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