A Pharmacovigilance Study Regarding the Risk of Antibiotic-Associated Clostridioides difficile Infection Based on Reports from the EudraVigilance Database: Analysis of Some of the Most Used Antibiotics in Intensive Care Units

Abstract

The Gram-positive anaerobic bacterium Clostridioides difficile (CD) can produce intense exotoxins, contributing to nosocomial infections, and it is the most common cause of health-care-associated infectious diarrhea. Based on spontaneous Individual Case Safety Reports from EudraVigilance (EV), we conducted a descriptive analysis of Clostridioides difficile infection (CDI) cases that reported a spontaneous adverse reaction related to using ceftriaxone, colistimethate, ciprofloxacin, gentamicin, linezolid, meropenem, and piperacillin/tazobactam. Most ADR reports registered in EV that were related to CDI were associated with ceftriaxone (33%), ciprofloxacin (28%), and piperacillin/tazobactam (21%). Additionally, the disproportionality analysis performed showed that all studied antibiotics had a lower reporting probability when compared to clindamycin. A causal relationship between a drug and the occurrence of an adverse reaction cannot be established from EV data alone because the phenomena of underreporting, overreporting, and reporting bias may affect the results. Based on the analysis of the collected data, this study underlines the importance of surveillance and monitoring programs for the consumption of antibiotics. Furthermore, it is essential to use standardized laboratory tests to define CDI's nature accurately. To prevent this infection, specialists should collaborate and adhere strictly to antibiotic stewardship programs, hygiene practices, and isolation protocols.

Keywords: Clostridioides difficile infection; EudraVigilance; antibiotic; descriptive analysis; disproportionality analysis; pharmacovigilance.

Figure 1

Total ADRs related to Clostridioides difficile infection reported in EV. CFT—ceftriaxone; COL—colistimethate; CPX—ciprofloxacin; GEN—gentamicin; LIN—linezolid; MER—meropenem; PIP/TAZ—piperacillin and tazobactam.

Figure 2

Total ADRs related to Clostridioides difficile infection. CFT—ceftriaxone; COL—colistimethate; CPX—ciprofloxacin; GEN—gentamicin; LIN—linezolid; MER—meropenem; PIP/TAZ—piperacillin and tazobactam.

Figure 3

Proportion of CDI reports from total ICSRs for each antibiotic. CFT—ceftriaxone; COL—colistimethate; CPX—ciprofloxacin; GEN—gentamicin; LIN—linezolid; MER—meropenem; PIP/TAZ—piperacillin and tazobactam.

Figure 4

Evolution of reports related to Clostridioides difficile infection in EV between 1 January 2003 and 31 December 2022. CFT—ceftriaxone; COL—colistimethate; CPX—ciprofloxacin; GEN—gentamicin; LIN—linezolid; MER—meropenem; PIP/TAZ—piperacillin and tazobactam.

Figure 5

Distribution of CDI-related reports by outcome. CFT—ceftriaxone; COL—colistimethate; CPX—ciprofloxacin; GEN—gentamicin; LIN—linezolid; MER—meropenem; PIP/TAZ—piperacillin and tazobactam.

Figure 6

Disproportionality analysis for ADRs related to Clostridioides difficile infection. (a) Ceftriaxone; (b) colistimethate; (c) ciprofloxacin; (d) gentamicin; (e) linezolid; (f) meropenem; (g) piperacillin and tazobactam. AMI—amikacin; CEF—ceftazidime; CLI—clindamycin; CFT—ceftriaxone; COL—colistimethate; CPX—ciprofloxacin; GEN—gentamicin; IMI—imipenem/cilastatin; LEV—levofloxacin; LIN—linezolid; MER—meropenem; PIP/TAZ—piperacillin and tazobactam. * p <0.05; ** p ≤ 0.01; *** p ≤ 0.001; **** p ≤ 0.0001.

Figure 6

Disproportionality analysis for ADRs related to Clostridioides difficile infection. (a) Ceftriaxone; (b) colistimethate; (c) ciprofloxacin; (d) gentamicin; (e) linezolid; (f) meropenem; (g) piperacillin and tazobactam. AMI—amikacin; CEF—ceftazidime; CLI—clindamycin; CFT—ceftriaxone; COL—colistimethate; CPX—ciprofloxacin; GEN—gentamicin; IMI—imipenem/cilastatin; LEV—levofloxacin; LIN—linezolid; MER—meropenem; PIP/TAZ—piperacillin and tazobactam. * p <0.05; ** p ≤ 0.01; *** p ≤ 0.001; **** p ≤ 0.0001.

Figure 6

Disproportionality analysis for ADRs related to Clostridioides difficile infection. (a) Ceftriaxone; (b) colistimethate; (c) ciprofloxacin; (d) gentamicin; (e) linezolid; (f) meropenem; (g) piperacillin and tazobactam. AMI—amikacin; CEF—ceftazidime; CLI—clindamycin; CFT—ceftriaxone; COL—colistimethate; CPX—ciprofloxacin; GEN—gentamicin; IMI—imipenem/cilastatin; LEV—levofloxacin; LIN—linezolid; MER—meropenem; PIP/TAZ—piperacillin and tazobactam. * p <0.05; ** p ≤ 0.01; *** p ≤ 0.001; **** p ≤ 0.0001.