DISCUSSION

In this large before-and-after evaluation of a probiotic agent to prevent CDI among hospital patients receiving antibiotic therapy, we found a possible delayed benefit from the intervention. Meta-analyses summarizing individual randomized controlled trials provide evidence that certain probiotic agents can significantly reduce the risk of CDI.Reference Goldenberg, Ma and Saxton ^{9 –} Reference Johnson, Maziade and McFarland ¹¹ Despite consistent findings across probiotic formulations (ie, low between-study heterogeneity), one challenge facing clinicians and institutions is to select the optimal probiotic agent. Here, 2 major decision points are (1) whether to choose bacterial probiotic (usually inclusive of a Lactobacillus spp.) or yeast probiotic (eg, Saccharomyces boulardii) and (2) whether the agent should have >1 organism. Such choices are driven by evidence of efficacy, safety, and cost. Because evidence from 3 randomized controlled trials and a single-center before-and-after study showed similar reductions in CDI, we chose a multispecies formulation comprising L. acidophilus (CL1285), L. casei (LBC80R), and L. rhamnosus (CLR2).Reference Beausoleil, Fortier and Guenette ^{12 –} Reference Maziade, Andriessen, Pereira, Currie and Goldstein ¹⁵ Although our implementation did not reduce overall CDI incidence during the entire 12-month intervention period, we found a reduction in CDI during the final 6 months of the intervention.

The delayed reduction in CDI rate is consistent with the following prior studies. In a before-and-after intervention similar to ours, the CDI rate declined several months after introduction of probiotic.Reference Maziade, Andriessen, Pereira, Currie and Goldstein ¹⁵ In a separate intervention focused on the detection of C. difficile with isolation of patients, the decline in CDI rate was not immediate but occurred over time.Reference Longtin, Paquet-Bolduc and Gilca ¹⁸ We speculate that the delayed probiotic effect could be due to several independent or synergistic factors. First, our intervention hospital had a relatively high baseline rate of CDI, which might have contributed to high-density environmental contamination. The effectiveness of a probiotic may be related to the environmental burden of C. difficile spores; for example, probiotic might be more effective during relatively low-inoculum exposures. Thus, a reduction in environmental burden (eg, surface contamination) would be needed before probiotic effect is realized. Such an explanation is supported by the known prolonged environmental survival of C. difficile spores.Reference Weber, Rutala, Miller, Huslage and Sickbert-Bennett ²² Second, probiotics might reduce the excretion of viable organisms, and because the intensity of environmental contamination contributes to patient acquisition,Reference Samore, Venkataraman, DeGirolami, Arbeit and Karchmer ²³ a gradual reduction in contamination would lead to reduced patient acquisition over time. Third, the possible ‘herd effect’ likely to result from saturating high-risk patients with probiotics was not achieved during our intervention given the substantial proportion of case patients ineligible for probiotic receipt (41%). Fourth, given the before-and-after design, enhancements or deteriorations in infection control practices may have been unrecognized by the project team. However, there were no changes in environmental cleaning policies, antimicrobial stewardship activities, or modifications to other infection control policies during the study period. Specifically, the laboratory assay (PCR) results for C. difficile toxin detection remained constant throughout the baseline and intervention periods.

Because we were unable to electronically extract patient-level antibiotic and probiotic receipt data, we evaluated the association between probiotic receipt and CDI through a matched case-control study. To control for known major confounders, we matched case-control pairs on age, patient-care unit, and date of onset for antibiotic administration. We found that cases had higher severity-of-illness scores than controls; however, after adjusting for severity of illness, we found no protective effect from the probiotic. Despite this negative finding, we expect that there were critical unmeasured factors that increased risk of CDI among case patients. Ideally, we would have had comprehensive assessments of each patient’s severity of illness on initiation of antibiotics. Also, prehospitalization antibiotic exposure data would have been a useful surrogate for disruption of a patient’s microbiome, but it was not available.Reference Halpin and McDonald ²⁴

It is possible that the probiotic mixture had a beneficial effect unmeasured in the case-control study, such as modulating C. difficile in antibiotic recipients who were colonized but not symptomatic. Such a possibility is suggested by Freedberg et alReference Freedberg, Salmasian, Cohen, Abrams and Larson ²⁵ in their proposed ‘herd effect’ of antibiotics, wherein antibiotics taken by individual patients puts other patients at risk for CDI.Reference Freedberg, Salmasian, Cohen, Abrams and Larson ²⁵ In the study by Freedberg et al, receipt of antibiotics by prior hospital room occupants was associated with increased risk for CDI in subsequent occupants of the same room. Their hypothesis is that antibiotics promote C. difficile proliferation and subsequent environmental contamination in colonized, but not necessarily symptomatic, patients. Our data were also limited by the fact that we did not have the resources to monitor antibiotic recipients after hospital discharge, a time during which patients remain at high risk to manifest CDI and when the full effect of probiotic receipt might be realized.

Despite the largely proven safety of the probiotic mixture, we and clinical staff were concerned about potential harms, particularly clinical infections by probiotic organisms. We believed that the 3 Lactobacillus spp were low risk given the frequency of patient exposure to probiotics and uncommon recovery from clinical specimens. During our intervention, only a single episode of Lactobacillus bacteremia was recorded for a probiotic recipient. When we performed blinded genetic analysis of the patient’s isolate to those recovered from the 3-strain probiotic capsules, we determined that the bacteremia was unrelated to probiotic receipt.Reference Aroutcheva, Auclair and Frappier ²⁶ Regarding safety, in prior studies, side effects were either reduced or unchanged in probiotic recipients compared with controls.Reference McFarland, Huang, Wang and Malfertheiner ^{27 ,} Reference Johnston, Ma and Goldenberg ²⁸

A fundamental limitation of our project was low intervention fidelity among intended recipients, and a substantial number of at-risk patients were ineligible for the intervention (eg, pre-hospital or perioperative antibiotic receipt, clinical ineligibility, and no in-hospital antibiotic receipt). Through a chart review for the case-control study, we discovered that only 1 in 4 eligible antibiotic recipients received probiotic per protocol. Among those not receiving the intervention per protocol, the most common event was complete omission of probiotic, that is, not a single administered dose. Monitoring probiotic distribution during the intervention was performed, but the results were inconsistent with our retrospective chart review. Particularly influential factors impeding probiotic receipt were (1) frequent initiation of antibiotics before admission, either in the community or emergency room; (2) intention to administer only perioperative antibiotics; and (3) our system of probiotic distribution required manual evaluation of eligibility lists by pharmacists combined with the need for episodic pharmacy staffing with temporary personnel during the intervention. Anecdotally, patient refusal was rare and clinician refusal was uncommon. Future projects that pair probiotic with antibiotic administration would benefit (1) from an electronic, automated clinical decision support rule; (2) from the inclusion of emergency room patients; and (3) from possibly relaxing criteria for clinical eligibility (eg, a lower leukopenia threshold or requiring active pharmacologic immunosuppression for transplant recipients).

In conclusion, we found a decreased rate of CDI during the final 6 months of a 12-month before-and-after quality improvement intervention of a 3-strain probiotic mixture for primary prevention of CDI. The delayed effect is consistent with prior literature and may have been related to poor fidelity to the protocol for probiotic administration and a delayed gradual reduction in environmental contamination. Our quality improvement intervention in a large hospital encountered substantial implementation challenges. It is critical that such real-world applications are evaluated and reported to guide future quality-improvement research efforts based on the lessons learned. Given the foundation of evidence supporting probiotics to prevent CDI, interventions that achieve better distribution of probiotic and focused environmental cleaning before intervention and control periods are needed to quantify the impact of probiotics on CDI.