5.0 - Neonatal Antibiotic Guideline [updated]

UNIVERSITY OF MALAYA MEDICAL CENTRE

NEONATAL INTENSIVE CARE UNIT NEONATAL SEPSIS MANAGEMENT AND ANTIBIOTICS GUIDANCE

1.0 OVERVIEW

Infection in neonates is a leading cause of mortality in newborns and a major cause of admission to NICU. The term neonatal sepsis or sepsis neonatorum commonly refers to a condition of bacterial, viral or fungal infection associated with haemodynamic changes and other clinical manifestations seen during the neonatal age group or older.

Early onset neonatal sepsis (EONS): <72 hours of life.

Late onset neonatal sepsis (LONS) : >72 hours of life.

Note: Definitions of late onset sepsis occurring at more than 7 days have been described in epidemiologic studies and in the description of the clinical course of Group B Streptococcus.

Epidemiology

• The overall incidence of neonatal sepsis varies from 1 to 5 for every 10,000 live births.

• Globally neonatal sepsis accounts between 13 to 26% of total neonatal deaths, with variable estimates of disease burden between various income levels. For example, the incidence of neonatal sepsis in Asia ranges from 7.1 to 38 per 1000 live births in comparison to 6 to 9 cases per 1000 live births in the United States and Australasian countries. A high proportion of newborns in developing countries die at home post-delivery with neonatal sepsis carrying a high impact on the overall newborn mortality.

• Data from the Malaysian neonatal registry reported the incidence of sepsis as 16.1% of very low birth weight (VLBW) infants, where 9.8% was EONS and 90.2% was LONS. High mortality rates of up to 43.8% is observed in infants with GBS EONS. Up to 66.7% of VLBW infants with gram negative sepsis die.

2.0 RISK FACTORS

Risk factors for early onset sepsis:

Maternal GBS (Group B Streptococcus) carrier (high vaginal swab [HVS], rectal swab, urine culture, previous pregnancy of baby with GBS sepsis)

• Prolonged Rupture of Membranes (PROM) (> 18 hours)

• Preterm labour/ Preterm prelabour rupture of membranes (PPROM)

• Maternal pyrexia > 38˚C, maternal peripartum infection, clinical chorioamnionitis, discoloured or foul-smelling liquor, maternal urinary tract infection

• Traumatic delivery

• Birth asphyxia

• Low birth weight

• Confirmed sepsis in co-twin (multiple pregnancy)

• Infant with galactosaemia (increased susceptibility to E. coli)

Risk factors for late onset sepsis:

• Any indwelling intravascular access - central venous line, arterial line, umbilical catheter

• Low gestational age

• Low birth weight

• Mechanical ventilation

• Prolonged hospital stay

3.0 AETIOLOGY

Table 1: Aetiology of Neonatal Sepsis

4.0 ASSESSMENT AND EVALUATION

• • • Early recognition is essential as sepsis onset is often subtle, with extremely rapid progression. Approximately 1% of well-appearing healthy infants at birth may develop signs of infection occurring after a variable time period.

• • Peripartum risk factors places an infant to be at higher risk of sepsis, e.g. prolonged rupture of membranes of more than 18 hours places an infant to be at 10-fold higher risk of sepsis

  • Careful perinatal history, and clinical examination is essential.

  • Sepsis risk calculators e.g. Kaiser Permanante study group neonatal sepsis calculator, may be used to calculate probability of sepsis risk.

Figure 2: Clinical Features of Neonatal Sepsis

5.0 INVESTIGATIONS

(A) Evidence of Infection and Inflammation

• • 1. White blood cell count and differentials: There is poor positive predictive value in total white cell count as an indicator of neonatal sepsis. Low white blood cell count of <5000/mm³ is associated with the diagnosis of sepsis. Often, the trend of white cell count taken 8 to 12 hours apart is a better indicator. The neutrophils are responsible for digestion of bacteria. However, its chemotaxis may be immature with poor response, especially in preterm infants resulting in release of immature neutrophils. White blood cell parameters which may be used to guide diagnosis include a) Absolute neutrophil count (ANC) – neutropaenia (<1800/mm³ at birth and <7800/mm³ at 12 – 14 hours), has better specificity compared with elevated neutrophils. Neutropaenia indicate depletion of the neutrophil storage pool which places the infant to be at risk of dying of sepsis b) Immature to total neutrophil ratio (I/T ratio)

IT ratio = [ Metamyelocytes + Band neutrophils ] / Total neutrophils

IT Ratio > 0.20: Infection highly suspicious

IT Ratio > 0.8: High risk of death from sepsis

I/T ratio has the best sensitivity amongst the neutrophil indices with high negative predictive value of up to 99%. However, it has a low positive predictive value of 25%. It indicates the proportion of immature neutrophils (metamyelocytes and band neutrophils) which are released from the neutrophil storage pool which are too immature to effectively ward off infection.

Figure 3: Neutrophil levels of neonates born at > 36 weeks’ gestation during the first 72 hours at birth.

(Source : Schmutz, N., Henry, E., Jopling, J., & Christensen, R.D. (2008). Expected ranges for blood neutrophil concentrations of neonates: the Manroe and Mouzinho charts revisited. Journal of Perinatology, 28, 275-281.)

1. Platelet Count: Low platelet count is a common manifestation of neonatal sepsis. This is more commonly associated with gram positive organism sepsis. The phenomenon may still be observed with gram negative organisms. The mechanism is uncertain,but is said to be caused by bacterial endothelial damage leading to platelet adhesion and aggregation. It has also been shown to be caused by presence of circulating of immune complex in the septic neonate.

2. Blood culture and sensitivity: A positive culture growing from blood or sterile body fluid remains the criteria in diagnosing neonatal sepsis. Up to two-thirds of younger infants <2 months of age have colony forming units of <10 CFU>ml. Therefore, an optimal amount of blood of 1 ml should be drawn for purpose of culture or else cultures may remain negative. Cultures may also remain negative in view of prenatal antibiotics administration. It may be difficult to determine whether positive culture is a contaminant, especially if coagulase negative Staphylococcus (CONS) is grown. Term infants without any indwelling catheters are less likely to grow CONS.

3. Lumbar puncture: In bacteraemic infants, the incidence of associated meningitis is as high as 23%. Therefore, performing a lumbar puncture for cerebrospinal fluid (CSF) examination (gram stain, culture, cell count and biochemistry – protein and glucose concentration), may be necessary in an infant with a positive blood culture, abnormal laboratory data, or in infants with a clinical course that is strongly suggestive of sepsis. If there is already a strong suspicion of clinical infection or meningitis from the outset, a CSF sample is best obtained before commencement of antibiotics but should not result in undue delay in antibiotics initiation.

Table 2: Normal CSF Ranges in Neonates

Adapted from: Chess PR 2019, Avery’s Neonatology Board Review. Srinivasan et al., J Pediatr 2012. Rodriguez et.al., J Pediatr 1990. Royal Berkshire NHS Sepsis Guidelines 2018.

5. C-Reactive Protein (CRP): CRP is an acute phase reactant produced in the liver. Approximately 10 to 12 hours is required for CRP to change significantly after the onset of an infection with low sensitivity during early stages, and is therefore, a late indicator of sepsis. A sequential analysis is more useful in interpretation compared with a single reading. Bacterial sepsis is less likely in infants with persistently low CRP of <1 mg/dL and is therefore often used as a guide to discontinue antibiotics therapy. Caution in interpretation should be taken especially in preterm infants where the response may be less apparent or in infants with meconium aspiration, intraventricular haemorrhage or perinatal asphyxia where the CRP may be responsively raised.

6. Procalcitonin (PCT): Release of PCT by parenchymal cells is triggered by bacterial toxins and are therefore a useful marker in neonates. Although the response more rapid than CRP where its concentrations increases within 2-4 hours with peaks at 6- 8 hours post-exposure, like CRP, a sequential or serial reading is more useful. In very low birth weight infants, PCT value of >2.4 ng/mL indicates a high risk of neonatal sepsis. Like CRP, it can also be falsely elevated in non-infective conditions. If used in conjunction with CRP, a positive level increases the diagnostic value up to 92%.

(B) Evidence of Multiorgan System Disease

The following may be performed based on clinical suspicion of associated organ involvement.

1. Blood gas analysis and lactate: Should be performed to determine extent of condition. Metabolic acidosis with lactic acidaemia indicating progression to anaerobic metabolism.

2. Renal function, liver function tests: Impairment indicating possible involvement.

3. Haematologic indices and coagulation profile: Manifested as anaemia and thrombocytopaenia, as well as disseminated intravascular coagulopathy.

4. Chest X-ray and/or Abdominal X-ray: If accompanying respiratory or abdominal signs are seen.

5. Liver and renal ultrasound – in cases of persistent sepsis

6. Echocardiography - In cases of persistent sepsis

6.0 MANAGEMENT

Preventive strategies have been described earlier with emphasis on recognition of peripartum risk factors. Initiation of antibiotics must be prompt. Recognition of complications before progression to organ failure may be difficult, but important as progression may be rapid.

Aims of Management

1. Early recognition with timely initiation of treatment

   1. Supportive therapy a) Prevent development of septic shock b) Recognise and halt progression of complication (1)

(1) Early Recognition with Timely Initiation of Treatment

Initiation of antibiotics

• Consideration of early or late-onset presentation as well as exposures e.g. nosocomial infection determines the choice of antibiotics. See antibiotic guidance in section 7.0

• Avoid undue delay in antibiotics initiation and initial empiric therapy should be initiated with penicillin and aminoglycoside for EONS. However, in babies determined not to have sepsis, antibiotic exposure should be minimised.

• Third generation cephalosporin should only be reserved for suspected gram- negative meningitis. The emergence of cephalosporin resistant organisms (e.g. Enterobacter cloacae, Klebsiella, and Serratia sp) can occur when cefotaxime is routinely used.

• Blood culture results should be traced within 48 to 72 hours and antibiotics regimen adjusted based on susceptibility pattern. Therapy may be discontinued should the results return as negative with no other parameters to support the diagnosis of sepsis.

Adjunctive Treatment Strategies

• Exchange transfusion may be performed should sepsis be accompanied with late features such as sclerema neonatorum. Exchange transfusion has been associated with significantly less mortality of up to 50% in the exchange group compared to 95% infants without exchange transfusion amongst infants who have developed sclerema.

• IVIg augments antibody dependent cytotoxicity with improvement on neutrophilic function. However, sufficient evidence for its use in reducing death in neonatal sepsis remains unproven

(2) Supportive Therapy

• Sepsis with rapid progression of its associated complications is termed fulminant sepsis, which may lead to death within 48 hours of its onset.

• Infants who acquire nosocomial sepsis, of lower gestation (extremely low gestational age/ELGAN), and lower birth weight (extremely low birth weight/ELBW <1000grams) are at higher risk of fulminant sepsis.

• Complications associated with fulminant sepsis include:

  • Worsening respiratory status

  • Haemodynamic instability leading to septic shock

  • Cardiac dysfunction

  • Coagulopathy

  • Multiple organ dysfunction

General supportive therapy aims to prevent progression of fulminant sepsis by ensuring adequate ventilation and maintenance of cardiovascular function.

Strategies to prevent multiorgan dysfunction include:

• Maintenance of the thermoneutral environment: Maintenance of thermoneutral environment is required to prevent the sequelae of anaerobic metabolism which worsens lactate acidaemia. The septic neonate often develop temperature instability due to the infant’s inability to auto-regulate the body temperature. Therefore, close temperature monitoring and provision of adequate warmth which may be provided via servo/auto-control warmer should be initiated.

• Provision of adequate haemodynamic support: An infant who has been determined to have sepsis should have close monitoring of vital signs and blood pressure. Timely intervention with crystalloids is required with signs of intravascular volume depletion, such as poor perfusion, prolonged capillary refill time, poor pulse volume and increasing tachycardia. There is insufficient evidence to support aggressive and repeated volume expansion in the hypotensive preterm neonate due to its possible association with intraventricular haemorrhage. Therefore, after an initiation of fluid bolus, unless there is evidence of acute volume loss, the neonate who remain hypotensive may be supported with inotropic support.

• Provision of adequate respiratory support: Septic infants often will have accompanying pneumonia and/or recurrent apnoea with poor respiratory effort. Ensure timely and adequate provision of respiratory supportive therapy and oxygenation e.g. intubate the infant with repeated apnoeic episodes.

• Glucose monitoring: Glucose is an essential brain fuel and the increasing metabolic demands can result in hypoglycaemia in the septic neonate. Conversely, the resultant increase in production of stress hormones such as adrenaline, cortisol and glucagons result in hyperglycaemia.

• Monitoring of urine output: Strict charting of the infant’s input and output is required to monitor for evidence of renal impairment. Fluids should be adjusted accordingly based on the infant’s haemodynamic and renal status.

7.0 ANTIBIOTICS GUIDANCE

The following tables cover the major indications, duration and dosages of common antibiotics used in the neonatal intensive care unit. The list is not exhaustive, and management strategies for other specific infections need to be discussed with the specialist in-charge.

The Four Moments/Principles of Antibiotics Decision and Administration

1. Identify source of infection

2. Ensure blood cultures and cultures from appropriate anatomical site performed and commence empiric therapy

3. Reassess at 48-72 hr:

a) Stop: if no evidence of infection

b) Targeted therapy: based on culture results

c) Narrow spectrum: based on clinical response (based on site of infection and if culture results negative (or no culture taken)

4. Duration of antibiotics based on the site of infection and types of microorganism isolated

Escalation of therapy: consider escalation of therapy if persistent or worsening signs of infection or deranged sepsis parameters after 48 -72 hours of adequate antibiotic therapy and source control.

7.1 Major Indications for the Use of Antibiotics in the NICU

Vancomycin

Loading dose: Birth weight < 1 kg - 15 mg

Birth weight > 1 kg - 15 mg/kg

Lo YL, van Hasselt JGC, Heng SC, Lim CT, Lee TC, Charles BG. Population Pharmacokinetics of Vancomycin in Premature Malaysian Neonates: Identification of Predictors for Dosing Determination. Antimicrob.Agents Chemother.2010;54:2626-2632.

* Blood for therapeutic drug monitoring must be performed if gentamycin, amikacin and vancomycin are chosen as the therapeutic agent of choice. Closer monitoring may especially be required in infants with hypoxia/ encephalopathy and those undergoing therapeutic hypothermia.

The dosage may be changed in accordance to the drug’s peak and trough blood levels.

REFERENCES

1. Shane AL, Sanchez PJ, Stoll BJ. (2017). Neonatal Sepsis. The Lancet. Oct 14;390(10104):1770-1780. doi: 10.1016/S0140-6736(17)31002-4.

2. Wynn JL, Wong HR, Shanley TP, Bizzarro MJ, Saiman L, Polin RA.(2014). Time for a neonatal-specific consensus definition for sepsis. Pediatr Crit Care Med; 15: 523–28

3. Wynn JL, Wong HR. Pathophysiology and Treatment of Septic Shock in Neonates. (2010). Clin Perinatol; June ; 37(2): 439–479. doi:10.1016/j.clp.2010.04.002

4. Boo NY, Cheah IGS. (2016) Factors Associated with Inter-Institutional Variations In Sepsis Rates Of Very-Low-Birth-Weight Infants In 34 Malaysian Neonatal Intensive Care Units. Singapore Med J; 57(3): 144-152. doi: 10.11622/smedj.2016056

5. Camacho-Gonzalez, A., Spearman, P. W., & Stoll, B. J. (2013). Neonatal Infectious Diseases. Evaluation of Neonatal Sepsis. Pediatric Clinics of North America, 60(2), 367–389. doi:10.1016/j.pcl.2012.12.003

6. Lo YL, van Hassen JGC, Heng SC, Lim CT, Lee TC, Charles BG. Population Pharmacokinetics of Vancomycin in Premature Malaysian Neonates: Identification of Predictors for Dosing Determination. Antimicrob. Agents Chemother. 2010; 54:2626-2632.

7. Hsu AJ, Tamma PD. Antibiotics Guidelines – Treatment Recommendations for Hospitalised Children. Johns Hopkins Medicine.

8. Neomed Consensus Group. Australasian Neonatal Medicines Formulary. https://slhd.nsw.gov.au/rpa/neonatal/NeoMedPapeCopy.html. Accessed in May 2020.

9. Edwards MS. (2019). Management and Outcomes of Sepsis in Term and Late Preterm Infants. UptoDate. https://www.uptodate.com/contents/management-and-outcome-of-sepsis-in-term-and-late-preterm-infants/print. Accessed in Jan 2019.