Health Care
Associated Infections
on the NICU
(aka: Nosocomial infections)
Catherine M. Bendel, MD
Associate Professor of Pediatrics
Director, Neonatal-Perinatal Medicine Fellowship Program
Objectives
• Define and differentiate between early-onset, late-onset
and health-care associated (nosocomial) infections on
the NICU.
• List the major micro-organisms responsible for each of
these types of infection.
• Understand the risk factors for NICU nosocomial
infections.
• Understand what laboratory tests are important in
making the diagnosis of each of these infections.
• Understand the primary prevention strategies
“Prematurity is an infectious disease.”
- James Todd, M.D.
Definitions
• Early Onset Neonatal
Sepsis (EONS)
• Late Onset Neonatal
Sepsis (LONS)
• Nosocomial or Health
Care Associated
Neonatal Infections
(HCANI)
 <5 days old
(prenatal or peripartum)
 5 days to 3 months old
(peripartum)
 Any infection that develops
while a patient is in the hospital
(peripartum or postnatal)
Bacterial/ Viral/ Fungal
Microbes
• Early Onset Neonatal
Sepsis (EONS)
• Late Onset Neonatal
Sepsis (LONS)
• Nosocomial or Health
Care Associated
Neonatal Infections
(HCANI)
 Maternal normal GU flora
(GBS/ E. coli)
 Maternal flora and pathogens
(GBS/Chlamydia/MRSA/HSV/HepB
/ CMV/ HIV/Candida….)
 Skin/GI/Resp - self/others/equipment
(CoNS/ gram negs/Candida/RSV)
Microbes - HCANI
• #1 Coagulase-negative Staphylococcus
• Infant skin or GI tract
• Care-provider hands
• #2 Gram-negative bacilli
• Infant skin, respiratory or GI tract
• Care-provider hands (artificial nails)
• Medical equipment
• #3 Candida spp (C. albicans, C. parapsilosis, C.
glabrata)
• Infant skin or GI tract
• Care-provider hands
• Medical equipment/treatments
Incidence
• Early Onset Neonatal
Sepsis (EONS)
• Late Onset Neonatal
Sepsis (LONS)
• Nosocomial or Health
Care Associated
Neonatal Infections
(HCANI)
 1-10/1,000 live births
 15-25/1000 premies
 0.5/1,000 live births (GBS)
 ~5% of all NICU admissions
11-32% of all VLBW (<1500)
Why are infants,
especially premies, more
susceptible to infections?
Risk Factors for HCANI: Intrinsic
• Prematurity
– ELBW > VLBW
•
•
•
•
Immunology of the neonate
Mechanical barrier to infection
Severity of illness
Abnormal microbial flora
Prematurity
• Risk of infection inversely related to BW/GA
• VO study looking only at bacterial sepsis:
–
–
–
–
26% if 501-750 grams
22% if 751-1000 grams
15% if 1001-1250 grams
8% if 1251-1500 grams
• Most likely a surrogate marker for immunologic
immaturity, immature barrier function and severity
of illness
Neonatal Immune System
• All neonates relatively immunocompromised
• Immature, Ineffective and Inadequate levels:
– Antibodies / complement
– Neutrophils
– T-cells / cytokines
Antibodies
Infectious agent
Immunity
Figure 1.1 Antibodies (anti- foreign bodies) are produced by host while cells on contact with the invading micro-organism
which is acting as an antigen (e.g. generates antibodies). The individual may then be immune to further attacks.
(Modified From: Roitt, I: Essential Immunology, 4th edition, Blackwell Scientific Publications, 1980)
Antibodies
Infectious agent
x
x
Immunity
No contact with infectious agents = no antibody production
Life in-utero
Premature Antibody levels
• Extremely low production, reduced opsonic activity
• Primary source - active placental transfer of
maternal antibodies
• Most maternal antibody transferred in the 3rd
trimester
• Maternal antibody concentrations low for 1o
pathogens
 So smaller and earlier = lowest levels and least
effective antibody
Remington and Klein, Sixth Edition, 2006
Neonatal Neutrophils (PMNs)
• Immature
–
–
–
–
 Chemotaxis
 Deformability
 Phagocytosis
 Storage pool
• Adults 14-fold >
circulating pool
• Neonates only 2-fold
Manroe et al, J Pediatr, 1979
7500
3600
ANC = absolute neutrophil count
Mouzinho et al, Pediatr 94:76, 1994
“Normal” VLBW neonates
Mouzinho et al, Pediatr 94:76, 1994
6000
1200
30 days
“Normal” VLBW neonates
(<1200 abnormal)
Neonatal Neutropenia
•
•
•
•
Prematurity
Maternal Hypertension
IUGR
Sepsis
Neonatal Barriers
to Infection
Impairments/alterations in
Neonatal Natural Barriers
• Immature Skin
– Thin, lacking multiple layers/keritin
– Easily damaged by
• Drying (phototherapy/open warmer)
• Adhesive tape/ monitor leads
• Handling / phlebotomy/ surgery
– Surgical wounds heal more slowly
Invasive Fungal Dermatitis in a VLBW infant
QuickTime™ and a
TIFF (Uncompressed) decompressor
are needed to see this picture.
JL Rowen, Sem Perinatal 27:406-413, 2003
QuickTime™ and a
TIFF (Uncompressed) decompressor
are needed to see this picture.
Impairments/alterations in
Neonatal Natural Barriers
• Umbilicus - colonization of
devitalized tissue
• GI tract
– Increased gastric pH with drip
feeds/H2 blockers
– Mucosal damage with NEC
Severity of Illness
• Direct correlation with rate of HCANI:
– Increased LOS
– Higher severity of illness scores
– Congenital anomalies
• Potential correlation:
– Prenatal insults/stress
Abnormal Microbial Flora
• Altered maternal transmission of
normal flora due to C/S, prenatal
antibiotics, etc
• Altered neonatal colonization due to
– Broad-spectrum antibiotics (favors
Candida)
– Delayed enteral feeds
Risk Factors for HCANI: Extrinsic
• Catheters
– UAC, UVC, PICC, ETT, Foley, CT, Peritoneal drains,
etc
• Hyperalimentation / intralipids
• Medications
• Understaffing / overcrowding
• Care-giver to patient transmission of
flora/pathogens
Central Venous/Arterial Catheters
•
•
•
•
•
Life-saving tools on the NICU
Necessary evil
Stasis, thrombin formation
Hyperal /IL
Length between tubing changes
– 72 hours significantly higher risk than <24 hours
Central Venous/Arterial Catheters
• Skin bugs colonize the hub or exit-site, migrate up
the catheter and enter the bloodstream or infect a
clot at the tip
– UVC > PICC / Broviac
– UAC > perc A-line
• Transient bacteremia results in tip infection (GI)
• Increased incidence of infection with time
UVC > UAC > PICC / Broviac
• Minimally at 7 days
• Significantly at 10-14 days or if clot present
Catheters
• Micro-organisms love to stick to plastic
• ANY CATHETER IS AT RISK!!
• ETT, Foley, CT, Peritoneal drains, etc
Hyperalimentation / Intralipids
• Associated with increased risk of CoNS, Candida
spp and Malassezia spp
• Exact etiology unclear
– Inhibition of IL-2 and lymphocytes
– Hyperglycemia
– Sugar and fat source that promotes growth of select
microbes
– Affects of delayed enteral nutrition on GI
flora/anatomy
Medications
• Broad spectrum antibiotics
– Alter normal flora (>5 days increases risk of
candidemia)
– Select for resistant microbes -- super bugs!
• Third generation cephalosporins (Cefotaxime)
– Emergence of beta-lactamase producing Klebseilla
pneumoniae
• Vancomycin - VRE
Antibiotic-resistant microbes
• Vancomycin- resistant
enterococcus (VRE)
– Theoretic risk on
NICU
–  risk with multiple
course of vanco
– Strict contact
isolation
• Methicillin-resistant
Staphylococcus
aureus (MRSA)
– Real risk on NICU
– Community /
maternal acquired
– Vanco use required
– Strict contact
isolation
Medications
• H2- blockers (ranitidine/Zantac) associated
with increased bacterial and fungal infections
• Steroids
•
•
•
•
Immunosuppression
Hyperglycemia
Skin compromise fragility
Poor healing
• Topical petrolatum ointment (aquaphor)
associated with increased fungal infections
Incidence of Systemic Candidiasis associated
with TPO in infants with BW ≤ 1500 grams
Campbell JR, Zaccaria E, & Baker CJ, Pediatrics 2000;105:1041-1045.
Understaffing and Overcrowding
• Understaffing / increase in census
associated with
– Decreased handwashing
– Epidemics of
•
•
•
•
•
Staphylococcus aureus
MRSA
Multi-drug resistant Enterobacter cloacae
Multi-drug resistant K. pneumoniae
Candida albicans
Care-giver to patient transmission
of flora/pathogens
• Hands of healthcare workers (HCW) a reservoir for
pathogens - controlled with adequate hand washing
• Persistent organisms on HCW hands due to:
–
–
–
–
Omitting or inadequate handwashing
Contaminated antimicrobial washes
Persistent organisms not addressed with antiseptic: Candida
Artificial, painted and long natural nails, hand jewelry
associated with infectious outbreaks
Health care associated infections
on the NICU:
Presentation and Diagnosis
Neonatal Infections
Sepsis
Meningitis
Pneumonia
NEC/perforation
candidemia
EONS

NEC
UTI
Osteomyelitis
Suppurative Arthritis
Conjunctivitis
Orbital Cellulitis
Cellulitis - - Omphalitis
Otitis Media
Diarrheal Disease
Bacterial / Viral / Fungal
HCANI -Any & All
Multi-organ
Signs/Symptoms
?
Laboratory Evaluation
•  Cultures 
• Complete Blood Cell
Count
• CSF glu, protein, WBC
• Glucose
• Bilirubin
• Liver Function Tests
• Coagulation studies
• C-reactive Protein (CRP)
•
•
•
•
•
Chest Radiograph
Abdominal X-ray
Cardiac ultrasound
Catheter ultrasound
Renal ultrasound (fungal
balls)
• Ophthalmologic exam
• Head ultrasound/ CT
New order-set in FCIS!
Cultures -- Who and Which?
• Blood culture -- indicated in ALL infants with
suspected sepsis. Repeat cultures indicated if
initial culture positive.
• ETT culture (with gram stain)-- indicated in all
intubated patients
• Urine culture -- more helpful in LONS/HCANI
– + in 1.6% EONS compared to 7.47% LONS
Klein, Sem in Perinat, 5:3-8
Cultures -- Who and Which?
• CSF culture -- should always be considered
Meningitis frequently accompanies sepsis
- Infants do not localize infections well
- 50-85% meningitis cases have + blood culture
- Specific signs & symptoms occur in less than 50% of
infants with meningitis
- Using “selective criteria” for obtaining CSF may result in
missed or delayed diagnosis in up to 37% of infants with
meningitis
Wiswell et al, Pediatrics, 1995
Laboratory Diagnosis of
Neonatal Meningitis
CSF
--
> 32 WBC/mm3
> 60% PMN
glucose < 50% - 75% of serum
protein > 150 mg/dl
organisms on gram stain
Complete Blood Cell Counts
• Is the CBC helpful as an indicator of
nosocomial neonatal sepsis?
– Thrombocytopenia frequently
associated with sepsis
– WBC may be high, low or “normal”
– Persistent low WBC more predictive
of sepsis than elevated WBC (ANC <
1200)
– I:T quotient unreliable
C-Reactive Protein
• Elevated CRP, > 10 mg/L (>1 mg/dl), highly associated with
sepsis --- but NOT diagnostic
• Limited by lack of “normal” reference values for preterm
infants
• Normal CRP in “rule-out NEC” evaluation correlates with
absence of infection
• Trend with multiple samplings correlates with persistence
(CRP) or resolution (CRP) of infection
• May be useful tool in determining the endpoint for antibiotics
C-Reactive Protein
Pediatrics, 1997, 99:216-221
C-Reactive Protein
• CRP levels <10mg/L, determined >24 hours
after beginning therapy correctly identified 99%
of infants not needing further therapy.
• CRP-guided determination of length of therapy,
shortened the treatment course for most infected
infants without increasing the rate of relapse.
• Limitations: no studies evaluating meningitis or
infections other than bacterial sepsis.
Specific Signs/Symptoms
• NEC - risk of CoNS
• GI perforation - risk of Candida /GI organisms/
anaerobes
• Liver Dysfunction - risk of virus
• Respiratory decompensation - risk GI bugs or
respiratory virus (influenza, RSV-especially with apnea)
• Renal insufficiency - risk of Candida
• CNS involvement - anything
• Thrombocytopenia - risk of Candida / HSV/
CMV
Empiric Therapy
• Vancomycin IV - gram positive coverage treats CoNS, MRSA, GBS, Group D
enterococcus
• Cefotaxime IV - gram negative coverage treats Klebsiella spp, E.coli
• Tailor therapy when culture results known
Additional Empiric Therapy
• Add
– Clindamycin when risk of anaerobes
(GI perforation)
– Acyclovir when risk of HSV
– Amphotericin when risk of Candida
Yeast Susceptibilities
Fairview-University Medical Center – 2006
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Health care associated infections
on the NICU:
Prevention!!!!!
Strategies for prevention:
Eliminate/reduce risk factors - intrinsic
– Prematurity - not likely/beyond our control
– Low IgG - IVIG not successful
– Low ANC - Granulocyte stimulating factor
(GCSF) moderate success
– Immature skin - Aquaphor not successful,
use extreme care with adhesives/handling
– Severity of illness - ????
Strategies for prevention:
Eliminate/reduce risk factors - extrinsic
Catheters
• Insert only when indicated/remove promptly when no
longer required
• Utilize protocols for sterile insertion and maintenance
(chlorhexidine, transparent dressings, etc)
• Minimize manipulations
• Remove if evidence of infection or clot formation
• Replace UVC/UAC when required > 10-14 days
– PICC / broviac / percutaneous a-line
Strategies for prevention:
Eliminate/reduce risk factors - extrinsic
Antibiotics
• Judicious use
• Avoid prolonged courses of BSA
• Avoid prolonged and frequent courses of 3rd
generation cephalosporins or vancomycin
• Nystatin prophylaxis - prevents fungal
overgrowth
Strategies for prevention:
Eliminate/reduce risk factors - extrinsic
Hyperalimentation
• Advance enteral feeds as rapidly as possible
• Minimize handling/breaks in line
Medications
• Avoid rantidine (zantac)
• Avoid/shorten courses of steroids
• Avoid topical petrolatum
Strategies for prevention:
Eliminate/reduce risk factors - extrinsic
#1 Preventative Measure:
GOOD HAND-WASHING!!!!!
Miscellaneous
Human papillomavirus (HPV)
•
•
•
•
•
HPV causes both common skin warts (benign) and cervical/vaginal
warts in the female (precursor to cervical dysplasia/cancer)
Generally asymptomatic
Infection can be passed to the infant during vaginal delivery
Symptoms usually occur between 2-5 years of age
– Respiratory tract
– Mouth
– Eye
Difficult to treat -- vaccine might prevent
Respiratory Syncytial Virus (RSV)
• Causes an acute respiratory illness
• Infants prone to severe bronchiolitis and apnea, often requiring
hospitalization with ventilation
• Preterm infants at high risk for complications
• May be associated with the development of asthma as an older
child
• Transmission is by direct or close contact with contaminated
secretions
• Good handwashing best prevention
• Virus can live on environmental surfaces for hours
Respiratory Syncytial Virus (RSV)
• Diagnosis
– Classic symptoms - respiratory with apnea
– Culture or rapid test on nasopharyngeal swab
• Treatment
– Symptomatic
– Supplemental oxygen or respiratory support
• Prevention
– Palivizumab (Synagis) - monoclonal antibody
– Passive immunization - monthly injections during RSV season
(roughly Nov - March)
Indications for Synagis
• Infants <24 mo with chronic lung disease who
have required therapy within the last 6 months
• Infants <24 months with hemodynamically
significant heart disease
• Infants born <32 weeks GA
– <28 weeks GA up to 12 mo
– 28-32 weeks GA up to 6 mo
AAP Redbook, 2006 Report of the Committee on Infectious Diseases
Indications for Synagis
• Infants 32 - 35 weeks GA with risk factors
–
–
–
–
–
Child-care attendance
School-age siblings
Exposure to environmental air pollutants
Congenital abnormalities of the airway
Infants with severe neuromuscular disorders
• Synagis is not indicated for the treatment of RSV
disease
AAP Redbook, 2006 Report of the Committee on Infectious Diseases
Candida Treatment — Parenteral
• Amphotericin B - mainstay of therapy
• Daily dosage:
• No “test dose” required in neonates
• Initial dose 0.5 mg/kg IV over 2-6 hours
• Increase by 0.25 mg/kg/d to goal of
1.0mg/kg/d
• Adjust for renal insufficiency
0.75-
Candida Treatment — Ampho B
• Treatment Course
• 10-14 days for uncomplicated line sepsis
• 3- 6 weeks for disseminated or complicated
sepsis. Cumulative dose of 30-35 mg/kg or
clearance of disease — whichever comes first!
• Monitor systemic involvement for
improvement/clearance — serial ultrasounds,
repeat cx, etc.
Candida Treatment — Ampho B
• Complications of therapy:
• Renal insufficiency
• Monitor UOP, BUN,Cr qod initially; then q week if stable
• Renal failure reversible, but dialysis may be required
• Profound hypokalemia / hypomagnesemia
• Monitor K and Mg levels closely
• Hematologic - bone marrow suppression
• Monitor CBC and platelets qod initially and then q week
• Liver dysfunction
Candida Treatment — Alternatives
• Liposomal Amphotericin B (Ambisome) or
Amphotericin B Lipid Complex (Ablecet) or
Amphotericin B colloidal dispersion
• Dosing: 3-5 mg/kg/day IV over 2hours
• Appears to be safe and effective, but not superior to
conventional Ampho B
• Diminished side effects, especially renal
• Limitations:
• Decreased renal absorption
Candida Treatment — Alternatives
• Fluconazole — IV (vorconazole next generation)
• Dosing, over 2-6 hours:
• Preterm ≤ 29 weeks: 5-6 mg/kg/72 hours
• Preterm 30-36 weeks: 3-6 mg/kg/48 hours
• Term: 6-12 mg/kg/24-72 hours
• Monitor levels
• Side effects: renal, hepatic and hematologic, but
less than Ampho B
Complement
Risk Factors
#1
PREMATURITY
ELBW > VLBW
Risk Factors for Neonatal
Nosocomial Infections
• Prematurity
– ELBW > VLBW
•
•
•
•
•
Increased LOS
Abdominal surgery / NEC
Hyperalimentation / Intralipids
Neutropenia, Thrombocytopenia
Catheters
– UAC, UVC, ETT, Foley, CT, Peritoneal drains, etc
Risk Factors for Neonatal
Nosocomial Infections
• Prematurity
– ELBW > VLBW
•
•
•
•
•
Increased LOS
Abdominal surgery / NEC
Hyperalimentation / Intralipids
Neutropenia, Thrombocytopenia
Catheters
– UAC, UVC, ETT, Foley, CT, Peritoneal drains, etc
Antibody
Neutrophils
Signs/Symptoms
Strongly suggestive
hypoglycemia / hyperglycemia
hypotension
metabolic acidosis
apnea
shock
DIC
hepatosplenomegaly
bulging fontanelle
seizures
petechiae
hematochezia
respiratory distress
Signs/Symptoms
Nonspecific
lethargy, irritability
temperature instability -- hypothermia or fever
poor feeding
cyanosis
tachycardia
abdominal distention
jaundice
tachypnea