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one study found it in 14% of samples taken
one study found it in 14% of samples taken
one study found it in 14% of samples taken
one study found it in 14% of samples taken
one study found it in 14% of samples taken
one study found it in 14% of samples taken
one study found it in 14% of samples taken
one study found it in 14% of samples taken
one study found it in 14% of samples taken
one study found it in 14% of samples taken
one study found it in 14% of samples taken
one study found it in 14% of samples taken
one study found it in 14% of samples taken
one study found it in 14% of samples taken
one study found it in 14% of samples taken
one study found it in 14% of samples taken
one study found it in 14% of samples taken
one study found it in 14% of samples taken
one study found it in 14% of samples taken
one study found it in 14% of samples taken
one study found it in 14% of samples taken
one study found it in 14% of samples taken
one study found it in 14% of samples taken
one study found it in 14% of samples taken
one study found it in 14% of samples taken
one study found it in 14% of samples taken
one study found it in 14% of samples taken
one study found it in 14% of samples taken
one study found it in 14% of samples taken
one study found it in 14% of samples taken
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one study found it in 14% of samples taken

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  • 1. 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
  • 2. 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
  • 3. 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
  • 4. 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
  • 5. 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
  • 6. Outline of Presentation
    • CDC investigation – TN, 2001
    • CDC investigation – TN, 2002
    • Additional case finding
    • Conclusions
  • 7. 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
  • 8. 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
  • 9. 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
  • 10. Study Objectives
    • Ascertain additional cases of E. sakazakii infection or colonization
    • Determine source of organism
    • Develop measures to prevent further infection
  • 11. 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
  • 12. 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
  • 13. Cohort Study Risk factors examined for association with E. sakazakii colonization or infection through medical chart review
    • 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
  • 14. 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
  • 15. 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
  • 16. 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
  • 17. 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
  • 18. PFGE Results Lanes 2-6: CSF, respiratory, stool, urine, formula isolates
  • 19. 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
  • 20. 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
  • 21. 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
  • 22. Formula Recall, April 2002
    • Voluntary recall of Portagen ® powder by Mead Johnson
      • batch BMC 17, exp. 01/03
  • 23. 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
  • 24. 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
  • 25. 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?
  • 26. Formula Issues
    • Manufacture
    • Screening
    • Preparation
    • Storage
    • Use
    • Treatment of Infection
    • Case Reporting/Surveillance
  • 27. 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
  • 28. 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
  • 29. 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
  • 30. PREVENTION IS PRIMARY! Protect patients…protect healthcare personnel… promote quality healthcare! Division of Healthcare Quality Promotion National Center for Infectious Diseases

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