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Marler Blog Providing Commentary on Food Poisoning Outbreaks & Litigation

Enterobacter sakazakii: Infections Associated with Powdered Infant Formula

Enterobacter sakazakii is a gram-negative rod-shaped bacterium within the family Enterobacteriaceae. The organism was called "yellow-pigmented Enterobacter cloacae" until 1980 when it was renamed Enterobacter sakazakii. The majority of cases of infection reported in the peer-reviewed literature have described neonates with sepsis, meningitis, or necrotizing enterocolitis as a consequence of the infection. (1)

E. sakazakii is a rare cause of bloodstream and central nervous system infections. The organism has also been associated with necrotizing enterocolitis; however, it has not been firmly established as a causative agent. Reported outcomes are often severe: seizures; brain abscess; hydrocephalus; developmental delay; and death in as many as 40%–80% of cases. Premature infants are thought to be at greater risk than more mature infants, other children, or adults, and outbreaks of disease have occurred in hospital units for newborns. (2)

E. sakazakii was first implicated in a case of neonatal meningitis in 1958, and since then there have been around 70 reported cases of E. sakazakii infection. However, it is likely that E. sakazakii is significantly under-reported in all countries. Although E. sakazakii can cause illness in all age groups, infants are believed to be at greatest risk of infection. (3)

Experts from the Food and Agriculture Organization of the United Nations (FAO) and the World Health Organization (WHO) met in 2004 to summarize information, and develop international guidelines and educational messages. The meeting confirmed that there is very little known about virulence factors and pathogenicity of E. sakazakii. The work done by Pagotto et al. (2003) was the first describing putative virulence factors for E. sakazakii. Enterotoxin-like compounds were produced by some strains. Using tissue cultures, some strains produced a cytotoxic effect. Two strains (out of 18 isolates) were capable of causing death in suckling mice by the peroral route. Therefore, there appear to be differences in virulence among E. sakazakii strains, and some strains may be non-pathogenic. (4)

Mortality rates from E. sakazakii infection have been reported to be as high as 50 percent or more, but this figure has declined to under 20 percent in recent years. Significant morbidity in the form of neurological deficits can result from infection, especially among those with bacterial meningitis and cerebritis. While the disease is usually responsive to antibiotic therapy, a number of authors have reported increasing antibiotic resistance to drugs commonly used for initial treatment of suspected Enterobacter infection. Long-term neurologic sequelae are well recognized. (4)

Enterobacter sakazakii kills 40%–80% of infected infants. In 2007, the CDC analyzed 46 cases of invasive infant E. sakazakii infection to define risk factors and guide prevention and treatment. Twelve infants had bacteremia, 33 had meningitis, and 1 had a urinary tract infection. Compared with infants with isolated bacteremia, infants with meningitis had greater birthweight (2,454 g vs. 850 g, p = 0.002) and gestational age (37 weeks vs. 27.8 weeks, p = 0.02), and infection developed at a younger age (6 days vs. 35 days, p<0.001). Among meningitis patients, 11 (33%) had seizures, 7 (21%) had brain abscess, and 14 (42%) died. (2)

Although E. sakazakii can cause illness in all age groups, infants (children <1 year) are at most risk, with neonates and infants under two months at greatest risk. The groups of infants at greatest risk includes in particular pre-term infants, low-birth-weight (<2.5 kg) infants or immunocompromised infants. However, infants who are compromised for any other reason may also be at greater risk of E. sakazakii infection. Infants of HIVpositive mothers are also at risk because they may be immunocompromised, and may specifically require powdered infant formula (PIF). (3)

There appear to be two distinct infant risk groups for E. sakazakii infection: prematureinfants who develop bacteraemia after one month of age, and term infants who develop meningitis during the neonatal period. Therefore, an FAO/WHO expert working group in 2006 concluded that while infants appear to be the group at particular risk, neonates and those less than two months of age are at greatest risk. (3)

In the United States of America, an incidence rate of 1 per 100 000 infants for E. sakazakii infection has been reported. This incidence rate increases to 9.4 per 100 000 in infants of very low birth weight, i.e. <1.5 kg. (3)

While the reservoir for E. sakazakii is unknown in many cases, a growing number of reports have established powdered infant formula as the source and vehicle of infection. In several investigations of outbreaks of E. sakazakii infection that occurred among neonates in neonatal intensive care units, investigators were able to show both statistical and microbiological association between infection and powdered infant formula consumption. These investigations included cohort studies which implicated infant formula consumed by the infected infants. In addition, there was no evidence of infant-to-infant or environmental transmission; all cases had consumed the implicated formula. The stomach of newborns, especially of premature babies, is less acidic than that of adults: a possible important factor contributing to the survival of an infection with E. sakazakii in infants. (4)

Limited information was available on the numbers of E. sakazakii organisms that ill patients were exposed to in any of the various outbreaks. It is therefore not possible to develop a dose-response curve for E. sakazakii. However, it is possible that a small number of cells present in PIF could cause illness. This risk increases rapidly when bacteria in the reconstituted formula are allowed to multiply, such as by holding at inappropriate temperatures for an extended period. (3)

The frequency of intrinsic E. sakazakii contamination in powdered infant formula is of concern, even though intrinsic concentration levels of E. sakazakii appear to be typically very low. In a study of the prevalence of E. sakazakii contamination in 141 powdered infant formulas, 20 were found culture-positive, yet all met the microbiological specifications for coliform counts in powdered infant formula (<3 cfu/g) of the current Codex code. Such formula has been linked to outbreaks. (4)

Furthermore, outbreaks have occurred in which the investigators have failed to identify lapses in formula preparation procedures. Thus, it seems that neither high levels of contamination nor lapses in preparation hygiene are necessary to cause infection from E. sakazakii in powdered infant formula. While it can be assumed that lapses in preparation hygiene or extended holding at non-refrigerated temperatures could lead to increases in the levels of contamination at the time of consumption, it is not possible to assess the contribution that these factors have on the cases of infection that have been associated with powdered infant formula that contained low levels of E. sakazakii. Thus it must be currently assumed that low levels of E. sakazakii in infant formula (<3 cfu/100 g) can lead to infections. (4)

In the April 12th 2002 issue of Morbidity and Mortality Weekly Report, the Centers for Disease Control and Prevention (CDC) reported on a fatal case of meningitis in an intensive care nursery in Tennessee. The infecting organism was E. sakazakii, an unusual but often fatal, invasive pathogen. In the fatal Tennessee case, the infection was traced to contaminated powdered infant formula. Other infants in the same nursery were screened for E sakazakii. Of 49 screened infants, 10 events were discovered (1 proven infection, 2 assumed infections, and 7 colonizations). This report detailed for the first time a direct link to an unopened product. The manufacturer voluntarily recalled the contaminated batch of powdered formula identified as the source. (5)

In 2004, PIF was microbiologically linked to two E. sakazakii outbreaks, in New Zealand and in France. The French outbreak involved nine cases, and resulted in the death of two infants. While eight of the cases were in premature infants of low birth weight (<2 kg), one case was in an infant born at 37 weeks and weighing 3.25 kg. The outbreak involved five hospitals, and a review of practices in the hospitals revealed that one hospital was not following recommended procedures for the preparation, handling and storage of feeding bottles, and four were storing reconstituted formula for >24 hours in domestic-type refrigerators, with no temperature control or traceability. (3)

The FDA points out that powdered infant formulas are not commercially sterile products. Powdered milk-based infant formulas are heat-treated during processing, but unlike liquid formula products they are not subjected to high temperatures for sufficient time to make the final packaged product commercially sterile. FDA has noted that infant formulas nutritionally designed for consumption by premature or low birth weight infants are available only in commercially sterile liquid form. However, so-called "transition" infant formulas that are generally used for premature or low birth weight infants after hospital discharge are available in both non-commercially sterile powder form and commercially sterile liquid form. Some other specialty infant formulas are only available in powder form. (1)

The FDA has become increasingly aware that a substantial percentage of premature neonates in neonatal intensive care units are being fed non-commercially sterile dry infant formula. In light of the epidemiological findings and the fact that powdered infant formulas are not commercially sterile products, FDA recommends that powdered infant formulas not be used in neonatal intensive care settings unless there is no alternative available. If the only option available to address the nutritional needs of a particular infant is a powdered formula, risks of infection can be reduced by:

• Preparing only a small amount of reconstituted formula for each feeding to reduce the quantity and time that formula is held at room temperature for consumption; Recognizing differences in infant formula preparation among hospitals, individual facilities should identify and follow procedures appropriate for that institution to minimize microbial growth in infant formulas;

• Minimizing the holding time, whether at room temperature or while under refrigeration, before a reconstituted formula is fed; and

• Minimizing the "hang-time" (i.e., the amount of time a formula is at room temperature in the feeding bag and accompanying lines during enteral tube feeding), with no "hang-time" exceeding 4 hours. Longer times should be avoided because of the potential for significant microbial growth in reconstituted infant formula. (1)

WHO recommends that infants should be exclusively breastfed for the first six months of life to achieve optimal growth, development and health. Thereafter, to meet their evolving nutritional requirements, infants should receive nutritionally adequate and safe complementary foods while breastfeeding continues for up to two years of age or beyond (WHO/UNICEF, 2003). It is important to support breastfeeding and promote its benefits to infants and young children. (3)

There are, however, instances where breast milk is not available, where the mother is unable to breastfeed, where they have made an informed decision not to breastfeed, or where breastfeeding is not appropriate, e.g. where the mother is taking medication that is contraindicated for breastfeeding or the mother is HIV-positive. Similarly, some very low-birth-weight babies may not be able to breastfeed directly, and in some cases expressed breast milk may not be available at all or available in insufficient quantities. Infants who are not breastfed require a suitable breast-milk substitute, for example, an infant formula prepared in accordance with the present guidelines. WHO Guidelines for infant formula preparation, storage, and handling (2007), in both care settings and at home, are specified at http://www.who.int/foodsafety/publications/micro/pif (3)

In January 2006, a second meeting (after the initial one in 2004) of experts from the Food and Agriculture Organization of the United Nations (FAO) and the World Health Organization (WHO) took place to summarize information, and develop international guidelines and educational messages. The meeting participants first re-endorsed the recommendations made by the 2004 FAO/WHO meeting on this issue. The additional recommendations made by the expert meeting to member countries included the following:

• Develop prevention strategies for E. sakazakii infections caused by contaminated PIF that address the different stages of production and preparation and use of PIF, taking into consideration the risk to infants ?both within and beyond the neonatal period and of any immune status.

• Develop educational messages on the safe handling, storage and use of powdered infant formula, including the health hazards of inappropriate preparation and use; target healthcare workers, parents and other caregivers, in both hospitals and the community, since E. sakazakii infections have occurred in hospital and home settings.

• Review and revise product labels, as appropriate, to enable caregivers to handle, store and use the product safely, and to make clear the health hazards of inappropriate preparation.

• Encourage member countries to establish surveillance and rapid response networks, and facilitate coordinated investigation by clinicians, laboratorians, and public health and regulatory officials, to enable the timely recognition and cessation of outbreaks of illness associated with E. sakazakii and the identification of contaminated PIF. (6)

(1) “Health Professionals Letter on Enterobacter sakazakii Infections Associated With use of Powdered (Dry) Infant Formulas in Neonatal Intensive Care Units”, U. S. Department of Health and Human Services, U. S. Food and Drug Administration, April 11, 2002; Revised October 10, 2002.
(2)“Invasive Enterobacter sakazakii Disease in Infants”, Emerging Infectious Diseases, Volume 12, Number 8–August 2006.
(3) “Safe Preparation, Storage and Handling of Powdered Infant Formula Guidelines” (2007), World Health Organization, in collaboration with Food and Agriculture Organization of the United Nations.
(4) “Enterobacter sakazakii and other microorganisms in powdered infant formula” Microbiological Risk Assessment Series 6, World Health Organization (2004).
(5) “Enterobacter sakazakii Infections Associated With the Use of Powdered Infant Formula—Tennessee, 2001”, JAMA. 2002; 287:2204-2205, Vol. 287 No. 17, May 1, 2002.
(6) “Enterobacter sakazakii and Salmonella in powdered infant formula: Meeting report, MRA Series 10”, Microbiological Risk Assessment Series 10, World Health Organization (2006).

  • Epifreek

    Thank you for your excellent review of what I believe is a largely unrecognized problem.
    However, one thing that wasn’t mentioned in the article was why there has been no requirement by FDA that specialty formulas for premature infants must be sterile.
    I understand that there are technical issues in sterilizing infant formula, but I don’t understand why some specialty infant formulas continue to be available only in powdered, non-sterile formulations.
    I am also surprised that no parent has ever sued an infant formula manufacturer after the death of an infant from E. sakazakii infection. E. sakazakii meningitis is a particularly devastating infection and virtually destroys the infant’s brain.

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  • inayah

    it’s nice to get a lot information about E. sakazakii that’s i need, one thing i still want to know is how much the amount of E. Sakazakii is required in infant formula?
    thank’s for your attention and respon

  • Lee

    My son had e-sakazakii at 8 days old, menengitis w/brain abcess. Treated w/imipenim. Spent several months in Boston Childrens. Pretty much full recovery, he is on meds for seizures. He never had powdered formula that we know of, unless the Hospital mixed it and gave it to him??

  • shellie lindsey

    My daughter Tritnie contracted this disease at 10 days after birth.I gave her powdered milk from the first day she came home from the hospital.She suffered severe reprocussions from this disease however, she is now 13 years old and doing great. She has hydrosephilus and delays in learning and retaining information. She is truely a living mirical in my book. The reason that i did not sue the formula company is because i am just learning that the formula is a link to her illness. I did a two year investigation into this i found other cases and worked with an attourney however, i came up empty handed.We as parents need to get together and hold these companies accountable for their neglegents. I did not loose my child but so many of you have. I lost my marriage of nearly 10 years and my children lost their family due th this illness. It effects people differently when your child becomes ill. Some loose their lives and others loose everything. Its devistation at so many levels.

  • Shelly

    My 7 month old grandson died in 2008 due to enterobacter sakazakii. Devestation, heartbreak and loss are just the beginning. The risk is there and the formula companies are aware of it. I hope that someday they are not willing to risk even one precious life. Even after a couple of years have past, Our family still deals with our loss everyday.

  • Shellie Lindsey

    I posted her back in 2009. I am reposting because my daughter had this disease and she is about to turn 16 years old on March 13, 2012. She is a loving brilliant child who may never be able to get behind the wheel of a car. She has learning issues such as short term memeory loss. She is now in 9th grade. She walks normal. She can talk see and hear fine. She has the biggest brown eyes and the cutest smile I have ever seen.
    When she was a baby at 10 days old, she contracted this disease. She develpoed siezues at 11 days old and hydrosephalis at 2 months old. She did not walk until she was 18 months old and her first word was “mama” at 13 months old. This disease is so devistating to say the least. My daughter spent the first 2 years of her life in and out of childrens hospital here in Ohio. It was always a roller coaster ride.
    I am very greatful to have my daughter. I realize with the death rate being so high, many of you do not have this advantage. I descided not to sue the formula company because I have my daughter here alive and well. Many parents have lost their children or they are severly handicapped. I urge you to seek professional help! I urge you to seek legal representation and pursue the law in your favor! These children have fell victim needlessly and so have you and your family! You need to make them pay for your hardships and loss. If I were to advocate in my defence, it would only be because I lost my marriage. My family went through so much. It devistated my children! I became someone I did not know hrough all the stress and anxiety of taking care of a sick child! I feel blessed every single day that I still have her. I wish my condolences to those that have lost their children due to this bacteria. It is a shame the FDA does not rule for strict regiments of formula companies.
    Since my daughter was born in 1996, I warned all new parents not to feed powdered formula from any institution! The risk is so real folks! The risks outway the benefits of feeding powder over concentrate! PLEASE! Head the warning on Powdered Formula.

  • Shellie Lindsey

    Shelly, I am so sorry for your loss of your grandson. You are so right, devistation at its greatest. My heart goes out to you and your family.
    Lee, how old is your son now? What are his complications? Can he see, hear and can he walk and talk? I was told my daughter would never do these things but, she is 16 years old and has learning difficulties but is doing very well. She can see, hear, talk and walk. All the things the doctor had said she would never do, she is doing like an expert! Praise Jesus!