Beta-lactam Allergy Assessment and Management

An Antimicrobial Stewardship Program clinical summary

These materials are intended for general clinical education and guidance. They are not a substitute for a clinician’s knowledge, skill or judgment in treating patients.

Introduction

Beta-lactam antibiotics (penicillins, cephalosporins, carbapenems) are the most common group of medications to which patients report an allergy. Although 10 per cent of patients report a reaction to Beta-lactams, only 0.5-1 per cent of patients would have an allergic reaction upon re-exposure. Additionally, certain types of reactions may decrease over time, making re-challenge a possibility.

This tool was created to help clinicians make antibiotic decisions for patients with self-reported beta-lactam allergies.

Classification of hypersensitivity reactions

Category	IgE reactions	Non-IgE reactions
Onset	Within 1 hour to up to 6 hours	More than 6 hours to weeks
Severity	Variable	Mild/Intolerance	Severe systemic/cutaneous adverse reactions (SCAR)
Symptoms	Mucosal: angioedema Dermatologic: urticaria Gastrointestinal: vomiting (with other IgE-related symptoms) Respiratory: bronchospasm Cardiovascular: hypotension, arrhythmia (Note: ≥2 organ system involvement is anaphylaxis)	Central nervous system: headache Dermatologic: itching without rash maculopapular/mobilliform rash Gastrointestinal: isolated nausea/vomiting	Symptoms: desquamation, mucous membrane involvement, vasculitis, arthritis/arthralgia, unexplained fever associated with organ damage unrelated to other causes, generalized pustulosis, lymphadenopathy,
Symptoms			Syndromes: Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), acute generalized exanthematous pustulosis (AGEP)
Prevalence	<1% of beta-lactam exposures	Common	<0.1% of beta-lactam exposures
Duration of reaction	Less than 24 hours	Days to weeks
Cross-reactivity	Related to drug molecule structure (see cross-reactivity chart)	Unknown, possible structural relationship
Management	Beta-lactam assessment and management algorithm		Avoid all beta-lactams

Frequently asked questions

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If the patient has an allergy to a beta-lactam antibiotic, what is the risk of the patient reacting to a different beta-lactam antibiotic?

The risk of cross-reactivity for IgE reactions is related to the side chain structure of the beta-lactam (see cross-reactivity chart). Beta-lactams with dissimilar side chains generally have a risk similar to that of the general population for IgE-mediated allergic reaction (approximately 2 per cent). While it is possible to have a core beta-lactam ring structure reaction, this is felt to be very uncommon.

There is insufficient evidence to assess cross-reactivity relationships for non-IgE reactions.

What should I do if my patient does not recall the nature of the reaction to the beta-lactam antibiotic?

If the patient’s reaction is sufficiently remote, such as more than 10 years ago, not remembering the reaction likely represents a low-risk history, as long as the patient does not recall needing medical care or that the reaction was life-threatening.

If a patient’s family member has a penicillin allergy, should I be concerned that the patient may have one too?

No. There has been no evidence for a genetic/familial relationship to beta-lactam allergies.

Does the patient’s allergy last forever?

For patients with IgE reactions, such as hives, angioedema, and anaphylaxis, research shows that 80 per cent of patients no longer have the reaction, even to the same antimicrobial, after 10 years.

For non-IgE reactions, little is known about the durability and longevity of the reaction.

What harm is associated with avoiding beta-lactams if the patient has a stated allergy?

A beta-lactam allergy label has been associated with worse outcomes at both the patient and health system levels. Avoidance of beta-lactams leads to the use of alternative antimicrobials that may be less effective or have a higher risk of adverse effects, such as C. difficile infection.

Does my patient need a skin test for beta-lactam allergy assessment?

Penicillin allergy skin testing can be helpful to assess patients with a history of IgE reaction to penicillin. It may be beneficial in assessing other allergy types and medications. Referral to an allergist or a drug safety clinic is suggested for individuals with a complex allergy history/multiple drug allergies.

Does my patient need a test/challenge dose prior to receiving non-cross-reactive beta-lactam therapy?

Data for the benefit of test doses and oral challenges is limited. Routine monitoring after administration of antimicrobial therapy is sufficient in patients with a history of beta-lactam allergy based on the algorithm below.

Beta-lactam allergy assessment algorithm

What drug was involved in the initial reaction?
How long ago was the reaction?
Describe what happened during the reaction?
- Examples suggestive of IgE reaction: face/throat swelling, itching with rash, hives, wheezing, dizziness or fainting.
- Examples suggestive of mild non-IgE reactions or drug tolerance: isolated nausea and/or vomiting.
- Examples suggestive of severe systemic or cutaneous adverse reactions: blistering or peeling of skin, mouth or other mucous membrane involvement, drug fever associated with organ damage/dysfunction, increased eosinophils (lab test), severely decreased platelets (lab test) not due to other causes.
Did you have to see a doctor, call an ambulance or go to the hospital for the reaction? If yes, see the chart below.

Allergy Assessment Algorithm (PDF)

Cross-Reactivity Chart (PDF)

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References

Zagursky RJ, Pichichero ME. Cross-reactivity in β-Lactam Allergy. J Allergy Clin Immunol Pract 2018; 6(1):72-81.
Caruso C, Valluzi RL, Colantuono S, et al. β-Lactam Allergy and Cross-Reactivity: A Clinician’s Guide to Selecting an Alternative Antibiotic. Journal of Asthma and Allergy 2021; 11:31-46.
Blumenthal KG, Peter JG, Trubiano JA, et al. Antibiotic allergy. Lancet 2019; 393:183-98.
Vardakas KZ, Kalimeris GD, Triarides NA, et al. An update on adverse drug reactions related to β-Lactam antibiotics. Expert opinion on Drug Safety 2018; 17(5): 499-508.
Lagace-Weins P, Rubinstein E. Adverse reactions to β-Lactam antimicrobials. Expert Opinions on Drug Safety 2012; 11(3):381-99.
Shenoy ES, Macy E, Rowe T, et al. Evaluation and Management of Penicillin Allergy: A Review. JAMA 2019; 321(2):188-99.
Macy E, Trautmann A, Chiriac AM, et al. Advances in the Understanding of Drug Hypersensitivity: 2012 Through 2022. J Allergy Clin Immunol Pract 2023; 11(1):80-91.
Romano A, Gaeta F, Valluzzi RL, et al. IgE-mediated hypersensitivity to cephalosporins: Cross-Reactivity and tolerability of alternative cephalosporins. J Allergy Clin Immunol 2015; 136:685-91.
Minaldi E, Phillips EJ, Norton A. Immediate and Delayed Hypersensitivity Reactions to Beta‑Lactam Antibiotics. Clinical Reviews in Allergy & Immunology 2022; 62:449–462.
Vyas L, Raja K, Morrison S, et al. Beta-Lactam comprehensive allergy management program in a community medical center. Antimicrob Steward Healthc Epidemiol 2023; 3(1): e189.
Wrenn RH, Trubiano JA. Penicillin Allergy Impact and Management. Infect Dis Clin N Am 2023; 37:793–822.
Trubiano JA, Vogrin S, Chua KYL, et al. Development and Validation of a Penicillin Clinical Decision Rule. JAMA Intern Med 2020; 180(5):1-9.
Copaescu AM, Vogrin S, James F, et al. Efficacy of a Clinical Decision Rule to Enable Direct Oral Challenge in Patients with Low-Risk Penicillin Allergy: The PALACE randomized Clinical trial. JAMA Intern Med 2023; 183(9):944-952.