1.    Introduction

2.    Definitions

3.    Epidemiology

4.    Microbiology

5.    Risk Factors

6.    Clinical Presentation

7.    Evaluation

8.    Management

9.    Questions and Controversies

2. definitions



Neonatal Sepsis - Clinical syndrome in an infant 28 days of life or younger manifested by systemic signs of infection and isolation of a bacterial pathogen from the blood stream  

• Early-onset
• Before 7 days of life
• Birth hospitalization
• Vertical transmission
• Ascending infection from maternal GI/GU tract bacteria
• Bacteremia or sepsis

3. epidemiology



Overall world incidence of early-onset sepsis is 1 to 5/1000 live births (WHO)

• Incidence has decreased due to a reduction in GBS sepsis, due to the use of intrapartum antibiotic prophylaxis (IAP)
• Late-onset sepsis has remained stable (CDC

4. microbiology

• GBS and E.coli are the most common causes: 2/3 of early-onset
• Listeria monocytogenes: rare
• Staphylococcus aureus: emerging pathogen, skin involvement
• Enterococcus: preterm infants

Impact of GBS Intrapartum Antibiotic Prophylaxis

• Center for Disease Control and Prevention’s Active Bacterial Core Surveillance Report, 2015
• Early-onset GBS infection rate in the US declined by 80%-from 0.6/1000 live births in 2000 to 0.25/1000 live births in 2013
• Late-onset GBS infection rates remained stable at 0.29/1000 live births

5. rsk factors

• There have been successful attempts to devise a sepsis risk calculator based on a multivariate model nested case control study

Risk factors

• Prompt initiation of antibiotic therapy is essential to prevent both maternal and fetal complications in the setting of clinical chorioamnionitis
• Risk factors for early-onset neonatal infection: Parenteral antibiotic treatment given to the woman for confirmed or suspected invasive bacterial infection at any time during labour, or in the 24-hour periods before and after the birth. 
• AAP Management of Neonates With Suspected or Proven Early-Onset Bacterial Sepsis

6. Clinical presentation



Wide range from subtle to shock. 

Can occur in infants with an initially reassuring status.

Temperature instability and respiratory distress are the most common.

Term newborns without risk factors with symptoms that improve over the first 6 hours usually do not have sepsis

7. evaluation

• Blood culture – Gold Standard
• Sepsis screen
• Radiology
• Lumbar Puncture
• Urine R/M, Culture
• RBS, Arterial blood gases, PT/Aptt
• Advanced Diagnostic Methods

Bloodculture

•  Gold standard
• A positive blood culture with sensitivity of the isolated organism is the best guide to antimicrobial therapy
• Cultures should be collected only from a fresh venepuncture site

Sepsis-screen


Consists of 5 items:

• C-reactive protein (CRP)
• Total leukocyte count
• Absolute neutrophil count (ANC)
• Immature to total neutrophil ratio (ITR)
• Micro-erythrocyte sedimentation rate (μ-ESR)i

CRP

• Nonspecific marker of inflammation and tissue necrosis
• Normal concentrations in neonates – variable
• Detectable increased CRP value-within 6 to 18 hours
• Peak CRP - 8 to 60 hours after onset
• Half-life is 5 to 7hours.
• Decreases promptly in the presence of appropriate therapy

Limitations

• Infants with on set of infection in the first 12 hours of life and with GBS infection may not have an elevated CRP
• Noninfectious processes, including meconium aspiration pneumonitis, asphyxia can have an elevated  CRP up to 10 times the normal concentration
• CRP has alow positive predictive value and should not  be used alone to diagnose sepsis

IT Ratio

• Immature neutrophils (band forms, metamyelocytes,     myelocytes)
• Mature + immature neutrophils early predictor of sepsis
• N value=  0.16 in first 24 hours, decreasing to 0.12 by 60  hours
• Upper limit >0.2
• Limitation-many noninfectious processes, including prolonged induction with oxytocin, stressful labor, and  even prolonged crying, are associated with Iincreased I:T  ratios

Micro-ESR



Positive Value (mm in first hour)- 3+ age in days (in the first week)

Limitations:

• increased in noninfectious (anemia, hyperglobulinemia)
• superficial infections and noninfectious processes, including asphyxia, aspiration pneumonia, and respiratory distress syndrome
• Values vary inversely with the haematocrit

Presence of two abnormal parameters in a screen is associated with sensitivity of 93-100%, specificity of 83%, positive and negative predictive values of 27% and 100% respectively in detecting sepsis


Advanced Diagnostic Methods



Cytokine measurement – IL-6, IL-8, IL-10, IL-1b, G-CSF, TNF- alfa

• IgM
• Polymerase chain reaction (PCR)
• DNA micro array technology

Role of procalcitonine

• PCT becomes detectable within 2 to 4 hours after a triggering event and peaks by 12 to 24hours.
• PCT secretion parallels -closely the severity of the inflammatory insult, with higher levels associated with more severe disease and declining levels with resolution of illness
• In the absence of an ongoing stimulus, ProCT is eliminated with a half-life of 24 to 35 hours, making it suitable for serial monitoring.

ProCT level of
  >2.0 ng/mL --- predicts sepsis and
  >10 ng/mL --- septic shock
  >20 ng/mL --- guarded prognosis
  higher the PCT level --- worse the prognosis.
When sepsis has been successfully treated, PCT levels should fall with a half-life of 24 to 35 hours.

Polymerase Chain Reaction (PCR)



Under investigation for bacterial and fungal infection 

• amplification of 16S rRNA a gene universally present in bacteria but absent in humans

Sensitivity                                      96%                                                          

Specificity                                      99,4%               



Positive predictive value                88,9%  

Negative predictive value              99,8%

Diagnosis

• Diagnosis of neonatal sepsis - established only by a positive blood culture
• Ongoing research - validated risk stratification strategies - predictive ability to detect neonatal sepsis

Diagnosis

• Culture-proven sepsis – Blood culture- diagnostic of sepsis when a bacterial pathogen is isolated
• Probable sepsis — Clinical course (e.g.-ongoing temperature instability; ongoing respiratory, cardiocirculatory, or neurologic symptoms not explained by other conditions; or ongoing laboratory abnormalities suggestive of sepsis [cerebrospinal fluid (CSF) pleocytosis, elevated ratio of immature to total neutrophil counts, or elevated C-reactive protein])

Diagnosis

• Infection unlikely — Infants with mild and/or transient symptoms (ie. fever alone or other symptoms that quickly resolve) who remain well-appearing with normal laboratory values and negative cultures at 48 hours are unlikely to have sepsis.
• Empiric antibiotic therapy should be discontinued after 48 hours in these neonates

8. management

• Aggressive supportive care
• Antimicrobial therapy
• Adjuvant therapies

Supportive care



1.Thermo-neutral environment- prevention of hypo or hyperthermia

2.Maintenance of normoglycemic status

3.Maintenance of Oxygen saturation (91 to 94%)

4.Maintenance of tissue perfusion and blood pressure using colloids and inotropes

5.Maintenance of adequate nutrition by enteral feeding if not feasible by parenteral nutrition

6.Blood products to normalize the coagulation abnormalities, correction of anemia and thrombocytopenia


Antimicrobial Therapy

• Choice of antimicrobial drug- based on predominant pathogen and antibiotic sensitivity pattern.

Indications for Starting Antibiotics:

• presence of >3 risk factors for early onset sepsis
• presence of foul smelling amniotic liquor
• presence of 2 antenatal risk factor and 
• a positive septic screen and strong clinical suspicion of sepsis

Antimicrobial Therapy


Choice of antimicrobial drug- based on predominant pathogen and antibiotic sensitivity pattern.

Indications for Starting Antibiotics:

presence of >3 risk factors for early onset sepsis

presence of foul smelling amniotic liquor

presence of 2 antenatal risk factor and 

a positive septic screen and strong clinical suspicion of sepsis


Duration of Antibiotic Therapy



1.Clinical sepsis (Based on clinical suspicion and/or sepsis screen positivity): 7-10 days

2.Culture positive sepsis (not meningitis), UTI -14 days

3.Meningitis-2 weeks after sterilization of CSF culture or for a minimum of 2 weeks for gram positive meningitis and 3 weeks for gram negative meningitis, whichever is longer

4.Bone and joint infection 4-6 weeks


Evidence for intrapartum antibiotics in GBS colonization



The incidence of early GBS infection was reduced with IAP 

compared to no treatment (risk ratio (RR) 0.17, 95% 

confidence interval (CI) 0.04 to 0.74, three trials, 488 infants; risk difference -0.04, 95% CI -0.07 to -0.01; number needed to treat to benefit 25, 95% CI. 

Evidence for intrapartum antibiotics in pprom


Erythromycin in pPROM – reduction in childhood disability prolongation of pregnancy, reductions in neonatal treatment with surfactant, decreases in oxygen dependence at 28 days of age and older, fewer major cerebral abnormalities on ultrasonography before discharge, and fewer positive blood cultures.

 Evidence for intrapartum antibiotics in pprom – childhood follow up



Neither antibiotic had a significant effect on the overall level of behavioural difficulties experienced, on specific medical conditions, or on the proportions of children achieving each level in reading, writing, or mathematics at key stage one

The prescription of antibiotics for women with preterm rupture of the membranes seems to have little effect on the health of children at 7 years of age


Evidence for intrapartum antibiotics in spl



None of the trial antibiotics was associated with a lower rate of the composite primary outcome than placebo (erythromycin 90 [5·6%], co-amoxiclav 76 [5·0%], both antibiotics 91 [5·9%], vs placebo 78 [5·0%]). However, antibiotic prescription was associated with a lower occurrence of maternal infection. 

Antibiotics should not be routinely prescribed for women in spontaneous preterm labour without evidence of clinical infection.


Evidence for intrapartum antibiotics in spl – childhood follow up



More children whose mothers had received erythromycin or co-amoxiclav developed cerebral palsy than did those born to mothers who received no erythromycin or no co-amoxiclav, respectively (erythromycin: 53 [3·3%] of 1611 vs 27 [1·7%] of 1562, 1·93, 1·21–3·09; co-amoxiclav: 50 [3·2%] of 1587 vs 30 [1·9%] of 1586, 1·69, 1·07–2·67). The number needed to harm with erythromycin was 64 (95% CI 37–209) and with 
 co-amoxiclav 79 (42–591).

The prescription of erythromycin for women in spontaneous preterm labour with intact membranes was associated with an increase in functional impairment among their children at 7 years of age

Intrapartum Antibiotics Prophylaxis (IAP)

• Penicillin or ampicillin 
• Cefazolin
• Clindamycin
• Erythromycin
• Vancomycin