total (I:T) neutrophil ratio >0.2]

Clotting profile

• If evidence of bleeding diathesis or in severe infection/septicaemia

CRP

• Acute phase protein synthesised in the liver in response to inflammatory cytokines
• Generally a delay of 18−24 hr between onset of symptoms and rise in serum CRP 
• Take sample at presentation and further sample 18–24 hr after first CRP sample; use this together with later readings to assess the likelihood of infection and response to treatment

Urine microscopy, culture and sensitivity

• Do not routinely perform urine microscopy or culture as part of the investigations for late-onset neonatal infection for babies in neonatal units
• For babies outside of neonatal units follow the NICE guideline on urinary tract infection in under 16s (CG54)

Lumbar puncture (LP)

• If safe to do so, perform LP to obtain cerebrospinal fluid sample when: 
  • strong clinical suspicion of neonatal infection or 
  • clinical symptoms or signs suggesting meningitis
• If baby unstable, deranged clotting or thrombocytopenia, discuss advisability with consultant
• Send CSF for urgent Gram-stain and culture (MC&S), protein and glucose
• PCR for bacteria and viruses where indicated
• In critically ill baby, consider PCR for HSV, especially term babies 

Others

• Chest X-ray
• If abdominal distension noted, abdominal X-ray
• Consider removing central lines for all infections (unless access major issue). Line removal should be a considered decision
• If line ‘precious’ and baby responding to treatment, consider infusing vancomycin down long line and leaving it to dwell for 1 hr before flushing

Documentation

• Always contemporaneously document symptoms and signs of infection at the time of taking all blood and CSF cultures (and abdominal radiographs) on BadgerNet ad-hoc reporting field

Late onset sepsis

Antibiotics

• If decision made to give antibiotics, aim to start within <30 min and always within ≤1 hr of decision
• First line: give combination of IV antibiotics (e.g. flucloxacillin plus gentamicin) (see Neonatal Formulary for dose) based on local or national susceptibility and resistance data 
• Give antibiotics effective against both Gram-negative and Gram-positive bacteria
• If necrotising enterocolitis suspected, include antibiotic that is active against anaerobic bacteria (e.g. metronidazole) (see Necrotising enterocolitis (NEC) guideline)
• Second line suggested: vancomycin + gentamicin − review local antibiotic susceptibility and resistance data (or national data if local data inadequate)
• Third line or if cultures dictate: meropenem +/- vancomycin, tazobactam + piperacillin alternative for Gram-negative infection
• Do not use vancomycin routinely (consult local policy):
  • for babies with indwelling catheters and on parenteral nutrition, unless they are very unwell
  • to treat endotracheal secretion colonisation with CoNS

Antifungals

• Give prophylactic oral nystatin to babies treated with antibiotics for suspected late-onset neonatal bacterial infection if:
  • birth weight ≤1500 g or
  • born <30 weeks' gestation
• Consider antifungals in post gut surgery babies at any gestation 
• If oral administration of nystatin is not possible, give fluconazole IV 

Review treatment at 36 hr

• Stop antibiotics if:
  • initial clinical suspicion of infection was not strong and
  • negative blood culture and
  • baby is well with no clinical indicators of possible infection and
  • levels and trends of CRP are reassuring i.e. CRP <15 mg/L on both tests

Treatment duration for late-onset neonatal infection without meningitis

• When culture results available, always change to narrowest spectrum antibiotic
• If positive blood culture, give for 7 days
  • consider continuing antibiotic treatment >7 days if:
    • baby not yet fully recovered or
    • longer treatment required due to pathogen identified on blood culture (e.g. Gram-negative bacteria or Staphylococcus aureus; seek expert microbiological advice if necessary) or
    • longer treatment required due to site of infection (e.g. intra-abdominal co-pathology, necrotising enterocolitis, osteomyelitis or infection of a central venous catheter)
• If baby makes prompt recovery, and either no pathogen identified/pathogen identified is a common commensal (e.g. coagulase negative staphylococcus), treat <7 days

Discharging eyes

• See Conjunctivitis guideline

Umbilicus sepsis (omphalitis)

• Systemic antibiotics required only if local induration or surrounding reddening of the skin 

Meningitis

Empirical treatment whilst CSF results pending

• If meningitis suspected but causative pathogen unknown, treat with amoxicillin IV and cefotaxime IV
• If meningitis caused by a Gram-negative infection, stop amoxicillin and treat with cefotaxime alone 
• If meningitis caused by Gram-positive organism, continue with amoxicillin and cefotaxime until culture result confirmed
• Seek microbiological advice where possible 
• If CSF culture positive for group B streptococcus, consider changing antibiotic treatment to benzylpenicillin for at least 14 days and gentamicin IV for 5 days
• If blood culture or CSF positive for Listeria, consider stopping cefotaxime and treating with amoxicillin and gentamicin
• If CSF culture identifies a Gram-positive bacteria other than group B streptococcus or Listeria seek microbiological advice

Table of normal CSF values

• Values are mean (range)
• Note: protein levels are higher in first week of life and depend on RBC count. WBC of >21/mm³ with a protein of >1.0 g/L with <1000 RBC is suspicious of meningitis
• If traumatic LP and strong suspicion of meningitis, repeat LP after 24–48 hr
• Manage baby as if he/she has meningitis. None of the ‘correcting’ formulae are reliable 

Urinary tract infection (UTI)

• Do not routinely perform urine microscopy or culture in babies suspected of late onset sepsis on neonatal units
  • if a urine microscopy and culture are requested this specimen should be a clean catch specimen. When it is not possible to collect urine by non-invasive methods catheter samples or suprapubic aspiration should be used

Necrotising enterocolitis

• See Necrotising enterocolitis (NEC) guideline

Fungal infection

• Mostly late onset
• Incidence in UK up to 1.2% in very-low-birth-weight babies and 2.6% in extremely-low-birth-weight babies (versus up to 28% in the USA), hence no routine prophylaxis in the UK

Risk factors

• <1500 g
• Parenteral nutrition
• Indwelling catheter
• No enteral feeds
• Ventilation
• H2 antagonists
• Exposure to broad spectrum antibiotics, especially cephalosporins
• Abdominal surgery
• Peritoneal dialysis

Symptoms and signs

• Non-specific
  • as for late onset infection

Additional investigations

• If fungal infection suspected or diagnosed, end-organ evaluation to include:
  • abdominal ultrasound
  • cerebral ultrasound
  • lumbar puncture
  • fundoscopy
  • echocardiogram
  • blood cultures 24–48 hrly to confirm clearance
  • suprapubic or catheter specimen of urine

Treatment

First choice

• Standard amphotericin starting at 1 mg/kg. Can increase dose as tolerated to 1.5 mg/kg. In renal failure can use liposomal amphotericin 1 mg/kg, increasing to a maximum of 5 mg/kg (see Neonatal Formulary for doses and intervals)
• Alternatives fluconazole and micafungin – see local formulary

• No substantive trials to date show benefit of immunoglobulin IV, recombinant cytokines etc.