From the MMWR April 12, 2002 / 51(14);298-300

http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5114a1.htm

Enterobacter sakazakii Infections Associated with the Use of Powdered
Infant Formula --- Tennessee, 2001

Enterobacter sakazakii, a gram-negative, rod-shaped bacterium, is a rare
cause of invasive infection with high death rates in neonates (1,2).
This report summarizes the investigation of a fatal infection associated
with E. sakazakii in a hospitalized neonate, which indicated that the
infection was associated with the presence of the organism in commercial
powdered formula fed to the infant. The implicated batch of formula has
been recalled by the manufacturer. Clinicians should be aware of the
potential risk for infection from use of nonsterile enteral formula in
the neonatal health-care setting.

In April 2001, a male infant (2 lbs, 13 oz [1,270 grams]) was delivered
by cesarean section at 33.5 weeks' gestation and was hospitalized in a
neonatal intensive care unit (NICU) because of low birthweight,
prematurity, and respiratory distress. The infant had fever,
tachycardia, decreased vascular perfusion, and neurologic abnormalities
(e.g., suspected seizure activity) at 11 days. Cerebrospinal fluid (CSF)
obtained by lumbar puncture was analyzed and revealed a white blood cell
count of 32/mm3 [normal=0--0.5/mm3], red blood cell count of 27/mm3
[normal=0], protein of 292 mg/dL [normal=15--45 mg/dL], and glucose of 1
mg/dL [normal= 40--70 mg/dL]. Culture of CSF grew E. sakazakii. The
infant was treated with intravenous antimicrobials for meningitis;
however, neurologic damage was progressive, and the infant died 9 days
later. Because the organism was a rare cause of neonatal meningitis,
hospital personnel, in collaboration with the Tennessee Department of
Health and CDC, investigated the source of infection.

During April 10--20, 2001 (i.e., the study period), enhanced case
surveillance was performed to determine if other infants in the NICU
were either infected or colonized with E. sakazakii. Patients were
assessed for colonization by stool culture; microbiology laboratory
records also were reviewed for reports of E. sakazakii growth from
clinical specimens during the study period. Confirmed infection was
defined as any E. sakazakii-positive culture from a normally sterile
site. Suspected infection was defined as an E. sakazakii-positive
culture from a nonsterile site with documented deterioration in clinical
status (e.g., increased respiratory rate without other evident cause) in
the 24 hours before collection of the specimen for culture. Colonization
was defined as an E. sakazakii-positive culture from a nonsterile site
without documented deterioration in clinical status in the 24 hours
before collection of the specimen for culture. A total of 49 infants
were screened. Ten E. sakazakii infection or colonization events were
identified: one confirmed infection in the index patient
(culture-positive from CSF), two suspected infections (both
culture-positive from tracheal aspirate), and seven colonizations (six
culture-positive from stool, one from urine). One patient was colonized
at two sites (urine and stool).

A cohort study was performed on the 49 patients who were screened to
determine possible risk factors for acquisition of E. sakazakii
infection or colonization. A case-patient was defined as any NICU
patient with E. sakazakii infection (confirmed or suspected) or
colonization during the study period. Medical records were reviewed to
assess possible risk factors during the study period, including
gestational age, birthweight, mechanical ventilator use, humidified
incubator use, oral medications, and feeding type (total parenteral
nutrition, formula [e.g., powdered or liquid], or breast milk) or method
(i.e., continuous or intermittent administration). Of the 49 patients
identified in the cohort, nine were case-patients and 40 were
noncase-patients. Analysis of risk factors identified only use of a
specific powdered infant formula product (Portagen [Mead Johnson
Nutritionals, Evansville, Indiana]) to be significantly associated with
E. sakazakii infection or colonization; all case-patients received
Portagen compared with 21 of 40 noncase-patients (p<0.01).

To determine the source of infection, microbiologic studies were
performed on samples of commercially sterile water used for formula
preparation and from samples of formula taken from opened cans of
Portagen from the same two batches used in the NICU during the study
period. Environmental swab cultures were taken from surfaces on which
the product had been prepared. Cultures also were performed on unopened
containers of Portagen supplied by the manufacturer with batch codes
matching those of opened cans. The water was cultured using membrane
filtration. The powdered infant formula was cultured using a
modification of a previously described enrichment method (3).
Specifically, for each culture of formula, 100 grams of Portagen were
inoculated in phosphate-buffered peptone water, incubated overnight,
subcultured, reincubated, and picked and streaked. Colonies that
demonstrated a yellow pigment characteristic of E. sakazakii were then
picked for identification. Cultures of formula taken from both opened
and unopened cans of Portagen from a single batch grew E. sakazakii.
Water and all environmental cultures were negative. Pulsed-field gel
electrophoresis revealed that isolates of E. sakazakii from the CSF
culture of the neonate with meningitis and from the culture of formula
from both opened and unopened containers were indistinguishable.

Hospital personnel reviewed NICU infection-control practices, policies,
and procedures for preparation, storage, and administration of powdered
infant formula. No breaches in infection control were detected. The
product was prepared in the NICU according to manufacturer's
instructions. Powdered formula was mixed with sterile water and was
immediately refrigerated and used within 24 hours of preparation. The
infant with E. sakazakii meningitis was given formula by continuous
administration; administration or "hang" time (i.e., the amount of time
the contents of a formula bag are fed to a patient) did not exceed 8
hours.

To prevent additional infections, the hospital made several policy
changes. Principal formula type for NICU patients was changed from
powdered formula to a commercially sterile, ready-to-feed liquid
formula. Portagen is no longer used; other powdered formula products are
reserved for specific needs and, when necessary, are prepared in a
designated formula preparation room in the pharmacy. The amount of
allowable administration or "hang" time has been reduced from 8 hours to
4 hours. As of April 10, 2002, no additional episodes of infection or
colonization have been detected at the reporting hospital.

Reported by: I Himelright, E Harris, V Lorch, M Anderson, Univ of
Tennessee Medical Center at Knoxville; T Jones, A Craig, Tennessee Dept
of Health. M Kuehnert, T Forster, M Arduino, B Jensen, D Jernigan, Div
of Healthcare Quality Promotion, National Center for Infectious
Diseases, CDC.

Editorial Note:

This report describes an association between fatal infection attributed
to E. sakazakii and use of a commercial powdered infant formula in a
NICU. E. sakazakii is a rare cause of invasive disease in neonates;
however, when meningitis occurs, severe neurologic complications,
including cerebral abscess formation, are common, and death occurs in
33%--80% of cases (1,2). E. sakazakii infection, including sepsis,
meningitis, or necrotizing enterocolitis, has been associated with use
of powdered infant formula (4--7). In previous studies and in this
report, the organism was detected in either prepared formula, the
environment in which it was prepared, or unopened products. This is the
first report of E. sakazakii infection associated with infant formula
prompting recall of a commercial product in the United States. Portagen
is a type of formula recommended by the manufacturer for infants with
nutritional malabsorption problems and is to be used under the
supervision of a health-care provider. The batch of Portagen implicated
in this investigation (coded BMC17) was recalled voluntarily by Mead
Johnson Nutritionals on March 29, 2002 (8). The manufacturer has
disseminated a letter to health-care providers about the risk of
powdered infant formulas.

Proper handling and use of infant formula products in the health-care
setting is an important patient safety issue. Clinicians should be aware
that powdered formulas are not sterile products and might contain
opportunistic bacterial pathogens such as those in the family
Enterobacteriacae, including E. sakazakii (3). These products commonly
are used at many hospitals. A recent survey indicated that of 16
responding facilities, nine used powdered formulas in the NICU setting;
four (25%) reported powdered formula as a principal source of patient
feeding, and five (31%) reported use of powdered formula along with
other formula types for principal feeding (National Association of
Children's Hospitals and Related Institutions, unpublished data, 2001).

Risk for infection might depend on several factors, including the number
of bacteria present in the product, handling after preparation, and
underlying patient characteristics (e.g., immunosuppression,
prematurity, or low birthweight). Because powdered formula is not
sterile and can provide a good medium for growth, prolonged periods of
storage or administration at room temperature might amplify the amount
of bacteria already present. Health-care providers might be able to
reduce risks for hospitalized neonates by choosing alternatives to
powdered forms when possible. Preparation of formula should follow
manufacturer's instructions, which might require steps beyond those
described on the product label. The American Dietetic Association (ADA)
has published guidelines for appropriate formula use, including details
concerning proper preparation, storage, and administration (9). On the
basis of these guidelines and input from ADA and the Food and Drug
Administration (FDA), interim recommendations have been proposed
concerning preparation of powdered infant formula in the NICU setting
[see box]. In addition, FDA has disseminated a letter to health-care
providers with further recommendations (10).

Health-care providers should report invasive disease attributed to E.
sakazakii in infants aged <12 months, particularly bloodstream infection
or meningitis with onset in the health-care setting, to state health
departments and CDC (800-893-0485); adverse events associated with
infant formula should be reported to FDA's MedWatch program
(800-332-1088 or at http://www.fda.gov/medwatch).

Acknowledgments

Office of Field Programs, Office of Scientific Analysis and Support,
Office of Field Products, Office of Nutritional Products, Labeling and
Dietary Supplements, Center for Food Safety and Applied Nutrition, Food
and Drug Administration. S Robbins, American Dietetic Association. D
Ben-Avram, American Society for Parenteral and Enteral Nutrition. C
Braden, R Tauxe, Div Bacterial and Mycotic Diseases, National Center for
Infectious Diseases; A Shane, EIS Officer, CDC.

References

1.Lai KK. Enterobacter sakazakii infection among neonates, infants,
children, and adults: case reports and a review of the literature.
Medicine 2001;80:113--22.
2.Nazarowec-White M, Farber JM. Enterobacter sakazakii: a review. Int J
Food Microbiol 1997;34:103--13.
3.Muytjens HL, Roelofs-Willemse H, Jaspar G. Quality of powdered
substitutes for breast milk with regard to members of the family
Enterobacteriaceae. J Clin Microbiol 1988;26:743--6.
4.Simmons BP, Gelfand MS, Haas M, et al. Enterobacter sakazakii
infections in neonates associated with intrinsic contamination of a
powdered infant formula. Infect Control Hosp Epidemiol 1989;10:398--401.

5.Biering G, Karlsson S, Clark NC, et al. Three cases of neonatal
meningitis caused by Enterobacter sakazakii in powdered milk. J Clin
Microbiol 1989;27:2054--6.
6.Clark NC, Hill BC, O'Hara CM, Steingromsson O, Cooksey RC.
Epidemiologic typing of Enterobacter sakazakii in two neonatal
nosocomial outbreaks. Diagn Microbiol Infect Dis 1990;13:467--72.
7.Van Acker J, DeSmet F, Muyldermans G, et al. Outbreak of necrotizing
enterocolitis associated with Enterobacter sakazakii in powdered milk
formula. J Clin Microbiol 2001;39:293--7.
8.FDA. Recalls and Safety Alerts. Powder Product Recall. Available at
http://www.fda.gov/oc/po/firmrecalls/meadjohnson03_02.html.
9.The American Dietetic Association. Preparation of formula for infants:
guidelines for healthcare facilities. Chicago, Illinois: The American
Dietetic Association, 1991.
10.FDA. Letter to health-care professionals. Available at
http://www.cfsan.fda.gov.


Box

Summary Interim Recommendations for Preparation of Powdered Infant
Formula in the Neonatal Intensive Care Unit Setting

1.Formula products should be selected based on nutritional needs;
alternatives to powdered forms should be chosen when possible.
2.Trained personnel should prepare powdered formula under aseptic
technique in a designated preparation room.
3.Manufacturer’s instructions should be followed; product should be
refrigerated immediately and discarded if not used within 24 hours after
preparation.
4.The administration or "hang" time for continuous enteral feeding
should not exceed 4 hours.
5.Written hospital guidelines should be available in the event of a
manufacturer product recall, including notification of health-care
providers, a system for reporting and follow-up of specific formula
products used, and retention of recall records.

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