β-lactam allergy

Background

• The rate of IgE-mediated penicillin allergies is decreasing with time
• Most patient reports of penicillin allergy are either unknown or a cutaneous reaction
• Patients with listed allergy often receive second-line, less effective, more expensive, or more harmful treatments

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)

Penicillin

• There is very low (~2%) cross-reactivity between penicillin allergy and carbapenems1

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.

All β-Lactams

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

• Many patients with listed penicillin allergy may be penicillin tolerant due to:
  • Benign delayed hypersensitivity rash is the most common reaction
  • IgE-mediated penicillin allergy wanes over time (80% are tolerant after a decade)
  • Many patients were never allergic
• Consider skin testing for patients with history of severe reaction

Massachusetts General Hospital Algorithm (2019)

• Developed at MGH23

Allergy History

• Intolerance: isolated GI upset, chills, headache, or fatigue
• Low-risk history: family history, itching, unknown and remote (>10 years ago), allergy on record but patient denies
• Moderate-risk: anaphylaxis, angioedema or swelling, bronchospasm, cough, nasal symptoms, arrhythmia, throat tightness, hypotension, flushing/redness, dyspnea, rash, syncope, wheeze, dizziness/lightheadedness
• High-risk history: Stevens-Johnson syndrome, serum sickness, thrombocytopenia, fever, organ injury (liver or kidney), erythema multiforme, dystonia, anemia, acute generalized exanthematous rash with pustules, DRESS
• Also assess age at time of reaction, time of onset relative to dose, any treatments received, and any other β-lactams that have been used in the past
• No challenges or testing should be done for patients with a history of penicillin-associated blistering rash, hemolytic anemia, nephritis, hepatitis, fever, or joint pains

Low-Risk History

• Okay to use cephalosporins and carbapenems
• For patients with a low-risk history with cutaneous reaction, IgE-mediated reaction, or hemodynamic instability, do skin testing first
• Otherwise, can follow test dose procedure by given a single dose of amoxicillin (250 mg or 500 mg) and observing

Moderate-Risk History (Type 1 Reaction)

• If penicillin skin testing is available, it is preferred; if not available, can consider proceeding with graded challenge
  • Give one dose of amoxicillin 25 or 50 mg and observe for 1 hour; then,
  • Given one dose of amoxicillin 250 mg or 500 mg and observe for 1 hour
• Okay to use 3rd generation or higher cephalosporin by a test dose procedure
• Alternatively, can use aztreonam or carbapenems
• Alternatively, can get skin testing if a penicillin or early-generation cephalosporin is preferred

High-Risk History (Type 2, 3, or 4 Reaction)

• Includes serum sickness, Stevens-Johnson syndrome, toxic epidermal necrolysis, acute interstitial nephritis, drug reaction with eosinophilia and systemic symptoms, hemolytic anemia, and drug fever
• Avoid all penicillins, cephalosporins, and carbapenems

Graded Test Dose Procedure

• 10% of the standard dose is given and they are monitored for an hour
• If no reaction is observed in 1 hour, a full dose is given and they are monitored for another hour

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