Enterobacter sakazakii FREE

MMWR. 2002:51:297-300

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.

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.

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.^1,2E. 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. 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).

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: 10 available

MMWR. 2002;51:234-237

1 table, 2 figures omitted

Haemophilus influenzae type b (Hib) was the leading cause of bacterial meningitis and a major cause of other serious invasive diseases among children aged <5 years in the United States before Hib conjugate vaccines became available in 1988.^1,2 In 1991, all infants starting at age 2 months were recommended to receive Hib conjugate vaccines; by 1996, incidence of Hib invasive disease (i.e., illness clinically compatible with invasive disease, such as meningitis or sepsis, with isolation of the bacterium from a normally sterile site) among children aged <5 years had declined by >99%.^1,3 This report presents 1998-2000 Haemophilus influenzae (Hi) surveillance data, which indicate that the incidence of reported Hib invasive disease remains low. Achieving the national health objective for 2010 of reducing to zero indigenous Hib invasive disease cases in children aged <5 years⁴ will require improved age-appropriate vaccination of children, complete reporting of vaccination and relevant medical histories, standardization of the serotyping procedure, and complete ascertainment and reporting of serotype for all Hi invasive disease cases.

In 1991, Hi invasive disease became a nationally notifiable disease. State health agencies, the District of Columbia, and New York City provide weekly reports of provisional cases of Hi invasive disease to CDC through the National Electronic Telecommunications System for Surveillance (NETSS) and the National Bacterial Meningitis and Bacteremia Reporting System (NBMBRS). Case reports include demographic data about persons with Hi invasive disease and supplemental information (e.g., the serotype that caused the illness, type of clinical illness, outcome, and Hib vaccination history). States were contacted to obtain and confirm supplemental data for cases of Hi invasive disease in children aged <5 years with onset in 1998, 1999, and 2000. Only Hib vaccine doses given ≥14 days before illness onset were considered valid. Annual population estimates for 1998 and 1999 from the U.S. Census Bureau were used to calculate incidence rates.

CDC also coordinates the Active Bacterial Core surveillance (ABCs) system with sites in selected states. Illnesses identified as Hi invasive disease (i.e., isolation of H. influenzae from a normally sterile site in a resident of the surveillance area) are reported to CDC and the various state health departments.³ During 1998-2000, project personnel contacted all microbiology laboratories serving acute care hospitals in each surveillance area every 2-4 weeks; specimens were sent to CDC for serotype confirmation. The population of children aged <5 years in the surveillance areas increased from 750,534 in 1989 to 2,208,625 in 2000. In 1998, the surveillance area covered three counties in the San Francisco Bay Area, five counties in Tennessee, seven counties in New York, 20 counties in Georgia, and the entire states of Connecticut, Maryland, Minnesota, and Oregon. By January 2000, the surveillance area had increased to include 15 counties in New York, 11 in Tennessee, and all of Georgia. Rates were race-adjusted to the annual U.S. population estimates.

During 1998-2000, a total of 824 Hi invasive disease cases was reported among children aged <5 years; rates were 1.4 per 100,000 children in 1998 and 1999 and 1.6 in 2000. Among children aged <5 years, serotype data were available for 219 (83%) of 265 cases in 1998, 214 (82%) of 262 cases in 1999 and 236 (79%) of 297 cases in 2000. Of the 669 cases with known serotype, Hib accounted for 75 (34%) cases in 1998, 71 (33%) cases in 1999 and 51 (22%) cases in 2000; annual Hib invasive disease rates were 0.4, 0.4, and 0.3, respectively. Compared with the rate in 1990 (23 cases per 100,000), the average annual rate for 1998-2000 (0.3 cases per 100,000) represents a 99% decline. During the 3-year period, the annual average for reporting of serotype information was 81%, representing a 98% improvement from 1994. By state, excluding Alaska, Hib invasive disease average annual incidence rates ranged from 0 to 2.1 per 100,000 children aged <5 years; in Alaska, the rate was 9.4.

For nontype b Hi invasive disease, the average annual incidence rate by state ranged from 0 to 5.8 with a national average of 0.8 per 100,000 children aged <5 years. For the 3-year period, the clinical outcome was known for 693 (84%) of the 824 Hi cases reported; 50 (7%) of the 693 patients died. Of 197 Hib cases reported, 169 (86%) had known outcome; 14 (8%) children died. By race/ethnicity, Hib invasive disease average annual incidence among children aged <5 years during 1998-2000 was 14.0 among American Indians/Alaska Natives, 1.0 among Hispanics, 0.9 among non-Hispanic whites, 0.6 among non-Hispanic blacks, and 0.4 among Asians/Pacific Islanders. Race/ethnicity data were missing for 10 (5%) Hib patients.

During 1998-2000, of 197 Hib patients, 86 (44%) were aged <6 months and had not completed the 2- or 3-dose primary Hib vaccination series. Of the 111 (56%) children who were aged ≥6 months and eligible to have completed the primary series, 19 (17%) had unknown vaccination status, 31 (28%) were unvaccinated, 22 (20%) were undervaccinated, and 39 (35%) had completed a primary series, 21 of whom received a booster dose (given at 12-15 months). Among the 14 Hib invasive disease deaths reported, 11 (79%) patients aged <6 months were unvaccinated and three (21%) patients aged ≥6 months were undervaccinated.

During 1998-2000, a total of 128 Hi invasive disease cases in children aged <5 years was reported from ABCs sites; 19 (15%) were caused by Hib, 95 (74%) by nontype b Hi, and 14 (11%) by unknown Hi serotypes. The annual race-adjusted incidence rates were 0.2, 0.6 and 0.2 per 100,000 children aged <5 years for Hib invasive disease compared with 1.8, 1.5 and 1.6 per 100,000 for nontype b Hi invasive disease in 1998, 1999, and 2000, respectively.

S Bath, MPH, K Bisgard, DVM, T Murphy, MD, Epidemiology and Surveillance Div, National Immunization Program; K Shutt, MPH, N Rosenstein, MD, Div of Bacterial and Mycotic Diseases, National Center for Infectious Diseases; C Ohuabunwo, MBBS, EIS Officer, CDC.

With widespread use of Hib conjugate vaccines beginning in 1990, the incidence of reported Hib invasive disease among children aged <5 years declined from an estimated 100 per 100,000 in the prevaccine era to a record low of 0.3 in 1996.^2,3 The findings in this report indicate that the incidence of invasive Hib disease remains low. During 1998-2000, although Hib remained an infrequent cause of invasive disease among children, illness and death occurred among infants aged <6 months who had not completed the 2- or 3-dose primary series of Hib vaccination and among unvaccinated or undervaccinated children; some of these cases might have been preventable. These data also suggest that primary or secondary vaccination failure occurs less frequently than failure to vaccinate. Understanding the reasons for Hib invasive disease among fully vaccinated children requires the reporting of full vaccination history (i.e., dates, dose, vaccine name, lot number, and manufacturer) and relevant medical histories (e.g., prematurity, immunosuppression, or other chronic diseases).

Localized populations with low vaccination coverage contribute to the continued circulation of Hib despite sustained national Hib vaccination coverage of >90%.⁵ In Pennsylvania, during December 1999–February 2000, eight Hib invasive disease cases occurred in unvaccinated children aged <5 years, six of whom were from communities with lower Hib vaccination coverage and higher Hib carriage rates than other groups.⁶ As in the prevaccine era, Hib invasive disease rates among American Indian/Alaska Native children remain persistently higher than in the general U.S. population,⁷ which suggests that Hib elimination will require additional characterization of colonization and disease among these high-risk populations.⁷ Attaining and maintaining high Hib vaccination coverage at the community level should reduce the Hib carriage rate among young children by decreasing exposure of susceptible infants and interrupting Hib transmission.⁷

Because Hib vaccines protect against type b and not other Hi strains, serotyping of all Hi isolates from patients with invasive disease is necessary to monitor the vaccination program effectiveness and national progress towards Hib elimination. Serotype information is needed to measure the sensitivity of the surveillance system and to detect the emergence of invasive disease from nontype b Hi strains.⁸ The reporting of serotype information on Hi cases among children aged <5 years has improved; however, to ensure that all Hi isolates from children aged <5 years are serotyped and to minimize false-positive results,⁹ continued promotion and standardization of the serotyping procedure by states is essential. Because of inconsistencies in Hi serotyping,⁹ until December 2002, CDC requests that state health laboratories send all Hi isolates associated with invasive disease in children aged <5 years to CDC (telephone [404] 639-3158) for serotyping.

The incidence of nontype b Hi invasive disease can be a useful indicator of the sensitivity of the surveillance system. Although Hib invasive disease in children aged <5 years declined to near-elimination levels during the last decade, the incidence of nontype b invasive disease from ABCs sites remained consistently >1 per 100,000 children aged <5 years. Adequate identification and reporting of nontype b Hi invasive disease might indicate sufficient sensitivity to readily identify cases of Hib invasive disease. States are encouraged to report invasive disease caused by all Hi strains as recommended by the Council of State and Territorial Epidemiologists and CDC.¹⁰

Public health efforts to achieve and document Hib invasive disease elimination in children aged <5 years will be advanced by (1) enhanced promotion of age-appropriate Hib vaccination at the community level, (2) complete reporting of vaccination and medical histories to characterize cases of Hib suspected to be vaccine failures, (3) standardization of the serotyping procedure, and (4) ascertainment and reporting of serotype for all Hi invasive disease cases in children.

This report is based on data contributed by state health departments to the National Notifiable Disease Surveillance System and by sites in the Active Bacterial Core surveillance (ABCs) system: L Gelling, MPH, P Daily, MPH, G Rothrock, MPH, A Reingold, MD, D Vugia, MD, State Epidemiologist, California Dept of Health Svcs. S Zansky, P Smith, MD, State Epidemiologist, New York State Health Dept. N Barrett, MS, JL Hadler, MD, State Epidemiologist, Connecticut State Dept of Health Svcs. W Baughman, MS, M Farley, MD, K McCombs, K Arnold, Georgia Dept of Human Resources, Div of Public Health. MA Pass, L Harrison, MD, J Roche, MD, State Epidemiologist, Maryland State Dept of Health and Mental Hygiene. J Rainbow, MPH, J Besser MS, R Lynfield, MD, R Danila PhD, H Hull MD, State Epidemiologist, Minnesota Dept of Health. KR Stefonek, MPH, PR Cieslak, MD, MA Kohn, MD, State Epidemiologist, Oregon Dept of Human Resources, State Health Div. W Schaffner, MD, B Barnes, Vanderbilt Univ, Nashville; A Craig, MD, State Epidemiologist, Tennessee Dept of Health.

References: 10 available

MMWR. 2002;51:187-189

2 figures omitted

Homicide is the 15th leading cause of death during the first year of life (i.e., infancy) in the United States. In addition, the risk for homicide is greater in infancy than in any other year of childhood before age 17 years¹ and is greatest during the first 4 months of life.² To determine how the risk for homicide varied by week during infancy and by day during the first week of life, CDC analyzed death certificate data for 1989-1998. This report summarizes the results of this analysis, which indicated that risk for infant homicide is greatest on the day of birth. Efforts to prevent infant homicides should focus on early infancy.

Most infant deaths are certified by medical examiners or coroners. Statistical information from death certificates is consolidated into a national database through the National Vital Statistics System.¹ Information on U.S. resident infant homicide deaths for 1989-1998 was obtained from CDC's National Center for Health Statistics. An infant was defined as a person aged <1 year at death. Homicide was defined as an underlying cause coded through the International Classification of Disease, Ninth Revision, codes E960–E969.³ Age at death in days was defined as one plus the difference between the dates of death and birth recorded on the death certificate. An infant killed on its date of birth had an age at death of 1 day. In comparison, homicide rates during different time periods within infancy were presented as rates per person-years of exposure. The U.S. infant population during 1989-1998 accounted for 39,941,628 person years of exposure, of which days of birth accounted for 109,354 person years, and the remainder of infancy accounted for 39,832,274 person years.

During 1989-1998, a total of 3,312 infant homicides were reported for a rate of 8.3 per 100,000 person years. Of these, 81 (2.4%) were excluded because of a missing date of birth. The proportion of homicides occurring each week of infancy varied, with 9.1% of homicides occurring during the first week of life; a secondary peak in the distribution of homicides occurred at week 8.

Among homicides during the first week of life, 82.6% occurred on the day of birth, 9.2% on the second day, and 8.2% during the remainder of the week. After the first 2 days of life, the number of deaths in the remainder of the first week was comparable to the number of deaths in the second week of life. Overall, 243 (7.3%) of all infant homicides occurred on the day of birth. When homicide rates on the first day of life and during the remainder of infancy were compared with homicide rates during later age groups, the homicide rate on the first day of life was at least ten times greater than the rate during any other time of life.

L Paulozzi, MD, Div of Violence Prevention, National Center for Injury Prevention and Control; M Sells, MS, Public Health Prevention Specialist Program, Div of Applied Public Health Training, Epidemiology Program Office, CDC.

The findings in this report highlight the high risk for homicide on the day of birth. Risk is comparatively small after the day of birth, even during the highest risk periods of adulthood. Among homicides on the first day of life, 95% of the victims are not born in a hospital. Among homicides later in infancy, 8% of infants are not born in a hospital.² Among homicides during the first week of life, 89% of known perpetrators are female, usually the mother.⁴ Mothers who kill their infants are more likely to be adolescents and have a history of mental illness.^2,5 The secondary peak in risk in week 8 might reflect the peak in the daily duration of crying among normal infants between weeks 6 and 8.⁶

The limitations of these findings include the potential under and overascertainment of homicides through vital records. Infant homicides probably are underascertained by being either labeled as unintentional injuries or attributed to sudden infant death syndrome (SIDS).⁷ Underascertainment probably does not vary by week of life and is unlikely to account for the observed pattern. Overascertainment might have occurred if some of the cases classified as homicides on the first day of life were actually stillbirths. It is not known what percent of cases of homicide on the day of birth might have been stillbirths. However, the percentage is probably small because medical examiners usually will attribute a death to infanticide only if autopsy evidence indicates that respiration had occurred, no evidence indicates death from natural causes, and circumstantial evidence is consistent with homicide.⁸

Preventing out-of-hospital births among high-risk women might help reduce the number of homicides on the day of birth. Home visitation and parenting programs, especially those that begin during pregnancy, might help reduce child abuse during infancy by focusing on the weeks of greatest risk early in infancy.⁹