Enterobacter sakazakii  meningitis and death associated with powdered infant formula Matthew J. Kuehnert, M.D. Medical Epi...
Background <ul><li>Enterobacter sakazakii </li></ul><ul><ul><li>gram-negative rod  </li></ul></ul><ul><ul><li>classified a...
Clinical Characteristics <ul><li>Pathogenic organism </li></ul><ul><ul><li>affinity for nervous system  </li></ul></ul><ul...
Potential Sources <ul><li>Powdered infant formula associated with outbreaks of  E. sakazakii  infections in neonates </li>...
Powdered Formula <ul><li>Powdered formula products associated with healthcare-associated outbreaks of meningitis, sepsis, ...
Outline of Presentation <ul><li>CDC investigation – TN, 2001  </li></ul><ul><li>CDC investigation – TN, 2002 </li></ul><ul...
Case Description <ul><li>Male patient admitted to neonatal intensive care unit (NICU) April 2001 </li></ul><ul><ul><li>ges...
Case Description <ul><li>Lumbar puncture consistent with meningitis </li></ul><ul><ul><li>white cells and red cells presen...
Facility Characteristics <ul><li>University of Tennessee Medical Center at Knoxville </li></ul><ul><ul><li>regional referr...
Study Objectives <ul><li>Ascertain additional cases of  E. sakazakii  infection or colonization   </li></ul><ul><li>Determ...
Case Finding <ul><li>Cross-sectional prevalence survey </li></ul><ul><ul><li>all patients in NICU during time case-patient...
Case Finding <ul><li>49 patients hospitalized during study period </li></ul><ul><li>9 case-patients </li></ul><ul><li>Site...
Cohort Study   Risk factors examined for association with  E. sakazakii   colonization or infection through medical chart ...
Cohort Study Variable ill/exposed ill/unexposed  P-value Powdered Formula Use 9/30 0/19 <0.01 Continuous Feeding 7/27 2/22...
Observational & Laboratory Studies <ul><li>Reviewed policies and observed procedures </li></ul><ul><ul><li>Formula prepara...
Laboratory Studies <ul><li>Studies performed by CDC </li></ul><ul><ul><li>identification confirmation of isolates from coh...
Laboratory Studies <ul><li>Environmental and formula cultures </li></ul><ul><ul><li>on-site cultures no growth </li></ul><...
PFGE Results Lanes 2-6: CSF, respiratory, stool, urine, formula isolates
Observational Studies <ul><li>No breaches in infection control detected </li></ul><ul><li>Formula prepared according to ma...
Intervention <ul><li>Powdered formula use </li></ul><ul><ul><li>Prescribed in ~50% of neonates in NICU  </li></ul></ul><ul...
Conclusion – TN, 2001 <ul><li>The source of a case of  Enterobacter sakazakii  infection was traced to receipt of powdered...
Formula Recall, April 2002 <ul><li>Voluntary recall of Portagen ®  powder by Mead Johnson  </li></ul><ul><ul><li>batch BMC...
Formula Preparation: Summary Interim Recommendations for the NICU <ul><li>Select formula products based on nutritional nee...
Reporting of Cases <ul><li>Reporting of invasive infection attributable to  E. sakazakii  in infants <12 months to: </li><...
Formula Issues <ul><li>Is this an emerging pathogen? </li></ul><ul><ul><li>reservoir of organism?  </li></ul></ul><ul><ul>...
Formula Issues <ul><li>Manufacture </li></ul><ul><li>Screening </li></ul><ul><li>Preparation </li></ul><ul><li>Storage </l...
Formula Issues <ul><li>Manufacture:  changes in processing or implementation of screening </li></ul><ul><li>Preparation, S...
Future Plans <ul><li>Epidemiology  </li></ul><ul><ul><li>Case investigations </li></ul></ul><ul><ul><li>Case-series descri...
Acknowledgements <ul><li>CDC </li></ul><ul><ul><li>Andi Shane </li></ul></ul><ul><ul><li>Chris Braden </li></ul></ul><ul><...
PREVENTION  IS PRIMARY! Protect patients…protect healthcare personnel… promote quality healthcare! Division of Healthcare ...
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one study found it in 14% of samples taken

  1. 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. 2. Background <ul><li>Enterobacter sakazakii </li></ul><ul><ul><li>gram-negative rod </li></ul></ul><ul><ul><li>classified as yellow-pigmented variant of E. cloacae until designated separate species in 1980 </li></ul></ul><ul><ul><li>reservoir unknown </li></ul></ul>Lai KK. Medicine 2001;80:113-22
  3. 3. Clinical Characteristics <ul><li>Pathogenic organism </li></ul><ul><ul><li>affinity for nervous system </li></ul></ul><ul><li>Complications serious </li></ul><ul><ul><li>necrotizing enterocolitis </li></ul></ul><ul><ul><li>sepsis </li></ul></ul><ul><ul><li>meningitis </li></ul></ul><ul><ul><li>cerebral abscesses, cysts or infarction </li></ul></ul><ul><li>Outcome poor </li></ul><ul><ul><li>impaired neurologic outcome expected </li></ul></ul><ul><ul><li>fatality rate 40 - 80% </li></ul></ul>Lai KK. Medicine 2001;80:113-22
  4. 4. Potential Sources <ul><li>Powdered infant formula associated with outbreaks of E. sakazakii infections in neonates </li></ul><ul><li>Organism has been traced to </li></ul><ul><ul><li>freshly prepared or refrigerated powdered formula </li></ul></ul><ul><ul><li>utensils and equipment used in formula preparation </li></ul></ul><ul><ul><li>unreconstituted product </li></ul></ul><ul><ul><li>unopened product </li></ul></ul><ul><ul><li>Biering G et al. J Clin Microbiol 1988 </li></ul></ul><ul><ul><li>Simmons BP et al. ICHE 1989 </li></ul></ul><ul><ul><li>Acker JV et al. J Clin Microbiol 2001 </li></ul></ul>
  5. 5. Powdered Formula <ul><li>Powdered formula products associated with healthcare-associated outbreaks of meningitis, sepsis, and necrotizing enterocolitis </li></ul><ul><li>Powdered infant formulas contaminated with Enterobacteriaceae at low levels </li></ul><ul><ul><li>52% of products from 35 countries </li></ul></ul><ul><ul><li>14% of powdered formula samples contaminated with E. sakazakii </li></ul></ul><ul><ul><li>concentrations of E. sakazakii < 1 CFU/ 100g </li></ul></ul><ul><ul><li>Muytjens HL et al. J Clin Microbiol 1988 </li></ul></ul>
  6. 6. Outline of Presentation <ul><li>CDC investigation – TN, 2001 </li></ul><ul><li>CDC investigation – TN, 2002 </li></ul><ul><li>Additional case finding </li></ul><ul><li>Conclusions </li></ul>
  7. 7. Case Description <ul><li>Male patient admitted to neonatal intensive care unit (NICU) April 2001 </li></ul><ul><ul><li>gestational age 33.5 weeks, C-section delivery </li></ul></ul><ul><ul><li>APGAR scores 4 and 7, birthweight 1,270 grams </li></ul></ul><ul><li>day 3: started on enteric feeding </li></ul><ul><ul><ul><li>powdered formula </li></ul></ul></ul><ul><ul><ul><li>breast milk </li></ul></ul></ul><ul><li>day 11: sepsis and neurologic symptoms </li></ul>
  8. 8. Case Description <ul><li>Lumbar puncture consistent with meningitis </li></ul><ul><ul><li>white cells and red cells present, high protein, low glucose </li></ul></ul><ul><ul><li>cerebrospinal fluid culture grew E. sakazakii </li></ul></ul><ul><li>Treated with ampicillin and cefotaxime </li></ul><ul><li>Infant pulseless, resuscitated on pressors </li></ul><ul><li>day 20: expired after withdrawal of support due to severe neurologic disease </li></ul>
  9. 9. Facility Characteristics <ul><li>University of Tennessee Medical Center at Knoxville </li></ul><ul><ul><li>regional referral and tertiary care center </li></ul></ul><ul><ul><li>360 beds </li></ul></ul><ul><ul><li>Level III NICU: 55 beds </li></ul></ul><ul><ul><ul><li>Intensive care nursery – 27 beds </li></ul></ul></ul><ul><ul><ul><li>Intermediate care – 28 beds </li></ul></ul></ul><ul><ul><li>no clinical reports of E. sakazakii from NICU in previous three years (Jan 1998-Dec 2000) </li></ul></ul><ul><ul><li>two isolates detected in March 2001 </li></ul></ul>
  10. 10. Study Objectives <ul><li>Ascertain additional cases of E. sakazakii infection or colonization </li></ul><ul><li>Determine source of organism </li></ul><ul><li>Develop measures to prevent further infection </li></ul>
  11. 11. Case Finding <ul><li>Cross-sectional prevalence survey </li></ul><ul><ul><li>all patients in NICU during time case-patient was ill (April 10-20, 2001, i.e., study period) assessed for stool colonization </li></ul></ul><ul><ul><li>clinical reports from microbiology laboratory reviewed for E. sakazakii </li></ul></ul><ul><ul><li>case-patient defined as any NICU patient with E. sakazakii -positive culture during study period </li></ul></ul>
  12. 12. Case Finding <ul><li>49 patients hospitalized during study period </li></ul><ul><li>9 case-patients </li></ul><ul><li>Site of infection or colonization* </li></ul><ul><ul><li>6 stool </li></ul></ul><ul><ul><li>2 tracheal aspirates </li></ul></ul><ul><ul><li>1 urine </li></ul></ul><ul><ul><li>1 cerebrospinal fluid </li></ul></ul>*exceeds case-patient total due to culture-positive at multiple sites in one patient
  13. 13. Cohort Study Risk factors examined for association with E. sakazakii colonization or infection through medical chart review <ul><li>Gestational age </li></ul><ul><li>Birth weight </li></ul><ul><li>Total Parenteral Nutrition receipt </li></ul><ul><li>Parenteral lipid receipt </li></ul><ul><li>Formula (powdered vs. liquid ready-to-feed) </li></ul><ul><li>Breast Milk </li></ul><ul><li>Continuous feed (vs. bolus) </li></ul><ul><ul><li>Ventilator usage </li></ul></ul><ul><ul><li>Aerosol therapy </li></ul></ul><ul><ul><li>Humidified isolette </li></ul></ul><ul><ul><li>Type of delivery </li></ul></ul><ul><ul><li>Premature Rupture Of Membranes </li></ul></ul><ul><ul><li>Maternal Group B Streptococcus colonization </li></ul></ul><ul><ul><li>Maternal antibiotics prior to delivery </li></ul></ul>
  14. 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. 15. Observational & Laboratory Studies <ul><li>Reviewed policies and observed procedures </li></ul><ul><ul><li>Formula preparation, storage, and administration </li></ul></ul><ul><ul><li>Measured refrigerator storage temperature </li></ul></ul><ul><li>Cultured environment and materials for formula preparation and patient care </li></ul><ul><ul><li>Prep area: sink, soap containers, blender </li></ul></ul><ul><ul><li>NICU: sink, humidified water, formula from continuous feeding bags </li></ul></ul><ul><li>Cultured lots in use during study period </li></ul><ul><ul><li>powdered formula from opened container </li></ul></ul>
  16. 16. Laboratory Studies <ul><li>Studies performed by CDC </li></ul><ul><ul><li>identification confirmation of isolates from cohort study </li></ul></ul><ul><ul><li>culture of opened cans of formula </li></ul></ul><ul><ul><li>culture of unopened cans of formula (identical lot number supplied by manufacturer) </li></ul></ul><ul><ul><li>culture method according to modified protocol of Muytjens et al.* </li></ul></ul><ul><ul><li>all study isolates and selected historical isolates compared by pulsed-field gel electrophoresis (PFGE) </li></ul></ul><ul><ul><li>*Muytjens HL et al. J Clin Microbiol 1988 </li></ul></ul>
  17. 17. Laboratory Studies <ul><li>Environmental and formula cultures </li></ul><ul><ul><li>on-site cultures no growth </li></ul></ul><ul><ul><li>CDC cultures grew E. sakazakii from single lot of powdered formula </li></ul></ul><ul><li>PFGE patterns indistiguishable between isolates </li></ul><ul><ul><li>cerebrospinal fluid of case-patient fatality </li></ul></ul><ul><ul><li>opened and unopened containers of powdered formula </li></ul></ul><ul><li>PFGE suggest pattern diversity among other isolates from cohort study and compared with previously collected strains </li></ul>
  18. 18. PFGE Results Lanes 2-6: CSF, respiratory, stool, urine, formula isolates
  19. 19. Observational Studies <ul><li>No breaches in infection control detected </li></ul><ul><li>Formula prepared according to manufacturer’s instructions on label </li></ul><ul><ul><li>mixed with sterile water </li></ul></ul><ul><ul><li>refrigerated <24 hours </li></ul></ul><ul><li>Mixed product used within 8 hours </li></ul><ul><ul><li>hang time ~6 hours </li></ul></ul>
  20. 20. Intervention <ul><li>Powdered formula use </li></ul><ul><ul><li>Prescribed in ~50% of neonates in NICU </li></ul></ul><ul><ul><li>Formula preparation site changed from NICU to pharmacy </li></ul></ul><ul><ul><li>Principal formula used switched to liquid ready-to-feed (still use some powder selectively except implicated type) </li></ul></ul><ul><li>Allowable hang time for mixed feeds decreased from 8 to 4 hours </li></ul><ul><li>No further E. sakazakii infections or clinical isolates detected from NICU </li></ul>
  21. 21. Conclusion – TN, 2001 <ul><li>The source of a case of Enterobacter sakazakii infection was traced to receipt of powdered infant formula </li></ul><ul><ul><li>only significant risk factor on epidemiologic study </li></ul></ul><ul><ul><li>matching isolate patterns on PFGE </li></ul></ul><ul><li>Powdered formula, a nonsterile product, can be contaminated with E. sakazakii, an organism that can cause fatal meningitis in neonates </li></ul><ul><li>Use of powdered formula should be carefully considered in the neonatal healthcare setting </li></ul>
  22. 22. Formula Recall, April 2002 <ul><li>Voluntary recall of Portagen ® powder by Mead Johnson </li></ul><ul><ul><li>batch BMC 17, exp. 01/03 </li></ul></ul>
  23. 23. Formula Preparation: Summary Interim Recommendations for the NICU <ul><li>Select formula products based on nutritional needs </li></ul><ul><li>Trained personnel should prepare products using aseptic techniques </li></ul><ul><li>Follow manufacturers’ recommendations </li></ul><ul><li>Administration/ hang time < 4 hours </li></ul><ul><li>Written hospital guidelines including notification, reporting, and follow-up available in the event of a product recall </li></ul>MMWR 2002;51(14): 297-300
  24. 24. Reporting of Cases <ul><li>Reporting of invasive infection attributable to E. sakazakii in infants <12 months to: </li></ul><ul><li>State Health Departments </li></ul><ul><li>CDC (800-893-0485) </li></ul><ul><li>FDA MedWatch Program (800-332-1088) </li></ul><ul><li>http://www.fda.gov/medwatch </li></ul>
  25. 25. Formula Issues <ul><li>Is this an emerging pathogen? </li></ul><ul><ul><li>reservoir of organism? </li></ul></ul><ul><ul><li>endemic rate of E. sakazakii colonization or infection due to powdered infant formula? </li></ul></ul><ul><ul><li>role of specific methods of preparation and use to promote growth and reach “threshold” of clinical significance, e.g., refrigeration, product hang time? </li></ul></ul><ul><ul><li>predisposing risk factors for infection? </li></ul></ul>
  26. 26. Formula Issues <ul><li>Manufacture </li></ul><ul><li>Screening </li></ul><ul><li>Preparation </li></ul><ul><li>Storage </li></ul><ul><li>Use </li></ul><ul><li>Treatment of Infection </li></ul><ul><li>Case Reporting/Surveillance </li></ul>
  27. 27. Formula Issues <ul><li>Manufacture: changes in processing or implementation of screening </li></ul><ul><li>Preparation, Storage, Use: development of guidelines or recommendations </li></ul><ul><li>Case Reporting/Surveillance: modification of record keeping concerning formula use and more active case finding </li></ul>
  28. 28. Future Plans <ul><li>Epidemiology </li></ul><ul><ul><li>Case investigations </li></ul></ul><ul><ul><li>Case-series description </li></ul></ul><ul><li>Policy on formula preparation </li></ul><ul><ul><li>American Dietetic Association </li></ul></ul><ul><ul><ul><li>hospital survey of preparation and use </li></ul></ul></ul><ul><ul><ul><li>revision of guidelines </li></ul></ul></ul><ul><li>Laboratory research </li></ul><ul><ul><li>Growth characteristics of E. sakazakii </li></ul></ul><ul><ul><li>Effect of competitive microbial flora and heat inactivation on growth </li></ul></ul>
  29. 29. Acknowledgements <ul><li>CDC </li></ul><ul><ul><li>Andi Shane </li></ul></ul><ul><ul><li>Chris Braden </li></ul></ul><ul><ul><li>Terri Forster </li></ul></ul><ul><ul><li>Matthew Arduino </li></ul></ul><ul><ul><li>Dan Jernigan </li></ul></ul><ul><li>University of Tennessee at Knoxville </li></ul><ul><ul><li>Inga Himelright </li></ul></ul><ul><ul><li>Eva Harris </li></ul></ul><ul><li>Hospital A, TN </li></ul><ul><li>State Health Departments </li></ul><ul><li>FDA </li></ul><ul><ul><li>Karl Klontz </li></ul></ul><ul><ul><li>Elisa Eliott </li></ul></ul><ul><ul><li>Charles Mize </li></ul></ul><ul><ul><li>Benson Silverman </li></ul></ul><ul><ul><li>Lynn Larson </li></ul></ul><ul><ul><li>Morris Potter </li></ul></ul><ul><li>EIN </li></ul><ul><ul><li>Larry Strausbaugh </li></ul></ul><ul><ul><li>Laura Liedtke </li></ul></ul><ul><li>ADA </li></ul><ul><ul><li>Sandra Robbins </li></ul></ul>
  30. 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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