The risk for opportunistic infection of Clostridioides difficile following antibiotic treatment of an unrelated condition can vary between antibiotics within the same class, according to a study that draws on both randomized controlled trials and national adverse event reports.1
"Previous studies have relied on aggregated antibiotic categories, leaving prescribers without detailed comparative risk information for individual antibiotics," the investigators relate.
Yangxi Liu, lead author and PhD student, Department of Pharmacy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China and colleagues integrated two methodologies to rank risk of C difficile infection (CDI) associated with individual and class of antibiotics.
A network meta-analysis (NMA) was used to analyze data from 61 randomized controlled trials (RCTs) conducted between January 1, 1990 to April 30, 2023, comprising almost 26,000 patients. In addition, to enrich the findings with "real-world" occurrences, the investigators conducted a disproportionality analysis of Food and Drug Adverse Event Reporting System (FAERS) reports from January 1, 2004 to June 30, 2023.
"The RCTs provided a robust baseline for comparing relative CDI risk among antibiotics, while the FAERS data allowed us to capture a broader range of outcomes, particularly those that might not be sufficiently powered in RCTs alone," Liu explained in discussing the study with Contagion.
"The FAERS data often reflects more diverse patient populations and usage scenarios, helping to validate the RCT findings and demonstrate that the results are not only statistically significant but also clinically relevant," he commented.
What You Need to Know
The study found that the risk of Clostridioides difficile infection (CDI) varies significantly between different antibiotics, even within the same class. For example, cefepime and imipenem/cilastatin were associated with a higher frequency of CDI compared to piperacillin/tazobactam.
The investigators used both network meta-analysis (NMA) of randomized controlled trials (RCTs) and disproportionality analysis of real-world FAERS data to assess CDI risk.
The study highlighted that oral third-generation cephalosporins, such as cefdinir, exhibit a higher risk for CDI, likely due to their impact on gut microbiota.
"However, it is important to note that FAERS data do not prove a causal link between antibiotics and CDI, only that both were observed," Liu noted. "Therefore, ORs (Odds Ratios) calculated from RCTs were essential in confirming the findings from FAERS."
Among the findings reported by Liu and colleagues was that exposure to cefepime and to imipenem/cilastin exhibited higher frequencies of CDI compared to piperacillin/tazobactam (OR 2.56, 95%CI 1.20-5.44 and OR 3.86, 1.61-9.29, respectively).Although there were no statistically significant differences between carbapenems, a trend indicated heightened CDI incidence of imipenem/cilastatin compared to meropenem (OR 3.89, 0.94-16.09).
In contrast to some previous studies, the investigators found a relatively low CDI risk associated with certain ß-lactamase inhibitors, such as piperacillin/tazobactam, in comparison to some antibiotics including ceftriaxone.
"This changes some previous assumptions and highlights the need for further investigation into the mechanisms behind these associations," Liu indicated.
The investigators found "nearly all" antibiotics were associated with CDI in the analysis of FAERS; with CDI risk signal clusters within the majority of antibiotic classes.The strongest association was found with lincomycin (OR 112.17, 51.68-243.43).In addition, they noted, oral third-generation cephalosporins exhibited higher CDI risk signals than earlier generations.
"In our NMA, cefdinir, ceftriaxone, and clindamycin, with P-scores of 0.19, 0.24, and 0.26, respectively, were identified as the top three antibiotics with the highest potential risk for CDI's," Liu recounted. "However, we could not identify a statistical difference between cefdinir and clindamycin.The FAERS signal analysis indicated that cefdinir, relative risk (ROR) 64.76, 53.47-78.44, has a higher CDI risk than clindamycin, ROR 30.41, 28.24-32.75."
"As mentioned earlier, FAERS analysis cannot establish causality; hence, we concluded that clindamycin and third-generation cephalosporins—particularly oral formulations—carry a high risk of triggering CDI, as indicated by their P- scores and ROR values," Liu said.
Liu attributed the higher risk for CDI associated with oral dosage form of the third-generation cephalosporin to the likely impact on gut micobiota.He noted that theyhave relatively low oral bioavailability, and suggested that accumulation in the gut could contribute to the increased risk.
Liu pointed out, however, that a statistical difference found in the study might not relate to clinical significance.
"In clinical practice, the choice of antibiotic may not only (be based) on CDI risk , but also on other factors such as infection severity, site of infection, and patient-specific factors.Although a statistically significant higher risk of CDI was noted for certain antibiotics, the decision to choose one antibiotic over another should be carefully balanced with these other considerations," Liu advised.
Reference
1.Liu Y, Dai M, Zhang K, et al.Clostridioides difficile infection risk following different antibiotics: Insights from multi-source medical data. Int J Antimicrob Agents. Online July 31 2024. https://doi.org/10.1016/j.ijantimicag.2024.107288.Accessed August 7, 2024.
