Review question/objective

The objective of this review is to assess the effectiveness of probiotics in reducing the incidence of Clostridium difficile-associated diarrhea in elderly patients (60 years and older) who are residents of acute- and post-acute care facilities.

Background

Penicillin was discovered less than a century ago1 and since then millions of lives have been saved with the use of antibiotics.2 Today, antibiotics are among the most frequently prescribed medications in healthcare.3-5 Even though antibiotics have numerous benefits, they can also have negative consequences that lead to other health related problems. An example of this is Clostridium difficile (C. difficile) infection that leads to Clostridium difficile associated diarrhea (CDAD). Since the first reported case of CDAD in 1978, this antibiotic associated bacteria has become a major public health threat as was identified by the Centers for Disease Control and Prevention (CDC).6,7

According to the CDC, the incidence of CDAD has tripled over the last decade.8 Patients diagnosed with CDAD have an increase in morbidity and mortality, prolonged hospital stays, and higher hospital costs.3 In the United States alone, the estimated treatment cost for patients with CDAD is $3.2 billion annually9 and this infection is associated with 14,000 deaths per year.8 Patients of any age are susceptible to CDAD; however, elderly patients taking antibiotics are at a particularly high risk.3 Patients aged 60 or older have age related changes in the gastrointestinal micro-flora, decreased immune function, and multiple chronic conditions that further increase their risk.10 In addition, the increased risk of CDAD among older adults may be related to defects in immune response, specifically impaired phagocytes activity of neutrophils and failure to develop IgG and IgM in response to toxin A. The capacity of serum to neutralize these toxins decreases with age.11 Finally, gastric acid secretion decreases with age, allowing harmful bacteria, such as C. difficile to survive.11,12

C. difficle is classified as an anaerobic, gram positive, spore-forming bacteria.4 Transmission of C. difficile is through the fecal-oral route. An infected individual sheds vegetative forms of the bacteria and spores into the environment. Although the bacteria are inactive in the spore form, once ingested the bacteria undergo several phases of pathogenesis to become active in the colon. When the host uses antimicrobial agents, this alters the normal balance of intestinal flora. This imbalance can lead to the proliferation of C. difficile in the colon. Antimicrobials, such as broad-spectrum antibiotics, (e.g. Bactrim, Clindamycin), the second and third generation of cephalosporins, and fluoroquinolones, are particularly associated with C. difficile infection.11

The process of C. difficile infection leading to diarrhea begins when bacterial growth is no longer suppressed by normal intestinal flora or gastric acid.13 The C. difficile bacteria produce two toxins: enterotoxin A and cytotoxin B. Both of these act synergistically14 and are highly virulent and cytotoxic.15 Enterotoxin A activates macrophages and mast cells that cause the production of inflammatory mediators. These mediators disrupt the cell wall junction, resulting in increased permeability of the intestinal wall and reduced water absorption for the gut, resulting in osmotic diarrhea.16 Toxin B leads to cells accumulating purulent and necrotic debris, a wide-spread colon inflammatory response, and the formation of characteristic ulcers called pseudo-membranes.17 The end result of both toxins A and B is the development of CDAD.

Prompt diagnosis and treatment of CDAD are imperative. Standard management of CDAD consists of discontinuing any medication contributing to diarrhea, correcting fluid and electrolytes imbalances, and initiating an antibiotic for treatment of CDAD.15 Metronidazole is considered a first-line of therapy for treatment of mild to moderate disease, whereas vancomycin is the medication of choice for severe cases and relapses.16,17 In addition, infection control measures can significantly decrease the incidence of CDAD.16,17

Alternative therapeutic approaches for prevention and treatment of CDAD include probiotics. The use of probiotics has grown in popularity for maintaining intestinal health and decreasing the risk of CDAD. Today, science is on the verge of understanding the benefits of probiotics and their effect on incredibly complex gastrointestinal micro-flora. Oral probiotics are hypothesized to decrease the incidence and prevalence of CDAD.18-24 They are nonpathogenic live bacteria and yeast microorganisms that are used to replenish and balance colonic micro flora.25 Because of these benefits, recommending probiotics as prevention and treatment in CDAD in elderly patients needs to be explored. To date, there have been several systematic reviews published on probiotic use and CDAD,26,27 but none have specifically focused on their effectiveness in elderly patients.

There have been a variety of studies conducted to evaluate the effectiveness of probiotics in preventing and treating CDAD in the elderly population.18-24 One randomized controlled trial on 138 elderly patients receiving antibiotic therapy identified that the incidence of stool samples positive for C. difficile toxins was significantly lower in the intervention group versus the control group (2.95% versus 7.25%, respectively).23 Statistical analysis of these findings indicated that incidence of CDAD toxins was 4.35% lower in the experimental group (95% CI of -0.132 to 0.038).23 This finding was also replicated in another randomized double blind controlled trial. The researchers in this study identified that consumption of a probiotic drink twice a day during antibiotic treatment and for one week after antibiotic treatment significantly (P=0.001) decreased morbidity related to CDAD in elderly patients.19 A placebo-controlled trial performed by Klarin, et al.20 reported that colonization with C. difficile in critically ill elderly patients treated with antibiotics and supplemented with Lactobacillus plantarum299v was reduced when compared to the control group (P=0.0485). In support of these findings, Gao, Mubasher, Fang, Reifer, and Miller18 found that a probiotic blend of Lactobacillus had a positive efficacy and lower incidence of CDAD of elderly patients. Zahoroniet al.24 findings also support that probiotics are effective in elderly populations. Using a randomized, double-blind, placebo-controlled trial, these investigators found that the incidence of diarrhea was significantly lower in the treatment group compared with the control group. In another study, Lahtinen, et al.21 identified that probiotics containing Lactobacillus tended to reduce the average level of C. difficile in intestinal microbiota in elderly subjects. Finally, Ouwehand and colleagues,22 in their randomized placebo-controlled study, identified that higher probiotic dosages decreased the number of daily liquid stools in older patients with CDAD.

Elderly patients are at high risk of morbidity and mortality from CDAD. In the literature, the use of probiotics in this population has shown promise, but needs further exploration. Therefore, this systematic review will provide a comprehensive and unbiased summary of the available research on the effectiveness of probiotics in decreasing the incidence and prevalence of CDAD in elderly patients.

Inclusion criteria

Types of participants

This review will consider studies that include participants aged 60 years and older who are residents of acute- and post-acute care facilities and are undergoing or planning to undergo antibiotic treatment. Studies that include participants undergoing treatment for CDAD will be excluded.

Types of intervention(s)

This review will consider studies that evaluate the effectiveness of probiotics for prevention of CDAD in elderly patients in acute- and post-acute care settings compared to usual care. Any brand or strength of a probiotic product will be considered for the review. The review will also include studies examining various forms of probiotics, such as yogurt, buttermilk, combination products or capsules.

Types of outcomes

This review will consider studies that include the following outcome measures: incidence or relapse of CDAD. Cases of CDAD will be defined by presence of diarrhea and verified by positive results for stool enzyme immunoassay (EIA) for toxins A and B. Absence of diarrhea verified by negative results for stool EIA for toxins A and B.

Types of studies

This review will consider both experimental and epidemiological study designs including randomized controlled trials, non-randomized controlled trials, quasi-experimental, before and after studies, prospective and retrospective cohort studies, case control studies and analytical cross sectional studies for inclusion.

This review will also consider descriptive epidemiological study designs including case series, individual case reports and descriptive cross sectional studies if randomized-controlled trials are not available for inclusion.

Search strategy

The search strategy aims to find both published and unpublished studies. A three-step search strategy will be utilized in this review. An initial limited search of MEDLINE and CINAHL will be undertaken followed by an analysis of the text words contained in the title and abstract, and of the index terms used to describe articles. A second search using all identified keywords and index terms will then be undertaken across all included databases. Thirdly, the reference list of all identified reports and articles will be searched for additional studies. Studies published in English will be considered for inclusion in this review. Authors of primary studies will be contacted for missing information or to clarify any unclear data. Introduction of probiotics was first described by Russian Nobel laureate Elia Metchnikoff in the early 1900s.²⁸ However, the timeframe for the search will be limited from 1978 to present, since this is when the first reported case of CDAD was recorded.

The databases to be searched include:

CINAHL

PubMed

EMBASE

ProQuest Nursing & Allied Health Source.

The search for unpublished studies will include:

Google Scholar and conference proceedings.

Initial keywords to be used will be:

C.difficile associated diarrhea, antibiotic associated diarrhea, probiotics, elderly, aged

Assessment of methodological quality

Papers selected for retrieval will be assessed by two independent reviewers for methodological validity prior to inclusion in the review using standardized critical appraisal instruments from the Joanna Briggs Institute Meta-Analysis of Statistics Assessment and Review Instrument (JBI-MAStARI) (Appendix I). Any disagreements that arise between the reviewers will be resolved through discussion, or with a third reviewer.

Data extraction

Data will be extracted from papers included in the review using the standardized data extraction tool from JBI-MAStARI (Appendix II). The data extracted will include specific details about the interventions, populations, study methods and outcomes of significance to the review question and specific objectives.

Data synthesis

Quantitative data will, where possible be pooled in statistical meta-analysis using JBI-MAStARI. All results will be subject to double data entry. Effect sizes expressed as odds ratio (for categorical data) and weighted mean differences (for continuous data) and their 95% confidence intervals will be calculated for analysis to determine if the treatment intervention does provide superior results. Heterogeneity will be assessed statistically using the standard Chi-square and also explored using subgroup analyses based on the different study designs included in this review. Where statistical pooling is not possible the findings will be presented in narrative form including tables and figures to aid in data presentation where appropriate.

Conflicts of interest

There are no conflicts of interests to declare.

Acknowledgements

We would like to thank Dr. Stannard, an Associate Chief Nurse Researcher at UCSF Medical center, for excellent JBI training course presentation. We would like to thank Debbie Sommer, Librarian, for her extensive knowledge and assistance in the development of search strategies of database systems. We would like to thank Mr Bruce T Abbott, UC Davis, Librarian, for assistance to get access to the EMBASE database. I would like to express my grateful appreciation to Dr Wolf for her encouragement and motivation in research for this topic. I would like to thank Dr Hampton for her extensive knowledge, mentorship and valuable advice to produce quality research.

References