Do prophylactic probiotics prevent the incidence of Clostridium difficile colitis infection in hospitalized patients?

Abstract

Clostridium difficile colitis infection is an opportunistic infection with as high as an estimated 30,000 deaths and 4.8 million dollars in healthcare costs recorded in 2011. The most common risk factor for infection is antibiotic therapy. Studies reviewed consisting of a meta-analysis of 19 randomized clinical trials demonstrate a beneficial effect of probiotics in preventing CDCI with the highest efficacy noted when initiated within 2 days of antibiotics. However, variations in dosing, initiation and species of probiotic have unknown effects in study results. The most significant correlation noted was the decreased incidence of CDCI by almost 50% when adjusting for timing of probiotic administration nearer to the first dose of antibiotics. The adverse effects of probiotics across studies were similar when comparing control and experimental groups.

Summary of the Issues:

Clostridium difficile colitis infection is an opportunistic infection due to alterations in normal gastrointestinal flora as a result of antibiotic therapy. Clindamycin, fluoroquinolones, broad-spectrum penicillins and cephalosporins are the most commonly associated antibiotics. CDCI varies in severity with the most severe cases requiring intensive care unit admission and can be fatal. Probiotics are live non-pathogenic bacteria capable of colonizing the gastrointestinal tract and offering host health benefits.² The theory of prophylactic probiotics is to maintain colonization of “good” bacteria to compete against overgrowth of Clostridium difficile (CD).

Specific probiotics have the capability to antagonize CD toxins A and B. Data from in vitro and pre-clinical trials show protective mechanisms of probiotics. For Example, Lactobacillus lactis can produce a lytic peptide with activity against several strains of CD and Saccharomyces boulardii produces a protease capable of inhibiting CD toxin activity.²

CDCI is highly contagious requiring patient isolation, water based hand washing and spore killing disinfectants to prevent spread of infection to staff and other patients. Major risk factors for CDCI include immunocompromised state, age greater than 65, comorbidities such as chronic kidney disease and exposure to antibiotic therapy. In 2011 CDCI was estimated to cause almost 30,000 deaths with approximately $4.8 million in healthcare costs.¹ More than 20% of patients have initial treatment failure and 40 to 60% of these will have a second re-occurrence.¹

Current prevention guidelines focus on antibiotic stewardship and environmental precautions. Prophylactic use of probiotics has been discussed for years as a possible adjunct to prevention of CDCI but current use still lacks adoption. Focusing on prevention of CDCI will offer the upmost benefit when considering the disease’s morbidity, re-occurrence, transmission and treatment cost. Risks of CDCI remain high, especially when greater than 50% of patients in the hospital receive antibiotic therapy.

Summary of the Evidence:

A systematic review with meta-regression analysis by Shen, et. al. comparing 19 randomized control trial studies and over six thousand patients evaluated the effectiveness of probiotics on preventing CDCI. The review compared the incidence of CDCI in patients that were given prophylactic probiotics with antibiotic therapy as compared to a control group receiving antibiotic therapy alone. Of the 6,261 subjects, 3,277 patients were included in the probiotic group and 2,984 patients in the control group. Mean age for subjects was 68 in the probiotic group and 69 in the control group. The trials primarily used four probiotic species (Lactobacillus, Saccharomyces, Bifidobacterium and Streptococcus) for a total of 12 probiotic formulations. Oral probiotics were administered at varying starting points and durations with respect to antibiotic therapy. Initiation of probiotic therapy ranged from one to seven days after antibiotic administration. The course of prophylactic probiotics ranged from 14 to 21 days, based on duration of antibiotic therapy. ¹

The incidence of CDCI between control and probiotic group ranged from 0 to 40% and 0 to 11% respectively with a relative risk (RR) of 0.42 (95% CI, 0.30–0.57;P<0.001). The number needed to treat (NNT) varied by the baseline incidence. For example, for a median incidence of 4%, the number needed to treat was 43 (95% CI, 36–58).¹ NNT was 144 in the 25^th percentile (1.2% baseline incidence) to a NNT of 23 in the 75^th percentile (7.4% baseline incidence)¹

Initiation of probiotic administration in conjunction with antibiotic therapy was noted to have a significant effect on incidence of CDCI. One study in the Shen et al meta-analysis by Allen initiated prophylactic antibiotics after seven days when the other 18 studies started probiotics no longer than three days after initiation of antibiotics. Meta-regression of the 19 studies with and without the PLACIDE (Allen) study) showed probiotics to be more effective closer to the timing of the first antibiotic dose with an increased odds ratio of 18% (P=0.04 decrease in efficacy of prophylactic probiotic) for each day in delay of probiotic administration from time of antibiotic therapy.¹ Ultimately results showed probiotics given within 2 days of antibiotic therapy resulted in greater reduction of risk.

Probiotics like other supplements or therapies carry potential side effects. The most common included cramping, nausea, fever, flatulence, soft stools and taste disturbance. Adverse events in the control and probiotic groups of Shen et. al. were similar, 15.9% and 14.2%, respectively. It is also important to note that no cases of bacteremia or fungemia were reported.

A Cochrane systemic review study by Goldenberg et. al. of thirty-one studies and 8,672 patients showed a 70% reduction in risk for CD in patients at a baseline risk of greater than 5% when compared to other patients in lower risk categories (P value = 0.01). The incidence in this systemic review demonstrated a CD incidence of 1.5% (70/4525) in the probiotic group compared to 4.0% incidence (164/4147) in the placebo group. The control group had more side effects. The authors felt that it is reasonable to offer probiotics to hospitalized patients for prevention.⁴

Limitations for both reviews were that the studies varied on type of probiotic, dosing, duration of therapy and excluded patients. The trials only focused on hospitalized patients but excluded intensive care unit patients. Of note, specific probiotics can have susceptibility to certain antibiotic therapies and therefore theoretically provide decreased efficacy. Transplant and immunocompromised patients were excluded, as well as patients undergoing chemotherapy/radiation; patients that were pregnant, patients with prosthetic valves or pre-existing gastrointestinal disorders were also excluded from the trials. Some trials excluded patients on proton pump inhibitors.

Currently, the Infectious Disease Society of America guidelines revised in 2017 make no recommendation toward probiotic use stating: “There is insufficient data at this time to recommend administration of probiotics for primary prevention of Clostridium difficile infection outside of clinical trials.” They felt that the amount of bias in the systematic reviews performed showing benefit was significant. In addition, the uncertainty about the dosing and type of formulation prevents a recommendation.

Conclusions:

Overall the studies show benefit of probiotics in high-risk groups with reduction in incidence of CD. However, further studies need to define protocols on dosing, species, initiation and duration of probiotic therapy to maximize effects on prevention of CDCI. Further trials can also serve to inform providers on the specific patients that would most benefit from probiotic prophylaxis.

Question: Do prophylactic probiotics prevent the incidence of Clostridium difficile colitis infection in hospitalized patients?

Hilda Rodriguez, D.O. (PGY-2), Jan Miller, MD (Faculty)

St. Anthony Family Medicine Residency Program

608 NW 9^th Street

Suite 1000

Oklahoma City, OK 73102

Answer: Probiotics seem effective in preventing Clostridium difficile colitis infection (CDCI). More studies are needed to determine adequate dosing, species and duration of probiotics.

Level of Evidence of Answer: Level A

Search terms: Probiotics and Clostridium difficile

Date Search conducted: August 2017 and February 2018

Inclusion Criteria: Medical journals published on or after 2008 consisting of meta-analysis and systematic reviews of randomized clinical trials.

Exclusion Criteria: Excluded studies published prior to 2008, studies using probiotics for chronic gastrointestinal conditions and studies in the outpatient setting.