By Richard R. Watkins, MD, MS, FACP, FIDSA

Associate Professor of Internal Medicine, Northeast Ohio Medical University, Rootstown, OH; Division of Infectious Diseases, Cleveland Clinic Akron General, Akron, OH

Dr. Watkins reports that he has received research support from Allergan.

SYNOPSIS: The authors of a before-and-after intervention study and a meta-analysis found that probiotics reduce the incidence of Clostridium difficile infection (CDI). The strategy seems to work best in hospital settings where the incidence of CDI is ≥ 5% and for patients receiving two or more antibiotics.

SOURCES: Trick WE, Sokalski SJ, Johnson S, et al. Effectiveness of probiotic for primary prevention of Clostridium difficile infection: A single-center before-and-after quality improvement intervention at a tertiary-care medical center. Infect Control Hosp Epidemiol 2018;39:765-770.

Johnston BC, Lytvyn L, Lo CK, et al. Microbial preparations (probiotics) for the prevention of Clostridium difficile infection in adults and children: An individual patient data meta-analysis of 6,851 participants. Infect Control Hosp Epidemiol 2018;39:771-781.

Clostridium difficile infections (CDI) cause significant morbidity, mortality, and cost to the healthcare system. Therefore, finding effective methods to prevent CDI is a laudable goal and an area of active research. One particular method that has gained attention for primary prevention of CDI is the use of probiotics. As part of a quality improvement initiative, Trick et al gave probiotics to patients about to start antibiotic therapy and evaluated the rates of CDI before and after the intervention. In another study, Johnston et al performed a meta-analysis to determine if probiotic prophylaxis reduces the odds of CDI in adults and children.

The before-and-after study was conducted at a single hospital in Chicago and compared 12-month baseline and intervention periods. Patients were excluded from receiving probiotics if they were on neonatal, pediatric, or oncology units. Additional exclusion criteria included receiving only perioperative antibiotics, having leukopenia (white blood cell count < 1,000 cells/mm3), being a transplant recipient, or being restricted from oral intake, although patients receiving enteral feedings were given a liquid probiotic preparation. The incidence of hospital-onset CDI was the primary outcome. Researchers performed a post-hoc analysis that compared the incidence between the intervention’s beginning six months and its final six months. The investigators also conducted a matched case-control study to determine a patient-level analysis. The meta-analysis included randomized controlled trials (RCTs) with children and/or adults who were given antibiotics for any reason along with concomitant probiotics and compared to placebo, alternative prophylaxis, or no treatment (i.e., standard of care). The primary outcome was the diagnosis of CDI, which was defined as diarrhea with C. difficile laboratory confirmation, the presence of pseudomembranes with endoscopy, C. difficile histological diagnosis, or toxic megacolon diagnosis. The secondary outcome was severe adverse event incidence.

In the first study, there was a decreased incidence of CDI during the second six months of the intervention period compared to the first six months (5.4 vs. 8.6 per 10,000 patient days, respectively; incident rate ratio [IRR], 0.6; 95% confidence interval [CI], 0.4-0.9; P = 0.009). However, in the case-control part of the study, logistic regression determined that probiotic receipt did not decrease the risk for CDI (adjusted odds ratio [aOR], 0.95; 95% CI, 0.8-1.2; P = 0.65). Missed doses of probiotic were common, but no associating factors were found.

In the meta-analysis, there were 18 studies that reported CDI outcomes. Receiving a probiotic lowered the unadjusted odds of developing CDI (OR, 0.37; 95% CI, 0.25-0.55; P < 0.0001). Receiving two or more antibiotics raised the odds for CDI significantly (OR, 2.20; 95% CI, 1.11-4.37; P = 0.0243). Factors such as age, sex, hospitalization status, and exposure to high-risk antibiotics (e.g., third- and fourth-generation cephalosporins, lincosamides, and fluoroquinolones) did not increase the odds for CDI significantly. A control group event rate of ≥ 5% had a significant association with CDI (aOR, 16.33; 95% CI, 7.79-34.26; P < 0.0001). For adverse events, there were no major differences between the intervention and control groups (OR, 1.06; 95% CI, 0.89-1.26; P = 0.536). No cases of bacteremia or fungemia were associated with probiotics, nor were there any serious adverse events deemed attributable to them. The number needed to treat to prevent one case of CDI was 96.

COMMENTARY

These two studies add to the evidence for using probiotics to help reduce the risk for CDI. The meta-analysis found probiotics to be very safe for most patients when used for CDI prevention. In the study by Trick et al, a single episode of Lactobacillus bacteremia was documented. A follow-up analysis determined the strain that caused the bacteremia was not part of the three-strain probiotic capsule the patient received. Yet, the authors of a recent study found that data about the harms of agents that modify the gut microbiome (i.e., probiotics, prebiotics, and synbiotics) are lacking in many RCTs and that a definitive recommendation about their safety cannot be made.1 Therefore, it seems prudent to recommend withholding probiotics in some circumstances, such as immunocompromised patients. There also has been a reported case of a patient with a central line who developed Lactobacillus bacteremia from the strain in the probiotic capsule.2

The main results of the study by Trick et al are somewhat difficult to interpret because of the delayed impact observed during the intervention period. The authors noted that a similar delay has been seen in previous studies and may be attributable to changes in the environmental burden of C. difficile spores over time. They also speculated that the reason no protective effect was found for probiotics in the case-control study was due to unmeasured confounding factors that increased the risk for CDI among the case patients.

The meta-analysis provides some insight regarding the populations that may benefit from probiotics, including settings with CDI incidence ≥ 5% and for patients receiving two or more antibiotics. Pragmatically, this means the greatest benefit is for populations with moderate to high baseline risk.

An interesting finding was that receipt of a “high-risk antibiotic” was not an independent risk factor for CDI. This suggests there should be less focus on these drugs and more on other interventions for reducing the incidence of CDI, such as shortening antibiotic durations, improving hand hygiene, and performing better environmental cleaning.

REFERENCES

  1. Bafeta A, Koh M, Riveros C, Ravaud P. Harms reporting in randomized controlled trials of interventions aimed at modifying microbiota: A systematic review. Ann Intern Med 2018 Jul 17; doi: 10.7326/M18-0343. [Epub ahead of print].
  2. Skljarevski S, Barner A, Bruno-Murtha LA. Preventing avoidable central line-associated bloodstream infections: Implications for probiotic administration and surveillance. Am J Infect Control 2016;44:1427-1428.