health care associated infections on the nicu (aka: nosocomial infections) catherine m. bendel, md...
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Health Care Associated Infections
on the NICU(aka: Nosocomial infections)
Catherine M. Bendel, MDAssociate Professor of Pediatrics
Director, Neonatal-Perinatal Medicine Fellowship Program
ObjectivesObjectives
• 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.
DefinitionsDefinitions• 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
MicrobesMicrobes
• 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 - HCANIMicrobes - 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
IncidenceIncidence
• 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: Risk Factors for HCANI: IntrinsicIntrinsic
• Prematurity – ELBW > VLBW
• Immunology of the neonate• Mechanical barrier to
infection• Severity of illness• Abnormal microbial flora
PrematurityPrematurity• 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 Neonatal Immune SystemSystem
• All neonates relatively
immunocompromised
• Immature, Ineffective and Inadequate
levels:
– Antibodies / complement
– Neutrophils
– T-cells / cytokines
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
Immunity
No contact with infectious agents = no antibody production
Life in-utero
Antibodies
Infectious agent
Immunity
x x
Premature Antibody Premature Antibody levelslevels
• 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 Neonatal Neutrophils (PMNs)(PMNs)
• Immature Chemotaxis Deformability Phagocytosis Storage pool
• Adults 14-fold > circulating pool
• Neonates only 2-fold
Manroe et al, J Pediatr, 1979
ANC = absolute neutrophil count
3600
7500
“Normal” VLBW neonates
Mouzinho et al, Pediatr 94:76, 1994
“Normal” VLBW neonates(<1200 abnormal)
Mouzinho et al, Pediatr 94:76, 1994
1200
6000
30 days
Neonatal Neonatal NeutropeniaNeutropenia•Prematurity•Maternal
Hypertension• IUGR•Sepsis
Neonatal Barriers to Infection
Impairments/alterations Impairments/alterations in Neonatal Natural in Neonatal Natural
BarriersBarriers• 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 aTIFF (Uncompressed) decompressor
are needed to see this picture.
QuickTime™ and aTIFF (Uncompressed) decompressor
are needed to see this picture.
JL Rowen, Sem Perinatal 27:406-413, 2003
Impairments/alterations Impairments/alterations in Neonatal Natural in Neonatal Natural
BarriersBarriers
•Umbilicus - colonization of devitalized tissue
• GI tract – Increased gastric pH with
drip feeds/H2 blockers– Mucosal damage with NEC
Severity of IllnessSeverity of Illness
• Direct correlation with rate of HCANI: – Increased LOS– Higher severity of illness scores– Congenital anomalies
• Potential correlation:– Prenatal insults/stress
Abnormal Microbial Abnormal Microbial FloraFlora
•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: Risk Factors for HCANI: ExtrinsicExtrinsic
•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 timeUVC > 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 Antibiotic-resistant microbesmicrobes
• 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 Understaffing and OvercrowdingOvercrowding
• 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 Care-giver to patient transmission of transmission of flora/pathogensflora/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 InfectionsNeonatal Infections
Sepsis MeningitisPneumonia
NECUTI
OsteomyelitisSuppurative Arthritis
ConjunctivitisOrbital Cellulitis
Cellulitis - - Omphalitis
Otitis MediaDiarrheal Disease
Bacterial / Viral / Fungal
EONS
HCANI -- Any & All
Multi-organ
NEC/perforationcandidemia
Signs/SymptomsSigns/Symptoms
??
Laboratory Laboratory EvaluationEvaluation
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?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?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 Laboratory Diagnosis of Neonatal MeningitisNeonatal Meningitis
CSF - - > 32 WBC/mm3
> 60% PMN
glucose < 50% - 75% of serum
protein > 150 mg/dl
organisms on gram stain
Complete Blood Cell Complete Blood Cell CountsCounts
• 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 ProteinC-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 ProteinC-Reactive Protein
Pediatrics, 1997, 99:216-221
C-Reactive ProteinC-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 Specific Signs/SymptomsSigns/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 TherapyEmpiric 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 Additional Empiric TherapyTherapy
• Add– Clindamycin when risk of
anaerobes (GI perforation)– Acyclovir when risk of HSV– Amphotericin when risk of
Candida
Yeast SusceptibilitiesFairview-University Medical Center –
2006
Yeast SusceptibilitiesFairview-University Medical Center –
2006
Candida
albicans
Candida
glabrata
Candida
krusei
Candida
tropicalis
Candida
parap-
silosis
Ampho B 99% 99% 100% 100% 100%
5-FC 99% 98% 0% 93% 99%
Flucon-
azole98% 50% O% 78% 96%
Itracon-
azole97% 51% 67% 80% 100%
Candida
albicans
Candida
glabrata
Candida
krusei
Candida
tropicalis
Candida
parap-
silosis
Ampho B 99% 99% 100% 100% 100%
5-FC 99% 98% 0% 93% 99%
Flucon-
azole98% 50% O% 78% 96%
Itracon-
azole97% 51% 67% 80% 100%
Health care associated infections
on the NICU:Prevention!!!!!
Strategies for prevention: Strategies for prevention: Eliminate/reduce risk factors Eliminate/reduce risk factors
- intrinsic- 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: Strategies for prevention: Eliminate/reduce risk factors - Eliminate/reduce risk factors -
extrinsicextrinsic
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: Strategies for prevention: Eliminate/reduce risk factors - Eliminate/reduce risk factors -
extrinsicextrinsic
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: Strategies for prevention: Eliminate/reduce risk factors - Eliminate/reduce risk factors -
extrinsicextrinsic
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: Strategies for prevention: Eliminate/reduce risk factors - Eliminate/reduce risk factors -
extrinsicextrinsic
#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 0.75-1.0mg/kg/d
• Adjust for renal insufficiency
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 Risk Factors
#1PREMATURITY
ELBW > VLBW
Risk Factors for Risk Factors for Neonatal Nosocomial Neonatal Nosocomial
InfectionsInfections• Prematurity
– ELBW > VLBW• Increased LOS• Abdominal surgery / NEC• Hyperalimentation / Intralipids• Neutropenia, Thrombocytopenia• Catheters
– UAC, UVC, ETT, Foley, CT, Peritoneal drains, etc
Risk Factors for Risk Factors for Neonatal Nosocomial Neonatal Nosocomial
InfectionsInfections• Prematurity
– ELBW > VLBW• Increased LOS• Abdominal surgery / NEC• Hyperalimentation / Intralipids• Neutropenia, Thrombocytopenia• Catheters
– UAC, UVC, ETT, Foley, CT, Peritoneal drains, etc
Antibody
Neutrophils
Signs/SymptomsSigns/Symptoms
Strongly suggestivehypoglycemia / hyperglycemiahypotensionmetabolic acidosisapneashockDIChepatosplenomegalybulging fontanelleseizurespetechiaehematocheziarespiratory distress
Signs/SymptomsSigns/Symptoms
Nonspecificlethargy, irritability
temperature instability -- hypothermia or fever
poor feeding
cyanosis
tachycardia
abdominal distention
jaundice
tachypnea