Neonatal infection and antibiotic policy

Guideline for the management of infection in the newborn on the neonatal unit

 

Background:

Background: Infection is a major cause of morbidity and mortality in the neonatal period. The UK NeonIN data demonstrate that, with the inclusion of CoNS, the incidence of all neonatal infection is 0.8% of live births and 7.1% of neonatal admissions. The mortality rate from neonatal infection is 13-30% with a higher rate in premature and VLBW infants. The combination of immature immune system, non-specific symptoms and signs together with ever changing infective pathogens leads to greater incidence of infection and consequent mortality and morbidity. Traditionally, neonatal infection is divided into congenital and acquired or early & late onset infection. The mortality rate for early-onset infection is 15% and for late-onset infection is 9%, according to a study reported in Australia. The incidence of late infection is now about 20 times that of early infection in VLBW babies (<1.5Kg)

 

Early-onset infection (EOS) occurs in the first 72 hours. The organisms involved are usually acquired from the mother. This may be due to haematogenous spread, or more commonly due to ascending infection from the vagina.  The organisms responsible could be both Gram positive and Gram negative bacteria that include GBS, E Coli, H Influenzae, Listeria etc. The overall incidence of EOS in the UK is 0.9/1000 of all live births and 0.9% of all neonatal admissions. GBS and Escherichia coli are the most common causative organisms, if CoNS are excluded, and account for 58% and 18% of bacteraemia respectively in the UK. Common risk factors are chorioamnionitis, maternal pyrexia (Temp >38oC), premature rupture of membranes, preterm labour, maternal UTI or bacteriuria and GBS colonisation.

 

Late-onset infection (LOS) occurs after 72 hours. LOS invariably occurs in preterm and low birth weight babies, the risk being indirectly proportional to their birth weight and gestational age. The incidence of LOS among VLBW infants ranges between 16% and 30%. Mortality rates vary between 17% and 21%. Incidence of LOS in the UK is 0.7% of live births and 6.1% of neonatal unit admissions. The organisms are usually acquired from the hospital environment or nosocomial infection. However, occasionally some of the organisms acquired from the birth may also be responsible. The usual organisms include CONS (45% – 55%), Staph aureus, Enterococcus, E Coli, Enterobacter, Klebsiella, GBS, Pseudomonas and Candida species.

 

Approach to management of Neonatal Infection:

 

History:

 

Literature review shows that the consequences of delays in recognising and treating infected babies could be very serious including death and serious morbidity. The symptoms and signs of neonatal infection are usually non-specific. A high degree of suspicion is necessary to treat neonatal sepsis effectively.

 

In each case, it is important to review the maternal notes to see if mother had received any antibiotics recently and in particular, during labour. Any known isolates on culture from blood, urine or vaginal swabs should be noted. Any other markers of maternal infection such as raised CRP, WCC should also be considered in the decision making process. Intra-partum antibiotic prophylaxis (IAP) may prevent the isolation of organism from the baby even though the baby may be infected.

 

Examination:

Any baby at risk or suspected of infection should be examined fully without delay including assessment of vital signs.

 

 

Clinical indicators suggestive of sepsis in babies admitted to neonatal unit:

Altered behaviour or responsiveness
Altered muscle tone (for example floppiness)
Feed intolerance (vomiting, excessive gastric aspirates, bilious aspirates, abdominal distension)
Abnormal heart rate (bradycardia or tachycardia)
Increase in respiratory support requirements
Onset of respiratory distress after 4 hours
Apnoeas
Signs of neonatal encephalopathy or seizures
Need for cardiopulmonary resuscitation
Need for mechanical ventilation in a term baby
Persistent pulmonary hypertension
Temperature instability (<36 degree C or > 38 degree C)
Signs of shock
Unexplained excessive bleeding, thrombocytopenia, abnormal coagulation
Altered glucose homeostasis (hypoglycaemia or hyperglycaemia)
Metabolic acidosis ( base deficit of 10 mmol/l or more)
Local signs of infection (for example eye, skin)
  • Babies presenting with any of the above signs, consider starting appropriate antibiotic treatment after performing partial or full sepsis screen. Howe
  • In babies where it’s being considered safe to withhold antibiotics, take CRP, FBC, blood gas and blood culture (at least 1 ml of blood for blood culture). Monitor vital signs closely and document clinical review including temperature, heart rate, perfusion, blood pressure and blood gas.
  • Continue close clinical monitoring, low threshold of starting antibiotics and repeat CRP in 18 – 24 hours

 

Investigations:                                                  

  • Partial septic work-up should include a FBC (+ differentials and a blood film), CRP and a blood culture. Do not forget the blood glucose.
  • Chest X-Ray may be indicated if symptoms refer to the respiratory system.
  • Lumbar puncture should be performed initially if –
      1. there is a strong clinical suspicion of infection and not just risk factor
      2. there are clinical symptoms and signs suggesting meningitis
      3. If blood culture is positive
      4. Lumbar puncture should not delay the administration of antibiotics
  • Urine culture is not routinely indicated in early onset sepsis but should be undertaken in late-onset sepsis. The diagnosis of UTI is made only on a SPA or catheter urine specimen.
  • Strict aseptic technique should be employed when collecting culture specimens to prevent the occurrence of false positive results – contaminant.
  • The ideal volume of blood for culture is 1ml. If it is difficult to collect this amount from the baby it is important to state the volume collected on the request form
  • Skin swabs are only performed if there are signs of localized infection. Routine skin swabs are misleading.
  • Swabs should be taken if there is conjunctivitis with purulent eye discharge to identify Chlamydia or Gonococcus.
  • When a line infection is suspected, blood specimens should be collected both from the line (only through Hickman Line) and a peripheral vein.

Antibiotic Policy:

  • Babies with suspected early onset neonatal sepsis should be treated as soon as possible and definitely within 1 hour of the decision to treat.
  • Explain to the parents where possible the reason for treatment, observation and investigations needed and likely duration of treatment. Treatment and care should take into account the needs and preferences of parents and carers, as appropriate. Parents and carers whose babies are at risk of or have an early-onset neonatal infection should have the opportunity to make informed decisions about their baby’s care and treatment, in partnership with their healthcare professionals. Where parents cannot be contacted, continue management without delay.
  • Prior to starting (or changing) antibiotic treatment, every baby should have blood cultures, and every intubated baby should have an endotracheal aspirate sent for culture. The results should be chased at 36 hours and the choice and need to continue antibiotics may need to be reviewed based on results and antibiotic sensitivities.
  • Please remember to discuss with the obstetricians and the laboratory staff the results of any swabs or cultures taken from the mother, particularly if the mother has received antibiotics prior to delivery. Maternal antibiotics can reduce the isolation of organisms from the baby even though the baby is infected.

First Line Antibiotics:

These are usually used within the first 72 hours or after birth for a presumed or suspected early onset sepsis

  • Benzyl Penicillin – 60mg/kg/dose

 

Use one dose 12 hourly in the first week.

One dose 8 hourly in babies 1-4 weeks and

One dose 6 hourly in babies of 4 weeks or more

The dosage interval should be increased in renal failure

 

AND

  • Gentamicin   The dose is as follows

Babies less than 1 week old – 5mg/Kg every 36 hourly

Babies greater than 1 week old – 5mg/Kg every 24 hourly

Babies > 28 days old – 7mg/Kg every 24 hourly

 

The interval may be shortened, based on clinical judgement, for example if the baby appears very ill or the blood culture shows a Gram-negative infection. Increase interval between dosages in renal failure.  If drug levels are not available do not withhold gentamicin unless there is suspicion of renal dysfunction (anuria / raised Creatinine)

 

Therapeutic drug level monitoring of Gentamicin:

 

Generally only trough levels are required. Check trough levels 4-6 hours before the 3rd dose, if Gentamicin needs to be continued beyond the 36 hours. If more than 3 doses of Gentamicin are used, check trough levels every 3rd dose.

 

Trough (pre-dose) <2 mg/L.

If more than 3 doses of Gentamicin are to be given then trough level of < 1mg/ L is advised.

Consider measuring peak blood gentamicin concentrations in selected babies

  • oedema
  • macrosomia (birth weight more than 4.5 kg)
  • an unsatisfactory response to treatment
  • proven Gram-negative infection.

Measure peak concentrations 60 minutes after gentamicin administration, if given by bolus or infusion.

If a baby has a Gram-negative or staphylococcal infection, consider increasing the dose of gentamicin if the peak concentration is less than 8 mg/litre.

 

How to write up 36 hourly Gentamicin?

When an infant needs Gentamicin to be prescribed 36 hourly, this needs to be written as below:

  1. Write on the ‘once only and pre-anaesthetic medical’ area of the prescription chart.
  2. Each dose must be written separately and the date & time for each dose to be clear.
  3. Write on the regular medications side of the prescription chart – ‘GENTAMICIN’ – please see once only’.
  4. As for all medications, print clearly and sign.

 

  • Amoxicillin and Gentamicin should be used if Listeria is considered on clinical grounds
    1. Maternal pyrexia and flu-like symptoms prior to delivery
    2. Meconium-stained liquor in a preterm infant
    3. Macular rash or other signs of sepsis
  • Metronidazole should be added to the Benzylpenicillin and Gentamicin if the focus of infection is within the gut. Refer to BNF / neonatal formulary for updated dose
  • Flucloxacilin and gentamicin is recommended if there are signs of umbilical infection ( purulent discharge or periumbilical cellulitis)

 

 Initial choice and modification of antibiotics in babies on NNU with meningitis:

If causative organism not known Treat with Amoxicillin and Cefotaxime
Gram negative organism confirmed Amoxicillin can be stopped and treat with Cefotaxime
Gram positive organism confirmed Continue Amoxicillin and Cefotaxime
GBS positive in CSF Consider changing to Benzylpenicillin and Gentamicin
Listeria in CSF Consider stopping Cefotaxime and treating with Amoxicillin and Gentamicin

Second Line Antibiotics:

  • If a baby becomes unwell after 72hrs of age i.e. late onset sepsis and there are no specific guiding factors, use Flucloxacillin and Gentamicin**. If Gram negative infection is suspected, add Cefotaxime to the existing initial antibiotic regimen. If gram negative infection is confirmed then penicillin based antibiotics should be stopped.
  • If the baby has a central line in-situ then consider removing the line. Vancomycin and Gentamicin should be considered if the baby is ill or if it is not practical to remove the line. Considering both drugs are considered nephro and ototoxic, therapeutic drug levels should be monitored closely and urine output and biochemical renal function reviewed on a regular basis. Cefotaxime should be considered if there is a strong  suspicion of meningitis on clinical examination  and / or CSF analysis or if a LP could not be performed on a very sick baby
  • If Necrotising Enterocolitis (NEC) is suspected after 72 hours of age use Flucloxacillin, Gentamicin** and Metronidazole. If suspected before 72 hours of age add metronidazole to penicillin and gentamicin.

** Please note that Gentamicin should be used as described in first line antibiotics

 Third Line Antibiotics:

  • Ceftazidime should be used in preference to Cefotaxime if Pseudomonas infection is suspected
  • Meropenem can be used in severe multi-resistant Gram-negative sepsis. In such circumstances Metronidazole can be stopped if Meropenem is being used – discuss with the Microbiologist.
  • Teicoplanin can be used to treat CONS infection especially when vascular access is a problem – can be given IM once daily. Even if IM route is contemplated for difficult venous access, it is preferable to give a loading dose through the intravenous route. It has no other advantage over Vancomycin apart from being marginally less nephrotoxic. Usually ineffective in Vancomycin Resistant Enterococcus (VRE) sepsis

16mg/kg        Loading dose; followed after 24hours by                              

8mg/kg          Maintenance dose daily

Prescription writing                      

  • Drug dosage given in the Neonatal Formulary is used unless stated otherwise in our protocols
  • Observe the principles of safe prescribing
  • Please prescribe in the main drug chart using special stickers.
  • Give the first dose immediately and always within 1 hour of the decision to treat.
  • Prescribe in a realistic manner – an easily measurable amount of the drug. It is pointless prescribing volumes to an accuracy of one thousandth of a ml (e.g. prescribe Gentamicin to the nearest 100 microgram and Benzyl Penicillin to the nearest milligram)

 

 

Monitoring of other drug levels:

The blood levels of Vancomycin need to be monitored and dosing and frequency of administration adjusted accordingly in order to prevent toxicity. Moreover, the dosage of most drugs may need to be adjusted in certain clinical conditions like renal and hepatic failure. Remember that the Pharmacist visits the unit every weekday and is an invaluable resource for advice in such circumstances.

 

Vancomycin:

 

Vancomycin levels are done in biochemistry department and sample needs to be sent in lithium heparin neonatal containers.

Acceptable levels

Trough (pre-dose) 5-15 microgram/ml

Peak (post-dose) 25-40 microgram/ml

 

Adjustments: 

                                       

< 5 mcg/ml Increase dose and repeat in 24 – 48 hours.

 

5 – 15mcg/ml Ideal range for babies on vancomycin. Higher trough levels may be desired for invasive infections.

 

> 15mcg/ml Increase interval and repeat levels with next dose. If next levels are high, dose may need to be reduced. Discus it with consultant.

 

  • Trough level is checked before the 4th dose.
  • In renal failure check the pre-dose before giving any further doses.

How to decide the duration of the antibiotic treatment?

  • Prolonged and unnecessary use of antibiotics leads to the development of drug resistance and should be avoided. Review the need for antibiotics daily on the consultant ward round. If needed, discuss with the microbiologist on Grand round
  • During antibiotic treatment, measure CRP 18 – 24 hours after presentation.
  • Lumbar puncture should be considered in a baby on antibiotics, who did not have this investigation at presentation, if blood culture is positive or who is not responding to the treatment either clinically or through persistent rise of inflammatory markers.
  • The duration of antibiotic treatment should be determined by whether or not infection is confirmed on bacteriological culture, the nature of the infecting organism and the focus of infection.
  • If cultures are negative after 36 hours, CRP levels are normal and the baby is well with no signs of infection, antibiotics may be discontinued. IF IN DOUBT – DISCUSS.  Remember, that all drugs have side effects, and it is not good practice to continue antibiotics without a good reason.

The following are “best practice” guide on antibiotic treatment duration in different clinical scenarios.

Scenario Duration
Low suspicion / well baby / negative blood culture / CRP remains less than 10 on 2 samples 18 – 24 hours apart Stop at 36 hours if blood culture negative.
Strong suspicion of infection with rise in CRP and or leucopenia, Good clinical and laboratory response to treatment  with negative blood culture Stop antibiotics once CRP < 10 (or a reasonable fall from baseline) or 5 days. Whichever is earlier
Pneumonia with negative blood culture 5 days
Gram positive organisms such as  Group B streptococcus in blood culture  without meningitis Usually 7-10 days. If in doubt discuss with microbiologist
Coagulase negative staphylococcus isolated in blood culture in babies who are clinically well and central line removed. Stop antibiotics once CRP < 10 (or a reasonable fall) or 5 days. Whichever is earlier
Gram negative organisms in blood culture Usually 14 days – If in doubt discuss with microbiologist
Group B streptococcal meningitis confirmed on CSF  culture At least 14 days of Benzyl penicillin. Stop Gentamicin after 5 days
Gram negative meningitis confirmed on CSF culture At least 3 weeks
Necrotising Enterocolitis – Grade 2 and above 7-10 days. Review clinically and  using biochemical markers
Systemic Staphylococcal infection At least 2 weeks

 

References and further reading:

  1. NICE clinical guideline 149: Antibiotics for the prevention and treatment of early-onset neonatal infection – guidance.nice.org.uk/cg149
  2. Janet M Rennie Ed. Roberton’s Textbook of Neonatology (4ed). USA. Elsevier Churchill Livingstone 2005. p1011-1092
  3. Khadilkar V, Tudehope D, Fraser S. A prospective study of nosocomial infection in a neonatal intensive care unit. Journal of Paediatrics and Child Health 1995; 31:387-391
  4. Isaacs D, Barfield C, Clothier T, et al. Late-onset infections of infants in neonatal units. Journal of Paediatrics and Child Health 1996; 32: 158-161
  5. Escobar GJ, Zukin T Usatin MS, et al. Early discontinuation of antibiotic treatment in newborns admitted to rule out sepsis: a decision rule. Pediatric Infectious Disease Journal 1994; 13: 860-866
  6. Hodge D, Puntis JWL. Diagnosis, prevention, and management of catheter related bloodstream infection during long-term parenteral nutrition. Archives of Disease in Childhood. Fetal & Neonatal Ed 2002; 87: F21-F24
  7. Hristeva L, Bowle I, Booy R, et al. Value of cerebrospinal fluid examination in the diagnosis of meningitis in the newborn. Archives of Disease in Childhood 1993; 69: 514-51
  8. Puopolo KM, Draper D, Wi S, et al. Estimating the probability of neonatal early-onset infection on the basis of maternal risk factors. Pediatrics 2011;128:e1155–63.
  9. VON iNICQ 2016 : Choosing antibiotics wisely. The Centers for Disease Control and Prevention and Vermont Oxford Network Partner to Tackle Antibiotic Overuse and Misuse.
  10. Wendy van Herk, Martin Stocker, Annemarie M.C. van Rossum. Recognising early onset neonatal sepsis: an essential step in appropriate antimicrobial use. Journal of Infection (2016) 72, S77eS82
  11. Ting JY et al. Association between antibiotic use and neonatal mortality and morbities in very low birth weight infants without culture proven sepsis or necrotising enterocolitis. JAMA Pediatrics 2016 ; 170(12) 1181-1187