The use of probiotics for critically ill patients in hospitals

Abstract

This article is based on a review of published literature, mainly from 2005 to 2008. Several reports demonstrate statistically significant beneficial health effects of probiotic supplementation, especially for the treatment of rotavirus-associated diarrhoea. The following main topics have been reviewed: bacterial translocation from the gut and infectious disease; virulence factors including toxicity; metabolic functions including host storage, platelet aggregation, deconjugation of bile acids, and degradation of mucin. Furthermore, resistance to antimicrobials, with emphasis on the location of the genes involved, has been reviewed. Studies concerning probiotic supplementation in hospital patients suffering from acute pancreatitis, antibiotic-associated diarrhoea, including Clostridium difficile infection, and non-alcoholic fatty liver disease are reviewed. Supplementation with probiotic bacteria in critically ill children, e.g. in intensive care, is also discussed. The use of probiotics for patients with diarrhoea, Helicobacter pylori infection and inflammatory bowel disease is mentioned, as well as for patients with AIDS, urogenital infections, and small intestinal bacterial overgrowth. Particular attention has been paid to a large Dutch study (PROPATRIA), which showed increased mortality in patients with acute pancreatitis who were given enteral nutrition to which probiotics had been added, compared with enteral nutrition alone. Similarities in some acquired resistance genes between probiotic microorganisms and other bacteria of human origin suggest the transfer of resistance genes between commensal microorganisms in the complex gastrointestinal tract ecosystem. Intake of probiotic microorganisms that carry transferable antimicrobial resistance genes may increase the risk of the transfer of such genes to the resident microbiota in patients. Although some beneficial effects have been reported in some patient groups, we conclude that the adverse effects that have been observed are well documented, thus indicating that caution should be observed in administering probiotic bacteria to critically ill patients.

Key words::

• Prebiotics
• microbiota
• PROPATRIA

Introduction

Probiotics have been defined as live microorganisms which, when administered in adequate doses, confer a health benefit on the host (1). Due to their long history of safety, lactic acid bacteria (LAB) and bifidobacteria are granted GRAS (generally regarded as safe) status in the United States (2). However, during the last 2–3 years a number of scientific papers have raised critical questions regarding the use of probiotics in some specific groups of critically ill patients.

This review is based on a risk assessment regarding use of probiotics in hospital patients, requested by the Norwegian Food Safety Authority, and carried out by the Norwegian Scientific Committee for Food Safety in 2009. This report is available at www. vkm.no.

The fate of probiotics in the intestine

The efficacy of probiotics depends upon their ability to initially survive passage through the stomach and duodenum and then their ability to be transiently present in, or to ‘colonize’, the intestinal lumen in eco-compartments for a period that is at present undefined. Probiotics may be able to interact with both the host and the indigenous microbiota. In both types of interactions, any health benefit incurred will depend on the functional profile of the probiotics and eco-compartments in which they are present. Interactions can be physiological, biochemical and/ or immunological. Some, but not all, probiotic strains can reduce intestinal transit time, improve the quality of migrating motor complexes (regularly occurring muscular contractions in the small intestine) and temporarily increase the rate of mitosis in enterocytes (3).

It is often claimed that probiotics can ‘normalize’ the indigenous flora, by mechanisms not yet satisfactorily described. Indeed, a definition of a ‘normal’ microbiota does not exist. The metabolism of probiotic bacteria may have a beneficial, neutral or deleterious effect on the microbes that are part of the host microbiota.

Translocation and infectious disease

The translocation of microorganisms in immuno-compromised patients has been documented in several papers. The review article by Isakow et al. (4) discussed the occurrence of such microorganisms in some nosocomial infections, as described below.

Endocarditis: may be due to the ability of some lactobacilli to aggregate platelets and/or bind to the extracellular matrix of endothelial cells (5–7).

Pneumonia: pneumonia due to Lactobacillus has been reported in immunosuppressed patients with AIDS (8), after lung transplantation (9) and after liver transplantation (10). However, it is not clear whether this was as a consequence of consumption of a probiotic. Ventilator-associated pneumonia due to Lactobacillus has also been also reported in a critically ill trauma patient (11).

Possible septicaemia and isolation from blood culture: over a 5-year period, 45 patients at a clinic in USA developed bacteraemia from which Lactobacillus was isolated (12). How many of these patients had underlying co-morbidities such as cancer, recent abdominal surgery, diabetes mellitus or immunosuppression, and in addition received probiotics, was not reported. The bacteraemia was polymicrobial in 27 cases. Thirty-one of the 45 patients died; 1 death was considered to be attributable to Lacto-bacillus bacteraemia.

Saccharomyces fungaemia has been found in critical care patients receiving Saccharomyces boulardii-containing probiotics (13,14). Lolis et al. (15) opined that the incidence of S. boulardii fungaemia is probably underestimated in critically ill patients.

Eighty-five Lactobacillus isolates from blood cultures in Finland were identified to species level and tested for antimicrobial susceptibility (16,17). Among those isolates, L. rhamnosus (n = 46), L. fermentum (n = 12) and L. casei (n = 12) were identified. Of the 46 L. rhamnosus isolates, 22 were shown to be LGG type by pulsed-field gel electrophoresis.

Virulence factors, aspects of probiotic metabolic functions

Platelet aggregation

Another area of concern is whether, and to what extent, probiotics may contribute to development of infectious endocarditis. Platelet aggregation contributes to the pathogenesis of infectious endocarditis and some microorganisms (e.g. some streptococci) may increase platelet aggregation (18). So far, there have been few studies in which probiotic strains have been investigated for their ability to aggregate platelets (5,6,19). As stated by Harty et al. (6), ‘platelet-aggregating property is not uncommon in this group of bacteria’.

Deconjugation

Conjugation is a mechanism by which the organism regulates the metabolism, function, excretion and recirculation of many endogenous and exogenous compounds, including many drugs. Most conjugation processes take place in the liver. The four molecules most often used for conjugation are glycine, taurine, glucuronic acid and sulphate. Many of the conjugated compounds are excreted in the bile into the small intestine and many of them undergo an enterohepatic circulation.

If deconjugating enzymes are present in the small intestine, the bile conjugates could be deconjugated, resulting in marked alterations in their physio-chemical properties. Intestinal deconjugation is always microbial (20).

Under physiological conditions, only a minor part of microbial deconjugation occurs in the upper part of the small intestine. In the case of increased deconjugation, some pathophysiological conditions may occur, such as decreased bile acid recirculation, steatorrhoea, and reduced efficacy of contraceptive drugs and other drugs with an enterohepatic circulation. Regarding lactobacilli and bifidobacteria, it has long been known that strains from both groups are able to deconjugate either glycine, taurine or both types of conjugates (21). Many probiotic strains produce beta-glucuronidases, enzymes capable of splitting glucuronic acid conjugates. Information is unavailable on whether, and to what extent, probiotic strains contain enzymes capable of splitting sulphate conjugates.

In general, deconjugated bile acids are more inhibitory to other bacteria than conjugated bile acids (22). Experimental data indicate that some bile acid derivatives may influence the production of cholecystokinin, which in turn may influence development of acute pancreatitis in an obstruction model (23,24). These observations might be of some value in explaining the aggravation of acute pancreatitis following jejunal administration of some probiotics.

It has been argued that since the probiotics are given once or twice a day, the microbes are present in the small intestine for a short period of time. However, studies in patients with ileostomy clearly show that orally given probiotics do not reach the stomi in a single bolus, but with a substantial ‘tail’. It therefore seems reasonable to assume that they are biochemically active for a substantial period (25).

In summary, deconjugation is an important intestinal microbial function, especially if it takes place in the small intestine. Under physiological conditions, an increased deconjugation may have minor consequences for the host. However, in some clinical conditions, such as in certain critically ill patients, any interference with compounds excreted by the bile and/ or with an enterohepatic circulation, deconjugation may have major consequences for the host. Therefore there may be a need for the patho physiological consequences to be evaluated, strain by strain, endogenous conjugate by endogenous conjugate, and drug by drug, before a probiotic is approved.

Degradation of mucin

The onset of mucin production by goblet cells and enterocytes parallels postnatal bacterial colonization of the gastrointestinal tract, and a wide array of bio-active factors that stimulate mucin production have been described. Mucin has many functions, and the most important one might be as a first line of defence for the underlying cells (26). Several antimicrobial peptides (defensins) are produced along the whole gastrointestinal tract and are retained by the surface-overlaying mucin, thereby providing a combined physical and antibacterial barrier influencing bacterial attachment and translocation (27).

Gastrointestinal mucin is broken down by the indigenous microbiota, and little mucin is excreted in faeces. It has been claimed, although never satisfactorily shown, that probiotics can regulate the balance between production and degradation of mucin. From the above, it can be summarized that decreased production or increased degradation of mucin due to the intestinal microbiota may have pathophysiological consequences, especially in critically ill patients. Administration of probiotics with these properties should be avoided in such patients.

Antimicrobial resistance

Probiotic strains belonging to Lactobacillus and Bifidobacterium may be resistant or susceptible to various clinically relevant antimicrobials. All lactobacilli, but not all bifidobactera, are intrinsically resistant against vancomycin. Additionally, it has recently been demonstrated that the vanA gene from enterococci may be transferred to a commercial strain of Lactobacillus acidophilus despite it already being intrinsically resistant to vancomycin (28,29). The transformation occurred not only in vitro, but also in vivo in the gut of mice with no antimicrobial pressure. The transconjugants arose at relatively high frequencies and were able to persist in the environment of the digestive tract. These studies confirm that horizontal gene transfer of antimicrobial resistance genes is possible in the gastrointestinal tract of mammals.

So far, multiresistance seems to be uncommon among LAB and bifidobacteria but, in particular, tetracycline and erythromycin resistance determinants may be isolated (30). There is a similarity between many of these gene determinants in LAB/ bifidobacteria and other bacteria of human origin. This supports the theory that resistance genes can spread between commensal microorganisms in the complex gastrointestinal ecosystem. Many of the antimicrobial resistance genes in probiotic microorganisms such as Lactobacillus and Bifidobacterium strains are located on the chromosome. Recently, however, several antimicrobial resistant determinants in these microorganisms have been found to be located on plasmids (31) and other mobile DNA elements (30,32–35).

If a probiotic carries antimicrobial resistant genes on mobile genetic elements (e.g. plasmids, transposons) then the potential exists for transfer to other gastrointestinal tract (GIT) microbiota, including oppor tunistic and pathogenic microorganisms.

As a safety precaution, it is recommended that probiotic microorganisms should not harbour genetic resistance determinants that encode resistance against clinically used antimicrobials. Thus, in a clinical setting, the absence of transferable resistance genes is a necessity if a probiotic is intended for use in hospitals (30).

However, it has also been argued that probiotic strains that are intrinsically antibiotic-resistant could be of value in patients receiving those antibiotic(s). Gould and Short (36) examined the antimicrobial susceptibility pattern of microorganisms in two commercially available probiotic products. The authors found that the strains isolated from these products were susceptible in vitro to many of the antibiotics used to treat antibiotic-associated diarrhoea (AAD) and Clostridium difficile-associated diarrhoea (CDAD) and they concluded that the bacteria contained in these products are therefore unlikely to have an effect in vivo in patients treated with those antibiotics. To the best of our knowledge, targeted administration of resistant probiotics, either prophylactically or therapeutically, to AAD- or CDAD-prone patients, has never been attempted.

Probiotics in a clinical setting

Enteral nutrition

Enteral nutrition is often used in critically ill patients because it is believed to reduce translocation and systemic spread of intestinal bacteria. Probiotics are sometimes added to the enteral feeding, with the aim of reducing overgrowth of other bacteria in the small bowel, restoring gastrointestinal barrier function and modulating the immune system (37,38). A possible enhancement of beneficial effects has been postulated if the enteral food contains synbiotics (39), i.e. both probiotics and prebiotics. Prebiotics are defined as non-viable food components that confer a health benefit by modulation of the gut microbiota (40).

Acute pancreatitis

In several studies, probiotics appeared to reduce infectious complications in patients undergoing elective abdominal operations (41,42) and in patients with acute pancreatitis (43,44). In 14 randomized clinical trials reviewed by van Sandwort et al. (45), 9 studies showed a significant decrease of total infectious complications in the patients treated with probiotics, whereas 5 studies could not demonstrate such an effect. Bacterial infections were significantly decreased in the groups that were given synbiotics (probiotic bacteria + prebiotic carbohydrates). Although all these studies were small and individually inconclusive, the review paper concluded that the use of prebiotics might enhance the effect of probiotics and may even be a prerequisite for clinical efficacy of some probiotic strains.

Acute pancreatitis is a serious disease with high mortality, especially when the inflammation leads to necrosis of pancreatic and peripancreatic tissues. Should the necrosis become infected, multiple organ failure may develop, and surgical removal of necrotic tissue may become necessary. Systemic antibiotic prophylaxis has been used for some time in an attempt to prevent the complications due to infection. A recent meta-analysis concluded that prophylactic treatment with antibiotics is associated with a significant reduction in pancreatic or peripancreatic infection, non-pancreatic infection and length of hospital stay. However, it does not reduce mortality or the need for surgical intervention in acute necrotizing pancreatitis (46).

With the aim of confirming the benefit of synbiotics in severe acute pancreatitis, a large, nationwide, multicentre, randomized, double-blind, placebo-controlled trial (the PRObiotics in PAncreatitis TRIAL (PROPATRIA)) was carried out in the Netherlands (47).

Patients with predicted severe acute pancreatitis were randomly assigned, within 72 h of the onset of symptoms, to receive a multispecies probiotic preparation (n = 153) or placebo (n = 145), administered enterally (as an adjunct to enteral nutrition) twice daily for 28 days. The primary end point was infectious complications, i.e. infected pancreatic necrosis, bacteraemia, pneumonia, urosepsis or infected ascites, during admission and at 90-day follow-up.

Infectious complications occurred in 46 (30%) patients in the probiotics group and in 41 (28%) of those in the placebo group (relative risk 1.06, 95% CI 0.75-1.51). However, 24 (16%) patients in the probiotics group died, compared with 9 (6%) in the placebo group (relative risk 2.53, 95% CI 1.22-5.25). Nine patients in the probiotics group developed bowel ischaemia (eight with fatal outcome), compared with none in the placebo group (p = 0.004). Hence, probiotic prophylaxis with this combination of probiotic strains did not reduce the risk of infectious complications and was associated with an increased risk of mortality in patients with predicted severe acute pancreatitis.

In comments on the study, Sand and Nordback (48) and Soeters (49) emphasize that several patients in PROPATRIA had indications of organ failure and probably therefore severe splanchnic hypoperfusion. The large numbers of bacteria administered may have aggravated mucosal inflammation, already present due to the pancreatitis, and increased the demand for substrate and oxygen at a site where the supply was already marginal. It was found that intestinal perforation (necrosis) and inflammation occurred close to the site where enteral nutrition and prebiotics were delivered to the duodenum. However, the bacteria responsible for the infectious complications were intestinal flora, not the administered probiotic strains.

Soeters (49) also stressed the fact that a major part of the increased mortality in the probiotics group occurred within 14 days. Organ failure in the patients developing bowel necrosis occurred, with one exception, after 1 or 2 days, as if there was an instantaneous effect of the treatment regimen. Both the probiotic and the placebo groups received prebiotics. The role of prebiotics is uncertain. Bowel necrosis was not diagnosed and mortality was low in the placebo group, i.e. those receiving only prebiotics. It appears therefore to be the combination of probiotics and prebiotics that resulted in increased mortality and it is unclear what would have happened if probiotics had been given alone.

Case reports of acute intestinal necrosis have been described previously in the presence of patent vasculature to the gastrointestinal tract and complications have been related to bacterial overgrowth, achlorhydria, malnutrition, old age, alcoholism, critical illness and several other debilitating conditions. Intestinal necrosis at the site of infusion from a jejunal feeding tube, as was seen in PROPATRIA, has also been described previously. Enteral nutrition containing probiotics that has bypassed normal digestion in the oral cavity, stomach and duodenum is possibly particularly damaging to the intestine.

Antibiotic-associated diarrhoea (AAD), including Clostridium difficile infection (CDAD)

Over the years, many probiotics have been clinically tested for prophylaxis and treatment of AAD and acute and recurrent C. difficile diarrhoea. However, so far there are few, if any, indications that probiotics can prevent AAD and CDAD (50,51).

There have been many publications showing that some probiotics (especially L. rhamnosus GG and S. boulardii) may have a therapeutic effect, but several studies have given negative results. Surawisz (51) showed that ‘various probiotics have variable efficacy’ in CDAD. Doron et al. (52) suggested that if probiotics are to be used for AAD ‘they should be used with caution in patients who have compromise of either the immune system or the integrity of the intestinal mucosa, and in the presence of a central venous catheter’ and ‘given the potential for complications in debilitated or immunosuppressed patients, the risks may outweigh benefits …’. In recent reviews, statements similar to the following can be found: ‘More studies are needed to define further their efficacies, roles and indications’ (51,53).

Diarrhoea, unrelated to antibiotic treatment

Probiotic bacteria have been widely used in cases of diarrhoea, in both children and adults, with somewhat conflicting results, but overall there are no documented adverse effects. Some authors report a shortening of the period of hospitalization in those given probiotics and a favourable influence on the course of the illness (54–57). Diarrhoea is frequent in the critically ill, especially in cases with sepsis and hypoalbuminaemia, and during treatment with enteral nutrition. The standard treatment for diarrhoea consists of liberal rehydration, replacement of electrolyte loss, use of antidiarrhoeal remedies, and continuation with enteral nutrition. The benefit of supplementation of enteral nutrition with soluble fibre, probiotics or prebiotics is not clear (58).

Paediatric patients

Children are generally not hospitalized nowadays unless they are seriously ill. Two important reports from paediatric units concern children at risk: pre-term neonates and paediatric patients in intensive care.

Deshpande et al. (59) conclude in a review that probiotics may reduce the risk of necrotizing enterocolitis (NEC) in preterm infants. However, the need for short- and long-term safety assessment in large trials is imperative. Many questions as to dose, duration of supplementation and type of probiotic agents are still unanswered.

The conclusion from the other study comprising children in intensive care (60) was: ‘The results of this preliminary investigation were unexpected but important in view of the increased use of probiotic preparations in medically fragile pediatric patients’. In this randomized, placebo-controlled trial, L. rhamnosus strain GG was not shown to be effective in reducing the incidence of nosocomial infections. Disturbingly, a statistically non-significant trend towards an increase in infection was seen (4 vs 11). Further studies with a larger patient population are needed to establish both safety and efficacy of probiotics in paediatric critical care.

Inflammatory bowel disease

The intestinal microbiota plays an important role in the pathogenesis of inflammatory bowel disease (IBD). Studies suggest that the composition of the flora is altered, and there are elevated levels of some bacterial species, and reduced levels of Bifidobacterium and Lactobacillus. Additionally, high concentrations of bacteria are found in association with the mucosa (61). No unequivocal effects on IBD have been demonstrated in the many attempts to alter this biotic imbalance by use of antibiotic and probiotic treatments (62–65).

A review of three studies examining the possible effect of probiotics on the general postoperative outcome in patients with Crohn's disease, concludes that ‘… probiotics have no proven role in postoperative prophylaxis’ (66). One of these studies observed that after administration of L. johnsonii as probiotic for 12 weeks, the percentage of severe recurrence, as assessed by endoscopic examination, was 19% in the treatment group compared with 9% in the placebo group, which was a near-significant negative effect (67).

Non-pathogenic Escherichia coli, strain Nissle 1917, has been used in several European countries as a probiotic treatment for IBD. In ulcerative colitis its prophylactic efficacy appears comparable to that of mesalazine. The precise mechanism of action remains unclear (68).

Helicobacter pylori infection

Although H. pylori is not eradicated by probiotic treatment, the amount of this bacterium in the stomach may be reduced. Probiotics, in combination with antibiotics, may increase eradication rate and reduce the side effects of treatment (69). In another study, probiotics have also been used as a supplement to ordinary triple treatment for H. pylori eradication, but without any convincing effect (70).

AIDS and Hodgkin's disease

A report on the isolation of L. acidophilus from bacteraemia in a patient suffering from AIDS and Hodgkin's disease, who had been taking a probiotic product, concluded that care should be taken with administering probiotics to patients with ‘significant medical problems’, including oncology patients (71). However, their conclusions are speculative since the isolated strain was not matched, using molecular methods, with the strain used in the product, and could have been part of the patient's own flora.

Small intestinal bacterial overgrowth

Experimental animal studies indicate that probiotics can improve the mucosal barrier and have antibacterial properties and immunomodulatory and anti-inflammatory effects, all of which can be positive against bacterial overgrowth in the small intestine and against small intestinal failure. However, in patients with these conditions positive effects have not been definitively demonstrated (72).

Concluding remarks

There is some evidence of a beneficial effect of probiotic bacteria when administered to children with infectious diarrhoea, especially virus-associated diarrhoea. However, most studies focus on short-term beneficial effects and not on long-term safety. Furthermore, a favourable effect on NEC in preterm babies is reported in some studies, but not in all.

For evaluation of a microorganism as probiotic, the following topics should be studied and documented: bacterial translocation from the gut and infectious disease; virulence factors including toxic-ity; metabolic functions including host storage, platelet aggregation, deconjugation of bile acids, degradation of mucus and resistance to antimicrobials, with emphasis on the genes involved.

There is no scientific evidence showing benefit from probiotic supplementation in critically ill or chronically ill patients with gastrointestinal disease.

There are reports on increased infections in critically ill hospitalized children when given probiotics. As the positive effects of probiotics in hospitalized children are uncertain, and as some negative effects have been reported, the administration of probiotics to this vulnerable group of children is not advisable. While many unanswered questions still remain concerning dose, type of strain, length of supplementation, etc., caution should be employed in treating this very vulnerable group of children.

A major pathogenic trait of microorganisms is platelet aggregation (26,73). Whether, and to what extent, the presence of other microbes (including probiotics) with platelet aggregating properties may aggravate haemolytic uremic syndrome (HUS) has not been investigated. There is no literature concerning administration of probiotics to hyper-emesis patients. However, the PROPATRIA study indicates that enteral nutrition combined with a mixture of probiotics delivered directly into the duodenum could be dangerous. Thus we also consider this treatment potentially dangerous not only in patients with predicted severe acute pancreatitis, but in all critically ill groups of patients. There are strong contraindications for the use of probiotics in hospital patients receiving enteral nutrition directly into the duodenum through a duodenal tube.

Probiotics should not be given to critically ill patients receiving parenteral nutrition. Recently operated patients given parenteral nutrition are in a critical situation (as long as their intestines are unable to handle enteral nutrients). They should therefore probably not have probiotics administered.

There are an increasing number of reports concerning acquired resistance genes in probiotic and potentially probiotic microorganisms and similarities have been shown between these gene determinants in bacteria of human origin and in probiotic microorganisms. This may indicate the spread of resistance genes between commensal microorganisms in the complex ecosystem of the GIT. Intake of probiotic microorganisms that bear mobile antimicrobial resistance genes may increase the risk of the transfer of such genes to the resident microbiota and thereby increase the problem of treating infections.

Acknowledgements

We would like to thank the Norwegian Scientific Committee for Food Safety where this risk assessment was performed.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.