- Open Access
Clinical review: Probiotics in critical care
Critical Carevolume 16, Article number: 237 (2012)
Patients in ICUs represent a relatively small subgroup of hospitalised patients, but they account for approximately 25% of all hospital infections. Approximately 30% of ICU patients suffer from infection as a complication of critical illness, which increases the length of ICU stay, morbidity, mortality and cost. Gram-negative bacteria are the predominant cause of ICU-related infections and with the rise in multidrug-resistant strains we should focus our attention on nonantibiotic strategies in the prevention and treatment of nosocomial infections. Probiotics have been proposed as one option in this quest; however, mechanisms of action in the critically ill population require further investigation. Some of the beneficial effects appear to be associated with improvement in gastrointestinal barrier function, restoration of normal intestinal permeability and motility, modification of the balance of intestinal microbiota and immunomodulation. However, the information we have to date on the use of probiotics in the critical care setting is difficult to interpret due to small sample sizes, differences in ICU populations, the variety of probiotic combinations studied and differences in administration techniques. In this review we shall examine the use of probiotics in the critical care setting, look at some of the proposed mechanisms of action and discuss their potential benefits and drawbacks.
During an episode of critical illness a number of significant changes occur in the microbiota of the human gut. These changes occur due to alterations in the stress hormone profile, impairment of blood supply to the gut, immunosuppression, antibiotic use and nutrient deficiency . In experimental models these changes have been shown to occur within 6 to 8 hours, with endogenous Lactobacillus strains being replaced by pathogenic bacteria . This change can lead to a breakdown in the intestinal barrier function that is likely to play a significant role in the pathogenesis of multiple organ dysfunction syndrome [3, 4].
Redressing this balance and exploiting the beneficial effects of probiotic bacteria is understandably an area of considerable interest. However, the mechanisms by which these microorganisms exert their effects are various and depend upon the dose used, the route(s) of administration and the dosing frequency . Furthermore, a number of these effects are strain specific.
Probiotics, prebiotics and synbiotics
Probiotics are defined as 'live microorganisms that confer a health benefit on the host when administered in adequate amounts' . Prebiotics are nondigestible food components that stimulate the growth and/or activity of bacteria in the digestive tract in ways that may be beneficial to health . Synbiotics are a combination of probiotics and prebiotics. There has been an explosion of interest in probiotics and their potential health benefits since 2000, with initial attention focusing on the gastrointestinal tract.
Probiotics and the gastrointestinal tract
The human intestine is home to hundreds of species of bacteria, archaea and eukarya, many of which are non-culturable but can now be identified using metagenomic approaches. The bacterial load tends to be highest in the large intestine (up to 1011 colony-forming units/g), and while the healthy human gut is dominated by Bacteroides, Firmicutes and Actinobacteria, each individual has their own distinct stool bacterial composition determined by environmental and genetic factors. This bacterial profile remains relatively constant over time unless altered by disease state or antibacterial treatment [8, 9].
Culture-based and molecular detection methods have demonstrated that it is possible to significantly alter the composition of gut flora in adults and infants by treatment with probiotics. Sepp and colleagues treated 15 neonates with Lactobacillus rhamnosus GG for the first 2 weeks of life. They found that L. rhamnosus GG persisted for 1 month in eight of these neonates. There were also significant differences in the bacterial composition of the stool compared with the control group, with increased numbers of coliforms, lactobacilli and Bifido-bacterium spp. . Benno and colleagues demonstrated a statistically significant increase in bifidobacteria in adults treated with L. rhamnosus GG for a 4-week period. They also found an increase in lactobacilli and a decrease in the proportion of Clostridium spp. . As these techniques are based on faecal profiling, they tend to reflect the large bowel bacterial composition with little information being available on the small bowel effects of probiotics.
Mechanisms of action of probiotics
Much of the information available on the mechanisms of action of probiotics is obtained from animal work and in vitro studies; hence we must be careful in extrapolating this to humans. What is clear, however, is that there are multiple mechanisms by which different probiotic bacteria exert their effects, and these effects may vary with the strain and population studied. Table 1 summarises the main mechanisms by which probiotics exert their effects, and Table 2 presents details of commonly used probiotic preparations.
Probiotics may alter the local environment within the lumen of the gut, producing antimicrobial effects on pathogenic organisms. Lactic acid-producing and acetic acid-producing probiotics reduce the luminal pH resulting in an unfavourable milieu for pathogens. This has been demonstrated in vitro with pathogen growth being reduced in a pH-dependent manner by Lactobacillus spp. . Venturi and colleagues demonstrated a significant reduction of luminal pH in vivo in ulcerative colitis patients treated with the probiotic mixture VSL#3 .
Probiotics also exert a direct antimicrobial effect via the production of bacteriocins. Bacteriocins are proteins produced by bacteria that inhibit the growth and virulence of other pathogenic bacteria. Probiotic bacteria deficient in the bacteriocin gene are less effective probiotics, as demonstrated in a murine model where a mutant form of Lactobacillus salivarius UCC118 failed to protect against infection with Listeria monocytogenes . A wide variety of bacteriocins is recognised, and their spectrum of action ranges from antagonism of similar bacterial strains to the inhibition of a wide range of Gram-positives, Gram-negatives, yeasts and moulds . One such example of a broad-spectrum bacteriocin is that produced by a subspecies of L. salivarius. The ABP-118 bacteriocin inhibits Bacillus, Staphylococcus, Enterococcus, Listeria and Salmonella spp. .
Bacteria communicate with each other using a mechanism known as quorum sensing. This involves the production and secretion of signalling molecules known as autoinducers. In their in vitro study, Medellin-Peña and colleagues demonstrated that Lactobacillus acidophilus La-5 secretes molecules that disrupt this interbacterial communication, reducing expression of virulence-related genes by Escherichia coli O157:H7 .
Probiotics have also been demonstrated to enhance intestinal barrier function. Intestinal barrier function is complex and its control involves cellular stability at a cytoskeletal and tight junction level, as well as mucus, chloride and water secretion. Probiotics have been shown to exert an effect, in vitro and in vivo, via these mechanisms . For example, Lactobacillus plantarum 299v can enhance mucus production and secretion in human intestinal epithelial cells . The probiotic strain E. coli Nissle 1917 appears to enhance mucosal barrier function by production of human β-defensin 2 . E. coli Nissle has also has been demonstrated in vitro to reduce adhesion and invasion of intestinal epithelial cells by an enteroinvasive E. coli.
In addition, by competing with pathogens for nutrients and adhesion in a microbiological niche, probiotics can prevent replication by pathogens, a phenomenon known as colonisation resistance . Probiotics can thus promote the integrity of the gut defence barrier and create an unfavourable environment for pathogen colonisation.
Probiotics can also exert a range of immunological effects. The interaction between the luminal bacteria and the underlying epithelial and mucosal lymphoid cells is referred to as bacterial-epithelial cross-talk. This crosstalk enables probiotics to have an effect on both the innate and adaptive host immune system  - for example, promotion of B cells into plasma cells, increased production of secretory immunoglobulin A and prevention of activation of the proinflammatory nuclear transcription factor NF-κB . Other immunologic mechanisms include alteration of the cytokine profile and activation of macrophages to present antigen to B lymphocytes and increase immunoglobulin production .
Probiotics in the critically ill
The efficiency of intestinal barrier function is demonstrated by the fact that the faecal bacterial concentration approaches 1012 organisms/ml in the caecum, while tissues one cell deep to the intact intestinal mucosa are usually sterile . Any significant insult to the gut or alteration to its microbiota is likely to play a role in promoting systemic inflammation and infection in the critically ill population . In contrast to the large bowel, the stomach, duodenum and jejunum have a relative paucity of bacteria (103 to 104 organisms/ml). The presence of enteric organisms in gastric aspirates is therefore abnormal and represents gastric colonisation. In the context of critical illness, this colonisation is the result of bacterial overgrowth in the proximal gastrointestinal tract .
Colonisation of the stomach by pathogens or potential pathogens is believed to occur due to a combination of poor gut motility, increased gastric pH (due to acid suppression) and the use of broad-spectrum antibiotics. This combination of factors leads to an overgrowth of bacteria in the duodenum, which reflux into the stomach and are ultimately regurgitated and aspirated into the lungs .
The normal intestinal microbiota of critically ill patients is altered and replaced by pathogens for a number of reasons. Therefore, it would seem logical to consider that probiotics may have a role in reducing intestinal colonisation by pathogens and thus in the prevention of infection and sepsis syndromes in this population.
Probiotics in the prevention of nonrespiratory infection
Probiotics have been studied in the prevention of postoperative infection. Three studies in patients undergoing major colorectal surgery have shown no significant reduction in postoperative infection rates [24–26]. In each study, however, the effectiveness may have been limited by a relatively short postoperative period of probiotic administration (4 to 5 days). In contrast, several studies in patients undergoing pancreatic resection [27, 28] and hepatic resection [29, 30] have shown significant reductions in postoperative infection rates of up to 30%. These patients received probiotic for 8 to 14 days post operatively.
Liver transplant patients have multiple risk factors for infection, including profound immunosuppression. Two randomised trials have shown probiotics to be safe and effective in this group of patients. In the first study 95 patients were randomised to receive standard enteral feed plus selective bowel decontamination, fibre-containing enteral feed plus live L. plantarum 299 (Lp299) or fibre-containing enteral feed plus heat-killed Lp299 . The live Lp299 group developed significantly fewer infections than the other two groups (48% vs. 13% vs. 34%, respectively). In addition, the mean duration of antibiotic therapy, the mean total hospital stay and the length of ICU stay were also shorter than in the groups with inactivated Lp299 and selective bowel decontamination. However, these differences did not reach statistical significance. The second study compared only Synbiotic 2000 and prebiotic fibre, reporting postoperative infection rates of 3% and 48%, respectively . No serious side effects or infections caused by the probiotics were noted in either study.
Oláh and colleagues randomised 45 patients with severe acute pancreatitis to receive enteral oat fibre and live Lp299 or enteral oat fibre and heat-killed Lp299 . In the group treated with the live probiotic, only one patient required surgery for a septic complication involving the pancreas, compared with seven such complications in the control group (P = 0.02). There was also a nonsignificant trend toward a shorter length of hospital stay (13.7 days vs. 21.4 days, respectively). The same group carried out a single-centre, double-blind, randomised placebo-controlled trial using Synbiotic 2000 in a further 62 patients with severe acute pancreatitis . This trial showed no statistically significant differences in the incidence of mortality, septic complications or development of multiorgan failure between the two groups. However, the total incidence of systemic inflammatory response syndrome, multiple organ failure and rate of complications was significantly less in the treatment group versus the control group (8 vs. 14, P <0.05 and P <0.05, respectively).
The trial that has raised most concern with regard to adverse outcomes and the use of probiotics is the PROPATRIA trial . In this multicentre, placebocontrolled trial, 296 patients with predicted severe acute pancreatitis were randomised to receive the synbiotic preparation Ecologic 641 or placebo. This was administered together with fibre-enriched enteral feed via the nasojejunal route for 28 days. The rate of infectious complications was similar in both groups (30% vs. 28%) but the mortality rate was higher in the synbiotic group. Nine patients in the synbiotic group developed bowel ischaemia, eight of these being small bowel ischaemia. There were no cases of bowel ischaemia in the placebo group. One possible explanation for this outcome is a difference in the two groups, with more patients in the synbiotic group having established organ failure at the time treatment began. Another theory is that such a significant intestinal burden of bacteria and high-fibre feed could result in increased oxygen consumption and local bowel ischaemia. Nevertheless, this is the first time such a complication has been reported.
Probiotics in the prevention of respiratory infection
The respiratory tract is consistently the most common site of nosocomial infection, accounting for 65% of ICU-acquired infections . Ventilator-associated pneu monia (VAP) complicates the care of up to 30% of patients receiving mechanical ventilation, accounting for 50 to 60% of total antibiotic days [37–40]. Patients with VAP present increased morbidity and mortality, prolonged ICU and hospital lengths of stay, and increased costs .
Current VAP prevention strategies aim to reduce colonisation of the oropharynx and upper gastrointestinal tract with pathogenic bacteria and prevent their subsequent aspiration. These measures include elevation of the head of the bed, silver-coated tracheal tubes, oral care, subglottic secretion drainage and use of sedation breaks and weaning protocols. Selective digestive tract decontamination using antibiotics in the oral cavity or whole gastrointestinal tract decontamination have been shown to reduce rates of VAP and mortality [42, 43]. However, these strategies have not gained widespread favour in critical care owing to concerns about promoting antibiotic resistance. Oostdijk's group demonstrated a statistically significant increase in intestinal colonisation with Gram-negative bacteria resistant to ceftazidime, tobramycin or ciprofloxacin (P <0.05) . These concerns were also borne out by a large-cluster, randomised cross-over study of selective decontamination of the digestive tract that showed a marked increase resistance to ceftazidime in faecal Enterobacteriaceae, together with a small but significant increase in bacterial resistance from the respiratory tract . In a previous study, the use of cefotaxime as part of selective decontamination of the digestive tract regime was found to select for an outbreak of extended-spectrum β-lactamase-producing E. coli and Klebsiella pneumonia .
To date there have been eight randomised controlled trials of probiotic therapy as a strategy to prevent VAP [38, 47–53]. The inclusion criteria, sample size (range 50 to 348), populations studied and diagnostic criteria for VAP varied between studies. The probiotic formula, dosing and route of administration also varied but all trials contained Lactobacillus spp. (see Table 3). Six of the eight trials showed a lower incidence of VAP in the probiotic group [38, 47, 48, 50–52], but this difference was statistically significant in only three of the studies [38, 47, 48]. Interestingly, one study used chlorhexidine oral disinfection as a control and found that probiotic Lp299 was at least as effective in preventing oropharyngeal colonisation (61.9% vs. 34.8% new colonisation, respectively; P = 0.13) . The study by Forestier and colleagues found no difference in incidence of VAP between groups but did demonstrate a median delay in respiratory colonisation with Pseudomonas aeruginosa of 50 days versus 11 days in controls (P = 0.01) . This is the most commonly isolated antibiotic-resistant Gramnegative species in VAP .
Conflicting results also arise from meta-analyses of probiotics in critical care. The work by Watkinson and colleagues in 2007 analysed the use of prebiotics, probiotics and synbiotics in 999 adult critical care patients from eight randomised controlled trials and concluded that there was no benefit in the probiotic prophylaxis of VAP . In 2010, however, Siempos and colleagues examined five randomised controlled trials (689 patients) and showed that probiotic administration was associated with a lower incidence of VAP when compared with standard care (odds ratio = 0.61; 95% confidence interval = 0.31 to 0.91) . Importantly, both of these were published before the studies by Morrow and colleagues , Oudhuis and colleagues  and Barraud and colleagues .
The trial by Morrow and colleagues is unique in that it included oropharyngeal slurry as one of the routes of administration for the probiotic . The research group randomised 146 ventilated patients who were considered at high risk for VAP to receive probiotic L. rhamnosus GG or placebo (inulin) within 24 hours of intubation until extubation, tracheostomy or death. The primary outcome was microbiologically confirmed VAP based on quantitative culture of distal airway samples obtained by bronchoscopy. The incidence of VAP was significantly reduced in the probiotic group (19.1% with probiotic vs. 40.0% with placebo, P = 0.007).
Morrow and colleagues also examined the incidence of Clostridium difficile and ICU-associated diarrhoea in their patients. The probiotic group had significantly less C. difficile cytotoxin-positive diarrhoea compared with the placebo group (5.6% vs. 18.6%, P = 0.02), although the duration of diarrhoea was not significantly lower. However, patients treated with probiotic received fewer days of antibiotics for C. difficile-associated diarrhoea (0.5 ± 2.3 days vs. 2.1 ± 4.8 days in placebo group, P = 0.02). The duration of ICU-associated diarrhoea was also significantly reduced in the probiotic group (4.1 ± 3.7 days vs. 5.9 ± 3.8 days in placebo group, P = 0.03).
The rates of oral colonisation with pathogenic species at 72 hours (70% for placebo vs. 38.2% for Lactobacillus, P <0.001) correlated with development of VAP (Pearson correlation coefficient = 0.22, P = 0.009). Interestingly, the probiotic treatment appeared to preferentially reduce rates of infection caused by Gram-negative pathogens (22.8% for placebo vs. 8.8% for Lactobacillus, P = 0.02) while having no statistically significant effect on Grampositive species (12.8% vs. 5.8%, P = 0.16).
To date, studies of probiotics in the critically ill have trialled a number of species, Lactobacillus featuring frequently. Currently unknown, however, is whether one species is superior in the prevention of infection associated with critical illness. Similarly, the optimal administration route, dosage and duration of treatment are not clear. Further research is undoubtedly warranted, perhaps considering Gram-negative probiotic species.
Administration of probiotics and monitoring of their effects
Probiotics are commercially available in various preparations including yoghurt-based products, capsules, powders and suspensions. The studies in critically ill patients discussed above involve enteral administration of a variety of probiotic strains using different dosing regimes.
In eight of the nine studies involving mechanically ventilated patients (Table 3), probiotic powder or capsule contents were dissolved in water and delivered via a feeding tube into the stomach. Morrow and colleagues used an oropharyngeal slurry of L. rhamnosus GG (suspended in a sterile water-based surgical lubricant) in addition to nasogastric administration . After 72 hours, the patients receiving this regime were found to have lower rates of oral (38.2% vs. 70%, P = 0.001) and gastric (32.3% vs. 45.7%, P = 0.03) colonisation with pathogenic species than those receiving placebo. Klarin and colleagues used topical application of Lp299 to the oral cavity alone and found it to be at least as effective as chlorhexidine 0.1% in reducing oropharyngeal pathogenic load .
Testing for colonisation of the gastrointestinal tract with the probiotic species is reported in only a minority of studies. McNaught and colleagues collected gastric aspirates at induction of anaesthesia in elective surgical patients who had received at least 1 week of oral Lp299 . The probiotic species was not isolated in any subject. In the study by Forestier and colleagues, however, gastric aspirates were taken at inclusion, at day 7 and at discharge. Lactobacillus casei rhamnosus was detected in 52 out of 102 patients on probiotic treatment after a median of 13 days . In the study by Klarin and colleagues described above, the probiotic species Lp299 was detected in all oropharyngeal cultures and in the tracheal cultures from 56% of patients in the probiotic arm . Knight and colleagues demonstrated detection of probiotic species in stool culture after 3 days treatment with Synbiotic 2000 Forte, indicating its survival from the stomach to the distal gut . However, they did not routinely analyse stool samples in their more recent study . None of the other studies cited in Table 3 reported detection of probiotic species in any microbiological specimens.
Quality and safety
Probiotics are now widely available and are being consumed daily in large quantities. Overall they have an excellent safety record, but there are some concerns that are likely to lead to caution in their widespread use in clinical practice.
The availability of different probiotics varies from country to country and there can be lack of consistency between manufacturers, and even batches, in terms of density of bacteria, adhesion characteristics, stability and viability . Strain-specific adhesion properties and viability have been shown to vary between batches from the same manufacturer, which could lead to conflicting clinical trial results .
There have been a number of publications reporting serious infections caused by Lactobacillus spp. related to those used as probiotics . The Finnish group of Salminen and colleagues examined 89 cases of Lactobacillus bacteraemia. In 11 cases, the strain was identical with the probiotic L. rhamnosus GG . However, they could not directly relate these cases to probiotic consumption. Salminen and colleagues also examined trends in Lactobacillus bacteraemia in Finland over the period 1990 to 2000. This period coincided with a rapid increase in the consumption of probiotic L. rhamnosus GG. The group concluded that increased probiotic use had not led to an increase in Lactobacillus bacteraemia .
There are case reports in the literature of Lactobacillus infection and bacteraemia that appear to be directly related to probiotic consumption [62–65]. All of the patients involved were immunocompromised to some degree and the causative organism was linked to the probiotic by molecular techniques. Infections caused by Lactobacillus spp. from probiotics have also been reported in immunosuppressed patients - including those with acquired immunodeficiency syndrome and those following lung and liver transplantation [66–68]. Lactobacillus bacteraemia has been associated with structural heart abnormalities, valve prosthesis or prior endocarditis . However, the majority of clinical trials using Lactobacillus spp. probiotics report few adverse effects.
The only reported infection associated with probiotic E. coli Nissle 1917 is in a premature neonate (gestational age 28 weeks) . The child had an extremely low birth weight of 935 g and developed gastroenteritis due to rotavirus and adenovirus 14 days into the postnatal period. E. coli Nissle treatment initially led to improvement but the child developed severe sepsis 10 days later and subsequently E. coli Nissle 1917 was isolated in blood cultures. The child was treated with antibiotics and made a full recovery.
A wide range of probiotic species is being investigated for an increasing number of indications. There has been little work carried out on the rationale behind which probiotics are used and in what combination. Timmerman and colleagues attempted to address this issue by examining specific strains in an attempt to produce an effective multispecies mixture . The symbiotic preparation Ecologic 641 was used in the PROPATRIA trial. This group selected six strains of Lactobacillus based on survival in a simulated gastrointestinal environment, antimicrobial activity and ability to induce IL-10, highlighting the point that there should be a disease-specific rationale for selection of probiotics.
Concerns are mounting about multidrug-resistant Gram-negative bacteria with the extensive spread of extended-spectrum β-lactamases , and in particular the emergence of Enterobacteriaceae with resistance to carbapenems conferred by metallo-β-lactamase NDM-1 . New antimicrobial agents with which to tackle resistant bacteria are in limited supply, and a recently announced EU-US taskforce has called for a commitment to the development of 10 new antibacterial agents by 2020. This will require a substantial public financial investment and will need to be sustained long term because continued antibiotic use will maintain the pressure on organisms to evolve new resistant strains. In the absence of universally effective treatments, strategies that could prevent the development of ICU-acquired infection are needed.
The human, animal and in vitro studies of probiotics carried out to date exhibit a high level of heterogeneity in the conditions targeted, models used and probiotics tested. These studies are likely to reflect an oversimplistic view of the mechanisms of action of probiotic species. As alluded to above, probiotics are likely to bring about their effects through multiple processes with different strains having very specific effects.
We are still far from understanding fully the probiotic-host interaction but, given the potential benefits that probiotic bacteria have to offer, further study is warranted. Careful consideration should be given to further well-powered studies addressing the questions of which probiotic by what route, in what dose and at what time.
Lactobacillus plantarum 299
tumour necrosis factor
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The authors declare that they have no competing interests.