Andres Camacho-Gonzalez,

Paul W Spearman, Barbara J Stoll

Pediatr Clin N Am 60 (2013) 367-389

Neonatal sepsis-most feared & serious complication among VLBW infants.

Divided into Early onset sepsis (EOS) & Late onset sepsis (LOS).

EOS-onset in the first week of life – infections occuring in the first 72 hrs , caused by maternal intra partum transmission of invasive organisms.

SOURCE RISK FACTORS

EARLY ONSET NEONATAL SEPSIS Maternal Group B Streptococcal colonization

Chorioamnionitis

Premature rupture of membranes

Prolonged rupture of membranes (>18 hr)

Maternal urinary tract infection

Multiple pregnancies

Preterm delivery

SOURCE RISK FACTOR

LATE ONSET NEONATAL SEPSIS Breakage of natural barriers (skin, mucosa)

Prolonged catheter use

Invasive procedures (endotrachealintubation)

Necrotizing enterocolitis

Prolonged antibiotic use

H2 receptor blocker use or PPI use

NEONATAL Prematurity

Decreased passage of maternal immunoglobulin & antibodies.

Immature function of immune system

LOS-infections occuring after 1week & attributed to pathogens acquired postnatally.

United states-intra partum antibiotic prophylaxis (IAP) to reduce vertical transmission of Group B Streptococcus (GBS) infections in high risk women –decline in EOS GBS infection.

NICHD & NRN study, incidence of EOS -0.98 cases per 1000 live births.

Studies have shown increase in EOS by E.coliamong VLBW preterm infants.

E.coli-severe infections & meningitis –leading cause of sepsis related mortality among VLBW infants-24.5 %

GBS & E.coli-70 % of EOS in neotal period.

LOS- common in preterm VLBW infants. NICHD & NRN -21% VLBW infants <1500 g

developed blood culture confirmed LOS with rates inversely related to geststional age (GA).

58 %-22 wks GA , 20 %-28 wks GA

VLBW preterm infants –risk for LOS –prolonged hospitalization, catheters, endotracheal tubes & other invasive procedures.

Several studies LOS rates-1.87-5.42 % with decreasing rates as birth weight increases.

Coagulase negative Staphylococci (CoNS) -emerged as commonly isolated pathogen –VLBW infants with LOS.

Development of immune system –changes that occur in first year of life.

Preterm infants-relatively immunocompromised –immaturity of immune system & decreased passage of maternal antibodies.

INNATE IMMUNE SYSTEM

Immediate immunological response without prior exposure to specific pathogen.

Neonatal cells-decreased ability to produce inflammatory cytokines & proinflammatory responses that activate adaptive immune system.

Reduction in cytokine –decreased activation of natural killer cells.

Increased susceptibility to bacterial & viral infections.

ADAPTIVE IMMUNE SYSTEM

Designed to eliminate specific pathogens.

Decreased cytotoxic function, immaturity, decreased memory –increases risk of infections .

Transplacental passage of maternal IgG-inversely related to gestational age.

Term infants protected against most vacccinepreventable neonatal infections

Preterm –lack adequate humoral protection.

Preterm –IgA, IgG, cytokines,& anti bacterial peptides in human milk compromised.

Lack of IgA decrease neonate ability to respond to pathogens.

COMPLEMENT Complement levels increase with increasing

gestational age. Reduced complement levels-associated with

deficient opsonization & impaired bacterial killing.

EARLY ONSET SEPSIS

Group B Streptococcus

Escherichia coli

Listeria monocytogenes

Streptococcus pyogenes, streptococcus viridans, streptococcus pneumoniae

Enterococci

Haemophilus influenza.

LATE ONSET SEPSIS

Coagulase negative Staphylococcus

Staphylococcus aureus

Enterococci

Gram negative rods-(E.coli, Klebsiella, Pseudomonas, Enterobacter)

Candida

GROUP B STREPTOCOCCUS (GBS)

Most common organism assoc. with EOS

Gram positive encapsulated bacteria-10 serotypes.

Serotype 3 –most common 54 %

Colonize gastrointestinal & genital tracts.

Infants –signs of respiratory distress & cardiovascular instability, meningitis.

ESCHERICHIA COLI

Gram negative rod –colonizes maternal urogenital & GI tract.

Second most common cause of neonatal sepsis in term & most common in VLBW neonates.

Neonatal sepsis, meningitis, thrombocytopenia & death in first days of life.

LISTERIA MONOCYTOGENES

Facultative anaerobic, gram positive bacteria Pregnant women 17 % higher risk –

spontaneous abortion & stillbirth. Respiratory distress, sepsis, meningitis. Granulomatous rash-granulomatosis

infantisepticum. Serotypes 1,2,4 Higher risk in mothers-consumed raw milk or

unpasteurized milk products.

EOS-OTHER BACTERIAL AGENTS

Streptococci (Streptococcus pyogenes, viridans, S.pneumoniae)

Enterococci Staphylococci H.influenza

Group A Streptococcus (S.pyogenes)-pneumonia & empyema (42 %), toxic shock syndrome (17 %)

CoNS & STAPHYLOCOCCUS AUREUS

CoNS:22 %-55 % LOS infections –VLBW infants

S.aureus-4 %-8 %

Colonizes human skin & mucous membranes.

Formation of biofilms-protect bacteria from antibiotic penetration & helps to evade immune system.

MRSA : 28% staphylococcal infections in preterm neonates.

GRAM NEGATIVE ORGANISMS

E.coli, Klebsiella, Pseudomonas, Enterobacter,Citrobacter, Serratia.

49 %-69 % of deaths Transmission-hands of health care workers,

colonization of GI tract, contamination of TPN, bladder catheterization.

Pseudomonas-highest mortality Citrobacter-brain abscess.

CANDIDA INFECTIONS

3rd leading cause of LOS in premature infants.

Risk factors-low birth weight, broad spectrum antibiotics, male gender, lack of enteral feedings.

Candida albicans, Candida parapsilosis

Higher mortality rates & neuro developmental delay.

SEPSIS / MENINGITIS Temperature instability

Respiratory distress

Apnea

Jaundice & feeding intolerance

Bulging fontanel

Seizures

Skin lesions-staphylococci, listeria, candida

Blood culture-gold standard for diagnosis of neonatal sepsis.

Rate of positivity low-intra partum administration of antibiotics & limitations of blood volume per culture obtained in neonates.

Blood, C.S.F, urine culture (after 3rd day)

CXR-respiratory symptoms.

Disseminated herpes-surface cultures from conjunctiva, mouth, skin & anus.

Maternal & exposure history , complete physical examination, skin & catheter insertion sites.

COMPLETE BLOOD COUNT

WBC count does not accurately predict infection in neonates.

Multicentre study of blood culture & CBC in neonates of 293 NICU-low WBC & absolute neutrophil count & high immature to total neutrophil ratio –assoc. with increasing infection.

CRP

Seriel measurement of CRP in first 24-48 hrs

Normal CRP-99 % negative predictive value.

PROM, maternal fever, PIH, prenatal steroid use, fetal distress-cause elevation of CRP.

Gestational age influences CRP kinetics-preterm neonates –lower & shorter response.

PROCALCITONIN (PCT)

Tissue release of Procalcitonin increases with infection.

Useful for detection of EOS.

Auriti & colleagues in a multicentre study of 762 neonates –increase in PCT level in neonates with sepsis.

Further studies needed to clarify use of PCT

MANNOSE BINDING LECTIN (MBL)

Plasma protein produced by liver –important role in immune defense.

MBL-activates complement system pathway –increases opsonozation & enhance phagocytosis.

Lower level of MBL-sepsis.

Needs further study

CYTOKINE PROFILE

IL-6, IL-8, IL-10, TNF-alpha.

IL-6, IL-8 increase very rapidly with bacterial invasion-but normalise within first 24 hrs.

Ratio of IL-10 & TNF-alpha –diagnosis of LOS in VLBW neonates.

NEUTROPHIL CD64 & NEUTROPHIL/ MONOCYTE CD11 B

Cell surface antigens –production increases after activation of leukocytes by bacteria.

Cost & processing time –barriers for the use.

MOLECULAR TECHNIQUES FOR EARLY DETECTION OF NEONATAL SEPSIS

Real time PCR

Meta analysis study done by Pammi –Blood culture studies found to be superior.

HSV PCR-gold standard for HSV encephalitis.

GENOMICS & PROTEOMICS

Genomics targets genes that are upregulatedwith infection.

Proteomics analyzes structure, function & interactions of proteins produced by particular gene.

Identification of sepsis & necrotizing enterocolitis.

Further studies needed.

PREVENTION

Maternal prenatal care-prevention of EO GBS sepsis.

Universal GBS screening for all pregnant women-35-37 weeks gestation.

Early recognition of chorio amnionitis & antimicrobial therapy for mother.

Intrapartum prophylaxis with penicillin, ampicillin, cefazolin 4hrs before delivery.

ANTIBIOTIC DOSE

PENICILLIN G 5 Million units iv as initial dose followed by 2.5 million units every 4 hrs until delivery.

AMPICILLIN 2 g iv as initial dose followed by 1 gm iv every 4 hrs until delivery

CEFAZOLIN 2 gm iv as initial dose followed by 1 gm iv every 8 hrs until delivery

Reduce hospital acquired late onset infections

Hand washing, infection control

Proper placement & management of central catheters.

Alcohol based products for hand hygiene.

PREVENTION STRATEGY NOTES

• INTRAVENOUS IMMUNOGLOBULIN No proven efficacy for prevention of neonatal sepsis

• ANTI STAPHYLOCOCCAL MONOCLONAL ANTIBODIES

Monoclonal antibodies against capsular polysaccharide antigen & clumping factor A –no effect in prevention of sepsis. Anti lipoteichoic acid antibodies (Pagibaximab)-have an effect.

• GRANULOCYTE MACROPHAGE COLONY STIMULATING FACTOR (GM-CSF)

No proven efficacy of neonatal sepsis

• GLUTAMINE No proven efficacy of neonatal sepsis

• PROBIOTICS No proven efficacy of neonatal sepsis. Useful as prevention of Necrotizing enterocolitis.

PREVENTION STRATEGY NOTES

• LACTOFERIN Glycoprotein in human milk.Immuno regulatory properties-increases cytokine prod. in gut & assoc. lymphoid tissue.Small studies show reduction of both fungal & bacterial infections.Large studies needed.

• FLUCONAZOLE Efficacious in prevention of candida species in VLBW infants.No neuro developmental outcomes.Fluconazole resistant strains.

Indiscriminate antibiotic use-multidrug resistant organisms-disseminated candida, necrotizing enterocolitis, vancomycin resistant enterococcus, beta lactamase producing organisms (E.coli, klebsiella, enterobacter )

Ampicillin & Gentamicin –empiric Rx. for suspected early onset neonatal sepsis.

Ampicillin resistant E.coli-3rd gen. cephalosporin.

LOS-Vancomycin –VLBW infants at risk for CoNS

Amphotericin & Fluconazole-antifungal drug of choice in neonatal candidiasis.

Newer antifungals-Echinocandins (MicafunginCaspofungin, Anidulafungin )

Micafungin-most studied drug-higher doses for CNS penetration.

• Empiric initiation of antibiotics Use when bacterial infections are likely & discontinue when they have not been identified.

• Switch antibiotics based on susceptibility

Change antibiotic agents to those with narrowest spectrum.

• Define duration of antibiotic therapy

Establish final duration of antibiotic based on disease process.

CLINICAL PRESENTATION DURATION OF ANTIBIOTIC THERAPY

Early onset sepsis without meningitis 10 days

Late onset sepsis without meningitis 10-14 days

Meningitis-Early onset or Late onset sepsis

14-21 days

Gram negative rod Meningitis 21 days

Neonatal sepsis-continues to be significant cause of mortality & morbidity in term & preterm infants.

Intrapartum antibiotic prophylaxis –decrease in GBS neonatal sepsis.

GBS & E.coli-common causes of EOS. CONS-common cause of LOS in VLBW neonates.

Seriel CRP & immature : total neutrophil count provide best negative predictive value for neonatal sepsis.

Newer biomarkers-Real time PCR –early detection of neonatal sepsis-further study needed.

Fluconazole prophylaxis in VLBW neonates-repeated efficacy in multiple trial studies.

Antistaphylococcal monoclonal antibodies & lactoferrin-early promise to prevent neonatal sepsis-needs larger studies.