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Case Definition- E. sakazakii infection

Enterobacter sakazakii Case Reports and Outbreaks Involving Infants as Reported in the Peer-Reviewed English Medical Literature Karl C. Klontz Epidemiology Team Center for Food Safety and Applied Nutrition Food and Drug Administration. Case Definition- E. sakazakii infection.

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Case Definition- E. sakazakii infection

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  1. Enterobacter sakazakii CaseReports andOutbreaksInvolving Infants asReported in the Peer-Reviewed English Medical LiteratureKarl C. KlontzEpidemiology TeamCenter for Food Safety and Applied NutritionFood and Drug Administration

  2. Case Definition- E. sakazakii infection An infant meeting at least one of the following criteria: • E. sakazakii recovered from > 1 of the following normally sterile sites: ▫ Blood ▫ Cerebrospinal fluid ▫ Brain tissue ▫ Urine • Outbreak of necrotizing enterocolitis and E. sakazakii recovered from blood, stool, or stomach aspirate of > 1 infant • Bloody diarrhea, E. sakazakii recovered from stool in pure culture

  3. Number Reports E. sakazakii Infection – English-Language Peer-Reviewed Literature Age groupNo. referencesNo. cases (%) Infants 20 48 (83) Children (>1 yr), adults 7 10 (17) Age groupNo. casesPercent 0 – 1 month 37 64 >1 – 12 months 10 17 >1 – 4 years 4 7 > 4 years 6 10 (median age = 74 yr) > Not stated 1 2(infant, but ? age) > Total 58 100

  4. Initial Reports of E. sakazakii infection: Chronology Urmenyi (1961) Jöker (1965) Monroe (1979) Kleiman (1981) Adamson (1981) Muytjens (1982) Jiménez (1982)* Muytjens (1983) Case series (1st study to propose possible link to powdered formula) Case reports

  5. E. sakazakii Infections in Infants: Selected Clinical Features – Peer-Reviewed Literature (N=48) • Gender: 52% female • Syndromes: Meningitis (58%), Sepsis/bacteremia (17%); Necrotizing enterocolitis (29%) • Overall case-fatality: 33%(15/46 for whom info available) • Birth weight (g)NumberNo. Died (%) < 1000 10 2 (20) 1000-1499 9 2 (22) 1500-2499 11 7 (64) > 2500 10 3 (30)

  6. Muytjens et al. (1983): Analysis of 8 cases of neonatal meningitis and sepsis due to E. sakazakii • Reanalyzed 20 Enterobacter strains isolated from CSF (going back 6 yrs) and 25 strains from blood (2 yrs) in the Netherlands • Hypothesis: E. sakazakii may not have been identified originally because organism produces minimal pigment at 36° C • Using various biochemical and growth parameter systems (25 ° C),8 strains identified as E. sakazakii • All 8 strains confirmed by CDC as E. sakazakii • Clinical data for E. sakazakii cases obtained retrospectively

  7. Muytjens et al. (1983): Clinical features of 8 cases of neonatal meningitis and sepsis due to E. sakazakii • 3/8 cases delivered by C-section • Progress in first few days of life was normal • First signs of illness occurred between days 4-8 of life • 2/8 cases had necrotizing enterocolitis + meningitis • 75% case-fatality rate; 2 survivors “retarded” • Death occurred within hours – several days • “Hemorrhagic encephalitis”

  8. Muytjens et al. (1983): Epidemiologic features of 8 cases of neonatal meningitis and sepsis due to E. sakazakii • 6/8 cases birth weights < 2,500 grams (lowest: 850 g) • 5/8 cases premature (gestation < 36 wk) • 5/8 cases occurred at same general hospital • Other 3 cases born in 3 other hospitals • Temporal clustering: 3/5 cases in general hospital became ill within 3 months; 2/3 cases in other hospitals within 2 months

  9. Muytjens et al. (1983): Environmental Sampling Results • Environmental sampling at pediatric ward of general hospital • E. sakazakii recovered from prepared formula, dish brush, and stirring spoon, but not from powdered formula and water • Plasmid profiles: “3 or 4 of 5 isolates from patients at the general hospital were probably the same strain” • Plasmid profiles differed between cases vs. prepared formula • (1990 note: “No cases observed at general hospital since powder formula replaced by liquid formula 8 years ago.”)

  10. E. sakazakii and Powdered Infant Formula: Developments From 1961-1988 • 1980 (Farmer): 1/57 isolates came from “can of dried milk” • 1983 (Muytjens) ▫ E. sakazakii recovered from prepared formula ▫ Recommended sampling of “milk” as part of investigations • 1988 (Muytjens) ▫ 141 powdered infant formula products obtained from 35 countries tested for presence of Enterobacteriaceae ▫ 52% samples + ▫ 20 powders (14%) from 13 countries yielded E. sakazakii ▫ Concentration of Enterobacteriaceae uniformly < 1 CFU/g

  11. Three Cases of Neonatal Meningitis Caused by E. sakazakii in Powdered Formula (Biering [1989-Iceland]) • Illnesses in 1986, 1987 (2 within one month) • 2 infants normal at birth (36- and 38-wk gestation); 1 Down’s • All 3 did well until day 5 when they became ill • 1 died, 2 recovered with severe neurologic sequelae • All 3 fed powdered infant formula • 1st study to show, in illness setting, E. sakazakii recovery (low numbers) from freshly prepared formula from previously unopened cans • No recovery from environment (milk kitchen, utensils, ward)

  12. Three Cases of Neonatal Meningitis Caused by E. sakazakii in Powdered Formula (Biering [1989-Iceland]) • In addition to 3 ill cases, 1 colonization • 4 E. sakazakii strains isolated from neonates had same plasmid profile as 22 formula strains • Anecdotal evidence that formula bottles occasionally kept at 35-37 C for extended periods in bottle heaters • But in 1 instance, recovery (direct plating) from bottle that had been refrigerated • “…milk powder can be the mode of transmission for E. sakazakii meningitis or sepsis in neonates…”

  13. Outbreaks of E. sakazakii infections linked to powdered infant formula: Historical cohort studies • Simmons et al. (1989): Enterobacter sakazakii Infections in Neonates Associated with Intrinsic Contamination of a Powdered Infant Formula (Infect Control Hosp Epidemiol) • Van Acker et al. (2001): Outbreak of Necrotizing Enterocolitis Associated with Enterobacter sakazakii in Powdered Milk Formula (J Clin Microbiol) • CDC. Enterobacter sakazakii Infections Associated with the Use of Powdered Infant Formula-Tennessee, 2001. MMWR 2002;51:297-300

  14. E. sakazakii Infections in Neonates Associated with Intrinsic Contamination of Powdered Infant Formula (Simmons-1989) • Feb-Mar 1988: bacteremia (2 infants), UTI (1), bloody diarrhea (1) • E. sakazakii recovered from stool of all 4 infants • Investigation revealed all 4 had been fed same powdered formula • Formula prepared in blender; rinsed with tap water between uses • Blender yielded heavy growth of E. sakazakii • No further clinical isolates once blender sterilized • Historical cohort study in NICU assessed risk factors for infection and colonization (2/7-3/13)

  15. E. sakazakii Infections in Neonates Associated with Intrinsic Contamination of Powdered Infant Formula (Simmons-1989) Infected/Colonized Yes No Yes 4 1 5 Formula No 0 40 40 Relative risk = undefined; p = 0.0006

  16. E. sakazakii Infections in Neonates Associated with Intrinsic Contamination of Powdered Infant Formula (Simmons-1989) • Implicated elemental formula given 1° to most premature infants • Samples obtained from opened, yet unmixed, can powdered formula • Powder cultured using method of Muytjens et al. • E. sakazakii (~ 8 CFU/100 g), E. cloacae (48 CFU/100 g) recovered • Same plasmid, multilocus enzyme profile (formula and patients)

  17. van Acker et al. (2001): Necrotizing enterocolitis associated with E. sakazakii in powdered formula • 12 cases NEC diagnosed June-July, 1998 in Belgium NICU • 50 neonates admitted to NICU during this period • All 12 had birth weights <2,000 g, fed powdered infant formula • 6/12 neonates had + cultures [blood, anal swab, or stomach aspirate] for E. sakazakii vs. 0/38 without NEC (p<0.001) • 10/12 neonates with NEC had been fed the same powdered formula: Alfaré (semi-elemental formula with low osmolarity)

  18. van Acker et al. (2001): Necrotizing enterocolitis associated with E. sakazakii in powdered formula E. sakazakii + (NEC) Yes No Yes 6 8 14 Formula No 0 36 36 Relative risk = undefined; p = 0.0002

  19. van Acker et al. (2001): Necrotizing enterocolitis associated with E. sakazakii in powdered formula • E. sakazakii recovered from prepared formula, unopened cans • Molecular typing (AP-PCR) confirmed partial strain similarity between powdered formula, patient isolates • No further cases of NEC observed after use of implicated powdered formula stopped • Inadvertent challenge test: • Implicated formula stopped on 7/10/98 • Released again on 7/20 • 7/23: new case NEC linked to formula (intrinsic formula contamination shown at same time)

  20. van Acker (2001): NEC-associated with E. sakazakii in powdered formula • Manufacturer’s quality control data for formula: • Of 5 samples analyzed: 1 yielded 20 coliforms/g; 4 < 1 coliform/g • Results fulfilled requirements of Codex Alimentarius: minimum of 4/5 control samples with < 3 coliforms g; maximum of 1/5 with >3 but < 20 coliforms/g • Did not meet Belgian law: < 1 coliform/g in all samples • Product recalled

  21. Manufacturer Actions: van Acker (2001): NEC Outbreak • Production facility in The Netherlands upgraded • More stringent standards adopted for products (< 0.3 coliform/g, 0 E. sakazakii isolates/10 g) • 1999: implicated powdered formula reintroduced • As of publication date, no further cases of NEC associated with E. sakazakii

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