What are the key concepts of probiotics for infection control?
Microorganisms compete with one another for space, including surfaces, and nutrients. The large pool of bacteria is in the large intestine and in most studies disturbances in the gastrointestinal tract (GIT) are the targets for probiotic therapy. Most microorganisms excrete metabolites that have a negative impact on the growth of other species or strains.
The normal gastrointestinal flora consists of a stable balance between microorganisms. This is easily disturbed in illnesses and especially when antibiotics are used.
The goals of probiotic therapy are to:
Prevent colonization and overgrowth of pathogenic microorganisms
Restore an acute or chronic deterioration of a microbiological balance
Maintain a reasonable ecological balance at involved sites
Stimulate the immune system
Prevent or reduce side effects of antibiotics
Improve and restore gut barrier function
Stimulate mucus production from the gut epithelium which contributes to an improved gut barrier function
What principles regarding probiotics are necessary for effective infection control?
Proper species and strains, or mixtures of those, must be used.
Probiotic strains should be well defined and characterized.
Probiotic strains should be of human origin.
To be able to interact with the microorganisms that reside at the targeted area the added numbers must to be sufficient, i.e., in the order of 10^9 – 10^11 per dose or per day.
Treatment should be started as soon as possible. Success is greater when probiotics are used as a prophylactic measure. If one can prevent overt microbiological deteriorations or imbalances, improvement in clinical gastrointestinal illness may appear.
For the probiotics used, properties such as metabolism and capability to survive transport to and ability to establish at the aimed location must be thoroughly examined and results of these investigations must be mainly positive.
Each strain has its own properties and it cannot be assumed that one specific strain should hold all desirable characteristics. Likewise, characteristics and effects of one strain of a certain species cannot be generalized to all strains within that species.
Susceptibility to different antibiotics must be known.
Safety characteristics in general and especially for the situation of interest should be known.
When given to patients with reduced immunological capacity (perhaps the category that may benefit the most from this type of treatment) there should be an elevated alertness for signs of unexpected infections.
Freeze dried preparations should not be handled at bedside before they have been dispersed in some fluid. The risk of contamination of airways, iv-lines especially central lines with a powder being spread in the room air should not be neglected.
What conclusions of clinical trials or meta-analyses regarding probiotics guide infection control practices?
It is safe to use probiotics for most people in sickness and in health.
In some applications there is support for positive effects of the use of probiotics, but on several indications or applications there are conflicting results.
Many studies show positive results but, due to small study sizes, statistical significance is lacking.
There is a tendency to judge all probiotics as being a single entity when reviews and meta-analyses are performed. Results from different protocols with different species, strains and mixtures of those are being pooled and results validated as it was a single microorganism.
Many studies have shown positive results for the group or groups of patients that has been given active treatment. In other studies results have been inconclusive.
Although studies where probiotic treatment groups have done worse than the controls do exist, it must be considered safe to use probiotics for most people in sickness and in health.
What are the consequences of ignoring the key principles and concepts of probiotics for infection control?
Unexpected effects, such as the risk of undesired infections caused by the treatment may appear instead.
Though infections of clinical significance with microorganisms characterized as probiotic are rare, they do exist and improper use or handling of preparations can result in such infections.
Using preparations that are not pure or containing other strains than those claimed on the package could give misleading information in case of infectious complications.
There are studies showing that the contents in some dairy products were not what were printed on the label. Wrong bacterium, too small numbers of viable bacteria or in some cases the stated bacterium could not be identified.
What other information supports the research regarding probiotics for infection control, e.g., case control studies and case series?
Most of the probiotics used in healthcare are strains with human origin.
Many preparations are also sold in the grocery store or otherwise on a free market. Studies from Finland compared the observed frequency of positive findings of Lactobacillus rhannosus GG in blood cultures before and after the launch of dairy products containing that strain. No difference in the incidence of infections with the strain could be demonstrated.
Summary of current controversies.
Probiotics can never replace antibiotics but should be looked upon as a valuable complement.
Probiotics for infection control or as prophylaxis are given to patients that have some kind of disturbance in their microbiological flora or are at risk of getting one.
Added probiotics are not those commensal bacteria lost by medication with antibiotics but do in a sense replace them and will help in getting back to the premorbid state what may take months.
Are probiotics dangerous?
In general the answer is a straight NO. Microorganism classified as probiotics are generally regarded as safe.
Do they give infections difficult to treat?
In general the answer is a straight NO. The species and strains that are connected to the rare cases of infections with bacteria with probiotic characteristics are susceptible to many standard antibiotics. Most of these cases have been outpatients that have ingested the bacterium within their normal diet.
Can probiotics transfer genetic material coding for antibiotic resistance?
In theory, yes. However, no evidence has been found to support such assumptions.
Do probiotics kill people?
Under certain circumstances it has occurred! However not the bacterium per se, but the setting and the particular patient population.
Can patients benefit from probiotics or are they only benefiting the producing companies?
Probiotics can make a difference. Specific strains that are well chosen and mixtures of such strains can reduce or inhibit certain infections or clinical manifestations of such infections and the side effects of the use of antibiotics.
What is the impact of probiotics for infection control, relative to infection control by other means?
Probiotics can reduce the frequency of certain infections and attenuate symptoms of such infections.
By using probiotics the use of antibiotics may be reduced and hence contribute to a reduction or a delay of the development of multi resistant bacteria. This increasing worldwide problem has the potential to bring about a catastrophic like situation in modern healthcare.
The use of probiotics in intubated critically ill patients is equally efficient in reducing secondary infections as is the use of Selective Digestive Decontamination with antibiotics.
Using probiotics for infection control or prophylaxis is a very important complement to standard treatment of infection as we see it today.
Probiotics work on a broad basis in the competition with other species, pathogenic or non-pathogenic, and with few side effects.
Overview of all important clinical trials, meta-analyses, case control studies, case series, and individual case reports related to infection control and probiotics.
See Table I and Table II below for a summary of relevant research.
|Ref||Diagnosis||Microorganism or “Probiotics”||Conclusion|
|JM Tung et al, 2009, McFarland LV, 2006||Clostridium difficile infection and associated disease||Saccharomyces boulardii||Secondary prevention good|
|Primary prevention poor evidence|
|McFarland LV, 2006, Pillai A et al, 2008||Clostridium difficile associated disease||Probiotics||Insufficient evidence|
|D’Souza AL et al, 2002, Cremonini F et al, 2002||Antibiotic associated diarrhea||Probiotics||Good effect as prophylaxis|
|McFarland LV, 2007||Travelers’ diarrhea||Probiotics||Reduces risk. Good prevention|
|Watkinson PJ et al, 2007||Critical illness||Probiotics||Inconclusive – “ No benefit”|
|Siempos II et al, 2010||Ventilator associated pneumonia||Probiotics||Reduces risk of VAP|
|Bonifait L et al, 2009||Oral health||Probiotics||Improves periodontal statusReduces pathogenic bacteria|
|Van Niel CW et al, 2002||Infectious diarrhea||Probiotics||Reduces intensity and length of disease|
|Thomas DW et al, 2010||Necrotising Entero Colitis||Probiotics||Beneficial for premature neonates|
|Ref||Diagnosis||Microorganism or “Probiotics”||Conclusion|
|Morrow LE et al, 2010, Hickson M et al, 2007, Klarin B et al, 2008||Clostridium difficile infection and associated disease||L PlantarumL rhamnosus GGLactobacillus casei||Reduces incidence|
|Reid G et al, 2001||Vulvo vaginitis||Lactobaccili||Reduces recurrence|
|Morrow LE et al, 2010||Ventilator associated pneumonia||L rhamnosus GG||Reduces risk of VAP|
|Sundén F et al, 2010||Recurrent Urinary tract infections||E coli||Protection against recurrent UTI|
|Besselink MG et al, 2008||Pancreatitis||Eco 641||Increased morbidity and mortality|
Controversies in detail.
The Dutch report on the use of probiotics for prevention of infectious complications in patients with expected severe pancreatitis [Besselink 2008] where the patients who received the Eco 641 probiotics preparation did significantly worse than those given the placebo, has somewhat divided physicians into a sort of cemented pro or con position. The study protocol has been criticised by many parties.
It is sound to be cautious when using live microorganisms in patients. Patients that have been diagnosed with infections caused by lactobacilli, bifidobacteria and other bacteria with assigned probiotic properties have with few exceptions been immune compromised in some way. Many of the reported cases have been outpatients and the found microorganism has been one used in food.
Blood cultures with positive findings of bacteria used in probiotic preparations are rare. In contrast, the degree of caution concerning the use of antibiotics is not.
What national and international guidelines exist related to the use of probiotics for infection control?
There are guidelines in the use of probiotics in food or as nutritional supplements (for humans and animals) from FAO/WHO, FDA and from the EFSA (European Food Safety Authority), but for the use as medical devices or as pharmaceutical preparations, there are no guidelines up till now.
Saccharomyces boulardii is registered as a pharmaceutical preparation in many countries on the indication of treatment of CDAD in combination with antibiotics or as prophylaxis against AAD.
What other consensus group statements exist and what do key leaders advise?
Consensus statements are lacking.
There is still a position of to either pro or con, a kind of black or white situation. Believers and doubters. Some see only complications but it must be considered that we see complications and side effects with almost any therapy in clinical medicine.
Probiotic bacteria and mixtures of those (and Saccharomyces boulardii) that have been tested in clinical trials with positive (or at least not negative) outcome can safely be given the enteral route since this is generally regarded as safe (GRAS) for most probiotics.
For defined groups of patients such as those suffering from pancreatitis one should be very cautious. However do remember that what is to be avoided is to give the Eco 641 via a nasodoudenal tube to patients with ongoing pancreatitis.
JM, Tung, LR, Dolovich, CH, Lee. “Prevention of Clostridium difficile infection with Saccharomyces boulardii: A systematic review”. Can J Gastroenterol. vol. 23. 2009. pp. 817-821.
McFarland, LV. “Meta-analysis of probiotics for the prevention of antibiotic associated diarrhea and the treatment of Clostridium difficile disease”. Am J Gastroenterol. vol. 101. 2006. pp. 812
Pillai, A, Nelson, R. “Probiotics for treatment of Clostridium difficle-associated colitis in adults”. Cochrane Database Syst Rev. vol. 1. 2008 Jan 23. pp. CD004611
D’Souza, AL, Rajkumar, C, Cooke, J. “Probiotics in prevention of antibiotic associated diarrhoea: meta-analysis”. BMJ. vol. 324. 2002. pp. 1361
Cremonini, F, Di Caro S, Nista, EC. “Meta-analysis: the effect of probiotic administration on antibiotic-associated diarrhoea”. Aliment Pharmacol Ther. vol. 16. 2002. pp. 1461
McFarland, LV. “Meta-analysis of probiotics for the prevention of traveler’s diarrhea”. Travel Med Infect Dis. vol. 5. 2007. pp. 97
Watkinson, PJ, Barber, VS, Dark, P, Young, JD. “The use of pre- pro- and synbiotics in adult intensive care unit patients: Systematic review”. Clin Nutr. vol. 26. 2007. pp. 182
Siempos, II, Ntaidou, TK, Falagas, ME. “Impact of the administration of probiotics on the incidence of ventilator-associated pneumonia:a meta-analysis of randomized controlled trials”. Crit Care Med. vol. 38. 2010 Mar. pp. 954-62.
Petrof, EO, Dhaliwal, R, Manzanares, W, Johnstone, J, Cook, D, Heyland, DK. “Probiotics in the critically ill: A systematic review of the randomized trial evidence”. . vol. 40. 2012.
Wan-Jie, Gu, Chun-Yin, Wei, Rui-Xing, Yin. “Lack of Efficacy of Probiotics in Preventing Ventilator-Associated Pneumonia: A Systematic Review and Meta-analysis of Randomized Controlled Trials”. . vol. 142. 2012. pp. 859-868.
Liu, KX, Zhu, YG, Zhang, J, Tao, LL, Lee, JW, Wang, XD, Qu, JM. “Probiotics effects on the incidence of nosocomial pneumonia in critically ill patients- “. vol. 16. 2012. pp. R109
Crooks, NH, Snaith, C, Webster, D, Gao, F, Hawkey, P. “Clinical review: Probiotics in critical care”. . vol. 16. 2012. pp. 237
Schultz, Mj, Haas, EH. “Antibiotics or probiotics as preventive measures against ventilator-associated pneumonia: a literature review”. . vol. 15. 2011. pp. R18
Morrow, LE, Goginemi, V, Malesker, MA. “Probiotics in the Intensive Care Unit”. Nutr Clin Pract. vol. 27. 2012. pp. 235
Bonifait, L, Chandad, F, Daniel Grenier,, D. “Probiotics for Oral Health: Myth or Reality?”. J Can Dent Ass. vol. 75. 2009. pp. 585
Van Niel, CW, Feudtner, C, Garrison, MM. “Lactobacillus therapy for acute infectious diarrhea in children: a metaanalysis”. Pediatrics. vol. 109. 2002. pp. 678-84.
Thomas, DW, Greer, FR. “Probiotics and Prebiotics in Pediatrics”. Pediatrics. vol. 126. 2010. pp. 1217
Williams, NT. “Probiotics (Review)”. Am J Health-Syst Pharm. vol. 67. 2010. pp. 449-58.
Goldin, BR, Gorbach, SL. “Clinical Indications for Probiotics”. CID. vol. 46. 2008. pp. S97
Morrow, LE, Kollef, MH, Casale, TB. “Probiotic Prophylaxis of Ventilator-associated Pneumonia:A Blinded, Randomized, Controlled Trial”. Am. J. Respir. Crit. Care Med. vol. 182. 2010. pp. 1058
Hickson, M, D’Souza, AL, Muthu, N, Rogers, TR, Want, S, Rajkumar, C, Bulpitt, CJ. “Use of probiotic Lactobacillus preparation to prevent diarrhoea associated with antibiotics: randomised double blind placebo controlled trial”. BMJ. vol. 335. 2007. pp. 80
Klarin, B, Wullt, M, Palmquist, I, Molin, G, Larsson, A, Jeppsson, B. “Lactobacillus plantarum 299v reduces colonisation of Clostridium difficile in critically ill patients treated with antibiotics”. Acta Anaesthesiol Scand. vol. 52. 2008. pp. 1096
Reid, G, Bruce, AW, Fraser, N. “Oral probiotics can resolve urogenital infections”. FEMS Immunol Med Microbiol. vol. 30. 2001. pp. 49
Sundén, F, Håkansson, l, Ljunggren, E, Wullt, B. “Escherichia coli 83972 bacteriuria protects against recurrent lower urinary tract infections in patients with incomplete bladder emptying”. J Urol. vol. 184. 2010 Jul. pp. 179
Besselink, MG, vanSantvoort, HC, Buskens, E. “Probiotic prophylaxis in predicted severe acute pancreatitis: a randomised, double-blind, placebo controlled trial”. Lancet. vol. 371. 2008. pp. 651-9.
Muñoz, P, Bouza, E, Cuenca-Estrella, M. “Saccharomyces cerevisiae fungemia: an emerging infectious disease”. Clin Inf Dis. vol. 40. 2005. pp. 1625
Coeuret, V, Geuguen, M, Vernoux, JP. “Numbers and strains of lactobacilli in some probiotic products”. Int J Food Microbiol. vol. 97. 2004. pp. 147
Salminen, MK, Tynkkynen, S, Rautelin, H. “Lactobacillus Bacteremia during a Rapid Increase in Probiotic Use of Lactobacillus rhamnosus GG in Finland”. CID. vol. 35. 2002. pp. 1155
Cannon, JP, Lee, TA, Bolanos, JT. “Danziger: Pathogenic relevance of Lactobacillus: a retrospective review of over 200 cases”. Eur J Clin Microbiol Infect Dis. vol. 24. 2005. pp. 31-40.
Oudhuis, GJ, Bergmans, DC, Dormans, T, Zwaveling, Kessels, A, Prins, MH, Stobberingh, EE, Verbon, A. “Probiotics versus antibiotic decontamination of the digestive tract: infection and mortality”. Intensive Care Med. vol. 37. 2011. pp. 110
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- What are the key concepts of probiotics for infection control?
- What principles regarding probiotics are necessary for effective infection control?
- What conclusions of clinical trials or meta-analyses regarding probiotics guide infection control practices?
- What are the consequences of ignoring the key principles and concepts of probiotics for infection control?
- What other information supports the research regarding probiotics for infection control, e.g., case control studies and case series?
- Summary of current controversies.
- What is the impact of probiotics for infection control, relative to infection control by other means?
- Overview of all important clinical trials, meta-analyses, case control studies, case series, and individual case reports related to infection control and probiotics.
- Controversies in detail.
- What national and international guidelines exist related to the use of probiotics for infection control?
- What other consensus group statements exist and what do key leaders advise?