Neonatal Late Onset Sepsis

Dr. Mitra Radfar

Neonatologist
Late Onset Sepsis
In term and Late preterm Occuring >7 days

In VLBW infants in NICU can be defined :

 Occuring >72 houres of life

Very-late-onset infections (onset after age 1 mo) may also
occur, particularly in very-low-birthweight (VLBW) preterm
infants or term infants requiring prolonged neonatal intensive
care.
Late-onset neonatal sepsis is defined:
as occurring from 8 to 90 days of life
 disease occurring in otherwise healthy term
infants in the community

 Hospital Acquired Sepsis) disease affecting

premature infants in the NICU )
.Incidence of neonatal late-onset sepsis

 The overall incidence of primary sepsis (EOS and LOS) is 1 to

2 per 1000 live births.

 A study that looked at late preterm infants hospitalized in the

first 3 months of life identified LOS in 6.3 per 1000 admissions

 late-onset GBS infection rates have remained relatively stable

over the past 20 years and are not impacted by intrapartum
antibiotics prophylaxis

 Incidence of LOS is much higher for VLBW infants

.Pathophysiology of neonatal late-onset sepsis

 LOS is usually more insidious

(compared to EOS), but it can be fulminant at times.

 these infants may have an identifiable focus, most often

meningitis in addition to sepsis.

 Bacteria responsible for LOS and meningitis include those

acquired after birth from the maternal genital tract (vertical
transmission) as well as organisms acquired after birth from
human contact or from contaminated equipment/environment
(nosocomial).
 In case of nosocomial spread, the pathogenesis is related to the
underlying illness and debilitation of the infant,

 the flora in the neonatal intensive care (NICU) environment

 invasive monitoring and other techniques used in the NICU

especially the use of peripherally inserted central catheters (PICCs).

 Breaks in the natural barrier function of the skin and intestine

allow opportunistic organisms to invade and overwhelm the neonate.

 underlying illnesses and immature immune defenses that are less

efficient at localizing and clearing bacterial invasion.
 Microbiology
Healthy term infants and near term in the community
Caused by
 GBS
 Gram-negative species such as E. coli and
Klebsiella spp
 Streptococus pneumoniae and Neisseria
meningitidis less frequently
Microbiology
Coagulase negative staphylococci(nearly half) is rarely fatal even to the VLBW infant nd
rarely cause meningitis or site specific infection

Other Gram positive organism 22%

(S aureos,Enterococci,GBS)
cause a wide range of serious disease includes bacteremia, meningitis, cellulitis, omphalitis,
osteomyelitis and arthritis.o
Enterococci. Formerly categorized as members of Group D
streptococci, both Enterococcus faecalis andEnterococcus faecium
cause LOS in premature infants.

Although disease can be complicated by meningitis and is sometimes

associated with NEC, enterococcal LOS is associated with low overall
mortality.
Enterococci. Formerly categorized as members of Group D
streptococci, both Enterococcus faecalis andEnterococcus faecium
.cause LOS in premature infants

Although disease can be complicated by meningitis and is

sometimes associated with NEC, enterococcal LOS is associated

with low overall mortality.

Gram negative organism 18%

Ecoli,Klbsiella,Pseudomonas,Enterobacter,Seratia )

Fungal 12%
Symptoms
 Change in behavier ,lethargy ,irritability ,change in tone
 increase in the in the the number or severity of apneic
spells
 feeding intolerance , feeding prolem
 temperature instability ,hypothermia ,hypertermia
 increase in ventilatory support

 all may be early signs of Los

 or may be part of the variability in the course of the VLBW
infant.
Symptoms .

 Skin.

 Cardiopulmonary

 Reduced variability and transient decelerations in heart rate (HR) may

be present in the hours to days before diagnosis of LOS. These

abnormal HR characteristics (HRC) in response to systemic

infection and inflammation have been character-ized mathematically,

and the resulting HRC index

 Some studies suggest that monitoring the HRC index in high-
risk premature infants may result in improved outcomes and
decreased mortality

 Metabolic.
Metabolic findings include hypoglycemia, hyperglycemia, or
metabolic acidosis.

 Focal infections.
These may precede or accompany LOS. Look for cellulitis,
impe-tigo, soft tissue abscesses, omphalitis, conjunctivitis,
otitis media, meningitis, or osteomyelitis
Laboratory studies of neonatal late-onset sepsis

 Cultures. Blood and other normally sterile body fluids (urine, spinal
fluid, and occasionally tracheal aspirate) should be obtained for
culture.
Body surface cul-tures are not recommended unless the infant has
pustules or a characteristic rash (eg, candida).

Blood cultures.Computer-assisted automated blood culture systems

identify up to 94% to 96% of all microorganisms by 36 to 48 hours of
incubation.

 Two blood cultures (1 from PICC and 1 peripheral) are recommended.

 With mild symptoms and a low suspicion for the presence of sepsis

 is reasonable to draw a CBC with differential, ± CRP, and a blood

culture

wait for the results of the tests (while monitoring the infant's
symptoms) before beginning empiric antibiotic therapy

If laboratory tests are abnormal or the infant's status worsens,

empiric antibiotic therapy should be started.
Ideally, CSF culture should also be obtained before antibiotic
,therapy

Urine cultures should also be

considered prior to beginning empiric antibiotic therapy.

If a previously well, convalescing premature infant presents primarily

with increased apnea with or without upper respiratory infection (URI)
symptoms, consideration should be given to a viral source of
infection .as well

Tracheal or nasal aspirate should be sent for rapid analysis and

culture to rule out respiratory syncytial virus(RSV),
parainfluenzae, .and influenzae A and B if seasonally appropriate
 Up to one third of VLBW infants with late-onset meningitis
have negative blood culture results.

 emphasizes the need for culture of CSF in VLBW infants

when late-onset sepsis is suspected and in all infants who
have positive blood culture results.

 analysis of CSF is usually deferred until the unstable

cardiorespiratory status (shock, respiratory failure) has
stabilized.
Other laboratory tests

a.Complete blood count with differential

both low and high WBC (<1000/mm3and >50,000/mm3),
high absolute neutrophil count (>17,670/mm3),
elevated I/T ratio (>0.2),
and low platelet count (<50,000/mm3).

b.Acute-phase reactants
Serial CRP determinations are helpful in ruling out infection
when normal
PCT may be better than CRP in the diagnosis and follow-up
of neonatal sepsis secondary to CONS
Imaging and other studies

1. Chest radiograph.

2. Urinary tract imaging.

Empiric antibiotic therapy.

 In nosocomial sepsis, the flora of the NICU must be con-

sidered in choosing antibiotics;

 staphylococcal coverage with vancomycin plus an

aminoglycoside such as gentamicin or amikacin is usually
begun.

 The empirical treatment for suspected LOS in a neonate

admitted from the community is ampicillin and gentamicin;

 cefotaxime can be added only when there is a concern for

meningitis.
Continuing therapy

 is based on culture and sensitivity results, clinical course,

and other serial laboratory studies

 If an ESBL-producing organism, such as K pneumoniae,

is suspected or identified, then carbapenem is the drug of
choice (with aminoglycoside for double coverage)

 Of the aminoglycosides, amikacin retains the most activity

against ESBL-producing strains

 An aminogly-coside or cefepime can be used if the organism is

susceptible,
 In late-onset infections, all treatment courses assume central
catheters have been removed.

 With CONS infections, the clinician may choose to retain the

catheter during antibiotic treatment, but if repeated cultures remain
positive, the catheters must beremoved.

 Many infectious disease specialists recommend repeat lumbar

punctures at the completion of therapy for meningitis to ensure
eradication of the infection.
 Administration of intravenous immunoglobulin to neonates
with suspected or proven LOS does not result in reduction in mortality

 G-CSF and GM-CSF, does not result in reduced mortality or

better neurodevelopmental outcome

might be a place for using G-CSF in cases of severe infection

complicated by severe neutropenia (absolute neutrophil count
<500/mm3)

 Research is also ongoing into blocking some of the body’s own

inflammatory mediators that result in significant tissue injury, including
endotoxin inhibitors, cytokine inhibitors, nitric oxide synthetase
inhibitors, and neutrophil adhesion inhibitors.
Treatment of LOS
Treatment of LOS
Prevention of LOS
 A subset of nosocomial sepsis is central line–associated
bloodstream infections (CLABSIs).

 Hand hygiene is the single most important strategy

 Poromotion of breast feeding ,early enteral feeding

Antibiotic restriction

 Possible use of probiotics may restore gut immune function

and help prevent NEC and sepsis.
 A recently published Cochrane review that included 6 trials

suggested that lactoferrin supplementation to enteral feeds

with or without probiotics may decrease LOS and NEC in
preterm infants.
 Prognosis

 Risk factors for LOS mortality include endotracheal

intubation,administration of vasopressors, hypoglycemia,
thrombocytopenia,development of NEC.

 VLBW infants who survive LOS are at risk for long term

neurodevelopmental impairment including cerebral

palsy.
 Healthcare-Acquired Infections
 The most common HAIs in the neonatal intensive
care unit (NICU) are bloodstream infections,
predominantly central line–associated bloodstream
infections.

 Ventilator-associated pneumonia (VAP) is the

next most common,

 surgical site infection

 catheter-associated urinary tract infection.

Central Line–Associated Bloodstream Infection

 Central line–associated bloodstream infection (CLABSI) is the

most common HAI in NICUs, imposing significant burden on
the affected infant and on healthcare systems.

 Coagulase-negative staphylococci (CoNS) are the most

common cause of CLABSI, accounting for approximately half
of cases.

CoNS are much more likely to cause clinically evident sepsis

in VLBW infants than in term infants
 CLABSI are defined as culture-proven bloodstream
infections occurring in the presence of a central
catheter for which there is no other obvious source
of infection

 Hand hygiene is the most important intervention to

prevent CLABSI in the NICU.
Components of Neonatal CLABSI Prevention
Components of Neonatal CLABSI Prevention
:Insertion bundles include
a combination of barrier precaution, .

hand hygiene standards,

skin disinfection,
dedicated teams and equipment,
.
catheter site evaluation,
checklists,
empowerment to stop the procedure.

Maintenance bundles include

aseptic technique when accessing the line, dressing change protocols,
prompt removal when the line is no longer required
 Healthcare-Associated Pneumonia
Ventilator-associated pneumonia (VAP) is overall the 2nd most
common HAI in neonatal units,

Definition of VAP requires at least 48 hr of mechanical

ventilation accompanied by new and persistent radiographic infiltrates
after the initation of mechanical ventilation (CDC).
worsening gas exchange and at least 3 of the following:
(1) temperature instability with no other recognized cause;
(2) leukopenia (white blood cell count <4,000/mm3);
(3) change in the character of sputum of increased respiratory
secretions or suctioning requirements;
(4) apnea, tachypnea, nasal flaring, or grunting;
(5) wheezing, rales, rhonchi, or cough;
(6) bradycardia (<100 beats/min) or tachycardia (>170 beats/min).
 FUNGAL INFECTIONS

 Mucocutaneous candidiasis

Candida can be acquired through the birth canal or through the hands or
breast of the mother.
Nosocomial transmission in the nursery setting has beendocumented, such
as transmission from feeding bottles and pacifiers.breast of the mother.

.
 Oral candidiasis

Nystatin oral suspension(100,000 U/mL) is standard treatment (1 mL is

applied to each side of the mouth every 6 hours for a minimum of10 to 14
days).
 Systemic fluconazole is also highly effective in treating chronic
mucocutaneouscandidiasis in the immunocompromised host.

Infants with chronic, severe thrush refractory to treatment should

beevaluated for an underlying congenital or acquired
immunodeficiency.

 Candidal diaper dermatitis is effectively treated with topical

agents such as 2% nystatin ointment, 2%miconazole ointment, or 1%
clotrimazole cream.

 It is reasonable to use simultaneous oral and topical

therapy for refractory candidal diaper dermatitis.

B. Systemic candidiasis.
Systemic candidiasis is a serious form of nosocomial infection in VLBW
infants.

Invasive candidiasis is associated with overall poorer neurodevelopmental

outcomes and higher rates of threshold retinopathy of prematurity, compared
to matched VLBW control infants.

The most significant epidemiologic factors specific to candidal LOS in

the .NICHDcohort studies were BW <1,000 g

The use of H2 blockers or systemic steroids have also been identified as

independent risk factor for the development of invasive fungal infection
 Disseminated candidiasis is primarily caused by C. albicans and C.
parapsilosis in preterm infants,

 The initial clinical features of late-onset invasive candidiasis are often

nonspecific and can include lethargy,increased apnea or need for
increased ventilatory support, poor perfusion, feeding intolerance, and
hyperglycemia.

 Both the total WBC and the differential can be normal early in the
course of infection, and although thrombocytopenia is a consistent
feature, it is not universally found at presentation

 Candidemia can be complicated by meningitis and brain abscess as well

as end-organ involvement of the kidneys, heart, joints, and eyes
(endophthalmitis).
 The fatality rate of disseminated candidiasis is high relative to that and
increases in the presence of CNS involvement.found in CONS
infections

 Diagnosis.Candida can be cultured from standard pediatric blood

culture systems; the time to identification of a positive culture is
usually by 48 hours, although late identification (beyond 72 hours)
does occur more frequently than with bacterial species.

 Both fungal culture and fungal staining (KOH preparation) of urine

obtained by SPA can be helpfulin making thediagnosis of systemic
candidiasis.

 Before the initiation of anti fungal therapy, CSF should be obtained

for cell count and fungal culture.
 Treatment. Systemic candidiasis is treated with amphotericin B, 0.5
to 1.0 mg/kg/day for durations of 7 to14 days after a documented
negative blood culture if the infection is considered to be catheter
associated the catheter has been promptly removed.

 There is increased experience in VLBW babies with liposomal preparations

ofamphotericin B and this formulation can be used for invasive candidiasis if
urinary tract and CNS involvementare excluded.
,Doses of 5 mg/kg/day can be used without toxicity

 CNS disease can be treated with non liposomal amphotericin alone;

an additional second agent,commonly 5-fluorocytosine (flucytosine 5-FC)
(50 to 150 mg/kg/day) or fluconazole (6 mg/kg/day) should be added only
if initial therapy with amphotericin is not effective.
 Removal of central catheters

 Further evaluation of the infant with invasive candidiasis

renal and brain ultrasonography

ophthalmologic examination

an echocardiogram