Cefepime Use in Ceftriaxone Allergy
Cefepime can generally be safely administered to patients with ceftriaxone allergy because these cephalosporins have different R1 side chain structures, making cross-reactivity unlikely. 1
Understanding the Mechanism of Cross-Reactivity
Cross-reactivity between cephalosporins depends primarily on R1 side chain similarity, not the shared beta-lactam ring structure. 2, 1 Ceftriaxone and cefepime have dissimilar R1 side chains, which is the key determinant of whether cross-reactivity will occur. 3, 1
The risk of cross-reactivity between cephalosporins with dissimilar side chains is approximately 2.11%, which is considered very low. 2, 3
Clinical Decision Algorithm
For Non-Severe Reactions to Ceftriaxone:
- Administer cefepime directly without skin testing, as the dissimilar side chains make cross-reactivity highly unlikely. 2, 1
- Monitor the first dose in a setting where anaphylaxis can be managed if needed. 1
For Severe/Anaphylactic Reactions to Ceftriaxone:
- Consider skin testing with cefepime before administration if the patient has multiple documented cephalosporin allergies or if there is concern for beta-lactam ring sensitivity. 1
- Use standard skin testing concentrations: epicutaneous (prick/puncture) at 2 mg/mL, followed by intradermal testing at 2 mg/mL if needed. 2
- A negative skin test supports safe administration of cefepime. 2
Important Caveats
This guidance does NOT apply to patients with severe delayed immunologic reactions such as Stevens-Johnson syndrome, toxic epidermal necrolysis, drug-induced liver injury, hemolytic anemia, or acute interstitial nephritis—in these cases, all beta-lactams should be avoided. 2
Rare Exception - Beta-Lactam Ring Sensitivity:
- In extremely rare cases (described in fewer than 1% of patients), individuals may be sensitized to the beta-lactam ring itself rather than side chains. 1, 4
- These patients would react to all beta-lactams, including cefepime, ceftriaxone, penicillins, and carbapenems. 1
- Consider this possibility only in patients with documented allergies to multiple structurally dissimilar beta-lactams. 1
FDA Labeling Considerations
The FDA label for cefepime states it is contraindicated in patients with immediate hypersensitivity to the cephalosporin class, and notes that cross-hypersensitivity among beta-lactams may occur in up to 10% of patients with penicillin allergy. 5 However, this 10% figure is outdated and applies primarily to penicillin-cephalosporin cross-reactivity with shared side chains, not to cross-reactivity between different cephalosporins with dissimilar structures. 6, 7, 8
Alternative Cephalosporins if Needed
If cefepime cannot be used for any reason, consider:
- Cefazolin - has a unique R1 side chain with negligible cross-reactivity to all other cephalosporins (0.7-0.8% risk). 3, 1
- Ceftazidime - has a different R1 side chain from ceftriaxone with low cross-reactivity risk. 3
Cephalosporins to Avoid
Do NOT use cefotaxime in patients with ceftriaxone allergy, as these two drugs share identical R1 side chains and have high cross-reactivity potential. 3