Β-lactam allergy

Hypersensitivity Reactions

• Type I (IgE-mediated)
  • Anaphylaxis
  • Itchy rash
  • Penicillins should be avoided
• Type II (IgG-mediated)
  • Non-itchy rash
  • Rash will improve if treatment continues, no need to avoid penicillins
• Type IV (cell-mediated)
  • Toxic epidermal necrolysis
  • Stevens-Johnson syndrome
  • Penicillins should be avoided

Cross-Reactivity

• The following applies to immediate, IgE-mediated hypersensitivity reactions
• Cross-reactivity within penicillins is mediated by homology of the R1 side chain (referring to the C6 side chain) and by the β-lactam ring itself
• Cross-reactivity between penicillins and cephalosporins is mediated by homology of the R1 side chains (referring to the C6 side chain in penicillins or the C7 side chain in cephalosporins)
• Cross-reactivity within cephalosporins is mediated both by homology of the R1 side chains and also R2 side chains (referring to the C3 side chain)
• There is very low (~2%) cross-reactivity between penicillin allergy and carbapenems1

Antibiotic	R1			R2
	G1	G2	G3	G1	G2	G3	G4	G5	G6	G7
Penicillins
Penicillin	X
Ampicillin		X
Amoxicillin		X
First-Generation Cephalosporins
Cefazolin
Cephalexin		X		X
Cefadroxil		X		X
Cephalothin	X					X
Second-Generation Cephalosporins
Cefotetan					X
Cefoxitin	X							X
Cefuroxime								X
Cefaclor		X
Third-Generation Cephalosporins
Cefotaxime			X			X
Ceftriaxone			X
Ceftazidime										X
Cefixime									X
Cefdinir
Fourth-Generation Cephalosporins and Higher
Cefipime			X
Ceftaroline

R1 Side Chains (C6 and C7)

• Group 1: penicillin, cephalothin, cefoxitin; similar to ticarcillin
• Group 2: amoxicillin, ampicillin, cefaclor, cephalexin, cefadroxil; similar to penicillin piperacillin
• Group 3: cefipime, cefotaxime, ceftriaxone; similar to ceftazidime and aztreonam
• Ceftazidime and aztreonam; similar to group 3

R2 Side Chains (C3)

• Group 1: cefadroxil, cephalexin
• Group 2: cefotetan
• Group 3: cefotaxime, cephalothin
• Group 4
• Group 5: cefuroxime, cefoxitin
• Group 6: cefixime
• Group 7: ceftazidime

Management

Penicillin Allergy

• Consider skin testing

Class	Cross-reactivity	Notes
Cephalosporin, 1st generation	2-8%	Based on poor studies. Avoid cephalexin and cefaclor in ampicillin allergy.
Cephalosporin, 2nd generation	2%	Avoid cefoxitin in penicillin allergy. Avoid cefadroxil and cefprozil in amoxicillin allergy.
Cephalosporin, 3rd generation	<1%	Generally considered safe.
Cephalosporin, higher generation	N/A	No data available, but generally considered safe.
Carbapenem	1%	Generally considered safe.
Monobactam	<1%	Avoid aztreonam in ceftazidime allergy.

• For those with penicillin allergy
  • 1st gen cephalosporins: cross-reactavoid cephalexin and cefaclor if ampicillin allergic
  • 2nd gen cephalosporins:

Further Reading

• Cross-reactivity in β-Lactam Allergy. J Allergy Clin Immunol Pract. 2018;6(1):72-81.e1. doi: 10.1016/j.jaip.2017.08.027
• Cross-Reactivity to Cephalosporins and Carbapenems in Penicillin-Allergic Patients: Two Systematic Reviews and Meta-Analyses. J Allergy Clin Immunol Pract. 2019;7(8):2722-2738.e5. doi: 10.1016/j.jaip.2019.05.038