probiotics to prevent c. difficile infection 767
have been hospitalized for at least 4 days and exposed to a course of at least 1 antibiotic on the list of high-risk antibiotics received by at least 1 case patient. We recorded data on age, sex, race–ethnicity, daily exposure to probiotic and antibiotics, timing of initial probiotic relative to initial antibiotic dose, presence of tube feeding, comorbidities, prior hospitalizations at the same facility, preadmission location (eg, home, hospital, long-term care facility), use of a proton pump inhibitor, and severity of illness and risk of mortality (range, 1–4 for each score) recorded at discharge.We inputted these data into proprietary software embedded in the electronic medical record (3M Health Information Systems, St Paul, MN).19,20 We defined per-protocol probiotic administration in the following 2 ways: (1) complete adherence to protocol (ie, on-time administration and no missed days) and (2) on- time administration of the first dose and receipt of ≥80% of inpatient doses.21 We did not monitor postdischarge probiotic receipt. We collected daily administration of probiotic and antibiotics.
Statistical Analysis
We compared cases to controls using the 2-sample t test and the McNemar χ2 test. To evaluate the protective effect of the probiotic mixture adjusting for exposure time, we performed survival analyses.We censored controls at the same duration of time from initial antibiotic exposure to when their corre- sponding case patient developed CDI, so the at-risk periods were similar. We constructed Cox proportional hazards regression models for time-varying covariates, inclusive of interaction terms. We constructed conditional logistic regression models with the dependent variable as case status (yes/no). In conditional logistic regression models, we summed probiotic and antibiotic exposure days and modeled cumulative exposure for each patient.
results Observational Study
For eligible hospital units, there were 177,184 patient days during the baseline period and 182,832 patient days during the intervention period. More C. difficile assays were performed in the baseline than in the intervention period: 210 versus 186 per 10,000 patient days (P<.001). However, the percentage of tests positive for C. difficile (ie, number of tests positive per number of tests performed×100) was similar during the baseline period (19%) and the intervention period (20%). The CDI incidence was similar in the baseline and intervention periods: 6.9 versus 7.0 per 10,000 patient days (P=.95). When we compared baseline and intervention periods by regression analysis, the decreasing incidence observed during the inter- vention was not significantly different from the baseline (Figure 1). We observed a decreased incidence of CDI during the second half of the intervention period (months 7–12)
figure 1. Comparison of CDI rates between the baseline and intervention periods. Antibiotic recipients in the intervention period were to receive probiotic. aShort-dash lines represents the fitted slope from the regression models; long-dash lines represent the mean values. Statistical tests: level change, baseline to intervention (P=.29); slope change, baseline to intervention (P=.22); incidence difference, baseline to last 6 months of the intervention (IRR, 0.8; 95% CI, 0.5–1.1; P=.13); incidence difference, first to last 6 months of the intervention (IRR, 0.6; 95% CI, 0.4–0.9; P=.009).
compared to the first half of the intervention period: 5.4 versus 8.6 per 10,000 patient days (IRR, 0.6; 95% CI, 0.4–0.9; P=.009). When compared to the baseline, we detected a trend toward a lower incidence in the second 6 months of the intervention that did not reach statistical significance (IRR, 0.8; 95% CI, 0.5–1.1; P=.13) (Figure 1). We observed a nonsignificant decrease in community-onset cases during the project period. However, adjustment for this decline in the regression models did not appreciably change our results.
Case-Control Study
When we reviewed the medical records of patients who developed CDI during the intervention period (N=128), slightly more than half (68, 53%) were included in the case- control study. Potential case patients were excluded for the following reasons: no in-hospital antibiotic receipt (21, 16%); preoperative antibiotic prophylaxis (16, 12%); clinically ineli- gible (11, 9%); CDI within 24 hours of antibiotic receipt (6, 5%); receiving antibiotics before hospitalization (3, 2%); unable to match to a control patient (2, 2%); and unavailable medical record for 1 patient. Among the 136 patients (68 matched pairs) in the case-control study, 35 (26%) received the probiotic according to the protocol (ie, dosed on time and every eligible day); 36 (26%) received no probiotic; 29 (21%) received their first
dose late; 25 (18%) missed doses; and, 11 (8%) received their first dose late and missed doses. Using 80% of doses received as the threshold for per-protocol dosing, 48 (35%) received the probiotic intervention per protocol. Among the 103 patients for whom the dosage form was recorded, most received
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