one study found it in 14% of samples taken
TRANSCRIPT
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 – classified as yellow-pigmented variant of E. cloacae
until designated separate species in 1980– reservoir unknown
Lai KK. Medicine 2001;80:113-22
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
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
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
Outline of Presentation
• CDC investigation – TN, 2001
• CDC investigation – TN, 2002
• Additional case finding
• Conclusions
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 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
• 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
• Ascertain additional cases of E. sakazakii infection or colonization
• Determine source of organism
• Develop measures to prevent further infection
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 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
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
Cohort Study
Variable ill/exposed ill/unexposed P-valuePowdered 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
• 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
• 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 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
PFGE Results
Lanes 2-6: CSF, respiratory, stool, urine, formula isolates
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
• 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
• 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
Formula Recall, April 2002
• Voluntary recall of Portagen® powder by Mead Johnson – batch BMC 17, exp. 01/03
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
Reporting of Cases
Reporting of invasive infection attributable to E. sakazakii in infants <12 months to:
1. State Health Departments
2. CDC (800-893-0485)
3. FDA MedWatch Program (800-332-1088)
http://www.fda.gov/medwatch
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 Issues
• Manufacture
• Screening
• Preparation
• Storage
• Use
• Treatment of Infection
• Case Reporting/Surveillance
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
• 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
PREVENTION IS PRIMARY!
PREVENTION IS PRIMARY!
Protect patients…protect healthcare personnel…
promote quality healthcare!Division of Healthcare Quality Promotion
National Center for Infectious Diseases