Introduction
Breastfeeding is essential for the healthy development of newborns, but it may not always be possible for all mothers In such cases, powdered infant formula (PIF) serves as a suitable supplement or alternative to breast milk, ensuring that infants receive the necessary nutrition.
PIF is a non-sterile product with low water activity, which may harbor various bacteria that can proliferate quickly after reconstitution Among these, Cronobacter spp (previously known as Enterobacter sakazakii) poses significant risks in powdered infant formula.
Cronobacter spp infections are associated with serious conditions such as neonatal meningitis, necrotizing enterocolitis, and bacteremia, leading to a concerning mortality rate Numerous studies have established a strong epidemiological link between these infections and powdered infant formula (PIF).
Cronobacter infections are uncommon, but they can be fatal to neonates
Despite the detection of only 3 cfu/g of Cronobacter sakazakii in powdered infant formula, improper handling and time-temperature abuse can lead to increased contamination levels, posing health risks Even low levels of this pathogen can cause illness without any mishandling According to a 2008 FAO/WHO report, there were at least 120 documented cases of Cronobacter spp infections in neonates and infants, resulting in 27 fatalities globally, though these figures may be underestimated due to unreported or misidentified cases.
In 2022, four cases of Cronobacter illness, including two fatalities, were linked to powdered milk, raising significant concerns when Abbott's powdered infant formula was identified as a potential source Recent FDA inspection reports revealed a troubling pattern of food safety deficiencies at Abbott's infant formula production facility, prompting questions about whether the manufacturing processes at this plant contribute to Cronobacter infections.
Given the significant risk of Cronobacter infections associated with formula milk, along with recent cases linked to both intrinsic and extrinsic contamination, our team has chosen to focus on the topic of Cronobacter infections.
Linked to Powdered Infant Formula with the desire to better understand
Cronobacter spp., the causes of infection, and as well as offer recommended solutions to limit the risk of infection.
Overview of Powdered infant formula
Processing of powdered infant formula
The production of powdered infant formula involves three main manufacturing processes: dry blending, wet mixing, and a combination of both Dry blending starts with individual ingredients, which are sourced in powdered form, heat-treated, and then blended without water, minimizing the risk of microbial contamination and reducing energy consumption and capital costs However, this method relies heavily on the quality of raw materials and cannot incorporate oils, leading to potential de-blending during transport In contrast, wet mixing allows for better control over quality parameters like concentration and pasteurization, resulting in improved microbiological and chemical properties of the final product Nonetheless, this technique comes with higher equipment costs, increased maintenance needs, and the complexity of managing both wet and dry processes within the same facility.
Figure 2 Manufacturing process of powdered infant formula by wet mixing- spray drying process
The three key stages of the wet mixing-spray drying process are always the same: mix preparation, evaporation, and drying.[15]
Table 1 outlines the essential components commonly found in powdered infant formula The physical properties of wet-mixes in powdered infant formula are significantly affected by the quality and pre-treatment of the ingredients For instance, heat-treated fresh skim milk demonstrates higher viscosities post-evaporation compared to its non-heat-treated counterpart.
Table 1 Typical raw material for powdered infant formula [16]
Casein Source Skim milk powder (SMP), evaporated skim milk, acid casein, sodium/calcium/potassium caseinate, milk protein concentrate (MPC*)
Whey Source Demineralised whey powder (DWP), whey protein concentrates (WPC*), whey protein isolates (WPI), hydrolysed whey ingredients
Soy milk, soy protein isolate, locust bean seed protein, amino acids
Oils Soy, corn, safflower, sunflower, colza, palm, copra, structured lipids
Carbohydrates Lactose, starch, sucrose, corn syrup, corn syrup solids
Major minerals Calcium carbonate, calcium phosphates, dibasic magnesium phosphate, potassium citrate, magnesium chloride
Minor minerals Potassium iodide, ferrous sulphate, manganese sulphate, copper sulphate, zinc sulphate
Vitamins A, D, E, K, B1, B2, B6, B12, niacin, folic acid, pantothenic acid, biotine, choline, inositol
Soy lecithin, mono- and diglycerides
To ensure effective mixing, it is essential to prepare and hydrate all components beforehand The hydration process typically involves multiple stages: wetting, sinking, dispersion, and dissolution High shear devices can be employed to reduce hydration time by efficiently scattering raw materials After hydration, the mixture is stored in a large tank, where water-soluble minerals are separately dissolved in hot water before being incorporated The pH of the mixture can be adjusted with alkali or citric acid solutions If oil-soluble vitamins are required, they must first be dissolved in oil before being added to the oil mix tank, and they can be premixed and stored or encapsulated for later use Regardless of whether batch or continuous processing is utilized, it is crucial to flush pipes and tanks with compressed air daily and conduct in situ cleaning of the mixing line The lactose content in raw materials plays a vital role in hydration, as it helps maintain the structural integrity of proteins during drying; however, lactose is somewhat insoluble, which means there is a specific dry matter concentration beyond which it becomes insoluble in the wet-mixing of powdered infant formula.
During the wet-mixing process of powdered infant formula, fat stabilization is essential to prevent separation Proteins, which possess both hydrophobic and hydrophilic properties, are crucial for emulsifying the formula Through homogenization, fat is broken down into small globules and stabilized by proteins that adhere to the fat-water interface, with their hydrophobic regions facing the fat and hydrophilic regions facing the water Additionally, powdered infant formula, particularly those with hydrolyzed proteins, may include low molecular weight surfactants that serve as emulsifiers, similarly interacting with the fat-water interface.
Heat treatment plays a crucial role in ensuring the microbiological purity of powdered infant formula, and it can be applied at various stages of the production process To achieve a more stable emulsion, it is often beneficial to conduct heat treatment prior to homogenisation, as this can prevent the disruption of fat globule aggregates formed during heating.
[19] [20], used heat treatment before homogenization in their research.
Evaporation is a cost-effective method for removing water from powdered infant formula wet-mixes prior to spray drying, commonly utilized in the dairy industry through falling film evaporators In this process, the wet-mix flows by gravity through tubes, forming a film as it descends, while live steam is sprayed on the outside to facilitate evaporation at a vacuum temperature of 50 to 70 °C, preserving heat-sensitive components The achievable concentration is limited by viscosity, with whole milk's post-evaporation viscosity ideally not exceeding 60-100 mPa.s for efficient drying Additionally, evaporation influences the physical properties of wet-mix elements; research by Liu et al (2012) indicated that the concentration of skim milk affects micellar hydration, aggregation, and calcium association, while McCarthy et al observed an increase in fat globule size during evaporation in IMF emulsions.
Spray drying is a key process in the production of powdered infant formula, where wet mixes are atomized into fine droplets (10-3400 μm) to enhance contact with hot air for efficient moisture removal Typically, two or three-stage spray dryers are employed, featuring a large drying chamber for initial water removal, followed by additional drying in an internal and/or external fluidized bed To improve the wettability and flowability of the powdered formula, powder particle agglomeration occurs through random collisions of atomized particles during drying This process involves positioning atomized particles from multiple machines to facilitate forced primary aggregation, while fine particles exiting the dryer's exhaust are reintroduced into the drying chamber for forced secondary agglomeration.
Cronobacter illnesses linked powdered infant formula
Cronobacter sakazakii
The Cronobacter genus consists of Gram-negative, facultative anaerobic rods that are part of the Enterobacteriaceae family, closely related to Enterobacter and Citrobacter Initially defined by reclassifying Enterobacter sakazakii, Cronobacter belongs to the taxonomic class Gammaproteobacteria and the family Enterobacteriaceae.
Cronobacter is a genus of facultatively anaerobic, Gram-negative, oxidase-negative, catalase-positive, non-spore forming rods that are typically motile These bacteria can reduce nitrate to nitrite, produce acetoin, and do not pass the methyl red test Since its initial classification, the Cronobacter genus has undergone three taxonomic revisions, resulting in a total of seven recognized species, including C sakazakii.
C malonaticus, C turicensis, C universalis, C muytjensii, C dublinensis, and C condimenti [29] [30] [31]
Figure 3 Seven species of Cronobacter genus [9]
Cronobacter sakazakii, previously known as Enterobacter sakazakii [30]
C sakazakii is an opportunistic Gram-negative, rod-shaped bacterium known for its ability to thrive in extremely dry environments, a trait referred to as xerotolerance This bacterium survives desiccation through the expression of various genes, and its level of xerotolerance may vary among different strains.
Cronobacter sakazakii, first identified in dried milk in 1950, has likely existed for millions of years Over the decades, it has been associated with numerous cases of infant meningitis and sepsis, particularly linked to powdered infant formula While adults represent the majority of C sakazakii cases, low-birth-weight preterm neonates and older infants are especially at risk This pathogen is a rare but severe cause of invasive infections in infants, with historically high case fatality rates ranging from 40% to 80% Approximately 50% of affected infants succumb to the infection, and survivors may face neurological impairments.
Between 1961 and 2018, the Centers for Disease Control and Prevention reported 183 cases of bloodstream infections or meningitis in infants, with a significant majority being neonates (67%) The mortality rate among these cases was 38%, and a concerning 79% of the infants had consumed potentially unsafe infant food (PIF) prior to their illness.
Table 2 Numbers of reported invasive Cronobacter infections among infants, by country, 1961-2018 [37]
During the final quarter of the study period from 2004 to 2018, case counts showed a significant increase, with a global average of 8.7 cases per year Notably, among cases reported in the US, a higher proportion was observed in full-term infants (56% [27 out of 48]) and nonhospitalized infants (78% [42 out of 54]).
All Cronobacter species, except C condimenti, have been retrospectively associated with clinical infections in both adults and infants Notably, multilocus sequence typing has identified that the majority of neonatal meningitis cases over the past 30 years are linked to a specific genetic lineage of Cronobacter sakazakii, known as 'Sequence Type 4' or 'ST4', indicating that this clone poses the greatest risk for infant infections.
Figure 4 Sources of C.sakazakii strains [9]
Cronobacter symptoms usually include the following in infants:
A Cronobacter sakazakii infection can also turn into meningitis, an inflammation of the membranes surrounding the brain and spinal cord Signs of meningitis in newborns include:
A bulge in the soft spot on the top of the head
Stiffness of the body and neck
Cases of Cronobacter sakazakii contamination in other products
Neonatal infections caused by C sakazakii are primarily linked to powdered infant formula, as certain strains can survive in a dried state for over two years However, not every case has been traced back to contaminated formula In November 2011, a significant recall of Kotex tampons occurred due to contamination with Cronobacter (E sakazakii).
[32] In one study, the pathogen was found in 12% of field vegetables and 13% of hydroponic vegetables [43] [44].
Some reported cases of Cronobacter spp infections related to powdered
Cronobacter spp (formerly Enterobacter sakazakii) infection is rare but can kill 40% 80% of infected infants[41] The first two documented cases of 3
Cronobacter species occurred in 1958 at St Albans, England[45] According to the Centers for Disease Control and Prevention (CDC) [46] and FAO/WHO [7], from
1958 to 2009, there was 120 cases of Cronobacter infection in infants have been reported, and at least 27 deaths from all parts of the world
The below table is the summary of some outbreaks and cases of Cronobacter species until 2017, according to Song et al in 2018[45]
Table 3 Outbreaks and cases of infections
Location Year Cease/Death References
St Albans, England 1958 2/2 Urmenyi and Franklin, 1961
Denmark 1965 1/None Joker et al., 1965
Macon, GA, USA 1979 1/Not mentioned
Indianapolis, IN, USA 1981 1/None Kleiman et al., 1981
The Netherlands 1983 8/None Muytjens et al., 1983; Muytjens,
Arseni et al., 1985 Reykjavik, Iceland 1986-1987 3/1 Biering et al., 1989; Clark et al.,
Memphis, TN, USA 1988 4/Not mentioned
Baltimore, MD, USA 1990 1/Not mentioned
Cincinnati, OH, USA 1990 1/Not mentioned
Belgium 1998 12/2 Van Acker et al., 2001
Israel 1997-2000 5/None Block et al., 2002; Bar-Oz B et al.,
2001 Knoxville, TN, USA 2001 10/1 Himelright et al., 2002; Weir, 2002
CDC unpublished data, Bowen and
CDC unpublished data; Bowen and
Coignard et al., 2004; Bowen and
CDC unpublished data; Bowen and
CDC unpublished data; Bowen and
New Mexico, USA 2008 2/None CDC, 2009
Queretaro, Mexico 2010 2/None Flores et al., 2011
Not mentioned 2012 1/None Broge and Lee, 2013
Cronobacter infections in neonates and infants have been increasingly reported, with C sakazakii not being recognized as a significant source of these infections prior to 1994 Since then, contaminated powdered infant formula (PIF) has been identified as the primary risk factor for neonatal Cronobacter spp infections in numerous studies Notably, Muytjens et al first linked Cronobacter spp to infant milk formula in 1983, citing inadequate hygiene and improper handling as potential causes for eight cases in the Netherlands Additionally, a tragic outbreak in Belgium involved 12 infants, resulting in the deaths of twin brothers, prompting a temporary halt in the use of the infant formula Although initial tests suggested the formula was not contaminated, further investigation revealed the tests were incorrect after a female child fell ill.
Cronobacter-associated necrotizing enterocolitis has been linked to contaminated infant formula, as evidenced by research from Van Acker et al in 2001, which identified C sakazakii in both implicated formula and unopened cans from the same batch Investigations revealed that the manufacturer's quality control regarding coliforms violated Belgian regulations, leading to a recall of all contaminated products In the United States, multiple cases of Cronobacter infections were reported, including a 1989 outbreak in a Memphis hospital involving four infants who consumed formula prepared in the same food blender, which tested positive for Cronobacter spp and E cloacae The food blender itself was also contaminated with various pathogens, highlighting the importance of stringent food safety measures.
Pseudomonas maltophilia may have originated from a food blender, highlighting potential contamination sources In 2001, the first reported case of C sakazakii infection linked to infant formula led to a significant product recall in the United States This incident prompted a cohort analysis to investigate the implications of the outbreak.
A study evaluated 49 patients to identify potential risk factors for C sakazakii infection or colonization, revealing nine case patients and forty noncase individuals The research identified specific infant formula as the source of the infection, with testing confirming the presence of the bacteria in both open and unopened cans of the formula.
In 2007, Cronobacter spp was identified as the cause of meningitis in a 17-day-old infant in Canada, with powdered infant formula linked to the infection That same year, India reported its first two cases of Cronobacter spp infection, with powdered infant formula suspected as the source for at least one case, although the pathogen was not isolated from the formula due to insufficient testing.
In 2022, four illness cases were reported, believed to be associated with powdered milk, particularly linked to Abbott Laboratories, a prominent U.S healthcare company known for nutrition brands like Pedialyte, Ensure, Glucerna, and the widely chosen baby formula, Similac In 2020, Similac had approximately 3.18 million consumers in the U.S., yet there were four notable customer complaints regarding the product.
Abbott voluntarily recalled Similac, Alimentum, and EleCare products manufactured in Sturgis, Michigan, on February 17, 2022, due to reports of Cronobacter sakazakii and Salmonella Newport infections in infants who consumed formula from this facility The FDA found evidence of Cronobacter sakazakii in non-product contact areas during inspections, but no evidence of Salmonella Newport Although retained samples related to the complaints tested negative, there were confirmed cases of infants infected with Cronobacter after consuming the formula The FDA has advised consumers to avoid using the recalled products while further investigations continue.
Figure 5 Recall for Similac, Alimentum, and EleCare powdered infant formulas
Products are included in the recall if they have all three items below[52]:
- The first two digits of the code are 22 through 37 and
- The code on the container contains K8, SH, or Z2, and
- The expiration date is 4-1-2022 (APR 2022) or later
Figure 6 Recall products have a code beginning from 22 to 37 and containing
On February 28, 2022, Abbott voluntarily recalled a specific lot of Similac PM 60/40 (Lot # 27032K80 for cans and Lot # 27032K800 for cases) produced in Sturgis, Michigan, following the tragic death of a child who tested positive for Cronobacter sakazakii and had consumed formula from this batch.
The FDA has disclosed documents indicating recurring food safety issues at the manufacturing facility for Similac PM 60/40 infant formula, as outlined in FDA Form 483.
The factory failed to test a representative sample of the powdered infant formula production aggregate at the final product stage prior to distribution, neglecting to ensure that it met essential microbiological quality standards.
+ The factory did not keep a building utilized in the production, processing, packing, or storage of infant formula clean and sanitary
Personnel involved in handling raw components, packaging, equipment, or surfaces that contact infant formula failed to adequately wash their hands in a designated handwashing facility at the appropriate temperature after potential contamination.
The factory failed to establish a comprehensive process control system, which is essential for ensuring that infant formula remains uncontaminated by microorganisms during both production and environmental exposure This oversight highlights the critical need for stringent safety measures throughout all processing stages.
Cronobacter sakazaldi were found in the packaging room for the filler line, and some other places in the factory
+ The factory failed to ensure that all surfaces that came into contact with the products were maintained clean to prevent contamination of infant formula from any source
These released documents showed the high potential risk for Cronobacter sakazaldi infection in Abbott9s infant formula
Recent analysis indicates that patient samples are not genetically linked to the Cronobacter strains found in environmental samples from Abbott Nutrition's Sturgis, MI facility, suggesting that the contamination is not directly tied to powdered milk production However, persistent food safety issues at the Sturgis factory must be addressed to mitigate the risk of infections from Cronobacter sakazakii and other pathogens Notably, a positive test for two strains of Cronobacter sakazakii was identified in an open container at the infant's home, one of which matched the strain responsible for the infant's infection The FDA has collected additional product samples for ongoing analysis following four reported infection cases, which may have contributed to the deaths of two newborns in Ohio These infections appear to stem from inadequate hygiene practices or improper handling of powdered infant formula.
Recent studies highlight a concerning link between powdered infant formula and Cronobacter infections The WHO/FAO report on Enterobacter sakazakii emphasizes that infant formula can serve as both a direct and indirect source of C sakazakii-related illnesses Data from the United States in 2003 further supports the notion of sporadic cases associated with this pathogen.
C sakazakii sepsis and meningitis, six of the seven incidents involved powdered infant formula This means that powdered baby formula was a possible source in at least 85 percent of these cases Besides, there were at least 25 cases per 48 cases (52%) that were directly linked to powdered infant formula from the review of C sakazakii cases in English language literature since 1961
In addition, the research of Kalyantanda et al in 2015 about the