Clinical trial NCT02544685: Prevention of Febrile Neutropenia by Synbiotics in Pediatric Cancer Patients
Official title: Prevention of Febrile Neutropenia in Pediatric Cancer Patients by Lactobacillus Rhamnosus GG and Bifidobacterium Animalis Subspecies. Lactis BB-12 in Combination With Inulin and Oligofructose
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
Conditions: Febrile Neutropenia
Neutropenia
Infection in an Immunocompromised Host
Cancer
Keywords: Febrile neutropenia
Synbiotic
Probiotic
Prebiotic
Safety
Cancer
Oncology
Chemotherapy
Symbiotic
Lead sponsor: S&D Pharma SK s.r.o.
Sponsor class: INDUSTRY
First posted: 2015-09-09
Enrollment: 120
Sex: ALL
Minimum age (years): 6
Maximum age (years): 19
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: Febrile neutropenia (FN) is a major life-threatening treatment complication in cancer patients undergoing intensive chemotherapy. Endogenous flora is considered to be one of the main sources of infections during neutropenia. Competitive inhibition of gut mucosal colonization by pathogenic microorganisms using synbiotics could represent one of the potential options for its prevention. Synbiotics represent combination of two components: probiotics and prebiotics. Probiotics are live microorganisms, which in form of drugs or food supplements administered at a sufficient dose help to maintain health beneficial microbial balance in the digestive tract of a human or other host. Prebiotics are food ingredients nondigestible for our digestive enzymes, but can be fermented by bacteria in our bowel and this way selectively stimulate growth or activity of specific saccharolytic bacterial strains. These changes in composition of our microflora may bring benefits on host well-being and health. Based on the results of human and animal studies, probiotics probably can not only decrease the level of gut colonisation with pathogenic bacteria, but may also lead to reduction in the duration of neutropenia, accelerate the restitution of the intestinal mucosa and boost immunity. Despite a significant number of studies on probiotics still only little evidence of their safety especially in immunocompromised patients is available.

To help find new options for increasing quality of healthcare for children cancer patients and also to evaluate safety of this new approach investigators designed double-blinded placebo controled multicenter study aimed to decrease the number of febrile episodes using prevention with synbiotic.

Detailed description: Febrile neutropenia (FN) is a major complication in cancer patients undergoing intensive chemotherapy. Endogenous flora is considered to be one of the main sources of infections in neutropenic patients. The first step in infection process is colonization of the intestine by pathogenic bacteria with their subsequent translocation through the intestinal mucosa and systemic dissemination.

The alterations of the intestinal flora occurs due to chemotherapy and also due to the use of broad spectrum antibiotics, which suppresses anaerobic growth of the normal gut flora leading to a damage of colonization resistance. Competitive inhibition of gut mucosal colonization by pathogenic micro-organisms using synbiotics could represent one of the potential options for the prevention of febrile neutropenia in cancer patients. Compared with the existing selective bowel decontamination with quinolones and/or trimethoprim-sulfamethoxazole, investigators may expect also reduction of the incidence of fungal and Gram-positive infections due to changes in the intestinal microflora. Based on the results of animal studies, probiotics could probably also lead to a reduction in the duration of neutropenia and boost immunity.

Synbiotics represent combination of two components: probiotics and prebiotics. Probiotics are live microorganisms, which in form of drugs or food supplements administered at a sufficient dose help to maintain health beneficial microbial balance in the digestive tract of a human or other host. Prebiotics are food ingredients nondigestible for our digestive enzymes, but can be fermented by bacteria in our bowel and this way selectively stimulate growth or activity of specific saccharolytic bacterial strains.

Lactic acid bacteria are currently widely used in prevention and treatment of certain infectious diseases. They stimulate the immune system, compete for substrate with pathogenic bacteria, produce bacteriocins, competitively inhibit bacterial adhesion sites, increase the transepithelial resistance and bind some mutagens.

Current evidence supporting probiotic use as adjunctive therapy to anticancer treatment is limited, especially in cancer patients treated with chemotherapy. Some of the reports support their beneficial effects on certain aspects of toxicity related to chemotherapy and radiation therapy; however, large properly designed clinical trials are needed to assess their real position as a part of anticancer treatment.

Eleven studies in cancer patients were included in meta-analysis to assess efficacy of probiotics. Results show that probiotics may reduce the severity and frequency of diarrhoea in patients with cancer and may reduce the requirement for anti-diarrhoeal medication, but still more studies are needed to assess the true effect. The importance of probiotics in the treatment of acute diarrhea is supported by meta-analysis of 34 randomized placebo-controlled studies, which showed significant reduction in diarrhea incidence with better effect especially in the pediatric group. Most of these studies were performed with the probiotic strain Lactobacillus rhamnosus GG (LGG). The duration of rotavirus diarrhea in children and diarrhea in immunocompromised HIV-positive patients was significantly shortened after administration of certain strains of Lactobacilli resp. Saccharomyces boulardii.

Investigators can find only anecdotal reports about use of probiotics in patients with neutropenia. In experimental models with cyclophosphamide-treated mice preventive treatment with immunomodulatory lactobacilli was successfully used to protect against myelosuppression and immunosuppression. Lactobacilli were able to induce an early recovery of neutrophils in blood, improve phagocytic cells recruitment to infectious sites and increase the resistance against the opportunistic pathogen C. albicans. In another similar study administration of heat-inactivated strain of Enterococcus faecalis shortened the duration of cyclophosphamide-induced neutropenia and speeded up the restitution of neutrophil count. The important feature of the lactic acid bacteria is ability to produce fatty acids with short chain, which is an important metabolite for colonocytes and this way they may participate in the faster restitution of the mucosa after chemotherapy.

Probiotics fall into the category of organisms classified as "generally regarded as safe". The safety concerns with probiotic administration in cancer patients are related mainly to risk of infection caused by probiotic bacteria and transfer of antibiotics resistance.

Many probiotics strains are naturally resistant to antibiotics, but majority of this resistance is intrinsic (chromosomally encoded) and therefore nontransmissible. This could be a danger, when probiotics become infectious agents, on the other hand probiotic strains with intrinsically antibiotic-resistance may benefit patients, whose normal intestinal microflora has become greatly reduced or unbalanced due to the administration of various antimicrobial agents. For some strains (e.g. LGG) the plasmid-free status was proven, but at the same time it was shown, that some strains may carry potentially transmissible plasmid-encoded antibiotic resistance genes, which could lead to the formation of new antibiotic-resistant pathogens. Therefore, one of the key requirement for probiotic strains is that they should not carry transmissible antibiotic resistance genes.

Despite the fact, that the incidence of infections caused by lactic acid bacteria is extremely low, there exists certain risk, that they can become pathogenic. In case reports probiotics are mentioned as causing local infections such as chest infections, digestive tract infections, urinary tract infections, and meningitis. Though reported lactobacilli bacteremia are very unusual and rare in the pediatric population. They were naturally more often observed in immunocompromised patients, such as in patients with bone marrow transplantation or in patients with AIDS, which also demonstrates low-virulency of these strains. Moreover, clinical isolates of L. rhamnosus captured in these cases had some significant phenotypical differences in one or more properties associated with virulence compared to those, which are used as probiotic strains. Concerns of iatrogenic infection are one of the main reasons for limited experience with administration of probiotics in granulocytopenic patients. In addition, due to chemotherapy it comes not only to neutropenia but also to local affection of gut mucosa and therefore hypothetically arise the possibility of bacterial translocation. This phenomenon is caused by a defective intestinal barrier, immunosuppression and also gut prematurity. It was described as the passage of viable indigenous bacteria from the gastrointestinal tract to extraintestinal sites and may result in the transfer of bacteria to other organs, thereby potentially causing bacteremia, septicemia, and multiple organ failure. However, evidence from animal model studies suggests that there is actually a reduction in the translocation of other bacteria when probiotics are given, as opposed to the transmigration of probiotic bacteria into the bloodstream.

The concerns around bacteraemia/fungaemia or blood culture growth are significant in cancer patients, but this risk needs to be considered alongside any potential benefit. Systematic review including 17 studies with cancer patients identified only five such case reports of the 756 cases described consuming probiotics. Moreover such cases were noted also in patients not known to be consuming probiotics. In addition, there is no evidence from population based studies of any increased risk of bacteremia or endocarditis due to probiotics and their incidence still remained extremely low despite current widespread use of probiotic. Even findings of some small studies in groups of specific immunocompromised patients (e.g., patients with HIV infection) support the safety of particular probiotic strains.

One of the most recent systematic reviews identified 11,977 publications, of which 622 studies (included 24,615 participants using a probiotics) were included in the review. Based on reported adverse events, randomized controlled trials showed no statistically significantly increased relative risk of the over all number of experienced adverse events (Relative risk (RR) = 1.00; 95% Confidence interval (CI): 0.93, 1.07, p = 0.999); gastrointestinal; infections; or other adverse events, including serious adverse events (RR = 1.06; 95% CI: 0.97, 1.16; p = 0.201), associated with short-term probiotic use compared to control group participants; long-term effects are largely unknown. Case studies suggested that participants with compromised health are most likely to experience adverse events associated with probiotics. However, randomized control trials (RCTs) in medium-risk and critically ill participants did not report a statistically significantly increased risk of adverse events compared to control group participants. In conclusion authors of this analysis state, that the available evidence in RCTs does not indicate an increased risk; however, rare adverse events are difficult to assess. However, despite the substantial number of publications, the current literature is not well equipped to answer questions on the safety of probiotic interventions with confidence, especially in group of critically ill patients. Nevertheless, in specific probiotics group, as lactobacilli and bifidobacteria, some authors report that current evidence suggests, that the risk of infection with these probiotic groups is similar to that of infection with commensal strains and though consumption of such products presents a negligible risk to consumers, including immunocompromised hosts. Moreover, this potential risk needs to be always considered alongside any potential benefit. Despite limited data, it seems that probiotic bacteria as live microorganisms could be safely administered even in setting of neutropenia. Future research should focus on selection of most effective and safe probiotic strains and their combinations, and/or administration of probiotics with prebiotics to increase their success in maintaining colonization resistance and in prevention of the adverse events of anticancer treatment.

In a comparable study phase I. probiotic strain was applied to 11 cancer patients to evaluate their benefits and safety. Subsequently, 14 patients with acute myeloid leukemia treated with chemotherapy were enrolled in phase II. None of reported febrile episodes was induced by probiotic strain and no severe adverse events were recorded. Despite limited number of patients, this was the first direct evidence of the safety of probiotics in patients receiving chemotherapy.

One of the causes of failed efficacy of probiotics in the prevention of febrile neutropenia may be the presence of other entries of infection such as central venous catheters. Also, the efficiency of colonization, mucosal damage due to chemotherapy dose and specific probiotic strain may be the causes of this. Another reason may be the inability of one probiotic strain to compensate all changes in the intestinal microflora induced by chemotherapy. One way to solve this problem may be use of combination of multiple probiotic strains. Appropriate selection of strains is required, cause they must not behave antagonistically to each other. Other option is to use combination of prebiotics with probiotics. This can lead not only to acceleration of gut colonization by probiotics, but also to stimulation of endogenous flora growth, which may enhance colonization resistance at another level.

Eligibility criteria: Inclusion Criteria:

* newly diagnosed cancer disease prior to initiation of chemotherapy
* Eastern Cooperative Oncology Group performance status = 0-1
* informed consent has to be given by patients, respectively their legal representatives
* age between 6 months to 19 years
* must be afebrile and no other signs of infection at least 24 hours before starting of prophylaxis
* must not taking other probiotic or prebiotic preparations or discontinued their use more than 14 days ago

Exclusion Criteria:

* impossibility of oral intake
* receiving any other type of experimental prophylaxis
* estimated survival time of less than 4 weeks
* allogeneic or autologous bone marrow transplantation
* inflammatory bowel disease

Primary outcomes:
measure: Reduction in the incidence of febrile neutropenia episodes
timeFrame: 3 months
Secondary outcomes:
measure: Safety evaluated according to Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0
timeFrame: 3 months
measure: Reduction of the total duration of febrile neutropenia
timeFrame: 3 months
measure: Time period to first febrile episode
timeFrame: 3 months
measure: Reduction in the number of septic complications requiring intensive care
timeFrame: 3 months
measure: Reduction in the number of infectious episodes outside the period of neutropenia
timeFrame: 3 months
measure: Reduction in the incidence of diarrhea and enterocolitis episodes related to chemotherapy
timeFrame: 3 months
Other outcomes:
Locations:
city: Banska Bystrica
country: Slovakia
facility: University Children's Hospital Banska Bystrica
Study officials:
affiliation: University Children's Hospital Banska Bystrica
name: Vladimir Holec, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Comenius University and National Cancer Institute
name: Michal Mego, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: University Children's Hospital Banska Bystrica
name: Pavel Bician, MD
role: STUDY_CHAIR
affiliation: Slovak Academy of Sciences
name: Vladimir Zajac, RNDr
role: STUDY_CHAIR
References:
citation: Cole GT, Halawa AA, Anaissie EJ. The role of the gastrointestinal tract in hematogenous candidiasis: from the laboratory to the bedside. Clin Infect Dis. 1996 May;22 Suppl 2:S73-88. doi: 10.1093/clinids/22.supplement_2.s73.
citation: Klastersky J. A review of chemoprophylaxis and therapy of bacterial infections in neutropenic patients. Diagn Microbiol Infect Dis. 1989 Jul-Aug;12(4 Suppl):201S-207S. doi: 10.1016/0732-8893(89)90137-5.
citation: Marshall JC. Gastrointestinal flora and its alterations in critical illness. Curr Opin Clin Nutr Metab Care. 1999 Sep;2(5):405-11. doi: 10.1097/00075197-199909000-00009.
citation: Schimpff SC, Young VM, Greene WH, Vermeulen GD, Moody MR, Wiernik PH. Origin of infection in acute nonlymphocytic leukemia. Significance of hospital acquisition of potential pathogens. Ann Intern Med. 1972 Nov;77(5):707-14. doi: 10.7326/0003-4819-77-5-707. No abstract available.
citation: Salva S, Marranzino G, Villena J, Aguero G, Alvarez S. Probiotic Lactobacillus strains protect against myelosuppression and immunosuppression in cyclophosphamide-treated mice. Int Immunopharmacol. 2014 Sep;22(1):209-21. doi: 10.1016/j.intimp.2014.06.017. Epub 2014 Jun 24.
citation: Satonaka K, Ohashi K, Nohmi T, Yamamoto T, Abe S, Uchida K, Yamaguchi H. Prophylactic effect of Enterococcus faecalis FK-23 preparation on experimental candidiasis in mice. Microbiol Immunol. 1996;40(3):217-22. doi: 10.1111/j.1348-0421.1996.tb03337.x.
citation: Shida K, Nomoto K. Probiotics as efficient immunopotentiators: translational role in cancer prevention. Indian J Med Res. 2013 Nov;138(5):808-14.
citation: Shida K, Nanno M, Nagata S. Flexible cytokine production by macrophages and T cells in response to probiotic bacteria: a possible mechanism by which probiotics exert multifunctional immune regulatory activities. Gut Microbes. 2011 Mar-Apr;2(2):109-14. doi: 10.4161/gmic.2.2.15661. Epub 2011 Mar 1.
citation: Perdigon G, Alvarez S, Rachid M, Aguero G, Gobbato N. Immune system stimulation by probiotics. J Dairy Sci. 1995 Jul;78(7):1597-606. doi: 10.3168/jds.S0022-0302(95)76784-4.
citation: Marin ML, Tejada-Simon MV, Lee JH, Murtha J, Ustunol Z, Pestka JJ. Stimulation of cytokine production in clonal macrophage and T-cell models by Streptococcus thermophilus: comparison with Bifidobacterium sp. and Lactobacillus bulgaricus. J Food Prot. 1998 Jul;61(7):859-64. doi: 10.4315/0362-028x-61.7.859.
citation: Neumann E, Oliveira MA, Cabral CM, Moura LN, Nicoli JR, Vieira EC, Cara DC, Podoprigora GI, Vieira LQ. Monoassociation with Lactobacillus acidophilus UFV-H2b20 stimulates the immune defense mechanisms of germfree mice. Braz J Med Biol Res. 1998 Dec;31(12):1565-73. doi: 10.1590/s0100-879x1998001200009.
citation: Fuller R. Probiotics in man and animals. J Appl Bacteriol. 1989 May;66(5):365-78.
citation: Gibson GR, Roberfroid MB. Dietary modulation of the human colonic microbiota: introducing the concept of prebiotics. J Nutr. 1995 Jun;125(6):1401-12. doi: 10.1093/jn/125.6.1401.
citation: Resta-Lenert S, Barrett KE. Live probiotics protect intestinal epithelial cells from the effects of infection with enteroinvasive Escherichia coli (EIEC). Gut. 2003 Jul;52(7):988-97. doi: 10.1136/gut.52.7.988.
citation: Vandenplas Y. Bacteria and yeasts in the treatment of acute and chronic infectious diarrhea. Part I. Bacteria. Clin Microbiol Infect. 1999 Jun;5(6):299-307. doi: 10.1111/j.1469-0691.1999.tb00148.x.
citation: Apas AL, Gonzalez SN, Arena ME. Potential of goat probiotic to bind mutagens. Anaerobe. 2014 Aug;28:8-12. doi: 10.1016/j.anaerobe.2014.04.004. Epub 2014 Apr 29.
citation: Mego M, Holec V, Drgona L, Hainova K, Ciernikova S, Zajac V. Probiotic bacteria in cancer patients undergoing chemotherapy and radiation therapy. Complement Ther Med. 2013 Dec;21(6):712-23. doi: 10.1016/j.ctim.2013.08.018. Epub 2013 Sep 1.
citation: Redman MG, Ward EJ, Phillips RS. The efficacy and safety of probiotics in people with cancer: a systematic review. Ann Oncol. 2014 Oct;25(10):1919-1929. doi: 10.1093/annonc/mdu106. Epub 2014 Mar 11.
citation: Sazawal S, Hiremath G, Dhingra U, Malik P, Deb S, Black RE. Efficacy of probiotics in prevention of acute diarrhoea: a meta-analysis of masked, randomised, placebo-controlled trials. Lancet Infect Dis. 2006 Jun;6(6):374-82. doi: 10.1016/S1473-3099(06)70495-9.
citation: Isolauri E, Juntunen M, Rautanen T, Sillanaukee P, Koivula T. A human Lactobacillus strain (Lactobacillus casei sp strain GG) promotes recovery from acute diarrhea in children. Pediatrics. 1991 Jul;88(1):90-7.
citation: Born P, Lersch C, Zimmerhackl B, Classen M. [The Saccharomyces boulardii therapy of HIV-associated diarrhea]. Dtsch Med Wochenschr. 1993 May 21;118(20):765. No abstract available. German.
citation: Saint-Marc T, Rossello-Prats L, Touraine JL. [Efficacy of Saccharomyces boulardii in the treatment of diarrhea in AIDS]. Ann Med Interne (Paris). 1991;142(1):64-5. No abstract available. French.
citation: Hasegawa T, Kanasugi H, Hidaka M, Yamamoto T, Abe S, Yamaguchi H. Effect of orally administered heat-killed Enterococcus Faecalis FK-23 preparation on neutropenia in dogs treated with cyclophosphamide. Int J Immunopharmacol. 1996 Feb;18(2):103-12. doi: 10.1016/0192-0561(96)00001-x.
citation: Vanderhoof JA, Young R. Probiotics in the United States. Clin Infect Dis. 2008 Feb 1;46 Suppl 2:S67-72; discussion S144-51. doi: 10.1086/523339.
citation: Swenson JM, Facklam RR, Thornsberry C. Antimicrobial susceptibility of vancomycin-resistant Leuconostoc, Pediococcus, and Lactobacillus species. Antimicrob Agents Chemother. 1990 Apr;34(4):543-9. doi: 10.1128/AAC.34.4.543.
citation: Handwerger S, Pucci MJ, Volk KJ, Liu J, Lee MS. Vancomycin-resistant Leuconostoc mesenteroides and Lactobacillus casei synthesize cytoplasmic peptidoglycan precursors that terminate in lactate. J Bacteriol. 1994 Jan;176(1):260-4. doi: 10.1128/jb.176.1.260-264.1994.
citation: Klein G, Pack A, Bonaparte C, Reuter G. Taxonomy and physiology of probiotic lactic acid bacteria. Int J Food Microbiol. 1998 May 26;41(2):103-25. doi: 10.1016/s0168-1605(98)00049-x.
citation: Charteris WP, Kelly PM, Morelli L, Collins JK. Antibiotic susceptibility of potentially probiotic Lactobacillus species. J Food Prot. 1998 Dec;61(12):1636-43. doi: 10.4315/0362-028x-61.12.1636.
citation: Salminen S, von Wright A, Morelli L, Marteau P, Brassart D, de Vos WM, Fonden R, Saxelin M, Collins K, Mogensen G, Birkeland SE, Mattila-Sandholm T. Demonstration of safety of probiotics -- a review. Int J Food Microbiol. 1998 Oct 20;44(1-2):93-106. doi: 10.1016/s0168-1605(98)00128-7.
citation: Tynkkynen S, Singh KV, Varmanen P. Vancomycin resistance factor of Lactobacillus rhamnosus GG in relation to enterococcal vancomycin resistance (van) genes. Int J Food Microbiol. 1998 Jun 16;41(3):195-204. doi: 10.1016/s0168-1605(98)00051-8.
citation: Ahn C, Collins-Thompson D, Duncan C, Stiles ME. Mobilization and location of the genetic determinant of chloramphenicol resistance from Lactobacillus plantarum caTC2R. Plasmid. 1992 May;27(3):169-76. doi: 10.1016/0147-619x(92)90018-6.
citation: Gevers D, Danielsen M, Huys G, Swings J. Molecular characterization of tet(M) genes in Lactobacillus isolates from different types of fermented dry sausage. Appl Environ Microbiol. 2003 Feb;69(2):1270-5. doi: 10.1128/AEM.69.2.1270-1275.2003.
citation: Ishiwa H, Iwata S. Drug resistance plasmids in Lactobacillus fermetum. J Gen Appl Microbiol 1980; 26:71-4.
citation: Fons M, Hege T, Ladire M, Raibaud P, Ducluzeau R, Maguin E. Isolation and characterization of a plasmid from Lactobacillus fermentum conferring erythromycin resistance. Plasmid. 1997;37(3):199-203. doi: 10.1006/plas.1997.1290.
citation: Tannock GW, Luchansky JB, Miller L, Connell H, Thode-Andersen S, Mercer AA, Klaenhammer TR. Molecular characterization of a plasmid-borne (pGT633) erythromycin resistance determinant (ermGT) from Lactobacillus reuteri 100-63. Plasmid. 1994 Jan;31(1):60-71. doi: 10.1006/plas.1994.1007.
citation: Morelli L, Wright AV. Probiotic bacteria and transferable antibiotic resistance-safety aspects. Demonstration of the Nutritional Functionality of Probiotic Foods News Letter 1997; 2:9-14.
citation: Saarela M, Mogensen G, Fonden R, Matto J, Mattila-Sandholm T. Probiotic bacteria: safety, functional and technological properties. J Biotechnol. 2000 Dec 28;84(3):197-215. doi: 10.1016/s0168-1656(00)00375-8.
citation: Salyers AA, Gupta A, Wang Y. Human intestinal bacteria as reservoirs for antibiotic resistance genes. Trends Microbiol. 2004 Sep;12(9):412-6. doi: 10.1016/j.tim.2004.07.004.
citation: Mathur S, Singh R. Antibiotic resistance in food lactic acid bacteria--a review. Int J Food Microbiol. 2005 Dec 15;105(3):281-95. doi: 10.1016/j.ijfoodmicro.2005.03.008. Epub 2005 Nov 8.
citation: Gasser S. Safety of lactic acid bacteria and their occurrence in human clinical infection. Bull Inst Pasteur 1994; 92:45-67.
citation: Fruchart C, Salah A, Gray C, Martin E, Stamatoullas A, Bonmarchand G, Lemeland JF, Tilly H. Lactobacillus species as emerging pathogens in neutropenic patients. Eur J Clin Microbiol Infect Dis. 1997 Sep;16(9):681-4. doi: 10.1007/BF01708560.
citation: Land MH, Rouster-Stevens K, Woods CR, Cannon ML, Cnota J, Shetty AK. Lactobacillus sepsis associated with probiotic therapy. Pediatrics. 2005 Jan;115(1):178-81. doi: 10.1542/peds.2004-2137.
citation: Kalima P, Masterton RG, Roddie PH, Thomas AE. Lactobacillus rhamnosus infection in a child following bone marrow transplant. J Infect. 1996 Mar;32(2):165-7. doi: 10.1016/s0163-4453(96)91622-9.
citation: Schlegel L, Lemerle S, Geslin P. Lactobacillus species as opportunistic pathogens in immunocompromised patients. Eur J Clin Microbiol Infect Dis. 1998 Dec;17(12):887-8. doi: 10.1007/s100960050216. No abstract available.
citation: Saxelin M, Chuang NH, Chassy B, Rautelin H, Makela PH, Salminen S, Gorbach SL. Lactobacilli and bacteremia in southern Finland, 1989-1992. Clin Infect Dis. 1996 Mar;22(3):564-6. doi: 10.1093/clinids/22.3.564.
citation: Ouwehand AC, Saxelin M, Salminen S. Phenotypic differences between commercial Lactobacillus rhamnosus GG and L. rhamnosus strains recovered from blood. Clin Infect Dis. 2004 Dec 15;39(12):1858-60. doi: 10.1086/425741. Epub 2004 Nov 19.
citation: Kirjavainen PV, Tuomola EM, Crittenden RG, Ouwehand AC, Harty DW, Morris LF, Rautelin H, Playne MJ, Donohue DC, Salminen SJ. In vitro adhesion and platelet aggregation properties of bacteremia-associated lactobacilli. Infect Immun. 1999 May;67(5):2653-5. doi: 10.1128/IAI.67.5.2653-2655.1999.
citation: Berg RD. Bacterial translocation from the gastrointestinal tract. Trends Microbiol. 1995 Apr;3(4):149-54. doi: 10.1016/s0966-842x(00)88906-4.
citation: Berg RD. Translocation and the indigenous gut flora. In: FullerR, editor. Probiotics: the scientific basis. London: Chapman &Hall 1992; 55-85.83.
citation: Pavan S, Desreumaux P, Mercenier A. Use of mouse models to evaluate the persistence, safety, and immune modulation capacities of lactic acid bacteria. Clin Diagn Lab Immunol. 2003 Jul;10(4):696-701. doi: 10.1128/cdli.10.4.696-701.2003.
citation: Chiva M, Soriano G, Rochat I, Peralta C, Rochat F, Llovet T, Mirelis B, Schiffrin EJ, Guarner C, Balanzo J. Effect of Lactobacillus johnsonii La1 and antioxidants on intestinal flora and bacterial translocation in rats with experimental cirrhosis. J Hepatol. 2002 Oct;37(4):456-62. doi: 10.1016/s0168-8278(02)00142-3.
citation: Shu Q, Gill HS. Immune protection mediated by the probiotic Lactobacillus rhamnosus HN001 (DR20) against Escherichia coli O157:H7 infection in mice. FEMS Immunol Med Microbiol. 2002 Sep 6;34(1):59-64. doi: 10.1111/j.1574-695X.2002.tb00603.x.
citation: Romond MB, Haddou Z, Mielcareck C, Romond C. Bifidobacteria and human health: regulatory effect of indigenous bifidobacteria on Escherichia coli intestinal colonization. Anaerobe. 1997 Apr-Jun;3(2-3):131-6. doi: 10.1006/anae.1997.0089.
citation: Durand JM, Rousseau MC, Gandois JM, Kaplanski G, Mallet MN, Soubeyrand J. Streptococcus lactis septicemia in a patient with chronic lymphocytic leukemia. Am J Hematol. 1995 Sep;50(1):64-5. doi: 10.1002/ajh.2830500116. No abstract available.
citation: Cairoli R, Marenco P, Perego R, de Cataldo F. Saccharomyces cerevisiae fungemia with granulomas in the bone marrow in a patient undergoing BMT. Bone Marrow Transplant. 1995 May;15(5):785-6.
citation: Salminen MK, Tynkkynen S, Rautelin H, Saxelin M, Vaara M, Ruutu P, Sarna S, Valtonen V, Jarvinen A. Lactobacillus bacteremia during a rapid increase in probiotic use of Lactobacillus rhamnosus GG in Finland. Clin Infect Dis. 2002 Nov 15;35(10):1155-60. doi: 10.1086/342912. Epub 2002 Oct 21.
citation: Wolf BW, Wheeler KB, Ataya DG, Garleb KA. Safety and tolerance of Lactobacillus reuteri supplementation to a population infected with the human immunodeficiency virus. Food Chem Toxicol. 1998 Dec;36(12):1085-94. doi: 10.1016/s0278-6915(98)00090-8.
citation: Cunningham-Rundles S, Ahrne S, Bengmark S, Johann-Liang R, Marshall F, Metakis L, Califano C, Dunn AM, Grassey C, Hinds G, Cervia J. Probiotics and immune response. Am J Gastroenterol. 2000 Jan;95(1 Suppl):S22-5. doi: 10.1016/s0002-9270(99)00813-8.
citation: Hempel S, Newberry S, Ruelaz A, Wang Z, Miles JN, Suttorp MJ, Johnsen B, Shanman R, Slusser W, Fu N, Smith A, Roth B, Polak J, Motala A, Perry T, Shekelle PG. Safety of probiotics used to reduce risk and prevent or treat disease. Evid Rep Technol Assess (Full Rep). 2011 Apr;(200):1-645.
citation: Agostoni C, Axelsson I, Braegger C, Goulet O, Koletzko B, Michaelsen KF, Rigo J, Shamir R, Szajewska H, Turck D, Weaver LT; ESPGHAN Committee on Nutrition. Probiotic bacteria in dietetic products for infants: a commentary by the ESPGHAN Committee on Nutrition. J Pediatr Gastroenterol Nutr. 2004 Apr;38(4):365-74. doi: 10.1097/00005176-200404000-00001. No abstract available.
citation: Naidu AS, Bidlack WR, Clemens RA. Probiotic spectra of lactic acid bacteria (LAB). Crit Rev Food Sci Nutr. 1999 Jan;39(1):13-126. doi: 10.1080/10408699991279187.
citation: Borriello SP, Hammes WP, Holzapfel W, Marteau P, Schrezenmeir J, Vaara M, Valtonen V. Safety of probiotics that contain lactobacilli or bifidobacteria. Clin Infect Dis. 2003 Mar 15;36(6):775-80. doi: 10.1086/368080. Epub 2003 Mar 5.
citation: Hammerman C, Bin-Nun A, Kaplan M. Safety of probiotics: comparison of two popular strains. BMJ. 2006 Nov 11;333(7576):1006-8. doi: 10.1136/bmj.39010.630799.BE. No abstract available.
citation: Mego M, Ebringer L, Drgona L, Mardiak J, Trupl J, Greksak R, Nemova I, Oravcova E, Zajac V, Koza I. Prevention of febrile neutropenia in cancer patients by probiotic strain Enterococcus faecium M-74. Pilot study phase I. Neoplasma. 2005;52(2):159-64.
citation: Mego M, Koncekova R, Mikuskova E, Drgona L, Ebringer L, Demitrovicova L, Nemova I, Trupl J, Mardiak J, Koza I, Zajac V. Prevention of febrile neutropenia in cancer patients by probiotic strain Enterococcus faecium M-74. Phase II study. Support Care Cancer. 2006 Mar;14(3):285-90. doi: 10.1007/s00520-005-0891-7. Epub 2005 Sep 21.