Study Details Risk of C Diff with Clindamycin, Other Antibiotics


Results from the study found a high risk of CDI associated with clindamycin and low risk associated with doxycycline and minocycline, also highlighting variation in CDI risk within and between classes of antibiotics.

Philip Polgreen, MD, MPH | Credit: Carver College of Medicine

Philip Polgreen, MD, MPH

Credit: Carver College of Medicine

A matched-case control study of patients with and without Clostridioides difficile infection (CDI) evaluated CDI risk associated with exposure to 27 different kinds of antibiotics, with results suggesting varied risk across antibiotic types, classes, and exposure windows.1

Results of the study, which included more than 150,000 patients with CDI, suggest the greatest risk for CDI was observed with use of clindamycin while the lowest risk was observed with doxycycline and minocycline.1

“Almost all antibiotics have been associated with an increased risk of developing CDI. However, some antibiotics impart more risk than others,” wrote investigators.1 “Most studies comparing CDI risks for different antibiotics have been underpowered to differentiate levels of risk between individual antibiotics.”

The US Centers for Disease Control and Prevention notes most cases of CDI occur while taking antibiotics or shortly after treatment is discontinued. People are 7-10 times more likely to get CDI while on antibiotics and during the month after, and it’s estimated to cause almost 500,000 infections in the US each year.2

A team of investigators led by Philip Polgreen, MD, MPH, of the University of Iowa Carver College of Medicine, sought to evaluate CDI risk across individual antibiotic types to better inform antibiotic prescribing. Using the Merative MarketScan Research Databases, investigators collected insurance claim data about health care encounters and medications to identify case patients diagnosed with CA-CDI.1

Investigators randomly matched each CDI case to 5 enrollees without CDI of the same age, sex, insurance type, and covering the same enrollment period before diagnosis. Patient age, sex, date of diagnosis, and insurance type were all accounted for in the study design during the matching process. In total, investigators identified 159,404 cases and 797,020 controls.1

The 5 most commonly prescribed antibiotics among cases were clindamycin, amoxicillin/clavulanate, ciprofloxacin, cephalexin, and cefdinir. For control patients, the most common antibiotics were amoxicillin, azithromycin, amoxicillin/clavulanate, ciprofloxacin, and cephalexin.1

Investigators used a conditional logistic regression model to estimate the likelihood of having CA-CDI as a function of antibiotic exposure and other patient risk factors, focusing on 27 individual antibiotic types with over 50 case and control observations.1

The greatest risk for CDI was observed for clindamycin (25.39; 95% Confidence Interval [CI], 24.11–26.72) and later-generation cephalosporins of cefixime, cefdinir, cefuroxime, and cefpodoxime along with the penicillin amoxicillin/clavulanate, which had odds ratios ranging from 8.53 to 12.04. Doxycycline (0.96; 95% CI, 0.89-1.02) and minocycline (0.79; 95% CI, 0.67–0.93) had the lowest observed risk for CDI.1

Investigators found notable variation in CDI risk within and between classes of antibiotics. Amoxicillin/clavulanate had a risk level similar to later-generation cephalosporins at 8.53 (95% CI, 8.23–8.85), which was more than 4 times the associated risk level of amoxicillin without clavulanate (1.96; 95% CI, 1.88–2.04). Ciprofloxacin had a risk level closer to later-generation cephalosporins (6.83; 95% CI, 6.56–7.10), while levofloxacin had a risk level similar to first-generation cephalosporins (2.49; 95% CI, 2.35–2.64). Cefeximine (12.04; 95% CI, 8.84–16.38) had more than 4 times the risk level of cefadroxil (2.84; 95% CI, 2.27–3.54).1

Of note, risk estimates for most antibiotics varied by a large degree when different exposure windows were considered. When investigators compared the 30-day and 90-day exposure windows, clindamycin went from an odds ratio of 25.39 (95% CI, 24.11–26.72) to 17.19 (95% CI, 16.58–17.81), cefixime went from 12.04 (95% CI, 8.84–16.38) to 5.01 (95% CI, 4.03–6.22), and amoxicillin/clavulanate went from 8.53 (95% CI, 8.23–8.85) to 5.06 (95% CI, 4.92–5.20).1

“These findings not only help inform strategies to reduce risk for CDI based on prescribing, but also help inform CDI risk modeling in general. Future risk estimates will need to carefully control for exposure windows when making comparisons across antibiotics. Future work should also examine the risk for CDI recurrence,” concluded investigators.1


  1. Miller AC, Arakkal AT, Sewell DK, et al. Comparison of Different Antibiotics and the Risk for Community-Associated Clostridioides difficile Infection: A Case-Control Study. Open Forum Infect Dis. 2023;10(8):ofad413. Published 2023 Aug 5. doi:10.1093/ofid/ofad413
  2. Centers for Disease Control and Prevention. What is C. diff? C. diff (Clostridioides difficile). Accessed August 31, 2023.
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