Cefepime is More Likely to Cause C. difficile Infection Than Unasyn
Based on the available evidence, cefepime poses a significantly higher risk for C. difficile infection compared to Unasyn (ampicillin/sulbactam), and should be avoided when Unasyn is a viable alternative for the clinical indication.
Evidence Supporting Higher Risk with Cefepime
Direct Comparative Data
Cefepime demonstrates a 3-fold increased risk for CDI with an odds ratio of 3.01 (95% CI, 1.96-4.65; P < 0.001) in a large case-control study of 463 patients 1
Recent causal inference analysis confirms cefepime increases CDI risk with an average treatment effect of 0.0074 additional cases per daily dose-equivalent (95% CI: 0.0022-0.0126) 2
Cefepime was associated with CDI development after a median time of only 8 days of therapy 1
Meta-analyses demonstrate higher mortality with cefepime compared to other β-lactams (RR, 1.39; 95% CI, 1.04-1.86), with the lowest mortality observed with piperacillin-tazobactam 3
Protective Effect of Ampicillin-Containing Regimens
Ampicillin/sulbactam (Unasyn) may actually provide protective effects against C. difficile colonization, as ampicillin-containing regimens have demonstrated in vitro inhibitory activity against C. difficile 4
Patients receiving ampicillin-based combinations were less likely to be asymptomatic carriers of C. difficile compared to those on non-inhibitory antibiotics 4
Antibiotic Risk Classification
High-Risk Antibiotics (Including Cefepime)
Third-generation cephalosporins, clindamycin, fluoroquinolones, and cephalosporins (which includes cefepime as a fourth-generation cephalosporin) are consistently identified as highest-risk antibiotics for CDI 3, 5
Cephalosporins as a class were targeted in 10 of 15 antibiotic stewardship studies aimed at reducing CDI incidence 3
Lower-Risk Alternatives
Ampicillin and amoxicillin, while historically associated with CDI risk, appear to have lower risk profiles than cephalosporins in contemporary data 6, 4
When continued antibiotic therapy is required in patients with CDI, parenteral aminoglycosides, sulfonamides, macrolides, vancomycin, or tetracycline/tigecycline are preferred as less frequently implicated agents 3
Clinical Implications
Risk Mitigation Strategies
Discontinue unnecessary antibiotics immediately when CDI is suspected or diagnosed, as continued antibiotic use significantly increases recurrence risk 3
Minimize duration of all antibiotic therapy - the risk of CDI increases with cumulative antibiotic exposure, with adjusted hazard ratios of 2.5 for 2 antibiotics, 3.3 for 3-4 antibiotics, and 9.6 for ≥5 antibiotics 3
Consider antibiotic stewardship interventions targeting cephalosporins, which have demonstrated 50-90% reductions in targeted antibiotic use and 33-90% reductions in CDI incidence 3
Common Pitfalls to Avoid
Do not assume all β-lactams carry equal CDI risk - the evidence clearly demonstrates significant variation within this class, with cefepime carrying substantially higher risk than ampicillin/sulbactam 3, 1, 4
Avoid prolonged courses of cephalosporins when narrower-spectrum alternatives are available, as duration of exposure directly correlates with CDI risk 3, 1
Do not overlook the protective potential of certain antibiotics like piperacillin/tazobactam and ampicillin-containing regimens that may achieve intestinal concentrations sufficient to inhibit C. difficile 4