Feasibility of Core Antimicrobial Stewardship Interventions in Community Hospitals.

Importance: The feasibility of core Infectious Diseases Society of America-recommended antimicrobial stewardship interventions in community hospitals is unknown. Objective: To determine the feasibility and results of implementing 2 core stewardship intervention strategies in community hospitals. Design, Setting, and Participants: Three-stage, multicenter, prospective nonrandomized clinical trial with crossover design. The setting was 4 community hospitals in North Carolina (median bed size, 305; range, 102-425). Participants were all patients receiving targeted study antibacterial agents or alternative, nonstudy antibacterial agents. The study dates were October 2014 through October 2015. All statistical analyses were completed as of October 2016. Interventions: Two antimicrobial stewardship strategies targeted vancomycin hydrochloride, piperacillin-tazobactam, and the antipseudomonal carbapenems on formulary at the study hospitals: (1) modified preauthorization (PA), in which the prescriber had to receive pharmacist approval for continued use of the antibiotic after the first dose, and (2) postprescription audit and review (PPR), in which the pharmacist would engage the prescriber about antibiotic appropriateness after 72 hours of therapy. Two hospitals performed modified PA for 6 months, then PPR for 6 months after a 1-month washout. The other 2 hospitals performed the reverse. Main Outcomes and Measures: The primary outcome was the feasibility of implementing the interventions, determined by (1) approval by hospital administration and committees at each study hospital; (2) completion of pharmacist training; (3) initiation and implementation as determined by number, type, and outcomes of interventions performed; and (4) time required for interventions. Secondary outcomes included antimicrobial use (days of therapy) compared with matched historical periods and length of hospitalization. Results: A total of 2692 patients (median age, 65 years; interquartile range, 53-76 years) underwent a study intervention; 1413 (52.5%) were female, 1323 (49.1%) were white, and 1047 (38.9%) were African American. Intervention approvals took a median of 95 days (range, 56-119 days); during these discussions, strict PA was deemed not feasible. Instead, the modified PA intervention was used throughout the study. Pharmacists performed 1456 modified PA interventions (median per hospital, 350 [range, 129-628]) and 1236 PPR interventions (median per hospital, 298 [range, 273-366]). Study antimicrobials were determined to be inappropriate 2 times as often during the PPR period (41.0% [435 of 1060] vs 20.4% [253 of 1243]; P < .001). Pharmacists recommended dose change more often during the modified PA intervention (15.9% [232 of 1456] vs 9.6% [119 of 1236]; P < .001) and de-escalation during PPR (29.1% [360 of 1236] vs 13.0% [190 of 1456]; P < .001). The median time dedicated to the stewardship interventions varied by hospital (range of median hours per week, 5-19). Overall antibiotic use decreased during PPR compared with historical controls (mean [SD] days of therapy per 1000 patient-days, 925.2 [109.8] vs 965.3 [109.4]; mean difference, -40.1; 95% CI, -71.7 to -8.6), but not during modified PA (mean [SD] days of therapy per 1000 patient-days, 931.0 [102.0] vs 926.6 [89.7]; mean difference, 4.4; 95% CI, -55.8 to 64.7). Conclusions and Relevance: Strict PA was not feasible in the study hospitals. In contrast, PPR was a feasible and effective strategy for antimicrobial stewardship in settings with limited resources and expertise. Trial Registration: ClinicalTrials.gov identifier: NCT02212808.

Identification of novel risk factors for community-acquired Clostridium difficile infection using spatial statistics and geographic information system analyses.

BACKGROUND: The rate of community-acquired Clostridium difficile infection (CA-CDI) is increasing. While receipt of antibiotics remains an important risk factor for CDI, studies related to acquisition of C. difficile outside of hospitals are lacking. As a result, risk factors for exposure to C. difficile in community settings have been inadequately studied. MAIN OBJECTIVE: To identify novel environmental risk factors for CA-CDI. METHODS: We performed a population-based retrospective cohort study of patients with CA-CDI from 1/1/2007 through 12/31/2014 in a 10-county area in central North Carolina. 360 Census Tracts in these 10 counties were used as the demographic Geographic Information System (GIS) base-map. Longitude and latitude (X, Y) coordinates were generated from patient home addresses and overlaid to Census Tracts polygons using ArcGIS; ArcView was used to assess "hot-spots" or clusters of CA-CDI. We then constructed a mixed hierarchical model to identify environmental variables independently associated with increased rates of CA-CDI. RESULTS: A total of 1,895 unique patients met our criteria for CA-CDI. The mean patient age was 54.5 years; 62% were female and 70% were Caucasian. 402 (21%) patient addresses were located in "hot spots" or clusters of CA-CDI (p<0.001). "Hot spot" census tracts were scattered throughout the 10 counties. After adjusting for clustering and population density, age ≥ 60 years (p = 0.03), race (<0.001), proximity to a livestock farm (0.01), proximity to farming raw materials services (0.02), and proximity to a nursing home (0.04) were independently associated with increased rates of CA-CDI. CONCLUSIONS: Our study is the first to use spatial statistics and mixed models to identify important environmental risk factors for acquisition of C. difficile and adds to the growing evidence that farm practices may put patients at risk for important drug-resistant infections.

Genetic screen of African Americans with Fuchs endothelial corneal dystrophy.

PURPOSE: Fuchs endothelial corneal dystrophy (FECD) is a genetically heterogeneous disorder that has been primarily studied in patients of European or Asian ancestry. Given the sparse literature on African Americans with FECD, we sought to characterize the genetic variation in three known FECD candidate genes in African American patients with FECD. METHODS: Over an 8-year period, we enrolled 47 African American probands with FECD. All participants were clinically examined with slit-lamp biomicroscopy, and when corneal tissue specimens were available, histopathologic confirmation of the clinical diagnosis was obtained. The coding regions of known FECD susceptibility genes collagen, type VIII, alpha 2 (COL8A2); solute carrier family 4, sodium borate transporter, member 11 (SLC4A11); and zinc finger E-box binding homeobox 1 (ZEB1 [also known as TCF8]) were Sanger sequenced in the 47 probands using DNA isolated from blood samples. RESULTS: Twenty-two coding variants were detected across the COL8A2, SLC4A11, and ZEB1 genes; six were nonsynonymous variants. Three novel coding variants were detected: a synonymous variant each in COL8A2 and SLC4A11 and one nonsynonymous variant in ZEB1 (p.P559S), which is predicted to be benign and tolerated, thus making its physiologic consequence uncertain. CONCLUSIONS: Variation in the COL8A2, SLC4A11, and ZEB1 genes is present in only a small fraction of our African American cases and as such does not appear to significantly contribute to the genetic risk of FECD in African Americans. This observation is on par with findings from previous sequencing studies involving European or Asian ancestry patients with FECD.

Polymorphic variants in tenascin-C (TNC) are associated with atherosclerosis and coronary artery disease.

Tenascin-C (TNC) is an extracellular matrix protein implicated in biological processes important for atherosclerotic plaque development and progression, including smooth muscle cell migration and proliferation. Previously, we observed differential expression of TNC in atherosclerotic aortas compared with healthy aortas. The goal of this study was to investigate whether common genetic variation within TNC is associated with risk of atherosclerosis and coronary artery disease (CAD) in three independent datasets. We genotyped 35 single nucleotide polymorphisms (SNPs), including 21 haplotype tagging SNPs, in two of these datasets: human aorta tissue samples (n = 205) and the CATHGEN cardiovascular study (n = 1,325). Eleven of these 35 SNPs were then genotyped in a third dataset, the GENECARD family study of early-onset CAD (n = 879 families). Three SNPs representing a block of linkage disequilibrium, rs3789875, rs12347433, and rs4552883, were significantly associated with atherosclerosis in multiple datasets and demonstrated consistent, but suggestive, genetic effects in all analyses. In combined analysis rs3789875 and rs12347433 were statistically significant after Bonferroni correction for 35 comparisons, p = 2 × 10(-6) and 5 × 10(-6), respectively. The SNP rs12347433 is a synonymous coding SNP and may be biologically relevant to the mechanism by which tenascin-C influences the pathophysiology of CAD and atherosclerosis. This is the first report of genetic association between polymorphisms in TNC and atherosclerosis or CAD.