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doi:10.1378/chest.06-2156
(Chest. 2007; 132:286-294)
© 2007 American College of Chest Physicians
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Probiotics for Preventing and Treating Nosocomial Infections*

Review of Current Evidence and Recommendations

Warren Isakow, MD; Lee E. Morrow, MD, FCCP and Marin H. Kollef, MD, FCCP

* From the Department of Internal Medicine (Drs. Isakow and Kollef), Pulmonary and Critical Care Division, Washington University St. Louis School of Medicine, St. Louis, MO; and Department of Internal Medicine (Dr. Morrow), Division of Pulmonary and Critical Care Medicine, Creighton University School of Medicine, Omaha, NE.

Correspondence to: Warren Isakow, MD, Pulmonary and Critical Care Division, Campus Box 8052, 660 South Euclid Ave, St. Louis, MO 63110; e-mail: wisakow{at}im.wustl.edu

Abstract

Objective: To review the available clinical data supporting the use of probiotics in preventing and treating serious nosocomial infections.

Data source: A Medline database from 1996 to July 2006 and references from identified articles were used to perform a literature search relating to the clinical applications of probiotics in preventing and treating Clostridium difficile-associated diarrhea (CDD) and prevention of hospital-associated pneumonia (HAP).

Conclusion: Nosocomial infections like HAP and CDD contribute significantly to health-care costs in the United States. These clinical problems are associated with prolonged hospital stays and increased mortality in critically ill patients. The emergence of multidrug-resistant pathogens in cases of HAP and the recent description of an epidemic, toxin gene-variant strain of C difficile, combined with the anticipated lack of new antimicrobial agents in the near future emphasize the need for new, innovative strategies to prevent and treat these diseases. Probiotics normally function as colonizers and contribute to the overall health of their hosts by multiple mechanisms including immune and antibacterial effects. There is no current clinical evidence to support the use of probiotics to restore the normal human flora in critically ill patients and reduce HAP rates. Probiotics can prevent episodes of antibiotic-associated diarrhea, but their utility in treating and preventing CDD requires demonstration of benefit in multicenter clinical trials, preferably sponsored by the National Institutes of Health.

Key Words: Clostridium difficile • hospital-associated pneumonia • lactobacillus, probiotics • ventilator-associated pneumonia

Patients admitted to hospitals and ICUs become susceptible to multiple nosocomial infections that significantly increase morbidity, mortality, and add to hospital costs. The normal flora in hospitalized patients is eradicated by broad-spectrum antibiotic therapy that creates an environment in which a pathogen not susceptible to the antibiotics can flourish, since the normal bacterial colonizers contribute to an unfavorable local milieu for pathogens. Hospital-associated pneumonia (HAP) is the leading cause of mortality attributed to nosocomial infections.12 The incidence of HAP is from 5 to 10 cases per 1,000 hospital admissions. While the incidence of ventilator-associated pneumonia is difficult to determine due to differences in the case definition, it is estimated that 9 to 27% of patients receiving mechanical ventilation for > 48 h are affected.34 HAP prolongs hospital stays for an average of 7 to 9 days and adds excess medical costs ranging from $12,000 to $40,000 per patient.345 "Attributable mortality" from HAP is estimated to be between 33% and 50%, with the higher mortality occurring in patients with bacteremia or infections with Pseudomonas aeruginosa or Acinetobacter species.6789 Antibiotic-associated diarrhea results from an imbalance in the endogenous flora as a result of antibiotic therapy. Some cases of antibiotic-associated diarrhea are related to overgrowth of Clostridium difficile, a Gram-positive, spore-forming anaerobe. The incidence of C difficile-associated diarrhea (CDD) is increasing in US hospitals, occurring in up to 1.2% of hospitalized patients and causing life-threatening disease in 3.2% of patients.1011 The excess health-care costs associated with this illness amount to > 1 billion dollars per annum in the United States. This article will review some basic concepts relating to probiotic products and assess the evidence supporting their roles in preventing and treating these two important clinical problems.

Definition of Probiotics

Probiotics are viable microorganisms that colonize the host GI tract by adhering to the intestinal mucosa,12 and each strain has unique characteristics with potentially different beneficial health effects on different organ systems (Table 1 ).13


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  		Table 1. Common Commercially Available Probiotic Products (This List Is Not All-Inclusive)

 
Normal GI Flora and Its Benefits on Immune Function

The normal human GI tract flora is a complex ecosystem that in normal health maintains balance between commensals and pathogens. Normal human GI flora has many roles, including immune modulation, digestion, metabolic activity, and a competitive effect on other GI microbes. A healthy flora promotes the integrity of the gut defense barrier by normalizing intestinal permeability. The immune benefit is manifested by modulation of intestinal secretory Ig function and control of intestinal inflammatory responses by balancing the release of cytokines. By preventing excessive generation of inflammatory mediators in the GI tract that have the potential to extend the immune response systemically, the normal flora contributes to the overall immune function of its host.14 Oral probiotic intake and maintenance of the normal GI flora microecology therefore has clinical effects at distant sites on an immunomodulatory basis. Additionally, these effects persist beyond the duration of actual colonization by the probiotic strain due to the memory capacity of the immune system.15

Probiotics: Antibacterial Effects

In addition to the immune and barrier function benefits noted above, probiotics are able to compete with the adhesion of pathogens to epithelial binding sites in the GI tract. These antibacterial and immune mechanisms are summarized in Table 2 and contribute to creating an unfavorable local milieu for pathogen colonization.1617181920212223242526272829303132


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  		Table 2. Beneficial Effects of Probiotic/Host Interactions in the GI Tract

 
Probiotics: Clinical Applications

Currently, probiotic products have been shown to be of some benefit in the following diseases: acute infectious diarrhea in children,33343536373839 prevention of necrotizing enterocolitis in very-low-birth-weight infants,4041 prevention of allergic atopic dermatitis in children,303132424344 and the prevention of relapses of ulcerative colitis.45464748 There has been a surge in interest in potential probiotic applications for a number of reasons. Increasing levels of multidrug-resistant pathogens in hospitals is a major driving force behind efforts to find alternatives to traditional pharmaceuticals. Additionally, probiotics offer numerous practical benefits including low-cost preparation, long shelf life, and ease of administration. However, the quality of the data that have been accumulated in support of the clinical applications of probiotic products is often inadequate and plagued by poor trial design.

Probiotics for Preventing Antibiotic-Associated Diarrhea and Treating CDD

Antibiotic-associated diarrhea results from an imbalance in the endogenous flora as a result of antibiotic therapy. Some cases of antibiotic-associated diarrhea are related to overgrowth of C difficile, a Gram-positive, spore-forming anaerobe. The incidence of CDD is increasing in US hospitals, occurring in up to 1.2% of hospitalized patients and causing life-threatening disease in 3.2% of patients.1011The excess health-care costs associated with this illness amount to > 1 billion dollars per annum in the United States.10 Twenty to 40% of hospitalized patients have C difficile colonization,4950 and increased complications have been noted especially in patients > 65 years old.51 Increased flouroquinolone use has been associated with outbreaks of the disease and in an outbreak in Pittsburgh, PA, there were 18 deaths and 26 colectomies performed in 253 nosocomial C difficile infections.52 A large study53 of C difficile isolates from eight outbreaks in US health-care facilities revealed that the epidemic strain was universally resistant to flouroquinolones and that this strain produces greater quantities of toxins A and B than control strains. New evidence from Loo et al54 in 1,703 patients at 12 hospitals in Quebec showed an attributable mortality of 6.9% from CDD and an absolute mortality of 14% in patients > 90 years old. These recent events have renewed interest in probiotics for preventing this clinical problem. Many different probiotic species have been studied as preventative agents for antibiotic-associated diarrhea, but data from randomized controlled trials (RCTs) show that S boulardii and lactobacilli are the most efficacious in preventing this problem.

McFarland55 recently performed a metaanalysis of all the RCTs investigating probiotics as a preventive strategy for antibiotic-associated diarrhea and as a treatment strategy for CDD. Twenty-five RCTs were included in the metaanalysis of probiotics as a preventive measure for antibiotic-associated diarrhea, and 6 RCTs were of sufficient quality to assess the effects of probiotics in treatment of CDD. Studies were graded for quality using the US Preventive Services Task force scale56 and trials of poor quality were excluded from the analysis. All included trials were published in peer-reviewed journals. Weights for the analysis were not based on study quality but on sample sizes.57 The major criticism of most of the included RCTs is that they were not adequately powered and there was no standardization of the probiotic product or dose, or of the concomitant antibiotic therapy in the studies investigating CDD.

The 25 RCTs provided data on 2,810 patients with antibiotic-associated diarrhea, with 13 of the trials reporting a significant reduction in the probiotic-treated groups. The median number of patients in each study was 79 (range, 18 to 388). Twelve of the 25 RCTs did not detect a benefit from probiotics in preventing antibiotic-associated diarrhea. The contradictory results could possibly be explained by differences in study populations, probiotic type and dose, as well as duration of therapy. Notably, 8 of the 12 RCTs that showed a benefit from probiotics used a high daily dose compared to only 2 of 12 RCTs that showed no difference yet used a high dose. The relative risk for antibiotic-associated diarrhea in patients receiving probiotics was 0.43 (95% confidence interval, 0.31 to 0.58; p < 0.001). The two most efficacious probiotic strains were S boulardii and L rhamnosus. There was most likely modest publication bias that could have affected the results of the meta-analysis.

Six RCTs provided data on the efficacy of probiotics in treating CDD in a total of 354 patients and are summarized in Table 3 . Two of the six trials reported a significant reduction of CDD recurrences in the probiotic group. The complicating factor in this analysis is that in five of the six RCTs, probiotic therapy was combined with standard antibiotics (either vancomycin or metronidazole) to treat CDD, and the type as well as dose of the antibiotic was not randomized for any of the studies. The relative risk for CDD was 0.59 (95% confidence interval, 0.41 to 0.85; p = 0.005), and only S boulardii was found to be efficacious. There were no cases of bacteremia or fungemia or other serious adverse events in the 31 RCTs.


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  		Table 3. Summary of Six Randomized Controlled Trials of Probiotics for Treating or Preventing CDD*

 
Probiotics in Patients With Critical Illness and Patients Undergoing Major Surgery

Patients in ICUs would intuitively seem to be ideal candidates for probiotic therapy. Their normal flora often becomes replaced with pathogens due to multiple factors, most importantly broad-spectrum antibiotic use, and the consequences of this includes the development of nosocomial infections. However, limited data currently exist in this patient population. Mcnaught et al64 performed a prospective, randomized trial in 103 critically ill patients to determine the effect of the probiotic L plantarum 299v on gut barrier function and the systemic inflammatory response. The probiotic had no identifiable beneficial effect on gastric colonization, intestinal permeability, serum C-reactive protein level, septic morbidity, and mortality. The serum interleukin-6 level on day 15 was significantly lower in the probiotic group than the control group, consistent with a late attenuation of the systemic inflammatory response but without discernible clinical benefit. The same group of investigators performed a randomized placebo-controlled trial using a synbiotic preparation of four probiotic species and the prebiotic oligofructose in 90 critically ill patients.65 There were significant differences in the incidence of potentially pathogenic bacteria in the nasogastric aspirates after 1 week of therapy (43% in the synbiotic group vs 75% in the control group, p = 0.05) but no differences in intestinal permeability, septic complications, or mortality between the groups.

Two studies6667 have been performed in liver transplant patients to decrease the rate of postoperative infections. The most recent prospective, double-blind trial by Rayes et al67 compared 66 liver transplant recipients who received enteral nutrition with fiber and 4 recipients who received lactic acid bacteria or enteral nutrition with fiber alone. Postoperative infections were reduced from 48% in the control group to 3% in the probiotic group, and duration of antibiotic therapy was shorter in the probiotic group.67 Notably, none of these immunosuppressed patients had an infection with any of the probiotic strains. The same group of investigators68 studied patients undergoing abdominal surgery and found fewer infections including pneumonia, shorter hospital stays, and fewer antibiotics prescribed in the patients randomized to a strategy utilizing probiotics as well as early enteral feeds.

Severe acute necrotizing pancreatitis is an illness characterized by prolonged ICU stays, the development of secondary nosocomial infections, and a high mortality. A study by Olah et al69 in patients with severe acute pancreatitis randomized 45 patients to enteral oat fiber and live L plantarum 299 (22 patients) vs enteral oat fiber and heat-killed L plantarum 299 (23 patients). In the group treated with the live probiotic, only one patient required surgery for a septic complication involving the pancreas, compared to seven such complications in the control group (p = 0.023). There was also a trend toward a shorter length of stay in the live probiotic group (13.7 days vs 21.4 days, p = not significant)

Not all studies in surgical patients have shown benefit from lactobacilli. Anderson et al70 randomized 137 patients prior to elective abdominal surgery to a 2-week course of symbiotic therapy (four probiotic strains and the prebiotic oligofructose) or placebo and could not demonstrate any differences in bacterial translocation, gastric colonization, systemic inflammation, or septic complications. An additional prospective randomized study71 in 129 patients undergoing elective major abdominal surgery receiving L plantarum 299v vs placebo for 1 week preoperatively and postoperatively did not show any reduction in complications.

There are currently no RCTs that have investigated probiotics as a preventive strategy to prevent HAP as a primary outcome. Based on a pathogenetic model, repetitive administration of probiotics should reduce the density of pathogenic organisms in the oropharynx and stomach with resultant lowering of HAP rates given our current understanding that HAP potentially occurs as a consequence of host colonization by pathogens followed by aspiration of these pathogens.727374757677 A multicenter randomized trial should be performed to test this hypothesis.

Safety of Probiotics

The safety of probiotics has been questioned due to reports787980818283848586 linking probiotic administration to numerous infectious illnesses including endocarditis, bacteremia, wound infections, and abscesses. Molecular DNA fingerprinting has related the probiotic product to the infecting pathogen in a number of these cases.8485 The relationship between lactobacilli and endocarditis has been presumed to be secondary to the ability of the organism to aggregate platelets.87 Husni et al83 reviewed the cases of 45 patients with lactobacillus bacteremia occurring over a 15-year period at the Cleveland Clinic. Underlying comorbidities like cancer (40%), recent abdominal surgery (38%), diabetes mellitus (27%), and immunosuppression (36%) were common, but there is no comment on how many of these patients were receiving probiotic products. Twenty-two of the 45 patients were in the ICU at the onset of the lactobacillus bacteremia, 11 of the 45 patients were receiving total parenteral nutrition, and 23 patients had received antibiotics without activity against lactobacillus prior to the occurrence of bacteremia. Notably, bacteremia was polymicrobial in 27 of the 45 cases. Thirty-one of the 45 patients died, with only one death attributable to lactobacillus bacteremia. Lactobacillus bacteremia was very rarely fatal in itself, but it does identify patients with serious and often fatal illness.

Lactobacillus pneumonia has been documented in immune-suppressed patients with AIDS,88 after lung transplantation,89 and after liver transplantation.90 Lactobacillus ventilator-associated pneumonia has only been reported once, in a critically ill trauma patient.91 Of greatest concern is the development of Saccharomyces cerevisiae fungemia in a critical care population receiving S boulardii-containing probiotics, and there are now > 50 cases in the literature, approximately half of whom were receiving probiotic products.9293 Munoz et al92 confirmed the relationship between the organism causing fungemia and the probiotic product in their series, and Lherm et al93 reported seven cases of S boulardii fungemia in 29 months in a single 12-bed ICU.

Salminen et al94 reviewed the risk factors and outcomes in 89 patients with lactobacillus bacteremia. In 11 of the 89 cases, the strains identified were identical to the probiotic L rhamnosus GG. Eighty-two percent of the patients with bacteremia had severe or fatal comorbidities, and predisposing factors to bacteremia were immune suppression, prior prolonged hospitalization, and prior surgical interventions. This cohort of 89 cases had a 1-month mortality of 26% and a 1-year mortality of 48%, attesting to the severe underlying comorbidities.

A significant proportion of patients in modern ICUs are immunocompromised either as a result of their primary disease process or therapy of the disease, so the administration of lactobacillus is potentially problematic. However, as documented by Rayes et al,6667 lactobacilli have been used in transplant populations with no documented adverse effects, as well as in HIV-positive patients receiving antiretroviral therapy, with no complications.95

Quality Control of Probiotics

Currently marketed probiotic products vary significantly between manufacturers in multiple respects including bacterial density, adhesion characteristics, acid and bile stability, and viability after processing and storage.96 Strain-specific products from the same manufacturer have been noted to exhibit different adhesion properties at different times and conflicting results in clinical trials of lactobacilli for antibiotic-associated diarrhea may be due to differences in viability between different batches of the same strain.97 If probiotics are to become a new component of the physician’s armamentarium, universal standard testing protocols are going to be required to ensure quality and safety of the product, similar to the fastidious testing performed on pharmaceutical products. Probiotics are currently viewed as a food product (dietary supplement) by the Food and Drug Administration and are not subject to the same regulations as pharmaceutical products. Probiotic products need to be evaluated in multicenter, well-designed clinical trials to assess their efficacy and safety profiles, so that physicians can safely prescribe them. This will require large amounts of funding, which is a problem for the smaller pharmaceutical and food companies who currently market these products. However such funding is necessary to advance understanding of different strain properties and unravel the mechanisms of benefit in different disease processes.

Conclusion

Further research into mainstream medical applications of probiotic products is justified given the anticipated problems with antibiotic resistance, soaring health-care costs, and dearth of new antimicrobial classes on the horizon. Research into these beneficial bacterial species, which have evolved ecologically as a means to maintain balance and health in human hosts, could add to clinician’s abilities to treat disease in a number of the medical disciplines. The advantage of these products includes ease of administration, low cost, and good safety profiles. Future probiotic studies need to be designed in a manner that controls for the receipt of confounding drugs that can impact the gut flora and will need standardization of the probiotic product and dosing (both daily dose and duration of therapy). Randomized, multicenter, double-blind, placebo-controlled trials with appropriate statistical power are lacking in this field and need to be performed. Development of such multicenter trials by an agency such as the National Institutes of Health may settle the controversies surrounding the use of probiotic products.

Footnotes

Abbreviations: CDD = Clostridium difficile-associated diarrhea; HAP = hospital-associated pneumonia; RCT = randomized controlled trial

The authors have no financial interests to disclose relative to this work.

Received for publication August 30, 2006. Accepted for publication October 20, 2006.

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