Β-lactam allergy: Difference between revisions

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Β-lactam allergy
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{{DISPLAYTITLE:β-lactam allergy}}
{{DISPLAYTITLE: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==
==Cross-Reactivity==


*The following applies to '''immediate, IgE-mediated''' hypersensitivity reactions
*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
*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 [[carbapenems]][[CiteRef::kula2014a]]

{| class="wikitable"
!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 ===
{| class="wikitable"
{| class="wikitable"
! rowspan="2" |Antibiotic
! rowspan="2" |Antibiotic
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|}
|}


===R1 Side Chains (C6 and C7)===
====R1 Side Chains (C6 and C7)====


*'''Group 1:''' [[penicillin]], [[cephalothin]], [[cefoxitin]]; similar to [[ticarcillin]]
*'''Group 1:''' [[penicillin]], [[cephalothin]], [[cefoxitin]]; similar to [[ticarcillin]]
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*[[Ceftazidime]] and [[aztreonam]]; similar to group 3
*[[Ceftazidime]] and [[aztreonam]]; similar to group 3


===R2 Side Chains (C3)===
====R2 Side Chains (C3)====


*'''Group 1:''' [[cefadroxil]], [[cephalexin]]
*'''Group 1:''' [[cefadroxil]], [[cephalexin]]
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*'''Group 7:''' [[ceftazidime]]
*'''Group 7:''' [[ceftazidime]]


== Management ==
==Hypersensitivity Reactions==


=== Penicillin Allergy ===
*'''Type I (IgE-mediated)'''

**Anaphylaxis
* Many patients with listed penicillin allergy may be penicillin tolerant due to:
**Itchy rash
** Benign delayed hypersensitivity rash is the most common reaction
**Penicillins '''should be avoided'''
** IgE-mediated penicillin allergy wanes over time (80% are tolerant after a decade)
*'''Type II (IgG-mediated)'''
** Many patients were never allergic
**Non-itchy rash
* Consider skin testing for patients with history of severe reaction
**Rash will improve if treatment continues, '''no need to avoid''' penicillins

*'''Type IV (cell-mediated)'''
=== Massachusetts General Hospital Algorithm (2019) ===
**Toxic epidermal necrolysis

**Stevens-Johnson syndrome
* Developed at MGH[[CiteRef::wolfson2019ac]][[CiteRef::shenoy2019ev]]
**Penicillins '''should be avoided'''

==== 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==
==Further Reading==

Latest revision as of 17:47, 19 September 2024


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)

R2 Side Chains (C3)

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)

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

References

  1. ^  Brittany Kula, Gordana Djordjevic, Joan L. Robinson. A Systematic Review: Can One Prescribe Carbapenems to Patients With IgE-Mediated Allergy to Penicillins or Cephalosporins?. Clinical Infectious Diseases. 2014;59(8):1113-1122. doi:10.1093/cid/ciu587.
  2. ^  Anna R. Wolfson, Emily M. Huebner, Kimberly G. Blumenthal. Acute care beta-lactam allergy pathways: approaches and outcomes. Annals of Allergy, Asthma & Immunology. 2019;123(1):16-34. doi:10.1016/j.anai.2019.04.009.
  3. ^  Erica S. Shenoy, Eric Macy, Theresa Rowe, Kimberly G. Blumenthal. Evaluation and Management of Penicillin Allergy. JAMA. 2019;321(2):188. doi:10.1001/jama.2018.19283.

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