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Enterobacter sakazakii meningitis and death associated with powdered infant formula Matthew J. Kuehnert, M.D. Medical Epidemiologist Division of Healthcare Quality Promotion National Center for Infectious Diseases Background Enterobacter sakazakii gram-negative rod

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enterobacter sakazakii meningitis and death associated with powdered infant formula

Enterobacter sakazakii meningitis and death associated with powdered infant formula

Matthew J. Kuehnert, M.D.

Medical Epidemiologist

Division of Healthcare Quality Promotion

National Center for Infectious Diseases

background
Background
  • Enterobacter sakazakii
    • gram-negative rod
    • classified as yellow-pigmented variant of E. cloacae until designated separate species in 1980
    • reservoir unknown

Lai KK. Medicine 2001;80:113-22

slide3

Clinical Characteristics

  • Pathogenic organism
    • affinity for nervous system
  • Complications serious
    • necrotizing enterocolitis
    • sepsis
    • meningitis
    • cerebral abscesses, cysts or infarction
  • Outcome poor
    • impaired neurologic outcome expected
    • fatality rate 40 - 80%

Lai KK. Medicine 2001;80:113-22

slide4

Potential Sources

  • Powdered infant formula associated with outbreaks of E. sakazakii infections in neonates
  • Organism has been traced to
    • freshly prepared or refrigerated powdered formula
    • utensils and equipment used in formula preparation
    • unreconstituted product
    • unopened product
  • Biering G et al. J Clin Microbiol 1988
  • Simmons BP et al. ICHE 1989
  • Acker JV et al. J Clin Microbiol 2001
slide5

Powdered Formula

  • Powdered formula products associated with healthcare-associated outbreaks of meningitis, sepsis, and necrotizing enterocolitis
  • Powdered infant formulas contaminated with Enterobacteriaceae at low levels
    • 52% of products from 35 countries
    • 14% of powdered formula samples contaminated with E. sakazakii
    • concentrations of E. sakazakii < 1 CFU/ 100g
  • Muytjens HL et al. J Clin Microbiol 1988
slide6

Outline of Presentation

  • CDC investigation – TN, 2001
  • CDC investigation – TN, 2002
  • Additional case finding
  • Conclusions
case description
Case Description
  • Male patient admitted to neonatal intensive care unit (NICU) April 2001
    • gestational age 33.5 weeks, C-section delivery
    • APGAR scores 4 and 7, birthweight 1,270 grams
  • day 3: started on enteric feeding
      • powdered formula
      • breast milk
  • day 11: sepsis and neurologic symptoms
case description8
Case Description
  • Lumbar puncture consistent with meningitis
    • white cells and red cells present, high protein, low glucose
    • cerebrospinal fluid culture grew E. sakazakii
  • Treated with ampicillin and cefotaxime
  • Infant pulseless, resuscitated on pressors
  • day 20: expired after withdrawal of support due to severe neurologic disease
facility characteristics
Facility Characteristics
  • University of Tennessee Medical Center at Knoxville
    • regional referral and tertiary care center
    • 360 beds
    • Level III NICU: 55 beds
      • Intensive care nursery – 27 beds
      • Intermediate care – 28 beds
    • no clinical reports of E. sakazakii from NICU in previous three years (Jan 1998-Dec 2000)
    • two isolates detected in March 2001
study objectives
Study Objectives
  • Ascertain additional cases of E. sakazakii infection or colonization
  • Determine source of organism
  • Develop measures to prevent further infection
case finding
Case Finding
  • Cross-sectional prevalence survey
    • all patients in NICU during time case-patient was ill (April 10-20, 2001, i.e., study period) assessed for stool colonization
    • clinical reports from microbiology laboratory reviewed for E. sakazakii
    • case-patient defined as any NICU patient with E. sakazakii-positive culture during study period
case finding12
Case Finding
  • 49 patients hospitalized during study period
  • 9 case-patients
  • Site of infection or colonization*
    • 6 stool
    • 2 tracheal aspirates
    • 1 urine
    • 1 cerebrospinal fluid

*exceeds case-patient total due to culture-positive at multiple sites in one patient

slide13
Gestational age

Birth weight

Total Parenteral Nutrition receipt

Parenteral lipid receipt

Formula (powdered vs. liquid ready-to-feed)

Breast Milk

Continuous feed (vs. bolus)

Ventilator usage

Aerosol therapy

Humidified isolette

Type of delivery

Premature Rupture Of Membranes

Maternal Group B Streptococcus colonization

Maternal antibiotics prior to delivery

Cohort StudyRisk factors examined for association with E. sakazakiicolonization or infection through medical chart review
cohort study
Cohort Study

Variable ill/exposed ill/unexposed P-value

Powdered Formula Use 9/30 0/19 <0.01

Continuous Feeding 7/27 2/22 0.16

Breast Milk Use (absence of) 7/27 2/22 0.16

Mechanical Ventilator Use 7/29 4/20 0.27

Lipid receipt 9/42 0/7 0.32

Delivery by Caesarian section 8/35 1/14 0.41

Aerosol therapy 5/20 4/29 0.45

Gestational Age (weeks, median) 33 32 0.54

TPN receipt 9/44 0/5 0.57

Birthweight (grams, median) 2000 1452 0.58

Humidified isolette 8/42 0/9 0.66

observational laboratory studies
Observational & Laboratory Studies
  • Reviewed policies and observed procedures
    • Formula preparation, storage, and administration
    • Measured refrigerator storage temperature
  • Cultured environment and materials for formula preparation and patient care
    • Prep area: sink, soap containers, blender
    • NICU: sink, humidified water, formula from continuous feeding bags
  • Cultured lots in use during study period
    • powdered formula from opened container
laboratory studies
Laboratory Studies
  • Studies performed by CDC
    • identification confirmation of isolates from cohort study
    • culture of opened cans of formula
    • culture of unopened cans of formula (identical lot number supplied by manufacturer)
    • culture method according to modified protocol of Muytjens et al.*
    • all study isolates and selected historical isolates compared by pulsed-field gel electrophoresis (PFGE)
  • *Muytjens HL et al. J Clin Microbiol 1988
laboratory studies17
Laboratory Studies
  • Environmental and formula cultures
    • on-site cultures no growth
    • CDC cultures grew E. sakazakii from single lot of powdered formula
  • PFGE patterns indistiguishable between isolates
    • cerebrospinal fluid of case-patient fatality
    • opened and unopened containers of powdered formula
  • PFGE suggest pattern diversity among other isolates from cohort study and compared with previously collected strains
slide18

PFGE Results

Lanes 2-6: CSF, respiratory, stool, urine, formula isolates

observational studies
Observational Studies
  • No breaches in infection control detected
  • Formula prepared according to manufacturer’s instructions on label
    • mixed with sterile water
    • refrigerated <24 hours
  • Mixed product used within 8 hours
    • hang time ~6 hours
intervention
Intervention
  • Powdered formula use
    • Prescribed in ~50% of neonates in NICU
    • Formula preparation site changed from NICU to pharmacy
    • Principal formula used switched to liquid ready-to-feed (still use some powder selectively except implicated type)
  • Allowable hang time for mixed feeds decreased from 8 to 4 hours
  • No further E. sakazakii infections or clinical isolates detected from NICU
conclusion tn 2001
Conclusion – TN, 2001
  • The source of a case of Enterobacter sakazakii infection was traced to receipt of powdered infant formula
    • only significant risk factor on epidemiologic study
    • matching isolate patterns on PFGE
  • Powdered formula, a nonsterile product, can be contaminated with E. sakazakii, an organism that can cause fatal meningitis in neonates
  • Use of powdered formula should be carefully considered in the neonatal healthcare setting
slide22

Formula Recall, April 2002

  • Voluntary recall of Portagen® powder by Mead Johnson
    • batch BMC 17, exp. 01/03
slide23

Formula Preparation: Summary Interim Recommendations for the NICU

  • Select formula products based on nutritional needs
  • Trained personnel should prepare products using aseptic techniques
  • Follow manufacturers’ recommendations
  • Administration/ hang time < 4 hours
  • Written hospital guidelines including notification, reporting, and follow-up available in the event of a product recall

MMWR 2002;51(14): 297-300

slide24

Reporting of Cases

Reporting of invasive infection attributable to E. sakazakii in infants <12 months to:

  • State Health Departments
  • CDC (800-893-0485)
  • FDA MedWatch Program (800-332-1088)

http://www.fda.gov/medwatch

formula issues
Formula Issues
  • Is this an emerging pathogen?
    • reservoir of organism?
    • endemic rate of E. sakazakii colonization or infection due to powdered infant formula?
    • role of specific methods of preparation and use to promote growth and reach “threshold” of clinical significance, e.g., refrigeration, product hang time?
    • predisposing risk factors for infection?
formula issues26
Formula Issues
  • Manufacture
  • Screening
  • Preparation
  • Storage
  • Use
  • Treatment of Infection
  • Case Reporting/Surveillance
slide27

Formula Issues

  • Manufacture: changes in processing or implementation of screening
  • Preparation, Storage, Use: development of guidelines or recommendations
  • Case Reporting/Surveillance: modification of record keeping concerning formula use and more active case finding
future plans
Future Plans
  • Epidemiology
    • Case investigations
    • Case-series description
  • Policy on formula preparation
    • American Dietetic Association
      • hospital survey of preparation and use
      • revision of guidelines
  • Laboratory research
    • Growth characteristics of E. sakazakii
    • Effect of competitive microbial flora and heat inactivation on growth
acknowledgements
CDC

Andi Shane

Chris Braden

Terri Forster

Matthew Arduino

Dan Jernigan

University of Tennessee at Knoxville

Inga Himelright

Eva Harris

Hospital A, TN

State Health Departments

FDA

Karl Klontz

Elisa Eliott

Charles Mize

Benson Silverman

Lynn Larson

Morris Potter

EIN

Larry Strausbaugh

Laura Liedtke

ADA

Sandra Robbins

Acknowledgements
slide30

PREVENTION IS PRIMARY!

Protect patients…protect healthcare personnel…

promote quality healthcare!

Division of Healthcare Quality Promotion

National Center for Infectious Diseases