health care associated infections on the nicu (aka: nosocomial infections) catherine m. bendel, md...

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