Chemistry: molecular biology and microbiology – Micro-organism – tissue cell culture or enzyme using process... – Preparing compound containing saccharide radical
Reexamination Certificate
2001-02-09
2003-09-02
Marx, Irene (Department: 1651)
Chemistry: molecular biology and microbiology
Micro-organism, tissue cell culture or enzyme using process...
Preparing compound containing saccharide radical
C424S093440, C424S093460, C424S093510, C435S252900, C435S252100, C435S253400, C435S254210
Reexamination Certificate
active
06613549
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to compositions and methods employing probiotic microbial compositions for treating and preventing intestinal and other infections which originate from the intestine, in newborn infants.
BACKGROUND OF THE INVENTION
Each year, intestinal infections kill more people in the world than any other disease. Many of the victims of intestinal infections are children in Third World Countries. The causative agents are mainly bacteria and viruses. Presuming the availability and access to antibiotics and other chemotherapeutic treatments (and many in the Third World do not have such access), these intestinal and urogenital infections are usually not fatal. However, increased antibiotic resistance and poor nutrition and hygiene result in continually elevated morbidity and mortality rates.
Once a child is born, intestinal infections are common (21-37 million diarrheal disease episodes in 16.5 million US children each year) and death can occur (around 200 annually in US and Canada). Necrotizing enterocolitis, for example, is one of the most devastating diseases that a preterm infant faces during its efforts to continue its fragile existence within a neonatal intensive care unit (NICU). The incidence of necrotizing enterocolitis, ranges from 10-25% of preterm infants (about 1,500 g in weight) admitted to the NICU, and may involve approximately one third to one half of all very low birth weight infants. Of those, approximately half will require surgery. The mortality ranges from 25-30%, and of those who survive, around 25% experience long term sequelae. In some cases, the sequelae result from multi-system organ failure which has damaged the lungs or other organs.
The infecting organisms are broad in their range, and include Clostridium, Escherichia, Klebsiella, Salmonella, Shigella, Campylobacter, Pseudomonas, Streptococcus, Enterococcus, Staphylococcus, coagulase-negative staphylococci, other Gram positive cocci, and other species including yeasts, viruses and protozoa.
A critical factor in protecting infants appears to be the formation of a protective intestinal flora. It is known that a flora high in protective bacteria (such as lactobacilli and bifidobacteria, believed to be transferred from the breast feeding mother), is critical to fighting off harmful organisms. However, the protective flora is not well established in these premature infants and by supplementing the flora with exogenous normal flora (either true probiotic organisms or the mother's own normal flora members) the risk of infection will be significantly reduced. Moreover, when infection ensues, treatment with probiotics will reduce the subsequent severity and longevity of the illness.
In recent years, Gregor Reid, Ph.D. and Andrew Bruce, M.D. have investigated the use of Lactobacillus to prevent and treat urogenital infections (Reid et al. (1998)
Int. Dairy J.
8:555-562). This has included the development of probiotics which are ingested and which colonize and pass through the intestine to the vagina. These organisms have been shown to inhibit the growth and adhesion of pathogens and coaggregate to form a balanced normal flora which protects the host against infection.
The present invention now takes into account an infectious state not previously investigated for the application of probiotics, namely intestinal infections, particularly necrotizing enterocolitis, in premature newborn infants. While the importance of the ability of probiotic organisms to adhere and produce substances and conditions inhibitory to growth and adherence by harmful pathogens has been recognized, it has only now been appreciated, in accordance with the present invention that probiotics are primary colonizers i.e. the first microbes to reach the intestine and colonize the intestines of newborns.
The nature of the probiotic organisms which are used in this patient population is also important. These must adhere to intestinal cells, grow and survive and provide a health benefit to the host. Examples of appropriate strains are
Lactobacillus rhamnosus
GR-1,
Lactobacillus fermentum
RC-14 and Bifidobacterium. GR-1 and RC-14 have been demonstrated to produce substance antagonistic to various enteric pathogens (unpublished data and Velraeds et al. (1998)
J. Med. Microbiol.
49:790-794). Bifidobacteria have been shown to effectively treat intestinal infections in Chernobyl patients in Russia, where the intestine has been damaged by exposure to radiation (unpublished data). There is also evidence to show that probiotics prevent and reduce the duration of diarrhea in older children whose intestinal flora has already been established. However, none of these studies have investigated newborns, nor addressed a situation where the newborn's intestine is undercolonized.
In studies of acute diarrhea (bacterial and rotaviral) in children 6 to 36 months of age, a
Lactobacillus reuteri
probiotic was given at 10e10 and 10e11 colony-forming units daily for 5 days and found to significantly reduce the duration of watery diarrhea compared with placebo (Shornikova et al. J. Pediatr. Gastroenterol. Nutr. 1997, 24: 399-404; and Shornikova et al. Pediatr. Infect. Dis. 1997, 16: 1103-1107). These studies described the safe application of probiotics to treat infection. The difference between these studies and the present invention is that the babies that are effectively treated by the present invention are premature, underweight newborns, who do not have a normal established flora, and the enterocolitis which they acquire is of a more serious nature to the child's survival.
SUMMARY OF THE INVENTION
The present invention demonstrates specially selected probiotic organisms with antagonistic properties against intestinal pathogens, can colonize, treat and provide protection against intestinal infection in newborns.
The present invention provides methods and compositions for the treatment and inhibition of intestinal infection caused by pathogenic organisms. Oral, rectal or intravenous administration of Lactobacillus and other probiotic compounds in a pharmaceutically acceptable carrier, such as milk or portions thereof provide a safe and effective means for colonizing the intestine, and treating, inhibiting or reducing the occurrence of intestinal infections in newborns.
In the practice of the compositions and methods of the present invention, the Lactobacillus may be administered as viable whole cells. The Lactobacillus species may be aerobically grown or microaerophillically grown and selected from
L. rhamnosus, L. acidophilus, L. crispatus, L. fermentum, L. plantarum, L. casei, L. paracasei, L. jensenii, L. gasseri, L. cellobiosis, L. brevis, L. delbrueckii, L. rogosae
and
L. bifidum.
In one embodiment the present invention provides a newborn infant composition having one or more probiotic organisms such as lactobacillus and bifidobacteria.
In another embodiment of the present invention a newborn infant composition is provided having one or more probiotic organisms which are isolated from the intestinal flora of the newborn infant's mother.
In still another embodiment of the present invention a method is provided for colonizing the gastrointestinal flora in newborns comprising administering a therapeutically effective amount of at least one probiotic organism and a pharmaceutically acceptable carrier. In a further embodiment of the method a therapeutically effective amount of a second probiotic organism is administered. Lactobacillus is the preferred probiotic organism. Bifidobacteria is the preferred second probiotic organism. The Bifidobacterium is preferably selected from the group consisting of
B. bifidum, B. breve, B. adolescentis, B. infantis, B. pseudolongum, B. angulatum, B. catenulatum
or
B. longum.
In yet another embodiment, the present invention describes a method of treating an infection in a newborn comprising administering a therapeutically effective amount of pharmaceutical composition comprising one or more isolated probiotic organisms and a pharmaceutically acceptable carr
Bruce Andrew W.
Han Victor
Reid Gregor
Marx Irene
Scully Scott Murphy & Presser
Urex Biotech, Inc.
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