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Sepsis

• Summary
• Introduction
• Risk Factors for Sepsis
• Recognition of systemic sepsis
• Investigations
• Management
• GBS Colonisation
• Prolonged Rupture of Membranes
• Fungal Sepsis
• Areas of Uncertainty in Clinical Practice

Summary 

• any baby who is unwell must be considered at risk of sepsis and appropriate antibiotics commenced as soon as possible after taking cultures
  
• inability to obtain cultures should not delay administration of antibiotics
• in babies where antibiotics are commenced until sepsis can be ruled out but who are otherwise well consider care in the postnatal ward provided antibiotics ban be provided there and the baby can be safely observed

Introduction

Neonatal sepsis occurs in 1 to 8 per 1000 live births with the highest incidence occurring among infants of very low birth weight and gestation. It is mandatory to have a high index of suspicion for the possibility of sepsis, as well as a low threshold for commencing antibiotic treatment. While more babies are treated than are infected the consequences of untreated sepsis are devastating.

Early onset sepsis (within the first 48 hours of life)

• often manifests with pneumonia and/or septicaemia
• equal male and female incidence
• characterised by high risk of mortality (10 to 30%)
• predominantly due to organisms acquired from the birth canal
• occasionally intrapartum haematogenous spread occurs eg Listeria
• over 80% of cases are due to GBS and gram negative bacteria

Late onset sepsis (after the first 48 hours)

• due to organisms acquired either around the time of birth or in hospital eg Coagulase Negative Staphylococcus during hospitalisation in the NICU
• male predominance
• infants < 1000gms are particularly at risk
• mortality rate approximately 5%
• > 70% due to Coagulase Negative Staphylococcus and Staphylococcus aureus, 10 - 15% due to Gram negatives. Candida is an important pathogen, particularly among extremely low birth weight infants
• gram negatives and GBS predominate among infections acquired outside the NICU setting

Risk Factors for Sepsis

Early onset sepsis

• prolonged ruptured membranes (> 18 hours)
• fetal distress
• maternal pyrexia (> 38° C) or overt infection eg UTI, gastroenteritis/diarrhoeal illness
• multiple obstetric procedures, including cervical sutures
• preterm delivery
• history of GBS infection in previous infant, GBS bacteriuria in this pregnancy

Late onset sepsis

• prolonged hospitalisation eg preterm infants in a NICU
• presence of foreign bodies eg intravenous catheters, endotracheal tubes, etc
• cross infection by staff and parents
• malformations such as urinary tract anomalies (eg vesico-ureteric reflux) or neural tube defects

Recognition of systemic sepsis

Signs are usually non-specific since other conditions cause similar clinical states (eg cardiac or respiratory failure, metabolic disorders)

• General features
  • pallor, lethargy, jaundice
  • fever, hypothermia, temperature instability (note 1/3 of confirmed sepsis cases are normothermic)
  • poor handling
  • hypoglycaemia/hyperglycaemia
  • blood gas derangements (including acidosis and lactate accumulation)
    
    
• Respiratory
  • increased respiratory rate
  • apnoea 
  • grunting
  • cyanosis
    
    
• Cardiovascular System 
  • tachycardia 
  • bradycardic episodes
  • poor perfusion
  • hypotension
    
    
• Cutaneous
  • petechiae 
  • bruising
  • bleeding from puncture sites
    
    
• GIT
  • poor feeding
  • vomiting
  • abdominal distension
  • feed intolerance
  • bilious aspirates/vomits
  • loose stools
    
    
• CNS
  • lethargy
  • irritability
  • seizures

Any baby who is unwell must be considered at risk of sepsis and appropriate antibiotics commenced as soon as possible after taking cultures. Inability to obtain cultures should not delay administration of antibiotics.

Investigations

General investigations include parameters important in assessment of general well being of the infant eg blood gases, true blood glucose

Infection related tests

• Non-specific markers eg C-reactive protein (CRP), Full Blood Examination

• Tests to identify the infective organism
  
  

Early onset sepsis

Late onset sepsis

Non-NICU infants suspected of being septic - LP should be performed to exclude CNS infection. If there is a high clinical index of CNS infection, appropriate treatment should be instituted early even if the LP is delayed until the baby is stable enough to tolerate the procedure.

Infants in NICU - The role of LP is limited since the commonest organism causing sepsis is the Coagulase Negative Staph (CONS). CONS rarely cause CNS infection unless a Ventriculoperitoneal shunt is present. LP when CONS is isolated from blood culture is reserved for infants who are not following the expected clinical course despite appropriate antibiotics. LP is performed when the infant's condition is suggestive of meningitis or blood culture identifies an organism other than CONS. .

• ETT cultures and skin swabs are of limited value for babies in NICU situations. Their value is as a guide to the profile and sensitivity of organisms in the nursery, particularly Staphylococcus aureus.

Management

Place of Care

The septic baby should be managed in the Special Care Nursery where they can be observed closely.

However in some cases where antibiotics are commenced whilst sepsis is being ruled out (eg brief unexplained respiratory distress or the GBS positive mother with inadequate intrapartum antibiotic prophylaxis) the baby is clinically well and the septic markers are benign.  In these cases it may be appropriate for the baby to be managed in the postnatal ward so as to keep mother and baby together.  In such cases it may be possible for the IV cannula to be flushed and the IV antibiotics given in the postnatal ward.  However the following caveats must apply

• Nursing staff caring for the baby must be competent to do so (ie as part of their employment be rostered from time to time in the Special Care Nursery)
• The baby is medically cleared by the Paediatrician to be managed in the postnatal ward on a case by case basis
• The baby remains under the care of the Paediatrician(s)
• The baby has regular observations of temperature, pulse rate and respiratory rate with IV cannula flushes.  Any abnormalities of these parameters must result in readmission to the Special Care Nursery

Where Hospital in the Home (HITH) facilities exist consideration may be given to completing the final dose(s) of antibiotics at home.

General Measures

In the septic baby in addition to the administration of antibiotics, great attention to supportive care is needed. Antibiotics should be considered as only part of the management of a septic neonate.

• General
  • thermal care
  • incubator nursing
  • phototherapy if warranted
  • monitoring of oxygen saturation, heart rate and blood pressure
    
    
• Respiratory - support for apnoea, hypoxia, hypercapnoea, and respiratory distress
  
  
• Cardiovascular
  • plasma volume expanders (normal saline - 10 to 20 mls/kg initially)
  • inotropic support is often needed (see management of shock)
    
    
• Correction of fluid, electrolyte, glucose and haematological derangements (including blood, platelets and clotting factors)
  
  
• the unstable infant usually needs enteral feedings withheld.

Antibiotic choice

Given the usual causative organisms the following regimes are recommended initially. Antibiotic choice can then be rationalised on the basis of culture results and clinical course.

Early onset sepsis

• Benzylpenicillin - 60mg/kg IV 12 hrly
                                 120mg/kg/dose 12 hrly if meningitis suspected
• Gentamicin - 5 mg/kg IV  36 hrly if >=1200g, 48hrly if <1200g.

Note: both can be given IM if IV access is not possible

If history or clinical appearance suggests the possibility of Listeria, amoxycillin 50mg/kg IV 12hourly can be used instead of benzylpenicillin (although data indicating that this is superior is lacking).

For treatment of meningitis (until sensitivities are known)

• Cefotaxime - 50mg/kg/dose 12 hourly for preterm babies or term babies in the first week of life, 8 hourly after that time
  
• Amoxycillin - 50mg/kg/dose 12 hourly for preterm babies or term babies in the first week of life, 8 hourly after that time

Late onset sepsis

Flucloxacillin and gentamicin are the usual first choice antibiotics except when suspected

septic shock due to Gram negative organism  use Vancomycin, Gentamicin +/- Vancomycin

meningitis use Amoxicillin and Cefotaxime

necrotizing enterocolitis use Amoxicillin, Gentamicin, Metronidazole

Vancomycin   15 mg/kg 18 hrly for term babies.
Gentamicin   5 mg/kg 36hrly for term babies <= 7days, 24hrly if > 7days.
Flucloxacillin  25mg/kg/dose 12 hourly for preterm babies or term babies in the first week of life, 6-8 hourly after that time.

Doses of antibiotics need to be adjusted for age of the baby and on the basis of levels in the case of gentamicin and vancomycin.

An aminoglycoside other than gentamicin may be used in some hospitals at times depending on the profile of prevalent organisms.

When to stop Antibiotics

Duration of antibiotic treatment depends upon the clinical condition of the infant and the organism identified on culture.

• where the likelihood of infection is low, with a baby in good condition and infective indices negative, antibiotics can be ceased if cultures are negative after 48 hours
  
  
• sepsis strongly suspected, despite negative blood culture at 48 hours. It is advisable to repeat blood culture and continue antibiotics for at least 5 days providing infective indices have normalised. Another approach is to continue antibiotics for 48 hours after indices have normalised
  
  
• proven gram negative bacteraemia, with clear CSF, treat for 10 days, antibiotics can be rationalised in the face of culture and sensitivities
  
  
• proven GBS bacteraemia, with clear CSF, 10 days treatment should be sufficient
  
  
• meningitis, treat for 14 days for GBS and 21 days for gram negative organisms. In some centres, 48-hourly LPs are performed in cases of gram negative meningitis, with treatment continuing for 14 days after the first negative culture - in practice this usually equates with a 21 day treatment course
  
  
• UTI - treat with IV antibiotics for at least 5 days, a total of 10 days treatment is needed. The infant can be managed with appropriate oral antibiotics for the latter half of the treatment course if clinical condition is satisfactory. Ongoing prophylactic antibiotics will be needed until renal investigations (ultrasound and/or MCU) are completed

Special Circumstances

• The GBS colonised mother

At delivery approximately 15% of women are colonised with GBS. Up to 70% of infants born to colonised women are themselves colonised. Infection occurs in 1% of colonised infants. 75% of early onset GBS disease in neonates occurs in term babies. The incidence of GBS disease varies, with the rate being 3 per 1000 live births in the USA, compared to 0.3 per 1000 in Australia and the UK. The risk is 3 times higher in the Aboriginal community.

Screening for GBS remains the subject of heated debate, but it is known that intrapartum administration of antibiotics (penicillin or amoxycillin) reduces neonatal colonisation by 90%, and early onset GBS disease by 90%.
The CDC in the USA recommends that all women be screened with anorectal and vaginal swabs at 35 -37 weeks' gestation.

Intrapartum antibiotics are given according to the following strategies

• if screening is performed administer to
  • GBS colonised women
  • Non-colonised women with risk factors present
    
    
• if screening is not performed administer to women with risk factors
  • Preterm onset of labour (<37weeks)
  • ROM for >18 hours
  • Maternal fever (>38°C)
  • Previous baby with invasive GBS disease
  • GBS bacteriuria this pregnancy

Use of the CDC guidelines is estimated to result in around 27% of women receiving antibiotics, with an associated reduction in early onset GBS disease of around 85%. The disadvantages of such an approach are the risk of maternal complications (anaphylaxis), and the cost (GBS rates of >0.5 per 1000 live births are needed to justify such an approach on a cost-effectiveness basis).

Intrapartum chemoprophylaxis consists of penicillin 1.2gms IV statim, then 0.6gms 4hrly (erythromycin can be used in cases of penicillin allergy). Should the infant be delivered before prophylaxis has been administered to the mother, or within 4 hours of the initial dose, the infant should be observed closely in hospital for 48 hours. Some workers recommend giving a single intramuscular injection of 100mg penicillin, IM, to such an infant while others recommend taking an FBE and blood culture prior to observation. Occasional treatment failure has been associated with the single IM dose regime.

If the infant is initially (or becomes) symptomatic, or if significant prematurity (<35 weeks gestation) is present, the infant should undergo a septic evaluation and treatment with intravenous antibiotics despite maternal intrapartum prophylaxis.

• Prolonged Rupture of Membranes (PROM)

The majority of women will come into labour within 24 hours of rupture of the membranes; however, this may be delayed in up to 4% of cases. PROM for greater than 18 hours may lead to increased risk of infection in mother and baby - particularly if the mother is GBS positive or undergoes repeated vaginal examinations. In practice, the risk is greatest for preterm infants, but 75% of early onset GBS sepsis occurs in term babies. Since there is a lack of evidence from trials available there is debate as to the role of prophylactic antibiotics in PROM. Obstetric staff will need to consider signs of possible maternal sepsis, as well as risk factors such as GBS colonisation in deciding to administer antenatal antibiotics. Babies born with a background of PROM need to be viewed as potentially at risk of sepsis.

Preterm infants, particularly those <35 weeks, are usually screened for sepsis and treated with IV antibiotics until infection in the baby has been excluded.

Term infants

• if there are no risk factors, apart from the PROM, the infant is usually observed closely and treated only if symptoms develop
• if there is a risk factor present in addition to PROM, such as GBS positive mother, maternal intrapartum fever or suspected chorioamnionitis that infant should be treated as potentially septic, even if completely asymptomatic
• any symptomatic baby needs septic evaluation performed and treatment for infection regardless of the presence or absence of risk factors
  

• Fungal sepsis

Generally seen in VLBW infants in NICU. Risk factors include multiple courses of IV antibiotics, presence of central lines and extensive areas of skin breakdown. Consideration of fungal sepsis is particularly necessary when such infants deteriorate whilst receiving antibiotics. Empirical treatment with Amphotericin until cultures are reported as clear for fungal organisms is appropriate. SPA of urine must be performed prior to starting Amphotericin as bag specimens will often be contaminated with Candida colonising the skin. If fungal sepsis is confirmed, then the addition of a further antifungal (e.g. fluconazole mg/kg stat, then 2mg/kg 48hrly) may be useful. Duration of treatment depends upon the site of infection but generally ranges from 3 to 6 weeks. Ultrasound of the kidneys and formal fundoscopy should be performed.

Areas of Uncertainty in Clinical Practice

• The role of antigen tests for GBS is controversial

Urine specimens for GBS antigen can be positive when babies are colonised, even when a SPA specimen is taken. If a bag specimen is used, then contamination with skin GBS colonisation will result in a positive test.
Antigen tests are more sensitive and specific for CSF specimens, but cannot be relied upon to exclude infection. Antigen testing results need to be viewed from the point of view of adding supplementary evidence of possible infection, but cannot be relied upon to prove or disprove GBS infection, and are thus of limited value. Similar limitations exist in testing for other bacterial antigens.

• Antifungal prophylaxis

A recent Cochrane review failed to demonstrate a reduction in fungal colonisation among patients receiving prophylactic oral nystatin compared to placebo. All patients in these trials were immuno-compromised but beyond the neonatal period.

A RCT of intravenous fluconazole compared to placebo during the first 6 weeks of life in 100 infants of less than 1000gm birthweight showed a reduction in fungal colonization and invasive fungal infection.

• Treatment with Granulocyte Colony Stimulating Factor (G-CSF)

G-CSF has been shown to increase PMN counts in VLBW babies, but the effect on sepsis reduction or mortality from sepsis has not been demonstrated.

• Intravenous immunoglobulin (IVIG)

Studies involving IVIG show a possible improvement in mortality in babies given IVIG as part of the treatment of sepsis. However, larger trials are needed to examine the role of IVIG in neonates with sepsis.

• Other ancillary treatments that have been used include exchange transfusion and neutrophil transfusions, but insufficient data is available to recommend their use.

Further Reading

Isaacs D, Moxon ER. Handbook of Neonatal Infections - a practical guide. WB Saunders, London. 1999.

Remington JS, Klein JO. Infectious Diseases of the Fetus and Newborn Infant 5Th Ed. WB Saunders, Philadelphia. 2000.

CDC (Center for Diseases Control). Prevention of perinatal group B streptococcal diseases: a public health perspective. MMWR 1996: 45(RR-7).

Smaill, F. Intrapartum antibiotics for Group B streptococcal colonisation. Cochrane Pregnancy and Childbirth Group. The Cochrane Library.

Flenady, V. King, J. Antibiotics for prelabour rupture of membranes at or near term. [Protocol] Cochrane Pregnancy and Childbirth Group. The Cochrane Library. 

Updated 01/12/2010

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