we reviewed the literature for reports of e. sakazakii disease in infants . using medical subject heading terms " e. sakazakii " or " enterobacter " in combination with " newborn , " " infant , " or " meningitis ,
finally , we reviewed e. sakazakii case consultations conducted by the centers for disease control and prevention ( cdc ) from 1998 to 2005 and reviewed results of a french outbreak reported to cdc in 2005 ( 14 ) .
we defined a case as an infant ( < 12 months of age ) with e. sakazakii cultured from an area of the body that is normally sterile : tissue , blood , cerebrospinal fluid , or urine aspirated through the bladder wall .
infants with cultures of cerebrospinal fluid or brain abscesses yielding e. sakazakii were considered to have meningitis . because bacteremia is usually an intermediate step during the process of developing meningitis , patients with both bacteremia and meningitis
bacteremia was defined as e. sakazakii grown from the blood of a case - patient without evidence of meningitis .
infants with gestational ages < 37 weeks , or those reported to be premature , were considered premature .
a gestational age of 40 weeks was assigned to 3 ( 27% ) of 11 infants with bacteremia and 4 ( 14% ) of 28 infants with meningitis who were reported as born following term gestation without a specific gestational age mentioned .
we defined birthweight < 2,500 g as low birthweight ( lbw ) , < 1,500 g as very low birthweight ( vlbw ) , and < 1,000 g as extremely low birthweight ( elbw ) .
descriptive analysis was performed by using sas software ( sas institute , cary , nc , usa ) .
forty - six infants met the case definition ( table 1 ) . reported onset years ranged from 1958 to 2005 ; 32 ( 70% ) cases
cases were reported in 7 countries in north america , europe , and the middle east .
thirty - three ( 72% ) infants had meningitis , 12 ( 26% ) had bacteremia , and 1 ( 2% ) had a urinary tract infection .
eight ( 40% ) of 20 infants for whom data were available were delivered by cesarean section .
twenty - nine ( 69% ) of 42 infants experienced disease onset within a hospital .
gestational duration was available for 38 infants ; 21 ( 55% ) were born prematurely , and the median gestational age overall was 36 weeks ( range 23.540 weeks ) .
the median birthweight was 2,063 g ( range 5403,401 ) ; 18 ( 56% ) of 32 infants had lbw ; 9 ( 28% ) of these met the definition for vlbw , and 7 ( 22% ) met the definition for elbw .
median age at the time of infection onset was 8.5 days ( range 2300 ) .
* lbw , low birth weight ; vlbw , very low birth weight ; elbw , extremely low birth weight .
although the proportion of infants who experienced nosocomial disease onset was not significantly different between the meningitis and bacteremia groups , other infant characteristics differed by site of infection ( figure ) .
the median gestational ages of infants with meningitis and bacteremia were 37 and 27.8 weeks , respectively ( p = 0.02 ) .
median birthweights were 2,454 g and 850 g , respectively ( p = 0.002 ) .
however , median age at infection onset was 6 days in the group with meningitis and 35 days in the group with bacteremia ( p < 0.0001 ) .
thirty ( 94% ) of 32 infants with meningitis , but only 2 ( 18% ) of 11 infants with bacteremia , were < 28 days old when infection was detected .
one infant ( 8% ) with bacteremia died ; this infant also had necrotizing enterocolitis . the single infant with a urinary tract infection recovered without complication .
of 19 surviving infants , only those with meningitis suffered adverse outcomes , including brain abscess ( 21% , p = 0.2 ) , developmental delays ( 53% , p = 0.004 ) , motor impairment ( 21% , p = 0.3 ) , and ventricular shunt placement ( 42% , p = 0.01 ) ; 74% experienced at least one of these outcomes .
box plot with each box indicating range ( vertical lines ) , first and third quartiles ( lower and upper boundaries of box , respectively ) , and median value ( horizontal solid line ) for gestational age in weeks , birth weight in grams , and age of onset in days for infants with bacteremia only or meningitis .
the dotted lines indicate median values for all cases . * significantly different values (  = 0.05 ) between groups .
twenty - four ( 92% ) received a powdered formula product , including an infant who received powdered breast milk fortifier but no powdered infant formula ; 1 additional infant received formula of an unspecified type .
e. sakazakii was cultured from formula associated with 15 ( 68% ) of 22 cases investigated .
isolates were obtained from prepared formula , opened formula tins , and previously unopened formula tins associated with 2 , 6 , and 7 cases , respectively .
thirteen ( 87% ) of the 15 formula isolates were indistinguishable from the corresponding clinical strain by biotype or genotype ; multiple formula manufacturers were implicated . in one of the remaining cases ,
multiple e. sakazakii strains were recovered from powdered formula , but none matched the clinical isolate by pulsed - field gel electrophoresis ( cdc , unpub .
, 2 e. sakazakii strains were isolated from blood and from rectal swabs ; a third strain , as determined by arbitrarily primed pcr , was recovered from the powdered infant formula ( 9 ) .
although numerous reports include infants with e. sakazakii isolated from nonsterile sites , such as respiratory secretions or stool , 46 infants identified from the literature and cdc sources met the case definition for this analysis ( 1,9,10,12 ) . of the infants with sterile - site infection
contrary to previous characterizations of e. sakazakii disease , we found that infants with meningitis and bacteremia alone fell into 2 distinct groups .
those in whom meningitis developed tended to be of greater gestational age and birthweight than those with bacteremia alone .
in fact , infants in whom meningitis developed tended to attain near - term gestational age and birthweight .
in contrast , infants in whom bacteremia alone developed tended to be born very prematurely and have elbw . a second major difference between the group with meningitis and the group with bacteremia was the infants ' chronological ages .
infants with meningitis were generally < 1 week of age at the onset of infection with e. sakazakii , whereas infants with bacteremia had generally surpassed the neonatal period at the onset of their disease .
rates of adverse outcome also differed between the 2 groups , although this was not unexpected .
most infants with e. sakazakii bacteremia fared better than those with meningitis . among those in whom
meningitis developed , rates of adverse outcome were similar to those reported in the literature : in this case series , 74% of meningitis survivors experienced an adverse neurologic outcome , while other studies cite adverse outcome in 20%78% of neonatal or infant meningitis survivors ( 2123 ) .
the division of the infant population into 2 distinct groups occurred for unclear reasons . that infants < 1 week of age comprised
the meningitis group was not surprising ; the disparities in other infant characteristics , however , are not intuitive . since infants in the 2 groups experienced similar rates of nosocomial disease onset , the infants with bacteremia were unlikely to have simply received treatment earlier in the disease course than the infants with meningitis .
powdered infant formula is a demonstrated source of e. sakazakii infection . a microbiologic survey of powdered infant formulas published in 1988 found e. sakazakii in 20 ( 14% ) of 141 samples tested ( 24 ) .
however , a survey of 82 powdered infant formula samples in 2003 yielded e. sakazakii in 2 ( 2.4% ) , which suggests that recent rates of powdered formula contamination may be lower ( 25 ) .
powdered formula has also been implicated both epidemiologically and microbiologically as a vehicle in several cases of e. sakazakii disease in infants ( 1,3,9,10,13 ) .
although we could not explore feeding exposures fully with the data available in this series , infant feeding practices may relate to the differences we describe in chronological age of infants at onset of meningitis and bacteremia .
infants with nearly normal gestational ages and birthweights are likely to be tended in normal newborn nurseries during the first 2472 hours of life . in such nurseries , powdered formula is frequently given to babies who are not breast - fed , and it may also be used as a supplement by mothers who have chosen to breast - feed . since infants are at highest risk for meningitis during the first several weeks of life , possibly because of immaturity of the blood - brain barrier , exposures to e. sakazakii in powdered formula or other sources during this time may quickly lead to central nervous system disease ( 26,27 ) .
conversely , in the intensive care settings where immature and low birthweight infants are tended , babies are not often fed powdered formula in the first few weeks of life .
they may be given parenteral nutrition initially and may be fed breast milk from their own mothers or from a banked source when they do begin enteral feeds . if breast milk is not available , they are more likely to be given sterile , premixed infant formula than powdered formula , since standard preterm infant formula is only available in this form ( 28 ) .
powdered breast milk fortifiers are not introduced until premature infants tolerate full - volume feeds , which may not occur for days or weeks after birth .
thus , infants in intensive care settings may not be exposed to nonsterile formula until they are more mature , which would lead to a greater proportion of e. sakazakii bacteremia than meningitis in this group if powdered formula is a source of infection . in this series
, we were unable to explore the roles of indwelling enteric tubes , prior gastrointestinal surgery , and antecedent antacid or antimicrobial drug use as risk factors for infection . while the reservoir for e. sakazakii is unknown ,
e. sakazakii has been isolated from factories used to produce milk powder , chocolate , cereal , potato flour , spices , and pasta ( 29 ) .
it also has been isolated from household vacuum cleaner bags and from the guts of the stable fly , stomoxys calcitrans , and the mexican fruit fly , anastrpha ludens ( 2931 ) .
although a human vaginal tract culture yielding e. sakazakii has been reported , vertical transmission is unlikely because nearly half of infants with e. sakazakii disease in this review were delivered by cesarean section , and symptoms developed in only 1 infant earlier than 3 days of age ( 32 ) .
although cases with more severe outcomes might have been investigated and published more frequently than uncomplicated cases , this possible bias would not likely affect the representativeness of baseline infant characteristics . assigning a gestational age of 40 weeks to term infants without a reported gestational age
may have falsely elevated the median gestational ages we report , since most term infants are born at < 40 weeks ' gestation ( 33 ) .
however , a greater proportion of bacteremic infants than meningitic infants received this assignment , and therefore the significance of the differences in gestational age between the groups may be even greater than we report .
we were unable to explore the effects of concomitant medical problems , treatments , and other environmental factors , and we relied on existing reports of feeding practices and formula testing .
clearly , additional study is needed to elucidate the lingering questions about e. sakazakii reservoirs , disease risk factors , and disease course .
other gram - negative organisms , including escherichia coli , enterobacter agglomerans , e. cloacae , klebsiella pneumoniae , k. oxytoca , and citrobacter freundii , can be found in powdered infant formula ( 24,25 ) .
powdered infant formula also has been associated with outbreaks of illness due to citrobacter and multiple salmonella serotypes ( 13,3438 ) . the degree to
which e. sakazakii is a marker for a range of neonatal infections possibly related to powdered infant formula remains to be defined .
certain steps can be taken immediately , however , to prevent or mitigate e. sakazakii disease . in a joint conference on infant formula safety in february , 2004 ,
the world health organization and food and agriculture organization of the united nations made the following recommendations : 1 ) encourage industry partners to develop a range of affordable sterile formula options ; 2 ) consider setting an industry standard for enterobacteriaecae and e. sakazakii in infant formula ; 3 ) inform infant caregivers of the risks associated with nonsterile , powdered formula ; and 4 ) consider feeding high - risk infants sterile formula if they can not breast - feed ( 39 ) .
the findings of our case review suggest that all neonates as well as premature infants should be included in this high - risk infant category .
the american dietetic association has issued guidelines for infant formula preparation , storage , and administration ; these should be followed by infant caregivers in hospitals and private homes ( 40 ) .
rapid reporting of cases by clinicians could streamline data collection by local health departments and more rapidly resolve remaining questions about this illness .
manufacturer warning labels on powdered infant formula packages should stress that powdered infant formula is nonsterile and requires proper preparation , handling , and storage , and that sterile , liquid formula alternatives are available
. these actions , adopted in whole or in part , may decrease the infectious risks associated with powdered formula and prevent this rare but potentially devastating disease .
 enterobacter sakazakii kills 40%80% of infected infants and has been associated with powdered formula . 
 we 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 . twenty - four ( 92% ) of 26 infants with feeding patterns specified were fed powdered formula . 
 formula samples associated with 15 ( 68% ) of 22 cases yielded e. sakazakii ; in 13 cases , clinical and formula strains were indistinguishable . 
 further clarification of clinical risk factors and improved powdered formula safety is needed . 
Methods
Results
Discussion