title: Cumulative antibiotic exposures over time and the risk of Clostridium difficile infection.
abstract: BACKGROUND
  Clostridium difficile infection (CDI) is a major cause of hospital-acquired diarrhea and is most commonly associated with changes in normal intestinal flora caused by administration of antibiotics. Few studies have examined the risk of CDI associated with total dose, duration, or number of antibiotics while taking into account the complex changes in exposures over time.
  
  
  METHODS
  A retrospective cohort study conducted from 1 January to 31 December 2005 among hospitalized patients 18 years or older receiving 2 or more days of antibiotics.
  
  
  RESULTS
  The study identified 10,154 hospitalizations for 7,792 unique patients and 241 cases of CDI, defined as the detection of C. difficile toxin in a diarrheal stool sample within 60 days of discharge. We observed dose-dependent increases in the risk of CDI associated with increasing cumulative dose, number of antibiotics, and days of antibiotic exposure. Compared to patients who received only 1 antibiotic, the adjusted hazard ratios (HRs) for those who received 2, 3 or 4, or 5 or more antibiotics were 2.5 (95% confidence interval [CI] 1.6-4.0), 3.3 (CI 2.2-5.2), and 9.6 (CI 6.1-15.1), respectively. The receipt of fluoroquinolones was associated with an increased risk of CDI, while metronidazole was associated with reduced risk.
  
  
  CONCLUSIONS
  Cumulative antibiotic exposures appear to be associated with the risk of CDI. Antimicrobial stewardship programs that focus on the overall reduction of total dose as well as number and days of antibiotic exposure and the substitution of high-risk antibiotic classes for lower-risk alternatives may reduce the incidence of hospital-acquired CDI.
authors.affiliation: Center for Health Outcomes, Pharmacoinformatics, and Epidemiology, Department of Pharmacy Practice, School of Pharmacy and Pharmaceutical Sciences, State University of New York at Buffalo, Buffalo, New York 14260, USA. vstevens@buffalo.edu
authors.forename: Vanessa
authors.initials: V
authors.lastname: Stevens
authors.forename: Ghinwa
authors.initials: G
authors.lastname: Dumyati
authors.forename: Lynn S
authors.initials: LS
authors.lastname: Fine
authors.forename: Susan G
authors.initials: SG
authors.lastname: Fisher
authors.forename: Edwin
authors.initials: E
authors.lastname: van Wijngaarden
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000009:adverse effects; D016360:Clostridioides difficile; D003428:Cross Infection / Q000453:epidemiology* / Q000382:microbiology; D004761:Enterocolitis, Pseudomembranous / Q000453:epidemiology* / Q000382:microbiology; D005260:Female; D024841:Fluoroquinolones / Q000008:administration & dosage; D006801:Humans; D008297:Male; D008795:Metronidazole / Q000008:administration & dosage; D008875:Middle Aged; D015999:Multivariate Analysis; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D012307:Risk Factors
chemical_list: D000900:Anti-Bacterial Agents; D024841:Fluoroquinolones; D008795:Metronidazole