Effectivestudyformula Study f Study e Effectivestudyformula t Effectivestudyformula v Daisy6122 Guarantee Daisy6122 asearchs6 Effectivestudyformula 2search search Effective e searche Guarantee o Guarantee t Effectivestudyformula dasearchd
Daisy6122 Formula osearchm Effective l Formula o Daisy6122 mlsearch seasearchch Effective Effective tsearchd isearchEfsearche Guarantee t Effective ve c Guarantee Gua Formula a Effective tsearche Daisy6122 d Study Gua
an Study eesearche Daisy6122 For Effectivestudyformula usearcha Study Effective ea Guarantee c Study i Esearchf
csearchivetudysearchom Formula l Guarantee 
esearch Effectivestudyformula Guarantee earchi Guarantee Effeti Daisy6122 esearche Study G Daisy6122 aran Daisy6122 ee Formula ssearchS Effective uy asearchsy
1 Effective 2 Guarantee searc Study Formula Dsearchi Formula ysearch122 Formula o Effective earchaisearchasearch Daisy6122 h Effective dsearchisearchgsearchisearch search Study rusearch Study f h Formula ssearchisearcha Guarantee i Formula e Effective isearchf Guarantee n Study ssearch(23). Formulas containing B. lactis and S. thermophilus have been marketed in Europe, Asia, and South America for years, without any known adverse effects. Given centuries of use
in the food supply, there has generally been little concern regarding the safety of these agents. Although exceptional, there
have been several reports of bacteremia associated with selected probiotic bacteria. Endocarditis, pneumonia, and meningitis
have very rarely been reported in association with lactobacilli, and extraordinary reports have been documented with B. eriksonii (6). No other study done with bifidobacteria or B. lactis has shown any adverse events. Most of these isolated reports, however, were in significantly compromised hosts, and we are
not aware of any infections ever reported with other bifidobacteria or S. thermophilus.
Prospective studies specifically using B. lactis (20, 23) showed adequate growth. In children followed prospectively for various clinical indexes while receiving bifidobacteria, no apparent problems with growth were reported (24–26). However, safety, gastrointestinal tolerance, and growth with long-term use of probiotic-supplemented products have not been adequately studied for most of the probiotic agents currently available for human consumption. Additionally, many of these products are sold with no regulatory control (27, 28). Studies are even scarcer in pediatric populations. The present study specifically addressed these issues.
Reporting of loose stools and indicators of severity (including fever or vomiting associated with loose and watery stools) were not significantly different between the groups. From the point of view of gastrointestinal tolerance, there was a lower reported frequency of colic or irritability associated with probiotic use. Probiotics may, by modifying patterns of fermentation, lead to less gas or water formation, which in turn may affect gastrointestinal tolerance, although this remains speculative.
In terms of general health indicators, all children showed normal growth, and the population as a whole had no significant change in SD scores for ponderal and linear gain. The frequency with which health care attention was sought for illness and the reported frequency of antibiotic use was lower for both supplemented groups than for the placebo group, although only the difference in antibiotic use was significant (P < 0.001). Several studies using probiotic agents, including B. lactis, have documented several immunologic effects of probiotics, including increases in secretory immunoglobulin A (25, 29) and enhancement of phagocytic activity (30–32). In addition, the protective effect of probiotics in infectious and inflammatory conditions has been shown. Several studies documented efficacy with several strains of bifidobacteria, in isolation or together with other probiotics (33–35), all showing a shortened duration and generally a less complicated course of acute diarrheal disease in young infants in different settings.
Interest also has emerged in the area of probiotic use in the treatment and prevention of allergic disease, in particular, atopic dermatitis (36). Isolaurei et al (20) showed that infants receiving an extremely hydrolyzed formula supplemented with Lactobacillus GG and B. lactis, compared with a control group receiving only extremely hydrolyzed formula, showed significant improvement in signs of skin atopy. The association between food and atopic disease has lead to work in understanding and preventing nutrient and gut interactions leading to allergic symptoms (37–39). The immune-mediated benefits seen in the trials mentioned may be reflected by the decreased use of antibiotic agents in the present healthy infant population.
The study formula was well accepted by the parents and the care providers, and the children tolerated both supplemented formulas without any apparent problems. Formula consumption was as expected, with energy intake from formula gradually decreasing with subject age. The intake of bacteria from the product decreased accordingly by 0.5 log CFU/kg body wt for both supplemented groups at 1 y of age. On the basis of this intake, mean daily bacterial consumption and cumulative consumption over the study period were calculated for each subject. Mean intakes were up to 4.1 x 107 CFU · kg-1 · d-1 and the cumulative bacterial load ingested over time was as high as 1.3 x 109 CFU/kg. Median daily average and cumulative bacterial load intakes were 2.7 x 107 CFU · kg-1 · d-1 and 1.1 x 109 CFU/kg, respectively. For those clinical outcomes for which trends or statistical differences were identified, the level of supplementation did not suggest a specific dose response.
The average child in this study consumed 7–8 log CFU live probiotic bacteria · kg body wt-1 · d-1 for 7 consecutive months. The highest absolute intakes and highest intakes per kilogram occurred in the youngest children because of higher formula intakes and lower body weights. This is further reassurance that even in very young populations, significant consumption of this specific combination of organisms is well accepted and safe.
To our knowledge, this is the first careful documentation of intake of live bacteria over any extended period of time in any population. The intakes studied can be used as a benchmark for well-tolerated, safe intake of these bacterial agents.
In conclusion, prolonged consumption by healthy infants of 2 formulas supplemented with live B. lactis (Bb12) and S. thermophilus at concentrations similar to those previously shown to have clinical benefits was studied. Consumption of bacterial loads in this population were as high as 1 x 108 CFU · kg-1 · d-1 for periods of up to 1 y, with cumulative consumption over time of up to 1 x 109 CFU/kg. Probiotic supplementation of these formulas resulted in adequate growth. The supplemented formulas were well accepted and tolerated and resulted in a significantly lower reported frequency of colic or irritability. Supplementation also resulted in a trend toward less frequent seeking of health care attention and a significantly lower frequency of antibiotic use.
The authors participated in the following aspects of this trial: JMS, design, execution, analysis, and manuscript writing; AA-H, design, execution, data management, analysis, and manuscript writing; NM, design, execution, data collection, data management, and manuscript writing; and RHY, design, analysis, and manuscript writing. None of the authors had a conflict of interest during the trial data analysis period.