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M A J O R A R T I C L E

e2512 • cid 2021:73 (1 November) • Wombwell et al

Clinical Infectious Diseases

Received 18 February 2020; editorial decision 8 May 2020; accepted 15 June 2020; published online June 23, 2020.

Correspondence: M.  E. Patterson, Division of Pharmacy Practice and Administration, University of Missouri–Kansas City School of Pharmacy, 4245 Health Sciences Bldg, 2464 Charlotte St, Kansas City, MO 64108-2718 ([email protected]).

Clinical Infectious Diseases® 2021;73(9):e2512–8 © The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: [email protected]. DOI: 10.1093/cid/ciaa808

The Effect of Saccharomyces boulardii Primary Prevention on Risk of Hospital-onset Clostridioides difficile Infection in Hospitalized Patients Administered Antibiotics Frequently Associated With C. difficile Infection Eric Wombwell,1,2 Mark E. Patterson,1, Bridget Bransteitter,3 and Lisa R. Gillen2

1Division of Pharmacy Practice and Administration, University of Missouri–Kansas City School of Pharmacy, Kansas City, Missouri, USA, 2Department of Pharmacy, Centerpoint Medical Center, Independence, Missouri, USA, and 3Department of Medicine, Centerpoint Medical Center, Independence, Missouri, USA

(See the Editorial commentary by McFarland on pages e2519–20.)

Background. Hospital-onset Clostridioides difficile infection (HO-CDI) is a costly problem leading to readmissions, morbidity, and mortality. We evaluated the effect of a single probiotic strain, Saccharomyces boulardii, at a standardized dose on the risk of HO-CDI within hospitalized patients administered antibiotics frequently associated with HO-CDI.

Methods. This retrospective cohort study merged hospital prescribing data with HO-CDI case data. The study assessed patients hospitalized from January 2016 through March 2017 who were administered at least 1 dose of an antibiotic frequently associated with HO-CDI during hospitalization. Associations between S. boulardii administration, including timing, and HO-CDI incidence were evaluated by multivariable logistic regression.

Results. The study included 8763 patients. HO-CDI incidence was 0.66% in the overall cohort. HO-CDI incidence was 0.56% and 0.82% among patients coadministered S. boulardii with antibiotics and not coadministered S. boulardii, respectively. In adjusted analysis, patients coadministered S. boulardii had a reduced risk of HO-CDI (odds ratio [OR], 0.57 [95% confidence interval {CI}, .33–.96]; P =  .04) compared to patients not coadministered S. boulardii. Patients coadministered S. boulardii within 24 hours of antibiotic start demonstrated a reduced risk of HO-CDI (OR, 0.47 [95% CI, .23–.97]; P = .04) compared to those coadministered S. boulardii after 24 hours of antibiotic start.

Conclusions. Saccharomyces boulardii administered to hospitalized patients prescribed antibiotics frequently linked with HO-CDI was associated with a reduced risk of HO-CDI.

Keywords. Clostridium infections; Clostridioides difficile; probiotics; nosocomial infection; infection control.

Clostridioides difficile infection (CDI) has become one of the most common healthcare-associated infections in the United States, with the incidence nearly doubling between 2001 and 2010 [1, 2]. The Centers for Disease Control and Prevention (CDC) con- siders CDI an urgent threat requiring prevention and monitoring [1]. Risk factors for CDI include increasing age, proton pump in- hibitor (PPI) use, and most significantly, broad-spectrum anti- biotics that are hypothesized to accelerate C. difficile colonization by reducing levels of beneficial bacteria that serve as barriers to

infection [3]. Coadministering probiotics with antibiotics may prevent CDI development by reinforcing the barrier of good bac- teria lost through antibiotic administration [4, 5].

Beyond restoring altered intestinal microflora, administering probiotics may stimulate the immune system to prevent path- ogen adhesion and invasion, and clear pathogens and toxins from the intestinal tract [6]. Saccharomyces boulardii, a spe- cific yeast-derived probiotic, may prevent CDI by inducing direct inhibitory actions against C.  difficile toxins [5, 6]. Two studies demonstrate upregulation of total and specific intes- tinal antibodies (immunoglobulin A) to toxin A in response to S. boulardii exposure, consequently reducing C. difficile path- ogenicity [7, 8]. Other evidence demonstrates that S. boulardii directly inhibits C. difficile toxin by releasing a protease to hy- drolyze C. difficile toxins [6, 9].

The available literature examining the clinical outcomes of probiotics in preventing hospital-onset C.  difficile infec- tion (HO-CDI) is contentious. Three randomized clinical trials

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[10–12] and 1 cohort study [13] demonstrate S.  boulardii’s pri- mary or secondary prevention effects on HO-CDI. In contrast, the largest randomized trial of probiotics to date [14] and 1 cohort study of S. boulardii [15] show no protective associations. Overall these studies are small in scale and do not take into account the timing of probiotic initiation relative to antibiotic start [5, 11, 15]. A meta-analysis found that administering probiotics >2 days after initiating antibiotics significantly reduced the efficacy by half [16]. Given mixed evidence, research needs to assess the extent to which administrative timing impacts probiotics’ beneficial effects.

Given the limitations of previous studies, the Infectious Diseases Society of America (IDSA) and the Society of Healthcare Epidemiology of America (SHEA) state that “there are insufficient data at this time to recommend administration of probiotics for primary prevention of CDI” [17]. The IDSA and SHEA guideline writers cite specific limitations such as studies including patients with abnormally high rates of CDI, using inconsistent probiotic formulations across studies, or as- sessing patient populations at low risk for CDI [17]. These lim- itations underscore the need for further research. The guideline recommendations from IDSA and SHEA conclude with sug- gested areas of further research including: (1) What preventive measures can be taken to reduce the incidence of CDI? (2) Can administration of probiotics effectively prevent CDI?

Our primary objective was to evaluate the effect of pre- scribing a single probiotic formulation S.  boulardii on risk of developing HO-CDI in a large cohort of hospitalized patients receiving antibiotics frequently associated with HO-CDI. Our secondary objective was to evaluate the extent to which timing of S. boulardii initiation relative to antibiotic start affects HO-CDI risk.

METHODS

This retrospective observational cohort study compares the risk of HO-CDI in hospitalized patients who only received anti- biotics frequently associated with HO-CDI vs those who re- ceived antibiotics in combination with S. boulardii. The study merged C.  difficile case data with medication administration records to evaluate associations between HO-CDI incidence and S.  boulardii administration occurring between 1 January 2016 and 31 March 2017. The study setting is a 220-bed level 2 trauma center nonacademic hospital.

In December 2015, our institution established S. boulardii at a dose of 500 mg twice daily as the only formulary probiotic. This decision resulted from an internally performed literature review of probiotic agents by the Pharmacy and Therapeutics Committee. The committee concluded from the literature re- viewed that the use of S.  boulardii at a dose of 500 mg twice daily was more often associated with positive outcomes for re- ducing antibiotic-associated diarrhea and CDI. Corresponding with the formulary change, an electronic pop-up box was added

to the physician electronic order entry system with an option to order S. boulardii. The pop-up box appeared following the entry of an antibiotic order for β-lactams, fluoroquinolones, or lincosamides. The S.  boulardii order was not an automatic reflex order. The pop-up box also listed precautions for use of S.  boulardii, including (1) a history of organ transplantation with current receipt of antirejection medication; (2) concom- itant receipt of chemotherapy or radiation; (3) low neutrophil count; (4) diagnosis of AIDS; or (5) active gastrointestinal ulcer.

The cohort included adult patients (1) admitted to an in- patient medical unit with an average length of stay equaling ≥3  days; and (2) having barcode administration evidence for reception of at least 1 dose of an antibiotic frequently as- sociated with HO-CDI, which was defined as clindamycin, fluoroquinolones, third- and later-generation cephalosporins, carbapenems, and penicillins [18–20]. For the purpose of this study, “antibiotic” will subsequently refer to these defined anti- biotics frequently associated with HO-CDI. The unit of analysis was defined as the first hospitalization during the study period. Only the first hospitalization per unique patient was included in the analytic dataset to remove within-patient changes in S. boulardii exposure across separate hospitalizations.

Patients were classified as either having been or not having been administered S.  boulardii during hospitalization, based upon having barcode administration evidence for reception of at least 1 dose of S.  boulardii, or no evidence of barcode scan for administration, respectively. Saccharomyces boulardii (Florastor Daily Probiotic Supplement, Biocodex, Redwood City, California) administration consisted of two 250-mg cap- sules by mouth twice daily. Each 250  mg capsule contains 5 billion colony-forming units (CFUs) for a total daily adminis- tration of 20 billion CFUs. The dose of 20 billion CFUs is con- sistent with previously published studies assessing CDI primary prevention [21].

The study used C. difficile case data defined by and reported to the National Health Safety Network from our institution’s infec- tion control office. HO-CDI cases were defined as positive if an unformed stool specimen tested positive for C. difficile ≥3 days after admission and >8 weeks from a previous positive spec- imen result, consistent with the CDC definition for HO-CDI [22–23]. Cases were laboratory confirmed by polymerase chain reaction for the gene encoding toxin B alone without a reflex al- gorithm. Patients required the following criteria prior to testing: (1) ≥3 loose stools within 24 hours; (2) no laxative/stool soft- eners within 48 hours; (3) no positive C. difficile test in the last 30 days; and (4) no negative C. difficile test in the last 7 days. Samples were required to be watery; if the stool sample received by the laboratory was formed or semiformed, the laboratory re- jected the sample.

To evaluate the effect of S.  boulardii administration on HO-CDI risk, we conducted our first multivariable lo- gistic regression to estimate the risk of HO-CDI during

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a hospitalization conditional upon the coadministration of S.  boulardii with antibiotic(s) vs antibiotic(s) without S.  boulardii. To account for both potential confounders and selection bias, the model included propensity scores gener- ated by a separate multivariable logistic model testing the likelihood of patients receiving S. boulardii conditional upon: (1) antibiotic(s) administered during hospital admission; (2) metronidazole administration during hospitalization but >48 hours prior to CDI diagnosis; (3) PPI administration at any time during hospitalization prior to CDI diagnosis; (4) intensive care unit (ICU) admission; (5) patient age of 65 years or greater; and (6) gender. Each hospitalization was assigned a propensity score used as a covariate in the final multivariate model.

To evaluate the extent to which the timing of S. boulardii in- itiation relative to the first dose of antibiotic affected HO-CDI risk, we conducted a second multivariable logistic regression among only the subgroup of patients receiving S. boulardii. This model tested the risk of HO-CDI conditional upon early vs late coadministration of S.  boulardii with antibiotics. “Early” was defined as S. boulardii administered within 24 hours of first an- tibiotic dose administration; “late” was defined as S. boulardii administered ≥24 hours after the first antibiotic dose. Similar to the model run in the full cohort, propensity scores for this second analysis were generated with a multivariable logistic model testing the likelihood of patients receiving early vs late S. boulardii conditional upon the same baseline covariates in- cluded in the primary model run in the full cohort. Each hospi- talization was assigned a propensity score used as a covariate in the final multivariable model. Receiver operating characteristic curves were used to calculate C-statistics to estimate the overall global fit for all multivariable logistic regressions, including those used to generate propensity scores. All statistical analyses were conducted using SPSS version 24.0 software (IBM SPSS, Chicago, Illinois).

RESULTS

A total of 8763 patients administered at least 1 dose of an an- tibiotic frequently associated with HO-CDI were assessed. The cohort was 39% male and averaged 64  years of age. Patients coadministered S. boulardii and antibiotics were more often male (P < .0001) and ≥65 years of age (P < .0001) com- pared to patients only administered antibiotics. Ceftriaxone, piperacillin-tazobactam, levofloxacin, and ciprofloxacin were the most frequently administered antibiotics, administered in 44%, 32%, 25%, and 21% of patients, respectively. Carbapenem, fluoroquinolone, and cephalosporin administration was signif- icantly higher in patients coadministered S. boulardii compared with those not coadministered S.  boulardii (P  <  .0001). PPIs were administered in 46% of patients. PPI administration was significantly higher in patients coadministered S. boulardii and

antibiotics (50%) compared with patients not coadministered S. boulardii (41%) (P < .0001; Table 1).

The overall incidence of HO-CDI during the study period was 0.66%. Patients admitted to the ICU and patients administered PPIs demonstrated a higher incidence of and risk for HO-CDI (Tables 2 and 3). The incidence of HO-CDI was lower in pa- tients coadministered S. boulardii and antibiotics (0.56%) com- pared to patients administered antibiotics without S. boulardii (0.82%). With respect to administration timing, the incidence of HO-CDI in patients receiving early S. boulardii was less than half of those patients administered antibiotics alone without S. boulardii (0.38% vs 0.82%) (Table 2).

When adjusting for possible confounders and selection bias using the propensity score, the risk for HO-CDI was signifi- cantly less in patients administered S. boulardii and antibiotics (odds ratio [OR], 0.57 [95% confidence interval {CI}, .33–.96]) (Table 4) compared to patients administered antibiotics alone. Early S. boulardii administration displayed a stronger HO-CDI preventive effect compared to late S.  boulardii administration (OR, 0.47 [95% CI, .23–.97]) (Table 5).

DISCUSSION

When adjusted for potential confounders, patients adminis- tered S. boulardii in conjunction with antibiotics frequently as- sociated with HO-CDI had a lower risk of developing HO-CDI compared with patients not administered S.  boulardii in this single-center study. The protective effect was more pronounced in the early S. boulardii subgroup vs the late S. boulardii sub- group, suggesting that early administration might offer greater HO-CDI risk reduction compared to late administration. A re- cent meta-analysis on the use of probiotics for primary pre- vention of HO-CDI revealed similar findings alluding to the importance of probiotic initiation timing relative to the first dose of antibiotic [16]. The meta-analysis observed that the pre- ventive effect was limited to probiotic initiation within 1–2 days of antibiotic start and a lack of benefit when administered out- side of 2 days.

To explore this idea further, we conducted a post hoc multivariable logistic regression conditional upon the coadministration of early S.  boulardii vs no S.  boulardii with antibiotics. The analysis resulted in a reduced odds risk of HO-CDI for early S. boulardii vs no S. boulardii (OR, 0.44 [95% CI, .23–.84]; P = .013; C-statistic = 0.601), demonstrating a con- sistent stronger effect for early S.  boulardii and HO-CDI risk reduction. Presumptively, an earlier initiation of a preventive therapy would have a greater effect than a preventive therapy started further from the inciting event. Here we provide data to support that assumption with S.  boulardii administration rel- ative to antibiotic initiation. The secondary analysis included a small number of events and therefore is considered a provi- sional finding requiring further investigation.

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Our study has several limitations. First, our sample originates from a single medical center and decreases the generalizability of the findings. Second, we were unable to assess preexisting conditions, such as immunosuppression and CDI history, or patient severity status as risk factors for HO-CDI within the study or provider-level preventive practices. To mitigate this limitation, we included ICU admission as a confounder to ac- count for patients at a higher acuity level with severe illness. Third, providers were cautioned to avoid prescribing probiotics in patients (1) with a history of organ transplantation currently receiving antirejection medication; (2) receiving chemotherapy or radiation; (3) with low neutrophil count; (4) diagnosed with AIDS; or (5) having an active gastrointestinal ulcer [24–26]. There was no system in place to ensure S. boulardii was not pre- scribed to a patient who met these criteria. Consequently, we cannot make conclusions regarding the probiotic effectiveness in these patient groups.

This study has several strengths. First, including propensity scores in our models helped us account for both confounding

and selection bias. The propensity score helps account for ob- servable risk factors either associated with an increase or de- creased risk of HO-CDI. In our analysis, patients administered S.  boulardii could be considered at higher risk for HO-CDI as they were more often ≥65 years of age, administered a PPI during hospitalization at a higher rate, and more likely to re- ceive a third- or fourth-generation cephalosporin, carbapenem, and fluoroquinolone than non–S. boulardii recipients. Adding age, PPI, and antibiotic class utilization as covariates in the multivariable model used to derive the propensity score allows the propensity score to account for all of these factors simul- taneously. Furthermore, the propensity score helps account for underlying factors driving selection bias that could not be measured in our dataset, including, but not necessarily lim- ited to, patient history of HO-CDI or provider-level behaviors. Second, our observational study design enables us to measure real-world effectiveness based upon daily clinical encounters in contrast to clinical trials that may not reflect outcomes or patients seen in everyday practice. Evidence from real-world

Table 1. Demographic and Baseline Characteristics, by Cohort

Characteristic Total Patients

(N = 8763) Patients Not Coadministered

Saccharomyces boulardii (n = 3276) Patients Coadministered

Saccharomyces boulardii (n = 5487) P

Value

Demographics

Age, y, mean ± SD 64.3 ± 18.4 62.3 ± 19.2 65.4 ± 17.7 <.001

Age ≥65 y 4631 (52.8) 1606 (49.0) 3025 (55.1) <.001

Male sex 3390 (38.7) 1259 (38.4) 2131 (38.8) <.001

Intensive care unit 467 (5.3) 223 (6.8) 244 (4.4) <.001

Concomitant medications

Metronidazole 1211 (13.8) 483 (14.7) 728 (13.3) .05

Proton pump inhibitor 4050 (46.2) 1331 (40.6) 2719 (49.6) <.001

Antibiotic(s) administered during hospitalization

Penicillins 3173 (36.2) 1231 (37.6) 1942 (35.4) .04

Amoxicillin 69 (0.8) 45 (1.4) 24 (0.4) <.001

Amoxicillin-clavulanate 292 (3.3) 82 (2.5) 210 (3.8) .001

Ampicillin 66 (0.8) 41 (1.3) 25 (0.5) <.001

Ampicillin-sulbactam 182 (2.1) 84 (2.6) 98 (1.8) .02

Piperacillin-tazobactam 2780 (31.7) 1030 (31.4) 1750 (31.9) .7

Cephalosporins 4228 (48.2) 1407 (42.9) 2821 (51.4) <.001

Ceftriaxone 3824 (43.6) 1278 (39.0) 2546 (46.4) <.001

Cefdinir 134 (1.5) 27 (0.8) 107 (2.0) <.001

Cefepime 408 (4.7) 123 (3.8) 285 (5.2) .002

Ceftaroline 58 (0.7) 12 (0.4) 46 (0.8) .008

Ceftolozane-tazobactam 4 (0.0) 1 (0.0) 3 (0.1) 1.0

Ceftazidime-avibactam 1 (0.0) 0 (0.0) 1 (0.0) 1.0

Carbapenems 187 (2.1) 40 (1.2) 147 (2.7) <.001

Ertapenem 120 (1.4) 20 (0.6) 100 (1.8) <.001

Meropenem 83 (0.9) 24 (0.7) 59 (1.1) .1

Fluoroquinolones 3768 (43.0) 1280 (39.1) 2488 (45.3) <.001

Ciprofloxacin 1863 (21.3) 661 (20.2) 1202 (21.9) .06

Levofloxacin 2168 (24.7) 695 (21.2) 1473 (26.8) <.001

Lincosamides 369 (4.2) 155 (4.7) 214 (3.9) .06

Clindamycin 369 (4.2) 155 (4.7) 214 (3.9) .06

Data are presented as no. (%) unless otherwise indicated. χ 2 statistical analysis of differences between groups. Abbreviation: SD, standard deviation.

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practice can better inform changes in clinical guidelines or for- mulary policies. Third, isolating our study to a single agent at a set dose improves our ability to determine the effects of uni- form doses and inform specific dose recommendations. In con- trast, previous studies included multiple probiotics in the same treatment group and could not tease out the effects of isolated

agents or dosages. Fourth, we conducted a subgroup analysis to explore the importance of S.  boulardii administration timing relative to antibiotic start and resultant HO-CDI incidence. This subgroup analysis suggests that earlier probiotic administration timing improves probiotic primary prevention efficacy. Finally, our point estimate of OR = 0.57 is similar with those found in

Table 2. Incidence of Hospital-onset Clostridioides difficile Infection for Baseline Characteristics

Characteristic Total Patients (N = 8763) HO-CDI Event (n = 58) No HO-CDI (n = 8705) P Value

Demographics

Age ≥65 y 4631 (52.8) 34 (0.7) 4597 (99.3) .4

Male sex 3390 (38.7) 25 (0.7) 3365 (99.3) .5

Intensive care unit 467 (5.3) 9 (1.9) 458 (98.1) .001

Concomitant medications

Metronidazole 1211 (13.8) 8 (0.7) 1203 (99.3) 1.0

Proton pump inhibitor 4050 (46.2) 35 (0.9) 4015 (99.1) .03

Antibiotic(s) administered

Penicillins 3173 (36.2) 36 (1.1) 3137 (98.9) <.001

Amoxicillin 69 (0.8) 0 (0.0) 69 (100.0) .5

Amoxicillin-clavulanate 292 (3.3) 1 (0.3) 291 (99.7) .5

Ampicillin 66 (0.8) 0 (0.0) 66 (100.0) .5

Ampicillin-sulbactam 182 (2.1) 4 (2.2) 182 (97.8) .01

Piperacillin-tazobactam 2780 (31.7) 34 (1.2) 2746 (98.8) <.001

Cephalosporins 4228 (48.2) 31 (0.7) 4197 (99.3) .4

Ceftriaxone 3824 (43.6) 24 (0.6) 3800 (99.4) .7

Cefdinir 134 (1.5) 1 (0.7) 133 (99.3) .9

Cefepime 408 (4.7) 8 (2.0) 400 (98.0) .001

Ceftaroline 58 (0.7) 2 (3.4) 56 (96.6) .009

Ceftolozane-tazobactam 4 (0.0) 1 (25.0) 3 (75.0) 1.0

Ceftazidime-avibactam 1 (0.0) 0 (0.0) 1 (100.0) .9

Carbapenems 187 (2.1) 5 (2.7) 182 (97.3) .001

Ertapenem 120 (1.4) 2 (1.7) 118 (98.3) .2

Meropenem 83 (0.9) 5 (6.0) 78 (94.0) <.001

Fluoroquinolones 3768 (43.0) 28 (0.7) 3740 (99.3) .4

Ciprofloxacin 1863 (21.3) 14 (0.8) 1849 (99.2) .6

Levofloxacin 2168 (24.7) 15 (0.7) 2153 (99.3) .8

Lincosamides 369 (4.2) 0 (0) 369 (100.0) .1

Clindamycin 369 (4.2) 0 (0) 369 (100.0) .1

Saccharomyces boulardii 5487 (62.6) 31 (0.56) 5456 (99.4) .2

Early S. boulardii 3936 (44.9) 15 (0.38) 3921 (99.6) .01

Late S. boulardii 1551 (17.7) 16 (1.03) 1535 (99.0) .5

Data are presented as no. (%) unless otherwise indicated. χ 2 statistical analysis for development of hospital-onset Clostridioides difficile infection. Abbreviation: HO-CDI, hospital-onset Clostridioides difficile infection.

Table 3. Risk Associations of Hospital-onset Clostridioides difficile Infection Determined by Unadjusted Bivariate Analysis (N = 8763)

Characteristic OR (95% CI) P Value

Demographics

Age ≥65 y 1.27 (.75–2.14) .4

Male sex 1.20 (.71–2.03) .5

Intensive care unit 3.31 (1.62–6.77) .001

Concomitant medications

Metronidazole 1.00 (.47–2.1) 1.0

Proton pump inhibitor 1.78 (1.05–3.01) .03

Intervention

Saccharomyces boulardii and antibiotic 0.68 (.41–1.1) .2

Abbreviations: CI, confidence interval; HO-CDI, hospital-onset Clostridioides difficile infection; OR, odds ratio.

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meta-analyses by Johnston et al (Relative Risk [RR], 0.34 [95% CI, .24–.49]) [27], Goldenberg et al (RR, 0.36 [95% CI, .26–.51]) [28], Lau et al (RR, 0.40 [95% CI, .29–.53]) [29], and Shen et al (RR, 0.42 [95% CI, .30–.57]) [16]. Similar results across multiple studies further strengthens confidence in our estimates.

We observed a number needed to treat for early S. boulardii administration of 228, amounting to 17 cases of HO-CDI that may have been prevented among the 3936 patients adminis- tered S.  boulardii within 24 hours of antibiotic start during the study period. Given the magnitude of benefit and the rel- atively low cost of probiotics compared to the high cost of treating CDIs during hospitalization and postdischarge, adding S. boulardii probiotic as a primary preventive strategy may be a valuable strategy to reduce HO-CDI. Furthermore, results from a cost-effectiveness analysis suggest that probiotic use is a cost-effective strategy in preventing CDI in hospitalized adults receiving antibiotics [30].

CONCLUSIONS

This study provides evidence to support prescribing a uni- form probiotic formulation as primary prophylaxis of HO-CDI in a high-risk population, a noted weakness in the existing literature [17]. We observed that coadministration of probiotic S. boulardii at a dose of 20 billion CFUs per day with antibiotic therapy frequently associated with HO-CDI in an older hospitalized patient population significantly re- duced the incidence of HO-CDI. Furthermore, initiating probiotics within 24 hours of antibiotic start appears to offer a more pronounced barrier to HO-CDI development. Our findings in conjunction with evidence from previous studies support continued exploration of probiotics for primary pre- vention of HO-CDI, with particular consideration of earlier probiotic administration timing.

Notes Disclaimer. The views expressed in this publication represent those of

the authors and do not necessarily represent the official views of Hospital Corporation of America (HCA) or any of its affiliated entities.

Financial support. This research was supported in part by HCA and/or an HCA-affiliated entity.

Potential conflicts of interest. The authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. 

References 1. Centers for Disease Control and Prevention. Antibiotic resistance threats in the

United States. Atlanta, GA: CDC, 2013. 2. Reveles KR, Lee GC, Boyd NK, Frei CR. The rise in Clostridium difficile infection

incidence among hospitalized adults in the United States: 2001–2010. Am J Infect Control 2014; 42:1028–32.

3. Loo VG, Bourgault AM, Poirier L, et al. Host and pathogen factors for Clostridium difficile infection and colonization. N Engl J Med 2011; 365:1693–703.

4. Johnson S, Maziade PJ, McFarland LV, et al. Is primary prevention of Clostridium difficile infection possible with specific probiotics? Int J Infect Dis 2012; 16:e786–92.

5. McFarland LV. Systematic review and meta-analysis of Saccharomyces boulardii in adult patients. World J Gastroenterol 2010; 16:2202–22.

6. Parkes GC, Sanderson JD, Whelan K. The mechanisms and efficacy of probiotics in the prevention of Clostridium difficile–associated diarrhoea. Lancet Infect Dis 2009; 9:237–44.

7. Buts JP, De Keyser N, De Raedemaeker L. Saccharomyces boulardii enhances rat intestinal enzyme expression by endoluminal release of polyamines. Pediatr Res 1994; 36:522–7.

8. Qamar  A, Aboudola  S, Warny  M, et  al. Saccharomyces boulardii stimulates in- testinal immunoglobulin A immune response to Clostridium difficile toxin A in mice. Infect Immun 2001; 69:2762–5.

9. Stier H, Bischoff SC. Influence of Saccharomyces boulardii CNCM I-745 on the gut-associated immune system. Clin Exp Gastroenterol 2016; 9:269–79.

10. McFarland  LV, Surawicz  CM, Greenberg  RN, et  al. A randomized placebo- controlled trial of Saccharomyces boulardii in combination with standard anti- biotics for Clostridium difficile disease. JAMA 1994; 271:1913–8.

11. Pozzoni P, Riva A, Bellatorre AG, et al. Saccharomyces boulardii for the prevention of antibiotic-associated diarrhea in adult hospitalized patients: a single-center, randomized, double-blind, placebo-controlled trial. Am J Gastroenterol 2012; 107:922–31.

12. Surawicz CM, McFarland LV, Greenberg RN, et al. The search for a better treat- ment for recurrent Clostridium difficile disease: use of high-dose vancomycin combined with Saccharomyces boulardii. Clin Infect Dis 2000; 31:1012–7.

13. Carstensen JW, Chehri M, Schønning K, et al. Use of prophylactic Saccharomyces boulardii to prevent Clostridium difficile infection in hospitalized patients: a con- trolled prospective intervention study. Eur J Clin Microbiol Infect Dis 2018; 37:1431–9.

Table 5. Adjusted Risk Association of Hospital-onset Clostridioides difficile Infection With Early Versus Late Saccharomyces boulardii (N = 8763)

Probiotic Timing HO-CDI Event Rate, No. (%) Adjusted Risk, OR (95% CI) P Value

Early Saccharomyces boulardii 15/3936 (0.38) 0.47 (.23–.97) .041

Late S. boulardii 16/1551 (1.0) Ref Ref

Adjusted multivariable logistic regression included propensity score. C-statistic from model used to derive propensity score = 0.616; C-statistic for adjusted risk association = 0.717.

Abbreviations: CI, confidence interval; HO-CDI, hospital-onset Clostridioides difficile infection; OR, odds ratio.

Table 4. Adjusted Risk Associations of Hospital-onset Clostridioides difficile Infection With Saccharomyces boulardii Using Propensity Scores in Multivariable Regression (N = 8763)

Cohort HO-CDI Event Rate,

No. (%) Adjusted Risk, OR (95% CI) P Value

No Saccharomyces boulardii (antibiotic only) 27/3276 (0.82) Ref Ref

S. boulardii and antibiotic 31/5487 (0.56) 0.57 (.33–.96) .035

Adjusted multivariable logistic regression included propensity score. C-statistic from model used to derive propensity score = 0.620; C-statistic for adjusted risk association = 0.634.

Abbreviations: CI, confidence interval; HO-CDI, hospital-onset Clostridioides difficile infection; OR, odds ratio.

e2518 • cid 2021:73 (1 November) • Wombwell et al

14. Allen SJ, Wareham K, Wang D, et al. Lactobacilli and bifidobacteria in the pre- vention of antibiotic-associated diarrhoea and Clostridium difficile diarrhoea in older inpatients (PLACIDE): a randomised, double-blind, placebo-controlled, multicentre trial. Lancet 2013; 382:1249–57.

15. Flatley EA, Wilde AM, Nailor MD. Saccharomyces boulardii for the prevention of hospital onset Clostridium difficile infection. J Gastrointestin Liver Dis 2015; 24:21–4.

16. Shen  NT, Maw  A, Tmanova  LL, et  al. Timely use of probiotics in hospitalized adults prevents Clostridium difficile infection: a systematic review with meta- regression analysis. Gastroenterology 2017; 152:1889–900.e9.

17. McDonald  LC, Gerding  DN, Johnson  S, et  al. Clinical practice guidelines for Clostridium difficile infection in adults and children: 2017 update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA). Clin Infect Dis 2018; 66:e1–48.

18. Slimings C, Riley TV. Antibiotics and hospital-acquired Clostridium difficile in- fection: update of systematic review and meta-analysis. J Antimicrob Chemother 2014; 69:881–91.

19. Tabak YP, Srinivasan A, Yu KC, et al. Hospital-level high-risk antibiotic use in re- lation to hospital-associated Clostridioides difficile infections: retrospective anal- ysis of 2016–2017 data from US hospitals. Infect Control Hosp Epidemiol 2019; 40:1229–35.

20. Kazakova  SV, Baggs  J, McDonald  LC, et  al. Association between antibiotic use and hospital onset Clostridioides difficile infection in US acute care hospitals, 2006–2012: an ecologic analysis. Clin Infect Dis 2020; 70:11–8.

21. Tung JM, Dolovich LR, Lee CH. Prevention of Clostridium difficile infection with Saccharomyces boulardii: a systematic review. Can J Gastroenterol 2009; 23:817–21.

22. Centers for Disease Control and Prevention. National Healthcare Safety Network (NHSN). 2018. Available at: https://www.cdc.gov/nhsn/about-nhsn/index.html. Accessed 27 November 2018.

23. Centers for Disease Control and Prevention. Multidrug-resistant organism and Clostridioides difficile infection (MDRO/CDI) module. Atlanta, GA: CDC, 2019.

24. Boyle RJ, Robins-Browne RM, Tang ML. Probiotic use in clinical practice: what are the risks? Am J Clin Nutr 2006; 83:1256–64; quiz 1446–7.

25. Stadlbauer  V. Immunosuppression and probiotics: are they effective and safe? Benef Microbes 2015; 6:823–8.

26. Doron  S, Snydman  DR. Risk and safety of probiotics. Clin Infect Dis 2015; 60:S129–34.

27. Johnston  BC, Ma  SS, Goldenberg  JZ, et  al. Probiotics for the prevention of Clostridium difficile-associated diarrhea: a systematic review and meta-analysis. Ann Intern Med 2012; 157:878–88.

28. Goldenberg JZ, Yap C, Lytvyn L, et al. Probiotics for the prevention of Clostridium difficile-associated diarrhea in adults and children. Cochrane Database Syst Rev 2017; 12:CD006095.

29. Lau CS, Chamberlain RS. Probiotics are effective at preventing Clostridium difficile–as- sociated diarrhea: a systematic review and meta-analysis. Int J Gen Med 2016; 9:27–37.

30. Shen NT, Leff JA, Schneider Y, et al. Cost-effectiveness analysis of probiotic use to prevent Clostridium difficile infection in hospitalized adults receiving antibiotics. Open Forum Infect Dis 2017; 4:ofx148.