Trends in U.S. Burden of Clostridioides difficile Infection and Outcomes.

BACKGROUND: Efforts to prevent Clostridioides difficile infection continue to expand across the health care spectrum in the United States. Whether these efforts are reducing the national burden of C. difficile infection is unclear. METHODS: The Emerging Infections Program identified cases of C. difficile infection (stool specimens positive for C. difficile in a person ≥1 year of age with no positive test in the previous 8 weeks) in 10 U.S. sites. We used case and census sampling weights to estimate the national burden of C. difficile infection, first recurrences, hospitalizations, and in-hospital deaths from 2011 through 2017. Health care-associated infections were defined as those with onset in a health care facility or associated with recent admission to a health care facility; all others were classified as community-associated infections. For trend analyses, we used weighted random-intercept models with negative binomial distribution and logistic-regression models to adjust for the higher sensitivity of nucleic acid amplification tests (NAATs) as compared with other test types. RESULTS: The number of cases of C. difficile infection in the 10 U.S. sites was 15,461 in 2011 (10,177 health care-associated and 5284 community-associated cases) and 15,512 in 2017 (7973 health care-associated and 7539 community-associated cases). The estimated national burden of C. difficile infection was 476,400 cases (95% confidence interval [CI], 419,900 to 532,900) in 2011 and 462,100 cases (95% CI, 428,600 to 495,600) in 2017. With accounting for NAAT use, the adjusted estimate of the total burden of C. difficile infection decreased by 24% (95% CI, 6 to 36) from 2011 through 2017; the adjusted estimate of the national burden of health care-associated C. difficile infection decreased by 36% (95% CI, 24 to 54), whereas the adjusted estimate of the national burden of community-associated C. difficile infection was unchanged. The adjusted estimate of the burden of hospitalizations for C. difficile infection decreased by 24% (95% CI, 0 to 48), whereas the adjusted estimates of the burden of first recurrences and in-hospital deaths did not change significantly. CONCLUSIONS: The estimated national burden of C. difficile infection and associated hospitalizations decreased from 2011 through 2017, owing to a decline in health care-associated infections. (Funded by the Centers for Disease Control and Prevention.).

Treatment of Clostridioides difficile Infection and Non-compliance with Treatment Guidelines in Adults in 10 US Geographical Locations, 2013-2015.

BACKGROUND: Infectious Diseases Society of America/Society for Healthcare Epidemiology of America (IDSA/SHEA) guidelines describe recommended therapy for Clostridioides difficile infection (CDI). OBJECTIVE: To describe CDI treatment and, among those with severe CDI, determine predictors of adherence to the 2010 IDSA/SHEA treatment guidelines. DESIGN: We analyzed 2013-2015 CDI treatment data collected through the Centers for Disease Control and Prevention's Emerging Infections Program. Generalized linear mixed models were used to identify predictors of guideline-adherent therapy. PATIENTS: A CDI case was defined as a positive stool specimen in a person aged ≥ 18 years without a positive test in the prior 8 weeks; severe CDI cases were defined as having a white blood cell count ≥ 15,000 cells/µl. MAIN MEASURES: Prescribing and predictors of guideline-adherent CDI therapy for severe disease. KEY RESULTS: Of 18,243 cases, 14,257 (78%) were treated with metronidazole, 7683 (42%) with vancomycin, and 313 (2%) with fidaxomicin. The median duration of therapy was 14 (interquartile range, 11-15) days. Severe CDI was identified in 3250 (18%) cases; of 3121 with treatment data available, 1480 (47%) were prescribed guideline-adherent therapy. Among severe CDI cases, hospital admission (adjusted odds ratio [aOR] 2.48; 95% confidence interval [CI] 1.90, 3.24), age ≥ 65 years (aOR 1.37; 95% CI 1.10, 1.71), Charlson comorbidity index ≥ 3 (aOR 1.27; 95% CI 1.04, 1.55), immunosuppressive therapy (aOR 1.21; 95% CI 1.02, 1.42), and inflammatory bowel disease (aOR 1.56; 95% CI 1.13, 2.17) were associated with being prescribed guideline-adherent therapy. CONCLUSIONS: Provider adherence to the 2010 treatment guidelines for severe CDI was low. Although the updated 2017 CDI guidelines, which expand the use of oral vancomycin for all CDI, might improve adherence by removing the need to apply severity criteria, other efforts to improve adherence are likely needed, including educating providers and addressing barriers to prescribing guideline-adherent therapy, particularly in outpatient settings.

Toxin Enzyme Immunoassays Detect Clostridioides difficile Infection With Greater Severity and Higher Recurrence Rates.

BACKGROUND: Few data suggest that Clostridioides difficile infections (CDIs) detected by toxin enzyme immunoassay (EIA) are more severe and have worse outcomes than those detected by nucleic acid amplification tests (NAATs) only. We compared toxin- positive and NAAT-positive-only CDI across geographically diverse sites. METHODS: A case was defined as a positive C. difficile test in a person ≥1 year old with no positive tests in the prior 8 weeks. Cases were detected during 2014-2015 by a testing algorithm (specimens initially tested by glutamate dehydrogenase and toxin EIA; if discordant results, specimens were reflexed to NAAT) and classified as toxin positive or NAAT positive only. Medical charts were reviewed. Multivariable logistic regression models were used to compare CDI-related complications, recurrence, and 30-day mortality between the 2 groups. RESULTS: Of 4878 cases, 2160 (44.3%) were toxin positive and 2718 (55.7%) were NAAT positive only. More toxin-positive than NAAT-positive-only cases were aged ≥65 years (48.2% vs 38.0%; P < .0001), had ≥3 unformed stools for ≥1 day (43.9% vs 36.6%; P < .0001), and had white blood cell counts ≥15 000 cells/µL (31.4% vs 21.4%; P < .0001). In multivariable analysis, toxin positivity was associated with recurrence (adjusted odds ratio [aOR], 1.89; 95% confidence interval [CI], 1.61-2.23), but not with CDI-related complications (aOR, 0.91; 95% CI, .67-1.23) or 30-day mortality (aOR, 0.95; 95% CI, .73-1.24). CONCLUSIONS: Toxin-positive CDI is more severe, but there were no differences in adjusted CDI-related complication and mortality rates between toxin-positive and NAAT-positive-only CDI that were detected by an algorithm that utilized an initial glutamate dehydrogenase screening test.

Burden of Clostridium difficile infection in the United States.

BACKGROUND: The magnitude and scope of Clostridium difficile infection in the United States continue to evolve. METHODS: In 2011, we performed active population- and laboratory-based surveillance across 10 geographic areas in the United States to identify cases of C. difficile infection (stool specimens positive for C. difficile on either toxin or molecular assay in residents ≥ 1 year of age). Cases were classified as community-associated or health care-associated. In a sample of cases of C. difficile infection, specimens were cultured and isolates underwent molecular typing. We used regression models to calculate estimates of national incidence and total number of infections, first recurrences, and deaths within 30 days after the diagnosis of C. difficile infection. RESULTS: A total of 15,461 cases of C. difficile infection were identified in the 10 geographic areas; 65.8% were health care-associated, but only 24.2% had onset during hospitalization. After adjustment for predictors of disease incidence, the estimated number of incident C. difficile infections in the United States was 453,000 (95% confidence interval [CI], 397,100 to 508,500). The incidence was estimated to be higher among females (rate ratio, 1.26; 95% CI, 1.25 to 1.27), whites (rate ratio, 1.72; 95% CI, 1.56 to 2.0), and persons 65 years of age or older (rate ratio, 8.65; 95% CI, 8.16 to 9.31). The estimated number of first recurrences of C. difficile infection was 83,000 (95% CI, 57,000 to 108,900), and the estimated number of deaths was 29,300 (95% CI, 16,500 to 42,100). The North American pulsed-field gel electrophoresis type 1 (NAP1) strain was more prevalent among health care-associated infections than among community-associated infections (30.7% vs. 18.8%, P<0.001). CONCLUSIONS: C. difficile was responsible for almost half a million infections and was associated with approximately 29,000 deaths in 2011. (Funded by the Centers for Disease Control and Prevention.).

NAP1 strain type predicts outcomes from Clostridium difficile infection.

BACKGROUND: Studies are conflicting regarding the importance of the fluoroquinolone-resistant North American pulsed-field gel electrophoresis type 1 (NAP1) strain in Clostridium difficile infection (CDI) outcome. We describe strain types causing CDI and evaluate their association with patient outcomes. METHODS: CDI cases were identified from population-based surveillance. Multivariate regression models were used to evaluate the associations of strain type with severe disease (ileus, toxic megacolon, or pseudomembranous colitis within 5 days; or white blood cell count ≥15 000 cells/µL within 1 day of positive test), severe outcome (intensive care unit admission after positive test, colectomy for C. difficile infection, or death within 30 days of positive test), and death within 14 days of positive test. RESULTS: Strain typing results were available for 2057 cases. Severe disease occurred in 363 (17.7%) cases, severe outcome in 100 (4.9%), and death within 14 days in 56 (2.7%). The most common strain types were NAP1 (28.4%), NAP4 (10.2%), and NAP11 (9.1%). In unadjusted analysis, NAP1 was associated with greater odds of severe disease than other strains. After controlling for patient risk factors, healthcare exposure, and antibiotic use, NAP1 was associated with severe disease (adjusted odds ratio [AOR], 1.74; 95% confidence interval [CI], 1.36-2.22), severe outcome (AOR, 1.66; 95% CI, 1.09-2.54), and death within 14 days (AOR, 2.12; 95% CI, 1.22-3.68). CONCLUSIONS: NAP1 was the most prevalent strain and a predictor of severe disease, severe outcome, and death. Strategies to reduce NAP1 prevalence, such as antibiotic stewardship to reduce fluoroquinolone use, might reduce CDI morbidity.

Potential underreporting of treated patients using a Clostridioides difficile testing algorithm that screens with a nucleic acid amplification test.

OBJECTIVE: Patients tested for Clostridioides difficile infection (CDI) using a 2-step algorithm with a nucleic acid amplification test (NAAT) followed by toxin assay are not reported to the National Healthcare Safety Network as a laboratory-identified CDI event if they are NAAT positive (+)/toxin negative (-). We compared NAAT+/toxin- and NAAT+/toxin+ patients and identified factors associated with CDI treatment among NAAT+/toxin- patients. DESIGN: Retrospective observational study. SETTING: The study was conducted across 36 laboratories at 5 Emerging Infections Program sites. PATIENTS: We defined a CDI case as a positive test detected by this 2-step algorithm during 2018-2020 in a patient aged ≥1 year with no positive test in the previous 8 weeks. METHODS: We used multivariable logistic regression to compare CDI-related complications and recurrence between NAAT+/toxin- and NAAT+/toxin+ cases. We used a mixed-effects logistic model to identify factors associated with treatment in NAAT+/toxin- cases. RESULTS: Of 1,801 cases, 1,252 were NAAT+/toxin-, and 549 were NAAT+/toxin+. CDI treatment was given to 866 (71.5%) of 1,212 NAAT+/toxin- cases versus 510 (95.9%) of 532 NAAT+/toxin+ cases (P < .0001). NAAT+/toxin- status was protective for recurrence (adjusted odds ratio [aOR], 0.65; 95% CI, 0.55-0.77) but not CDI-related complications (aOR, 1.05; 95% CI, 0.87-1.28). Among NAAT+/toxin- cases, white blood cell count ≥15,000/µL (aOR, 1.87; 95% CI, 1.28-2.74), ≥3 unformed stools for ≥1 day (aOR, 1.90; 95% CI, 1.40-2.59), and diagnosis by a laboratory that provided no or neutral interpretive comments (aOR, 3.23; 95% CI, 2.23-4.68) were predictors of CDI treatment. CONCLUSION: Use of this 2-step algorithm likely results in underreporting of some NAAT+/toxin- cases with clinically relevant CDI. Disease severity and laboratory interpretive comments influence treatment decisions for NAAT+/toxin- cases.

Characteristics of Patients With Initial Clostridioides difficile Infection (CDI) That Are Associated With Increased Risk of Multiple CDI Recurrences.

Background: Because interventions are available to prevent further recurrence in patients with recurrent Clostridioides difficile infection (rCDI), we identified predictors of multiple rCDI (mrCDI) in adults at the time of presentation with initial CDI (iCDI). Methods: iCDI was defined as a positive C difficile test in any clinical setting during January 2018-August 2019 in a person aged ≥18 years with no known prior positive test. rCDI was defined as a positive test ≥14 days from the previous positive test within 180 days after iCDI; mrCDI was defined as ≥2 rCDI. We performed multivariable logistic regression analysis. Results: Of 18 829 patients with iCDI, 882 (4.7%) had mrCDI; 437 with mrCDI and 7484 without mrCDI had full chart reviews. A higher proportion of patients with mrCDI than without mrCDI were aged ≥65 years (57.2% vs 40.7%; P < .0001) and had healthcare (59.1% vs 46.9%; P < .0001) and antibiotic (77.3% vs 67.3%; P < .0001) exposures in the 12 weeks preceding iCDI. In multivariable analysis, age ≥65 years (adjusted odds ratio [aOR], 1.91; 95% confidence interval [CI], 1.55-2.35), chronic hemodialysis (aOR, 2.28; 95% CI, 1.48-3.51), hospitalization (aOR, 1.64; 95% CI, 1.33-2.01), and nitrofurantoin use (aOR, 1.95; 95% CI, 1.18-3.23) in the 12 weeks preceding iCDI were associated with mrCDI. Conclusions: Patients with iCDI who are older, on hemodialysis, or had recent hospitalization or nitrofurantoin use had increased risk of mrCDI and may benefit from early use of adjunctive therapy to prevent mrCDI. If confirmed, these findings could aid in clinical decision making and interventional study designs.

Does doxycycline protect against development of Clostridium difficile infection?

BACKGROUND: Receipt of antibiotics is a major risk factor for Clostridium difficile infection (CDI). Doxycycline has been associated with a lower risk for CDI than other antibiotics. We investigated whether doxycycline protected against development of CDI in hospitalized patients receiving ceftriaxone, a high-risk antibiotic for CDI. METHODS: We studied adults admitted to an academic county hospital between 1 June 2005 and 31 December 2010 who received ceftriaxone to determine whether the additional receipt of doxycycline decreased the risk of CDI. Patients were followed from first administration of ceftriaxone to occurrence of CDI or administrative closure 30 days later. RESULTS: Two thousand three hundred five unique patients comprising 2734 hospitalizations were studied. Overall, 43 patients developed CDI within 30 days of ceftriaxone receipt, an incidence of 5.60 cases per 10 000 patient-days. The incidence of CDI was 1.67 cases per 10 000 patient-days in those receiving doxycycline, compared to 8.11 per 10 000 patient-days in those who did not receive doxycycline. In a multivariable model adjusted for age, gender, race, comorbidities, hospital duration, pneumonia diagnosis, surgical admission, and duration of ceftriaxone and other antibiotics, for each day of doxycycline receipt the rate of CDI was 27% lower than a patient who did not receive doxycycline (hazard ratio, 0.73; 95% confidence interval, .56-.96). CONCLUSIONS: In this cohort of patients receiving ceftriaxone, doxycycline was associated with lower risk of CDI. Guidelines recommend this combination as a second-line regimen for some patients with community-acquired pneumonia (CAP). Further clinical studies would help define whether doxycycline-containing regimens should be a preferred therapy for CAP.

Significant and sustained decrease in non-SARS-CoV-2 respiratory viral infections during COVID-19 public health interventions.

Public health interventions to decrease the spread of SARS-CoV-2 were largely implemented in the United States during spring 2020. This study evaluates the additional effects of these interventions on non-SARS-CoV-2 respiratory viral infections from a single healthcare system in the San Francisco Bay Area. The results of a respiratory pathogen multiplex polymerase chain reaction panel intended for inpatient admissions were analyzed by month between 2019 and 2020. We found major decreases in the proportion and diversity of non-SARS-CoV-2 respiratory viral illnesses in all months following masking and shelter-in-place ordinances. These findings suggest real-world effectiveness of nonpharmaceutical interventions on droplet-transmitted respiratory infections.

Examining the association between hospital-onset Clostridium difficile infection and multiple-bed room exposure: a case-control study.

OBJECTIVE: To determine whether assignment to a multiple-bed room increased the risk of hospital-onset C. difficile diarrhea (HO-CDI). DESIGN: Case-control study. SETTING: San Francisco General Hospital and Trauma Center.PopulationAdult general medical and surgical inpatients. METHODS: Consecutive cases of HO-CDI were identified between January 1, 2010, and December 31, 2015. To investigate the effect of multiple-bed room exposure both at admission and at the time of symptom onset, 2 sets of controls were selected from the general medical/surgical inpatient population using incidence density sampling. Conditional logistic regression was used to estimate the relationship between room assignment (single bed vs multiple beds) and the development of HO-CDI. RESULTS: In total, 187 cases were identified and matched with 512 and 515 controls for the admission and at-diagnosis analyses, respectively. The adjusted rate ratio (RR) associated with the development HO-CDI associated with multiple-bed room exposure during the 7 and 14 days immediately prior to HO-CDI diagnosis were 1.08 (95% confidence interval [CI], 0.93-1.25; P=.31) and 0.96 (95% CI, 0.93-1.18; P=.12), respectively. Furthermore, no significant association was detected in the analysis of the first 7 and 14 days after case admission or among patients with Charlson comorbidity scores ≥4 in either period. CONCLUSION: Assignment of patients to multiple-bed rooms on general medical and surgical wards was not associated with an increased risk in the development of HO-CDI. Future investigation should be performed with larger cohorts in multiple sites to more definitively address the question because this issue could have implications for patient room assignment and hospital design.

Trends in incidence of long-term-care facility onset Clostridium difficile infections in 10 US geographic locations during 2011-2015.

During 2011-2015, the adjusted long-term-care facility onset Clostridium difficile infection incidence rate in persons aged ≥65 years decreased annually by 17.45% (95% confidence interval, 14.53%-20.43%) across 10 US sites. A concomitant decline in inpatient fluoroquinolone use and the C difficile epidemic strain NAP1/027 among persons aged ≥65 years may have contributed to the decrease in long-term-care facility-onset C difficile infection incidence rate.

Risk Factors for Community-Associated Clostridium difficile Infection in Adults: A Case-Control Study.

BACKGROUND: An increasing proportion of Clostridium difficile infections (CDI) in the United States are community-associated (CA). We conducted a case-control study to identify CA-CDI risk factors. METHODS: We enrolled participants from 10 US sites during October 2014-March 2015. Case patients were defined as persons age ≥18 years with a positive C. difficile specimen collected as an outpatient or within 3 days of hospitalization who had no admission to a health care facility in the prior 12 weeks and no prior CDI diagnosis. Each case patient was matched to one control (persons without CDI). Participants were interviewed about relevant exposures; multivariate conditional logistic regression was performed. RESULTS: Of 226 pairs, 70.4% were female and 52.2% were ≥60 years old. More case patients than controls had prior outpatient health care (82.1% vs 57.9%; P < .0001) and antibiotic (62.2% vs 10.3%; P < .0001) exposures. In multivariate analysis, antibiotic exposure-that is, cephalosporin (adjusted matched odds ratio [AmOR], 19.02; 95% CI, 1.13-321.39), clindamycin (AmOR, 35.31; 95% CI, 4.01-311.14), fluoroquinolone (AmOR, 30.71; 95% CI, 2.77-340.05) and beta-lactam and/or beta-lactamase inhibitor combination (AmOR, 9.87; 95% CI, 2.76-340.05),-emergency department visit (AmOR, 17.37; 95% CI, 1.99-151.22), white race (AmOR 7.67; 95% CI, 2.34-25.20), cardiac disease (AmOR, 4.87; 95% CI, 1.20-19.80), chronic kidney disease (AmOR, 12.12; 95% CI, 1.24-118.89), and inflammatory bowel disease (AmOR, 5.13; 95% CI, 1.27-20.79) were associated with CA-CDI. CONCLUSIONS: Antibiotics remain an important risk factor for CA-CDI, underscoring the importance of appropriate outpatient prescribing. Emergency departments might be an environmental source of CDI; further investigation of their contribution to CDI transmission is needed.

Preoperative use of mupirocin for the prevention of healthcare-associated Staphylococcus aureus infections: a cost-effectiveness analysis.

OBJECTIVE: Staphylococcus aureus is the most common cause of healthcare-associated infections. Intranasal mupirocin treatment probably decreases S. aureus infections among colonized surgical patients. Using cost-effectiveness analysis, we evaluated the cost-effectiveness of preoperative use of mupirocin for the prevention of healthcare-associated S. aureus infections. METHODS: Three strategies were compared: (1) screen with nasal culture and give treatment to carriers, (2) give treatment to all patients without screening, and (3) neither screen nor treat. A societal perspective was taken. Adverse outcomes included bloodstream infection, pneumonia, surgical site infection, death due to underlying illness or infection, readmission, and the need for home health care. Data inputs were obtained from an extensive MEDLINE review and from publicly available government data sources. The following base-case data inputs (and ranges) for sensitivity analysis were used: rate of S. aureus carriage, 23.1% (19%-55%); efficacy of mupirocin treatment, 51% (8%-75%); mupirocin treatment cost, 48.36 US Dollars (24.18-57.74 US Dollars); and hospital costs of bloodstream infection, 25,128 US Dollars (6,194-40,211 US Dollars), pneumonia, 18,366 US Dollars (5,574-28,952 US Dollars), and surgical site infection 16,256 US Dollars (5,119-22,553 US Dollars). Widespread use of mupirocin has been associated with high levels of mupirocin resistance; therefore, a broad range of estimates for efficacy was tested in the sensitivity analysis. PATIENTS: The target population included patients undergoing nonemergent surgery requiring postoperative hospitalization. RESULTS: Both the screen-and-treat and treat-all strategies were cost saving, saving 102 US Dollars per patient screened and 88 US Dollars per patient treated, respectively. In 1-way sensitivity analyses, the model was robust with respect to all data inputs except for the efficacy of mupirocin treatment. If the efficacy is less than 16.1%, then the screen-and-treat strategy is cost incurring. A treat-all strategy was more cost saving if the rate of S. aureus carriage was greater than 42.7%, the mupirocin cost was less than 29.87 US Dollars, or nursing compensation was greater than 64.21 US Dollars per hour. CONCLUSION: Administration of mupirocin before surgery is cost saving, primarily because healthcare-associated infections are very expensive. The level of mupirocin efficacy is critical to the cost-effectiveness of this intervention.

Burden of Nursing Home-Onset Clostridium difficile Infection in the United States: Estimates of Incidence and Patient Outcomes.

Background. Approximately 4 million Americans receive nursing home (NH) care annually. Nursing home residents commonly have risk factors for Clostridium difficile infection (CDI), including advanced age and antibiotic exposures. We estimated national incidence of NH-onset (NHO) CDI and patient outcomes. Methods. We identified NHO-CDI cases from population-based surveillance of 10 geographic areas in the United States. Cases were defined by C difficile-positive stool collected in an NH (or from NH residents in outpatient settings or ≤3 days after hospital admission) without a positive stool in the prior 8 weeks. Medical records were reviewed on a sample of cases. Incidence was estimated using regression models accounting for age and laboratory testing method; sampling weights were applied to estimate hospitalizations, recurrences, and deaths. Results. A total of 3503 NHO-CDI cases were identified. Among 262 sampled cases, median age was 82 years, 76% received antibiotics in the 12 weeks prior to the C difficile-positive specimen, and 57% were discharged from a hospital in the month before specimen collection. After adjusting for age and testing method, the 2012 national estimate for NHO-CDI incidence was 112 800 cases (95% confidence interval [CI], 93 400-131 800); 31 400 (28%) were hospitalized within 7 days after a positive specimen (95% CI, 25 500-37 300), 20 900 (19%) recurred within 14-60 days (95% CI, 14 600-27 100), and 8700 (8%) died within 30 days (95% CI, 6600-10 700). Conclusions. Nursing home onset CDI is associated with substantial morbidity and mortality. Strategies focused on infection prevention in NHs and appropriate antibiotic use in both NHs and acute care settings may decrease the burden of NHO CDI.

Association Between Outpatient Antibiotic Prescribing Practices and Community-Associated Clostridium difficile Infection.

Background. Antibiotic use predisposes patients to Clostridium difficile infections (CDI), and approximately 32% of these infections are community-associated (CA) CDI. The population-level impact of antibiotic use on adult CA-CDI rates is not well described. Methods. We used 2011 active population- and laboratory-based surveillance data from 9 US geographic locations to identify adult CA-CDI cases, defined as C difficile-positive stool specimens (by toxin or molecular assay) collected from outpatients or from patients ≤3 days after hospital admission. All patients were surveillance area residents and aged ≥20 years with no positive test ≤8 weeks prior and no overnight stay in a healthcare facility ≤12 weeks prior. Outpatient oral antibiotic prescriptions dispensed in 2010 were obtained from the IMS Health Xponent database. Regression models examined the association between outpatient antibiotic prescribing and adult CA-CDI rates. Methods. Healthcare providers prescribed 5.2 million courses of antibiotics among adults in the surveillance population in 2010, for an average of 0.73 per person. Across surveillance sites, antibiotic prescription rates (0.50-0.88 prescriptions per capita) and unadjusted CA-CDI rates (40.7-139.3 cases per 100 000 persons) varied. In regression modeling, reducing antibiotic prescribing rates by 10% among persons ≥20 years old was associated with a 17% (95% confidence interval, 6.0%-26.3%; P = .032) decrease in CA-CDI rates after adjusting for age, gender, race, and type of diagnostic assay. Reductions in prescribing penicillins and amoxicillin/clavulanic acid were associated with the greatest decreases in CA-CDI rates. Conclusions and Relevance. Community-associated CDI prevention should include reducing unnecessary outpatient antibiotic use. A modest reduction of 10% in outpatient antibiotic prescribing can have a disproportionate impact on reducing CA-CDI rates.