probiotics for c.difficile infection 775


table 2. Summary Data From Trials Providing Individual Patient Data Probiotics group (n=3,482)


Variable


Age, mean y (SD) <1


1to <18 18 to <65 65+


Sex (male, %) Hospitalized, no. (%)


Length of hospital stay, median d (IQR) Antibiotics class (any)a Aminoglycoside Beta-lactam ±


Beta-lactamase inhibitor Carbapenem


Cephalosporin (1st generation) Cephalosporin (2nd generation) Cephalosporin (3rd generation)b


3,317 3,480 2,608 2,812


165 2


874 299


Valid Sample Missing


3,151 331 Measure


63.8 (23.3) 34


211 832


2,074


1,747 (52.7) 3,054 (87.7) 7 (4–15) 2,812 31


1,755 49


296 445 130


323 148 97


3,201 3,369 2,498 2,697


168 0


871 307


Control Group (n=3,369)


Valid Sample Missing


3,047 322 Measure


63.3 (24.1) 35


217 781


2,014


1,587 (49.6) 2,953 (87.7) 7 (4–15) 2,697


52 1,701 48


254 471 138


Cephalosporin (4th generation)b 13 Fluoroquinoloneb Glycopeptide Lincosamide Macrolide Others


322 130 66


570 697


High risk antibiotic at any time, no. (%)b No. of antibiotics, median (IQR) Antibiotic exposure, median d (IQR)a


Probiotics or Control Exposure, median d (IQR) C. difficile infection, no. (%) Serious adverse events, no. (%)


2,982 3,179 1,447 3,012 3,384 2,556


500 303


1,474 470 98


683


599 (20.1) 2 (1–2)


10 (7–14) 15 (11–21) 38 (1.1)


318 (12.4)


2,887 3,064 1,337 2,916 3,261 2,434


482 305


1,592 453 108 935


data (43–45 were not included). bHigh-risk antibiotics were considered 3rd- and 4th-generation cephalosporins, lincosamides, and fluoroquinolones.


interaction with the treatment effect (P=.007). Compared to no probiotics, multispecies probiotics (OR, 0.33; 95% CI, 0.20–0.56; P<.0001; n=5,074) (Figure 2) significantly reduced CDI, whereas the effect of single-species probiotics was not statistically significant (OR, 0.41; 95% CI, 0.17–1.00; P=.051; n=5,074) (Figure 2). Compared to no probiotics, a 1 billion CFU per day increase in dose did not significantly reduce CDI risk (OR, 0.99; 95% CI, 0.99–1.00; P=.108; n=5,074) (Figure 2). Post hoc, we conducted a subgroup analysis of 5 trials using


S. boulardii (n=1,473), the probiotic most commonly used among RCTs for CDI prevention, and compared it with trials using other strains (n=5,381). We found no significant difference (OR, 0.86; 95% CI, 0.10–7.04) (Figure 2).


Sensitivity Analyses


When treating age as a categorical variable in the multivariate analysis, the effect of probiotics remained similar (OR, 0.35;


95% CI, 0.22–0.55; P<.0001) (Figure 2). In a post hoc ana- lysis, we removed infants <1 years of age, which resulted in a similar summary estimate (OR, 0.37; 95% CI, 0.23–0.59; P<.0001) (Figure 2). Results remained similar for the 18 studies in the unadjusted model regarding random-effects aggregate-data meta-analysis (n=6,447 participants; OR, 0.45; 95% CI, 0.30–0.68; P<.0001; I2=8%), for the 13 studies included in the adjusted model (n=5,341 participants; OR, 0.42; 95% CI, 0.24–0.72; P=.002; I2=21%), and when using GEE for the adjusted analysis (OR, 0.47; 95% CI, 0.29–0.76; P=.0022) (Figure 2).


Secondary Outcome: Serious Adverse Events


Of the 14 studies reporting on the incidence of SAEs, 318 of 2,556 cases (12.4%) were in the intervention group and 295 of 2,434 cases (12.1%) were in the control group (Table 1). There was no significant difference between groups (OR 1.06; 95% CI, 0.89–1.26; P=.536) (Figure 3). There were no cases of


556 700


565 (19.6) 2 (1–2)


10 (7–14) 15 (10–21) 82 (2.5)


295 (12.1) aValues for antibiotic class and median, IQR for antibiotic exposure were computed based on studies who had these measures available within


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