UNIVERSITY OF MALAYA MEDICAL CENTRE

NEONATAL INTENSIVE CARE UNIT NEONATAL SEPSIS MANAGEMENT AND ANTIBIOTICS GUIDANCE

 

 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 

Early-onset Pathogens	Late-onset Pathogens
Group B Streptococcus (Streptococcus agalactiae) Escherichia coli Klebsiella sp Staphylococcus aureus Coagulase-negative Staphylococcus (CONS) Listeria monocytogenes Enterococci Other Streptococci: Streptococcus pyogenes, Streptococcus viridans, Streptococcus pneumoniae Other gram-negative bacteria:  Haemophilus spp	Coagulase-negative Staphylococcus (CONS) Group B Streptococcus (Streptococcus agalactiae) Escherichia coli Klebsiella sp. Staphylococcus aureus Candida albicans Enterococci Pseudomonas aeroginosa Acinetobacter sp Others : Enterobacter, Citrobacter, Serratia Other Candida species (Non-albicans Candida) e.g. C glabrata, C parapsilosus, C kruseo, C tropicalis Aspergillus fumigatus, Aspergillus spp

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
2. 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

 

Indications	Preferred	Alternative	Comments
Early onset sepsis Commonest organisms: Group B Streptococcus  Gram negative rods (E. coli, Klebsiella sp.) Less common:  Staphylococci Streptococci  Enterococci                     Haemophilus influenza            Listeria monocytogenes	C-Penicillin AND Gentamicin*	C-Penicillin   AND Cefotaxime	Targeting infecting organism acquired antenatally or intrapartum (The commonest organisms are from the vaginal flora). Ampicillin is preferred choice and to replace Penicillin if Listeria infections suspected. Cefotaxime should be used judiciously in the neonatal unit. It is associated with increased rates of colonization with strains resistant to the empirical therapy, with higher rates of Extended Spectrum Beta Lactamase (ESBL) infections, invasive candidiasis and death. However, it should be considered in infants with meningitis.
Late onset sepsis ·     Coagulase negative Staphylococci,        Staphylococcus aureus ·     Gram negative rods (Pseudomonas aeruginosa) ·     Enterococci ·     Candida spp.	C-Penicillin OR Cloxacillin   AND   Gentamicin* OR Amikacin*	C-Penicillin OR Cloxacillin   AND   Cefotaxime	Cloxacillin may be indicated if there are risk factors for sepsis from skin organisms, e.g. multiple venepuncture or other invasive procedures. Reserve cephalosporin ONLY for treatment of meningitis. Consider adding cefotaxime if meningitis is suspected.      Cefotaxime should be used judiciously in the neonatal unit. It is associated with increased rates of colonization with strains resistant to the empirical therapy, with higher rates of Extended Spectrum Beta Lactamase (ESBL) infections, invasive candidiasis and death.   Ceftriaxone should be avoided in neonate because it displaces bilirubin from albumin binding sites, resulting in a higher free bilirubin with subsequent blood brain barrier penetration.
Hospital acquired/ nosocomial sepsis	Vancomycin* AND           Cefepime	Escalation of therapy:  Vancomycin AND   Piperacillin-Tazobactam OR Meropenem	Targeting nosocomial infections and translocation of organisms across the immature gut wall.  Associated with indwelling lines, catheters and ET tubes.   Piperacillin-Tazobactam is a reasonable second line option in pneumonia & intraabdominal sepsis (non-CONS sepsis with good coverage against Gram positive, Gram negative & anaerobes) with good sensitivity for Klebsiella, E.coli and moderate sensitivity for Acinetobacter from UMMC antibiogram.     Cefepime is the preferred agent when there are Gram negative bacterial with extended spectrum cephalosporin resistance due to AmpC-β-lactamases (Antibiogram shows reduced sensitivity for Cefotaxime to Acinetobacter baumanii and Escherichia coli).   Targeted therapy for Acinebacter baumanni is Ampicillin-Sulbactam
Meningitis	C-Penicillin AND      Cefotaxime	Hospital Acquired: Vancomycin* AND Meropenem	Consider Vancomycin and Meropenem in hospital acquired sepsis with meningitis.
Ventilator-associated/ Nosocomial pneumonia	Target the recent tracheal secretion or throat swab culture result, if negative, target the most prevalent organisms in the unit. If there is no specific pattern of colonization or infection, follow the regime for hospital acquired infection.
Catheter related blood stream and local skin and soft tissue infections	Vancomycin*		Vancomycin is preferred for catheter related blood stream infection, but to descalate therapy if culture is Methicillin Sensitive Staphylococcus Aureus (MSSA).
Necrotising enterocolitis and other intra-abdominal sepsis Klebsiella spp.                   Escherichia coli Clostridia spp. Coagulase negative Staphylococci Enterococci Bacteroides	First 7 days of life:  Ampicillin        AND             Gentamicin*             AND  Metronidazole > 7 days of life: Cefepime AND  Metronidazole  WITH/WITHOUT Vancomycin*	Escalation of therapy  *Meropenem or Piperacillin-Tazobactam WITH or WITHOUT Vancomycin*	Use Vancomycin instead of ampicillin for suspected MRSA and ampicillin-resistant enterococcal infection.     *Meropenem has the propensity to select out multi-drug response organisms. To be used if persistent signs of infection or deranged sepsis parameters after 48 -72 hours of adequate antibiotic therapy and source control.     Consider adding antifungal if patient continue to deteriorate despite on appropriate antibiotic or second line therapy.
Fungal sepsis	Fluconazole	Escalation of therapy Lipid complex amphotericin B	In infants with persistent signs, deranged sepsis parameters, and without improvement in clinical symptoms despite on adequate antibiotic coverage and source control, fungal sepsis should be considered.   Risk factors for fungal sepsis including use of TPN, gut perforation/ abdominal surgical intervention, mechanical ventilation and prolonged use of broad spectrum antibiotics.

7.2 General Guidance on the Recommended Duration of Antibiotic Treatment

Types of Infection	Days
Suspected sepsis	If negative blood culture, initial clinical suspicion not strong, reassuring clinical condition & low CRP, consider stopping antibiotics at 48 hours   If negative blood culture, very strong clinical suspicion of sepsis or elevated CRP, consider 5 days of antibiotics
Gram Positive Bacteraemia     Gram Negative Bacteraeemia       Fungaemia	Repeat blood culture at 48 to 72 hours of antibiotic. At least 7 days of antibiotics as guided by microorganism, clinical response, CRP and repeated blood culture.   Repeat blood culture at 48 to 72 hours of antibiotic. At least 7-10 days of antibiotics as guided by microorganism, clinical response, CRP and repeated blood culture.   Repeat blood culture every 72 hours of antifungal therapy. Screening for invasive fungal infection including opthalmological examination and ultrasound abdomen. At least 3 weeks of antifungal from the time of negative blood culture.
Meningitis Gram positive meningitis Gram negative meningitis Listeria meningitis	Repeat CSF biochemistry and culture at 48 hours of antibiotics. 14 days                                                                                                              21 days                                                                                                           21 days
Pneumonia	5 – 10 days depending on screening and extent of infection.
Catheter related blood stream infections	As in bacteraemia. At least 7 to 10 days of antibiotics as guided by microorganism, clinical response, CRP and repeated blood culture. Remove catheter (source control) if persistent bacteraemia.
Joint infection (Septic arthritis/ osteomyelitis)	4 – 6 weeks
Other specific infections such as urinary tract, skin and eye infections	5 – 10 days

 

7.3 Recommended Dosages for Common Antibiotics Prescribed in Neonates

 

Drug Name	Postmenstrual Age	Postnatal Day	Dose
C-Penicillin			100,000 units/kg/dose IV q12h
Ampicillin	< 30 weeks     30 – 36 weeks     37 – 44 weeks     ≥ 45 weeks	0 – 28 days > 28 days                                                                     0 – 14 days > 14 days   0 to 7 days > 7 days   All	50mg/kg/dose IV  q12h 50mg/kg/dose IV  q8h   50mg/kg/dose IV  q12h 50mg/kg/dose IV  q8h   50mg/kg/dose IV  q12h 50mg/kg/dose IV  q8h   50mg/kg/dose IV  q6h
Gentamicin*	< 30 weeks 30 – 35 weeks > 35 weeks		2.5 mg/kg/dose IV q24h 3.5 mg/kg/dose IV q24h 4mg/kg/dose IV q24h
Amikacin*	< 30 weeks 30 – 35 weeks > 35 weeks		7.5 mg/kg/dose IV q24h 10 mg/kg/dose IV q24h 15 mg/kg/dose IV q24h
Cefotaxime	< 30 weeks     30 – 36 weeks     37 – 44 weeks     ≥ 45 weeks	0 – 28 days > 28 days   0 – 14 days > 14 days   0 to 7 days > 7 days   All	50mg/kg/dose IV  q12h 50mg/kg/dose IV  q8h   50mg/kg/dose IV  q12h 50mg/kg/dose IV  q8h   50mg/kg/dose IV  q12h 50mg/kg/dose IV  q8h   50mg/kg/dose IV  q6h
Metronidazole	Loading dose   Maintenance dose < 27 weeks   27 – 33 weeks     34 – 40 weeks     ≥ 41 weeks	0 – 26 days                   0 – 14 days                               0 to 7 days   All	15mg/kg/dose IV x 1     7.5mg/kg/dose IV q24h   7.5mg/kg/dose IV q12h   7.5mg/kg/dose q8h   7.5mg/kg/dose IV q6h
Piperacillin + Tazobactam	< 30 weeks     30 – 36 weeks     37 – 44 weeks     ≥ 45 weeks	0 – 28 days                 > 28 days   0 – 14 days > 14 days                                 0 to 7 days > 7 days   All	100mg/kg/dose IV q12h 100mg/kg/dose IV q8h   100mg/kg/dose IV q12h 100mg/kg/dose IV q8h   100mg/kg/dose IV q12h 100mg/kg/dose IV q8h   100mg/kg/dose IV q8h
Cefepime		0 – 28 days                 > 28 days	30mg/kg/dose IV q12h 50mg/kg/dose IV q12h   (Meningitis and severe infection due to Pseudomonas aeruginosa / Enterobacter spp): 50mg/kg/dose IV q12h
Meropenem	< 32 weeks     ≥ 32 weeks	< 14 days ≥ 14 days   < 14 days ≥ 14 days	20-40 mg/kg/dose q12h 20-40 mg/kg/dose q8h   20-40 mg/kg/dose q8h 30-40 mg/kg/dose q8h

 

Vancomycin

Loading dose: Birth weight < 1 kg - 15 mg                       

Birth weight > 1 kg - 15 mg/kg

 

Post Menstrual Age (weeks)	Appropriate For Gestational Age	Small For Gestational Age < 10th Centile
< 26	12.5 mg/kg daily	10 mg/kg daily
26 to < 27	15 mg/kg daily	12.5 mg/kg daily
27 to < 28	15 mg/kg daily	12.5 mg/kg daily
28 to < 29	10 mg/kg 12 hourly	15 mg/kg daily
29 to < 30	10 mg/kg 12 hourly	15 mg/kg daily
30 to < 31	12.5 mg/kg 12 hourly	10 mg/kg 12 hourly
31 to < 32	12.5 mg/kg 12 hourly	10 mg/kg 12 hourly
32 to < 33	15 mg/kg 12 hourly	10 mg/kg 12 hourly
33 to < 34	15 mg/kg 12 hourly	12.5 mg/kg 12 hourly
34 to <37	Loading dose 20 mg/kg then 20 mg/kg 12 hourly	15 mg/kg 12 hourly

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

 

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