NEONATAL SEPSIS

Dr. Yohanes Hailu(pediatrician)

Gonder CMHS
Department of pediatrics and child health

20/9/24 1
 Neonatal sepsis
• It’s a systemic bacterial infection confirmed by a
positive blood culture in the first month of life.
Incidence and Mortality
• Two types of Neonatal sepsis:
• Early-onset sepsis(EONS)
• Occurs in the first 7 days of life
• Is usually a fulminant &multisystem infection
• Acquired by vertical transmission from the mother; and
• Has a higher case fatality rate.
• Late-onset sepsis(LONS) is usually more insidious but may
have an acute onset course & occur after 7 days.

20/9/24 2
 Cont…
• Very-late-onset sepsis
• Occurs after 3 months of life and affects premature VLBW infants
in the NICU.
• Is often caused by Candida species or by CONS.
• Associated with prolonged instrumentation, such as indwelling
intravascular lines and endotracheal intubation.
• The incidence of neonatal sepsis varies from 1 to 5
cases per 1000 live births.
• The case fatality rate is 5% to 20% for early-onset
sepsis and 5% for late-onset sepsis.

20/9/24 3
Cont…
LATE ONSET (≥7 VERY LATE
EARLY ONSET (<7
DAYS TO 3 ONSET (>3
DAYS)
MONTHS) MONTHS
Intrapartum
Often present Usually absent Varies
complications
Vertical or through Usually
Vertical from
Transmission postnatal postnatal
mother’s genital tract
environment environment
Fulminant course,
Clinical Insidious or acute,
multisystem
manifestation focal infection, Insidious
involvement,
s meningitis common
pneumonia common
Case-fatality
5%–20% 5% Low
rate
20/9/24 4
 Microbiology
• Etiologic Agents in Neonatal Sepsis
• Bacteria Causing Early-Onset Neonatal Sepsis
• Group B Streptococcus
• Escherichia coli
• Listeria monocytogenes
• Enterococcus species
• Viridans streptococci
• Staphylococcus aureus
• Pseudomonas species

20/9/24 5
 Cont…
• Etiologic Agents in LONS:
• Escherichia coli
• Klebsiella
• Group B Streptococcus
• Listeria monocytogenes
• Coagulase-negative Staphylococcus
• Staphylococcus aureus
• Candida albicans
• Enterococcus species
• Pseudomonas

20/9/24 6
 PATHOGENESIS
The mechanisms by which neonates get infection are:
• Transplacental
• Listeria monocytogenes.
• Ascending intra-amniotic infection followed by
aspiration of infected amniotic fluid:
• Especially if ROM lasts longer than 18/24hours.
• ~1% to 4% of neonates born to mothers with intra-amniotic
infection develop systemic infection.
• Aspiration of bacteria colonizing the mother’s lower
genital tract.

20/9/24 7
 Cont…
• The use of contaminated instruments during delivery
• Cross contamination from an infected to an
uninfected infant or from the hands of colonized
caregivers to the newborn.

20/9/24 8
 Risk Factors
• Maternal
• Maternal malnutrition and recently acquired STD.
• GBS colonization.
• Immunoglobulin against gram negative bacteria is formed
in the form of IgM which can’t cross the placental barrier
to the neonate as passive immunity.

20/9/24 9
 Cont…
• Peripartal
• Untreated or incompletely treated focal infections of the
mother (UTI, vaginal, or cervical infections), as well as
systemic infections( septicemia or maternal fever without a
focus).
• Uncomplicated ROM lasting >24 hours is associated with a
1% incidence of neonatal sepsis .

20/9/24 10
 Cont…
• Coexist of both chorioamnionitis and prolonged ROM
increases risk by fourfold.
• Prematurity and low birth weight.
• Use of fetal scalp electrodes is associated with a 4.5% risk
of sepsis.
• Cephalhematomas and PNA.
• Neonatal risk factors
• M>F
• Impairment of the oxidative respiratory burst of neonatal
neutrophils is a factor in the increased risk of sepsis,
especially in preterm infants.

20/9/24 11
Cont…
• low birth weight (< 2500 g)
• preterm birth (< 37 weeks’ gestation)
• Decreased ability of neonatal neutrophils to phagocytose
gram-negative (but not gram-positive) bacteria in the
presence of infectious or noninfectious stress.
• Decreases in adhesion, aggregation, and deformability of
neonatal neutrophils , which may delay the response to
infection.
• Impaired opsonic activity because of low level of
complement.

20/9/24 12
 Cont…
• Other risk factors
• Bottle feeding
• Use of prepared formula which has no protective
immunity.
• Prolonged hospital stay.
• High infant to nurse ratio.
• Presence of foreign materials(VP shunt, CVC, ET tube etc.)

20/9/24 13
 SYMPTOMS AND SIGNS
• Nonspecific
• Temperature instability.
• Fever that is sustained longer than an hour is frequently
associated with infection.
• Fever without other signs of infection is infrequent.
• Respiratory signs distress.
• CNS
• failure to suck, irritability, lethargy
• seizures and full fontanels may present even in the absence
of meningitis.

20/9/24 14
 Cont…
• GI
• Hepatomegaly, abdominal distention, vomiting, diarrhea,
guaiac-positive stools, and jaundice may be present.
• The presence of certain focal infections can suggest
the causative agent, such as streptococci with
cellulites, staphylococci with abscesses, and
Pseudomonas aeruginosa with necrotic skin lesions.

20/9/24 15
 Diagnosis
1. Cultures
• Blood, urine, and CSF should be obtained from all infants
suspected of having sepsis.
• Cultures of gastric aspirates obtained on the first day of life
reflect amniotic fluid infection and do not predict the
development of neonatal infection.
2. Buffy Coat Examination
3. Antigen Detection Assays

20/9/24 16
 Cont…
4. Complete blood count
• Reference Ranges for Neutrophil (per mm3) Indexes
≥120
INDEX BIRTH 12 HOURS 24 HOURS 48 HOURS 72 HOURS
HOURS

ANC 1800–5400 7800–14,400 7200–12,600 4200–9000 1800–7000 1800–5400

INC ≤1120 ≤1440 ≤1280 <800 <500 <500

WBC 9.1-34.0x 103

I:T <0.16 <0.16 <0.13 <0.13 <0.13 <0.12

• ANC, absolute neutrophil count (mature and immature forms); INC, immature neutrophil count (all
neutrophils except segmented ones); I:T, ratio of INC divided by ANC.

20/9/24 17
Clinical Factors Affecting Neutrophil Counts
Total
Immature
Total Neutrophils I:T Ratio *
Neutrophi
ls
DURATION
Decreased Increased Increased Increased
(hours)
Maternal hypertension ++++ 0 + + 72

Maternal fever, healthy neonate 0 ++ +++ ++++ 24

≥6 Hours of intrapartum oxytocin 0 ++ ++ ++++ 120

Stressful labor 0 +++ ++++ ++++ 24

Asphyxia (5-min Apgar score <5) + ++ ++ +++ 24–60

MAS 0 ++++ +++ ++ 72

Pneumothorax with uncomplicated
0 ++++ ++++ ++++ 24
respiratory distress syndrome
Periventricular hemorrhage +++ + ++ ++++ 120

+, 0%–25%; + +, 25%–50%; + + +, 50%–75%; + + + +, 75%–100%

20/9/24 18
 Total
Total Neutrophils Immature I:T Ratio *
Neutrophils
DURATIO
Decreased Increased Increased Increased
N (hours)

Seizures 0 +++ +++ ++++ 24

Prolonged crying (≥4 min) 0 ++++ ++++ ++++ 1

Asymptomatic hypoglycemia (≤30

0 ++ +++ +++ 24
mg/dL)

7–28
Hemolytic disease ++ ++ +++ ++
days

Surgery 0 ++++ ++++ +++ 24

High altitude 0 ++++ ++++ 0 6

+, 0%–25%; + +, 25%–50%; + + +, 50%–75%; + + + +, 75%–

100%
20/9/24 19
 Cont…
• The upper limit of normal I:T ratio for neonates of 32
weeks’ gestation or less is slightly higher, at 0.2
therefore I:T ratio of >0.2 always is abnormal for all
neonates.
5. Acute-Phase Reactants(APR)
• APRs are proteins produced by hepatocytes in response to
inflammation.
• Are elevated but doesn't distinguish between infectious
and noninfectious causes of inflammation.

20/9/24 20
 Cont…
a. C-Reactive Protein
• Normal concentrations are 1 mg/dL or lower.
• The serum half-life is 5 to 7 hours.
• An increasing value is usually detectable within 6 to 18
hours, and the peak CRP is seen at 8 to 60 hrs after onset of
the inflammatory process.
b. Fibronectin
• Fn has been found to be decreased in neonates with
infection and also in neonates with asphyxia, respiratory
distress syndrome, and bronchopulmonary dysplasia.

20/9/24 21
 Cont…
c. Erythrocyte Sedimentation Rate
• It reflects changes in many serum protein APRs.
• A micro-ESR has been developed for use in infants. The
maximal normal rate in the first 2 weeks of life can be
obtained by adding 3 to the age of the newborn in days.
Beyond 2 weeks of life, the maximal rate varies between 10
and 20 mm per hour.
• Micro-ESR values vary inversely with the hematocrit

20/9/24 22
 Treatment
• Empirical antimicrobial therapy is initiated after
obtaining samples for culture.
• The choice of empirical therapy is based on:
• timing and setting of the disease
• microorganisms most frequently encountered
• susceptibility profiles for those organisms
• site of the suspected infection and
• penetration of the specific antibiotic to that site, and
• safety of the antibiotic.
• Availability of the drug and its affordability.

20/9/24 23
 Cont…
• Ampicillin plus aminoglycosides( gentamicin) is the
commonly used drugs.
• Vancomycin and gentamicin /Ceftazidime for the
treatment of nosocomial infection, if not available
possible to use cloxacillin with gentamicin/
Ceftazidime.
• The dosage and frequency of antimicrobial agents
vary with gestational age, postnatal age, birth weight,
and status of hepatic and renal function.

20/9/24 24
 Indications, Pharmacology, and Toxicity of
Antibiotics Commonly Used in Newborn Infants

PHARMACOLO
ANTIBIOTIC INDICATIONS TOXICITY COMMENTS
GY
Initial treatment of sepsis
and meningitis; gram-
positive organisms except
Seizures when
staphylococci; gram-
Ampicillin Renal excretion high dosages
negative organisms if
are given
susceptible (Salmonella,
Shigella, Hemophilus,
Escherichia coli)
Active against
streptococci;
Primarily renal routine use can
Sepsis, meningitis caused
excretion; good result in
Cefotaxime by susceptible gram-  
penetration into emergence of
negative organisms
CSF resistant gram-
negative
organisms
20/9/24 25
 Cont…
ANTIBIOTIC INDICATIONS PHARMACOLOGY TOXICITY COMMENTS

Can be used in
combination with an Renal excretion;
Ceftazidime aminoglycoside for penetrates blood-brain
treatment of barrier
Pseudomonas infection

Sepsis, meningitis, soft

tissue and bone/joint
30%–65% excreted by May displace
infections caused by
the kidneys, the Potential bilirubin from
susceptible organisms; not
Ceftriaxone remainder excreted in gallbladder albumin-
effective against
bile; penetrates blood- sludging binding sites in
staphylococci, Listeria sp,
brain barrier neonates
enterococci, or
Pseudomonas sp

20/9/24 26
Cont…
PHARMACO
ANTIBIOTIC INDICATIONS TOXICITY COMMENTS
LOGY
Pseudomembran
Treatment of susceptible ous colitis in
Clindamycin  
anaerobic infections older children but
rare in neonates
Can be used for initial
treatment of neonatal
Possible Toxicity rare if the
sepsis; not effective
Renal ototoxicity, appropriate
alone but can be
excretion; nephrotoxicity, dosage is used
Gentamicin synergistic when used
activity low in and and blood
with ampicillin against
CSF neuromuscular concentrations
group B streptococci,
blockade are monitored
enterococci, and Listeria
sp

20/9/24 27
Cont…
TOXICI
ANTIBIOTIC INDICATIONS PHARMACOLOGY COMMENTS
TY

Penicillin-resistant
Excretion is renal and
Staphylococcus
hepatic for nafcillin and
Nafcillin, oxacillin, aureus infections;
oxacillin; nafcillin and
cloxacillin active against
oxacillin are highly
streptococci, but not
protein bound
a first-line agent

Most streptococci,
Can be used to
Treponema pallidum,
Renal excretion; fair treat infections
Bacteroides spp
Penicillin G penetration of inflamed   caused by
(except Bacteroides
meninges susceptible
fragilis), Neisseria
organisms
meningitidis

20/9/24 28
Cont…
PHARMAC
ANTIBIOTIC INDICATIONS TOXICITY COMMENTS
OLOGY
Effective against
coagulase-negative Possible
staphylococci, ototoxicity; Flushing or
methicillin-resistant S. Renal previous hypotension may
Vancomycin
aureus; most gram- excretion preparations result from rapid
positive aerobic associated with infusion
organisms are nephrotoxicity
susceptible

20/9/24 29
 PREVENTION
• Intrapartum antibiotic prophylaxis (IAP) for prevention of
early-onset GBS disease.
• Indication:
• Positive lower vaginal and rectal cultures obtained at 35 to 37
weeks’ gestation.
• Delivery of a previous infant with invasive disease and
• GBS bacteriuria.
• Not indicated for planned cesarean section before ROM and
onset of labor.
• Risk factors (labor onset or ROM before 37 weeks’ gestation,
ROM 18 hours or more before delivery, or intrapartum fever)
should be used only when the results of cultures are not known
at the onset of labor.

20/9/24 30
 Cont’d
• The management of infants born to women receiving
IAP depends on the infant’s status at birth, the
duration of prophylaxis, and the gestational age of the
infant.
• If a woman receives IAP for suspected
chorioamnionitis, her infant should have a full
diagnostic evaluation and empirical therapy pending
culture results.

20/9/24 31
 Cont’d
• Evaluations with CBCD and blood culture plus
observation for at least 48 hours is indicated for
asymptomatic infants of <35 weeks’ gestation and for
those whose mothers received chemoprophylaxis for
< 4 hours before delivery.
• Observation is appropriate for asymptomatic infants
of at least 35 weeks’ gestation whose mothers
received chemoprophylaxis at least 4 hours before
delivery.

20/9/24 32
 Meningitis
• INCIDENCE
• Meningitis presents in as many as 25% of cases of
neonatal sepsis.
• Higher in premature infants, male infants, and infants
born to mothers with complicated pregnancies or
deliveries.
• Premature newborns with LBW have a 10-fold higher
risk of meningitis than do term infants.
• ETIOLOGY
• Caused by the same pathogens associated with
neonatal sepsis.
20/9/24 33
 PATHOGENESIS
• There are three mechanisms by which the meninges
can become infected:
1. Primary sepsis with hematogenous seeding;
2. Focal infection outside the CNS, with either secondary
bacteremia and resulting hematogenous dissemination
or direct extension (e.g., from an infected sinus); and
3. Direct inoculation after head trauma or neurosurgery, or
from an open congenital defect such as
myelomeningocele or dermal sinus.

20/9/24 34
Cont’d
• Endotoxins and bacterial cell wall components
released from dying bacteria initiates an intense
inflammatory reaction by stimulating the
production of TNF, IL-1, and other mediators by
monocyte & macrophage cells.
• Tumor necrosis factor and IL-1 induce
phospholipase A2 activity, production of other
mediators, and receptor-ligand interactions
between leukocytes and endothelia.
Cont’d
• Phospholipase A2 then acts on membrane
phospholipids to produce a variety of lipid
proinflammatory substances such as platelet-
activating factor, leukotrienes, prostaglandins, and
thromboxanes.
• The inflammatory changes result in vascular injury
and alterations in the permeability of the blood-
brain barrier, with resultant vasogenic edema.
Cont’d
• Cytokines activate adhesion-promoting receptors
on cerebral vascular endothelial cells, which leads
to recruitment of leukocytes to sites of stimulation.
• These polymorphonuclear leukocytes subsequently
enter the subarachnoid space, release toxic
substances, and cause cytotoxic edema leading to
development of increased ICP and severe brain
edema.
Cont’d
• Cerebral edema, increased intracranial pressure,
systemic hypotension, decreased CPP, and a variety
of vascular changes result in global or regional
reductions of CBF and can lead to brain ischemia .
• The pathophysiologic aberrations ultimately cause
focal or diffuse neuronal injury, which may be
irreversible.
 PATHOLOGY
• Subarachnoid exudate.
• Ventriculitis.
• Diffuse encephalopathy
• Hydrocephalus.
• Thrombosis and cerebral.

20/9/24 39
 CLINICAL MANIFESTATIONS
• Clinical feature:
• lethargy, reluctance to feed, emesis, respiratory distress,
irritability, and temperature instability.
• Signs suggestive of a CNS infection may be less common
• E.g. out of 255 neonates with meningitis convulsion, bulged
fontanel, and nuchal rigidity was observed in 40%,25% and 15%
respectively.

20/9/24 40
 DIAGNOSIS
CSF analysis
• Gram-stained
• Culture and sensitivity
• Polymerase chain reaction (PCR)
• GBS
• HSV-71-100% sensitive but 98-99% specific.
• Enteroviruses

20/9/24 41
Normal CSF value
• Opening pressure
• Newborn ………80-110 mm H2O
• Infant ………......<200 mm H2O
• Glucose
• preterm higher; 70–80% of serum glucose
• Protein
• Premature ……….65-150 mg/dL
• Term …………………20-170 mg/dL
• White blood cell count
• Normal healthy neonates may have as many as 30 leukocytes/mm3
(usually <10/mm3)

20/9/24 42
Laboratory Diagnosis of
Neonatal Meningitis

• CSF
• > 30 WBC/mm3 with > 75% PMN
• glucose < 50% - 75% of serum
• protein > 150 mg/dl
• organisms on gram stain or culture
Blood culture
• 15-30% of infants with CSF-proven meningitis have
negative blood cultures.
•
 TREATMENT
• Empirical therapy should provide coverage for GBS,
gram-negative bacillary enteric organisms, and L.
monocytogenes.
• Ampicillin and gentamicin or ampicillin and
cefotaxime are recommended for initial empiric
therapy of neonatal meningitis.
• The minimum duration in uncomplicated GBS or
Listeria meningitis is 14 days.

20/9/24 44
Cont’d
• Therapy for meningitis is continued for a minimum
of 2 weeks after sterilization of CSF cultures.
• This equates to 14 days of therapy for meningitis
caused by gram positive organisms and a minimum
of 21 days of therapy for meningitis caused by
gram-negative pathogens

20/9/24 45
Complication
• cerebral edema
• hydrocephalus
• hemorrhage
• ventriculitis (especially
with bacterial infection)
• cerebral infarction.
• Cerebral abscess
• Residual epilepsy
• Cognitive impairment
• Hearing loss
• Visual impairment
• Spastic paresis, and
microcephaly
 PROGNOSIS
• Poor prognosticators of GBS meningitis are:
• Comatose or semi comatose state,
• Poor perfusion,
• Total peripheral leukocyte count <5000/mm3,
• Absolute neutrophil count <1000/mm3, and
• CSF protein >300 mg/dL.
 Cont’d
• Poor prognosticators of gram-negative bacillary meningitis
include :
CSF profile of:
• protein level > 500 mg/dL,
• leukocyte count >10,000/mm3,
• Persistent positive CSF cultures, and
Presence and persistence of elevated IL-1α and TNF.
• Late complications of meningitis occur in 40-50% of
survivors and include hearing loss, abnormal behavior,
developmental delay, cerebral palsy, focal motor
disability, seizure disorders, and hydrocephalus.

20/9/24 48
Cont’d
• Over all poor prognostic factor:
• Low birth weight
• Prematurity
• Significant leukopenia or neutropenia
• High levels of protein in CSF
• delayed sterilization of the CSF
• Coma at presentation
• Seizures lasting longer than 72 hours and
• The need for inotropes
 Pneumonia
• ETIOLOGY
• Causes of congenital pneumonia :
• CMV, rubella virus, and T. pallidum
• Microorganisms causing pneumonia acquired during
labor and delivery
• GBS is the most common.
• E. coli, gram-negative enteric aerobes, Listeria
monocytogenes, T. pallidum, genital Mycoplasma,
Chlamydia trachomatis, CMV, HSV, enteroviruses,
adenovirus, and rubella, Candida species.

20/9/24 50
PATHOGENESIS AND
PATHOLOGY
• Pneumonia may be acquired :
1. Transplacentally
2. Aspiration of contaminated amniotic fluid
3. Aspiration of infected materials
4. Inhalation of infected aerosols
5. Hematogenously (septicemia or from another
focus of infection).

20/9/24 51
 Cont….
• Pathology
• Areas of densely cellular exudate with bacteria.
• Vascular congestion, hemorrhage, and necrosis can be
observed.
• Micro abscesses and empyema (S. aureus or Klebsiella
pneumoniae).
• Pneumatocele formation(S. aureus, E. coli and Klebsiella
species).
• Fatal cases of GBS pneumonia have had evidence of hyaline
membranes disease.

20/9/24 52
 CLINICAL MANIFESTATIONS
• Those with congenital pneumonia often die in utero
or are critically ill at birth.
• Spontaneous respirations may not occur or may be
established with difficulty. If respirations are
established, tachypnea, moderate retractions, and
grunting may be observed.
• Fever may or may not be noted but is often a
prominent sign of neonatal herpes simplex and
enterovirus disease.
• Cough is not common.
• Cyanosis

20/9/24 53
 Cont’d
• Infants who acquire the infection during delivery or
postnatally may have:
• Systemic signs, like fever, reluctance to feed, and lethargy
• Respiratory signs; coughing, grunting, costal and sternal
retractions, flaring of the alae nasi, tachypnea or irregular
respirations, rales, decreased breath sounds, and cyanosis.

20/9/24 54
 Cont’d
• Chlamydial pneumonia
• present at 4 to 11 weeks of age with a prodrome of nasal
congestion followed by tachypnea and a paroxysmal,
staccato cough.
• Conjunctivitis is present or occurred earlier in
approximately half of these infants.
• Rales may be present, but expiratory wheezes are not
commonly seen.
• Infants are afebrile and frequently gain weight slowly.

20/9/24 55
 DIAGNOSIS
• Chest x ray
• radiographic abnormalities are visible by 24 to 74 hours.
• bilateral homogeneous consolidation when pneumonia is
acquired in utero
• diffuse bronchopneumonia with postnatally acquired
disease.
• Bilateral, symmetric interstitial infiltrates in C. trachomatis
pneumonia.
• Pneumonia caused by GBS has similar radiographic feature
of ARDS.

20/9/24 56
 Cont’d
• MAS mimics bronchopneumonia, but the radiologic
changes tend to be maximal early and disappear rapidly
during the ensuing days where as the patchy opacifications
noted with bronchopneumonia tend to be minimal early
and become more impressive during the subsequent days.

• Blood cultures
• Gram-stained smears of tracheal secretions if
obtained before 8 hours of age.
• Culture or antigen detection from nasopharyngeal
samples or secretions for diagnosis of Chlamydia
pneumonia.

20/9/24 57
 TREATMENT
• Ampicillin and either an aminoglycoside or
cefotaxime.
• Vancomycin and an aminoglycoside/ceftazidim for
late-onset nosocomial infection.
• Azithromycin/Erythromycin for pneumonia caused by
Chlamydia or Pertussis organisms.
• Acyclovir if HSV pneumonia is suspected.
• Treatment for bacterial pneumonia is continued for 10
to 14 days.

20/9/24 58
 PROGNOSIS
• Poor prognosticators:
• Congenital pneumonia
• Prematurity.

20/9/24 59
 Prevention of infection in
neonates
• Maternal immunization( rubella, hepatitis B, VZV) as
well as Tetanus
• Appropriate diet and avoidance of exposure to cat
feces.
• Chemoprophylaxis for malaria and use of insecticide-
treated bed nets.
• Selective intrapartum chemoprophylaxis for GBS.
• Identification and treatment of infected pregnant
women( C. trachomatis, syphilis).
• PMTCT

20/9/24 60
 Principles for the prevention of
nosocomial infection
• Adherence to universal precautions with all patient
contact
• Avoiding nursery crowding and limiting nurse-to-
patient ratios
• Strict compliance with hand washing
• Meticulous neonatal skin care
• Minimizing the risk of catheter contamination

20/9/24 61
 Cont…
• Decreasing the number of venipunctures and heel
sticks
• Reducing the duration of catheter and mechanical
ventilation days
• Encouraging appropriate advancement of enteral
feedings
• Providing education and feedback to nursery
personnel, and
• Ongoing monitoring and surveillance of nosocomial
infection rates in the NICU.
20/9/24 62
Thank you for your attention!!!!!!!

20/9/24 63