Probiotics for Prevention: Can You 'C' a DIFFerence?

Probiotics may offer a potential treatment for clostridium difficile infection.

Clostridium difficile, a gram-positive, anaerobic, spore forming bacteria, can cause profuse diarrhea, abdominal cramping, leukocytosis, fever, and in severe situations, toxic megacolon, sepsis, and death.^1,2

Clostridium difficile infection (CDI) is a growing concern as an emerging pathogen. The US Centers for Disease Control and Prevention (CDC) estimates that half a million infections occurred in the United States in 2011 with 29,000 deaths within 30 days of diagnosis.

It has surpassed methicillin-resistant staphylococcus aureus (MRSA) as the number 1 cause of nosocomial infections.^3,4

Due to the intolerable symptoms of the disease, which can include 10-15 cases of watery diarrhea in a day and often bloody stools, weight loss, and dehydration; it is important that patients are treated quickly and appropriately.

Although there have been many advances in the treatment of CDI, more methods are being reviewed for prevention of CDI. Due to the increased length of hospital stay in many of these patients, it is vital that to treat appropriately and also strive to prevent readmissions.

The cost to the health care system is immense, with an estimated $1.5 billion in the United States due to hospitalization secondary to CDI. The average cost for patients with a diagnosis of C. difficile is almost 3 times higher than patients without C. difficile ($23,190 vs. $8,860).^5,6

Risk factors for clostridium difficile associated diarrhea (CDAD) include older age, hospitalization, administration of antibiotics, use of proton pump inhibitors and histamine-2 blockers, chemotherapy, renal failure, gastrointestinal surgery, and mechanical ventilation.⁷

While some risk factors are non-modifiable such as age or length of hospitalization, risk of CDI can be increased via dispersion throughout environments that are not properly sanitized when transitioning between patients or transmission between patients and health care workers.

Within 3 days of antibiotic initiation, more than 56% of Bifidobacteria and Lactobacilli in the gut are destroyed.⁸

Probiotics are postulated to rebalance gut flora disturbed by medications and illnesses, therefore reducing the risk of colonization of pathogenic bacteria, such as C. difficile.^7,9

The 2013 Guidelines for Diagnosis, Treatment, and Prevention of Clostridium difficile Infections by the American College of Gastroenterology stated, “Although there is moderate evidence that two probiotics (Lactobacillus rhamnosus GG and Saccharomyces boulardii decrease the incidence of antibiotic associated diarrhea, there is insufficient evidence that probiotics prevent C. difficile infection” and more randomized controlled trials are needed in regards to evidence of efficacy before a recommendation could be made for utilizing probiotics.¹⁰

Probiotic use has mixed results and there is not enough information to recommend routine use for prevention or treatment, however, newer studies have continued the discussion.¹¹

Are Probiotics the Answer?

With CDI rates on the rise, it is important to evaluate the potential benefits of initiating probiotics in patients taking antibiotics. There is supporting evidence that the addition of probiotics may reduce CDI incidence.

A systematic review and meta-analysis was conducted by Johnston et al. to assess the efficacy and safety of probiotics for the prevention of CDI in adults and children receiving antibiotics.¹²

Selected studies included randomized, controlled trials that compared any strain or dose of probiotics with placebo (or no treatment) with reported incidence of CDI.

Twenty studies that included 3818 patients total were included in the analysis. Overall, probiotics were found to reduce the risk of CDI.

Trials that used multiple species as the probiotic of choice showed larger effects than studies that used a single species. No trial reported a serious adverse event linked to the use of probiotics.

The overall results of this systematic review and meta-analysis provide moderate-quality evidence. It was concluded that probiotic therapy is a safe, beneficial treatment option for prevention of CDI in at-risk patients receiving antibiotics based on risk reduction results and reported adverse events.

A quasi-experimental, prospective cohort study by Maziade P, et al. evaluated the efficacy and safety of Lactobacillus acidophilus CL1285, Lactobacillus casei LBC80R, and Lactobacillus rhamnosus CLR2 (Bio-K+) in addition to augmented standard preventative measures for the reduction of primary CDI rates.¹³

During this 10-year observational study, all adult patients (n=44,835) were given Bio-K+ within 12 hours of starting any antibiotic.

The standard preventative measures that were continued throughout the study included isolation of CDI patients, cleansing and disinfection procedures, monitoring of antibiotic use, hand washing, and hand disinfection of patients.

The initial 8-year intervention with Bio-K+, resulted in a 73% reduction of CDI cases (p<0.001), a 76.4% (p<0.001) reduction of severe cases, and 39% (p<0.001) of relapse.

In the extended 10-year observation, the annual incidence rate at the study hospital was lower than rates observed at other hospitals in the network (2.3 vs. 7.5 cases per 10,000 patient-days).

The rates were also lower than equivalent-sized hospitals (8.3) and similarly sized hospitals with comparable services in the area (12.8).

Laboratory findings showed no incidences of Lactobacillus bacteremia during the 10-year observation. The study results suggest that the addition of probiotic Bio-K+ to standard preventative measures is safe and effective at decreasing CDI incidence.

Serious adverse events from probiotics have not yet been reported. A systematic review by Goldenberg JZ, et al. assessed adverse events in 26 studies.

The analysis showed that probiotic use helps reduce adverse events such as abdominal cramping, nausea, fever, soft stools, flatulence, and taste disturbances by 20%.⁹

Limitations to Probiotic Use

Although the literature shows favorable results for the role of probiotics in the prevention of CDI, the application of the evidence to clinical practice may be limited. There is a lack of randomized clinical trials comparing the combination of probiotics and standard preventative precautions to standard precautions alone.

Various trials have demonstrated non-pharmacological prevention strategies alone are effective in the prevention of CDI.

Khanafer et al. conducted a literature review on the efficacy of different practices to reduce hospital CDIs in non-outbreak settings.¹⁴

Twenty-one studies were included in the review, with the majority coming from university hospitals.

Local baseline CDI control policies included isolation in private rooms, contact precautions (gloves and gowns), adequate handwashing with soap and water, daily disinfection of furniture and equipment, and disinfection of rooms after patient discharge.

Study interventions included antibiotic stewardship, antibiotic “teams,” daily patient bathing, and mandatory reporting of CDI cases. Four studies found a reduction in CDI rates between 36.4 and 73% by just restricting the use of cephalosporin prescribing and increasing staff education.

One particular study included in the review evaluated the effect of a “Prevention Checklist” on CDI rates.¹⁵

This checklist included staff responsibilities such as recognition of signs and symptoms of CDI with early lab testing, initiating early contact precautions such as gowns and gloves, discontinuation of non-essential antibiotics or anti-peristaltic medications, and reminders to wash hands with soap and water.

The incidence rate of CDI decreased from an average of 1.10 per 1000 patient days in the pre-intervention period to 0.66 cases per 1000 patient-days during the post-intervention period. This improvement was sustained for 21 months and correlated with a 40% decrease in CDI rates, which was statistically significant.

A potential barrier to the initiation of probiotics is the additional cost of therapy. The approximate cost per unit of probiotics ranges from $0.11 to $1.71 per McKesson.

The economic burden of CDI has been well documented. However, a cost-effectiveness analysis of the addition of probiotics for the prevention of CDI has not yet been published, making it difficult to justify the added cost.

The systematic review and meta-analysis by Johnston et al. acknowledged the use of probiotics in immunocompromised patients based on adverse event data that was analyzed.¹²

The authors concluded that short-term courses of probiotics may be used in this population with moderate confidence, as no trial reported any serious adverse effects related to probiotics.

However, the risk of serious adverse events related to probiotics in an immunocompromised host cannot be ruled out.

The package insert for Florastor (Saccharomyces boulardii lyo) states that administration is contraindicated in patients with a central line due to the increased risk for fungemia.¹⁶

This risk could potentially be extrapolated to an immunocompromised patient as well.

Conclusion

With CDI surpassing MRSA as the number 1 nosocomial acquired infection, we are obligated as practitioners to do our part in keeping our patients protected while they are in the hospital.

It is vital that each health care institution develop a policy for practitioners to utilize when making clinical decisions on whether to initiate probiotics in patients receiving antibiotics. While previous trials suggest that probiotics may reduce CDI prevalence rates, more evidence is needed in order for a clear answer.

Randomized clinical trials that compare standard preventative measures alone to probiotics in addition to these measures would aid in developing policies.

Institutions need to critically evaluate the available literature and decide what to do while keeping patients’ well-being at the center of the decision.

References

• Venuto C, Butler M, Ashley ED, et al. Alternative therapies for Clostridium difficile infections. Pharmacotherapy 2010;30(12):1266-78.
• Cocanour CS. Best strategies in recurrent or persistent Clostridium difficile infection. Surg Infect 2011;12(3):235-9.
• Centers for Disease Control, 2011. Healthcare-associated Infections Clostridium difficile Infection. http://www.cdc.gov/HAI/organisms/cdiff/Cdiff_infect.html. Accessed October 3, 2015
• Hitt E. C Difficile Surpasses MRSA as the Leading Cause of Nosocomial Infections in Community Hospitals 2010. Medscape multispecialty. http://www.medscape.com/viewarticle/719053. Accessed October 5, 2015
• Zimlichman E, Henderson D, Tamir O, et al. Health care-associated infections: a meta-analysis of costs and financial impact on the US health care system. JAMA Intern Med 2013;173:2039-46
• Magill SS, Edwards JR, Bamberg W, et al. Multistate Point-Prevalence Survey of Health Care—Associated Infections. N Engl J Med 2014;370:1198-208.
• Varughese CA, Vakil NJ, Phillips KM. Antibiotics-associated diarrhea: a refresher on causes and possible prevention with probiotics-continuing education article. J Pharm Pract 2013;26:476-82.
• Graul T, Cain AM, Karpa KD. Lactobacillus and bifidobacteria combinations: a strategy to reduce hospital-acquired Clostridium difficile diarrhea incidence and mortality.
• Goldenberg JZ, Ma SSY, Saxton JD, et al. Probiotics for the prevention of Clostridium difficile-associated diarrhea in adults and children. Cochrane Database of Systematic Reviews 2013;5:Art. No. CD006095.
• Surawicz, CM, Brandt LJ, Binion DG, et al. 2013 Guidelines for Diagnosis, Treatment, and Prevention of Clostridium difficile Infections. Am J Gastroenterol 2013; 108:478-498
• Leffler DA, Lamont JT. Clostridium difficile Infection. N Engl J Med 2015; 372: 1539-48.
• Johnston BC, Ma SSY, Goldenberg JZ, et al. Probiotics for the Prevention of Clostridium difficile-Associated Diarrhea: A Systematic Review and Meta-analysis. Ann Intern Med. 2012;157:878-888.
• Maziade P, Pereira P, Goldstein EJ. A Decade of Experience in Primary Prevention of Clostridium difficile Infection at a Community Hospital Using the Probiotic Combination Lactobacillus acidophilus CL1285, Lactobacillus casei LBC80R, and Lactobacillus rhamnosus CLR2 (Bio-K+). Clin Infect Dis. 2015;60:S144-7.
• Khanafer, N. et al. 'Hospital Management Of Clostridium Difficile Infection: A Review Of The Literature'. Journal of Hospital Infection 90.2 (2015): 91-101.
• Abbett, Sarah K. et al. 'Proposed Checklist Of Hospital Interventions To Decrease The Incidence Of Healthcare‐Associated Clostridium Difficile Infection'. Infection Control and Hospital Epidemiology 30.11 (2009): 1062-1069.
• Florastor [package insert]. San Bruno, CA: Biocodex; 2011.

About the Authors

Jeana Kett is a 2016 PharmD candidate from the University of Florida Jacksonville campus.

Kacie Clark is a 2016 PharmD candidate from the University of Florida Jacksonville campus.

Alyssa Claudio is a 2016 PharmD candidate from Palm Beach Atlantic University.