A pharmacist’s guide to allergy assessment, risk stratification, cross-reactivity, and de-labeling

The Allergy Label May Be the Problem

Few entries in the electronic health record can influence antimicrobial prescribing as much as a documented penicillin or beta-lactam allergy.

A patient may have received amoxicillin decades ago, developed a rash during an illness, experienced gastrointestinal intolerance, or simply been told as a child that they were “allergic.” Years later, that label may still determine antibiotic selection.

The result can be unnecessary avoidance of first-line beta-lactams and greater reliance on broader-spectrum or alternative agents.

A large body of evidence now supports a different approach: investigate the allergy label rather than automatically accepting it at face value.

The CDC currently reports that approximately 10% of U.S. patients report a penicillin allergy, but fewer than 1% are found to be truly allergic when appropriately evaluated.

The stewardship implications are substantial. In a hospital-based study, patients with active penicillin allergy labels were much more likely to receive antibiotics classified as “Watch” or “Reserve” under the WHO AWaRe framework than patients whose allergy labels had been removed.

The clinical question should therefore shift from:

“Does this patient have a penicillin allergy?”

to:

“What actually happened when this patient received the drug, and what does that history mean for today’s antibiotic decision?”

Step 1: Reconstruct the Allergy History

The allergy field in the electronic health record is not a substitute for a clinical history.

When evaluating a beta-lactam allergy, pharmacists should establish:

• Which antibiotic caused the reaction?
• What symptoms occurred?
• How soon after administration did symptoms begin?
• How many doses had been received?
• How was the reaction treated?
• Did the patient require emergency care or hospitalization?
• How long ago did the reaction occur?
• Has the patient subsequently tolerated a penicillin or cephalosporin?
• Was the patient experiencing a viral or other infection when the reaction occurred?

The CDC specifically recommends obtaining details about the timing, medication exposure, symptoms, treatment, and subsequent beta-lactam exposures before deciding how to evaluate a reported allergy.

Why the details matter

Consider three patients:

Patient A:
“I was told I was allergic to penicillin because my mother is allergic.”

Patient B:
“I took amoxicillin 15 years ago and developed diarrhea.”

Patient C:
“Within 30 minutes of receiving penicillin, I developed hypotension, wheezing, and generalized hives.”

All three may appear in the EHR as “penicillin allergy.”

Clinically, however, they represent very different risk profiles.

Not Every Adverse Reaction Is an Allergy

One of the most important stewardship skills is distinguishing intolerance, nonimmune adverse effects, and immune-mediated hypersensitivity.

Gastrointestinal symptoms such as nausea or diarrhea generally do not establish an immune-mediated penicillin allergy. Similarly, headache or a family history of penicillin allergy should not automatically produce an allergy label. The 2022 drug allergy practice parameter recommends against allergy testing when the history is inconsistent with penicillin allergy.

A rash can be more complicated.

A patient may have developed a rash because of the underlying infection rather than because of the antibiotic. This is particularly relevant when aminopenicillins are prescribed during certain viral illnesses.

Clinical pearl

“Rash with amoxicillin” is a description, not a diagnosis.

The pharmacist’s job is to determine what the rash looked like, when it appeared, how long it lasted, whether mucosal or systemic features were present, and whether the patient has tolerated related antibiotics since the event.

Risk Stratification: Who Is Low Risk?

A structured approach can make allergy assessment more reproducible.

One of the best validated tools is PEN-FAST, which incorporates:

• PENicillin allergy
• Five years or less since the reaction
• Anaphylaxis/angioedema or severe cutaneous adverse reaction
• Severe reaction requiring Treatment

In the original derivation and validation study involving more than 1,500 patients, a PEN-FAST score below 3 identified a low-risk group with a negative predictive value of approximately 96%.

This tool is particularly useful because it translates a complicated allergy history into a practical risk assessment.

Important limitation

PEN-FAST should not replace clinical judgment.

It is a risk-stratification tool, not an independent authorization to administer a beta-lactam. Patients with histories suggestive of severe delayed hypersensitivity—such as Stevens-Johnson syndrome/toxic epidermal necrolysis, DRESS, acute generalized exanthematous pustulosis, or drug-induced organ injury—require specialist evaluation rather than routine direct challenge.

Direct Oral Challenge: An Evidence-Based Option for Low-Risk Patients

Historically, penicillin allergy evaluation often centered on skin testing followed by an oral challenge.

That approach remains important for selected patients, particularly those with histories concerning for IgE-mediated reactions.

However, evidence increasingly supports direct oral challenge for appropriately selected low-risk adults.

The landmark PALACE randomized clinical trial compared direct oral penicillin challenge with the traditional approach of skin testing followed by oral challenge in adults with PEN-FAST scores below 3.

Among 377 evaluable participants, immune-mediated reactions occurred in 0.5% of patients in each group. No serious adverse events occurred. Direct challenge was therefore demonstrated to be noninferior to the traditional testing pathway in this low-risk population.

What this means for practice

For an appropriately selected low-risk patient, a direct oral challenge can:

• Avoid unnecessary skin testing
• Simplify the evaluation pathway
• Expand access to de-labeling
• Allow earlier use of preferred beta-lactam therapy
• Reduce reliance on broader-spectrum alternatives

But the challenge must occur under an appropriate protocol, with trained personnel, observation, and access to treatment for an acute reaction.

De-labeling Is More Than Removing a Checkbox

Successful de-labeling is not simply deleting “penicillin allergy” from the EHR.

The goal is to establish an accurate, clinically useful allergy history and ensure that the result follows the patient.

This requires:

Assessment → Risk stratification → Appropriate testing/challenge → Documentation → Patient education → Communication

The importance of the final steps is highlighted by emerging 2026 data.

In a prospective longitudinal study of 141 adults undergoing standardized penicillin allergy evaluation, 83% were ultimately de-labeled. However, among patients with complete follow-up, 17% were incorrectly re-labeled within 12 months, demonstrating that de-labeling can be undermined by subsequent documentation errors.

The lesson

A successful challenge is only half the intervention.

The allergy result must be documented clearly, communicated to the patient, and incorporated into future medication reconciliation.

Does De-labeling Actually Change Antibiotic Use?

Yes.

A 2024 primary-care cohort involving 2,911 patients evaluated for penicillin allergy found that 86.4% were de-labeled. Among de-labeled patients, penicillin use increased substantially after evaluation, while fluoroquinolone and macrolide use decreased toward levels observed in the background population.

Another prospective hospital study found that both direct de-labeling and direct oral challenge increased subsequent penicillin use. At 90 days, re-labeling was uncommon in both groups.

These findings reinforce an important stewardship principle:

De-labeling is not merely an allergy intervention; it changes prescribing behavior.

What About Cephalosporins? Think Side Chains, Not Just the Beta-Lactam Ring

A penicillin allergy label does not automatically mean that every cephalosporin should be avoided.

Modern understanding of beta-lactam cross-reactivity emphasizes molecular structure, particularly the R1 side chain.

The 2022 practice parameter notes that immediate hypersensitivity to cephalosporins is more commonly directed toward side-chain structures than the shared beta-lactam core, with the strongest evidence for cross-reactivity involving identical R1 side chains.

This distinction has practical consequences.

Cefazolin is a particularly important example

Cefazolin has unique side chains and is widely used for surgical prophylaxis.

A 2024 study evaluated 112,817 surgical encounters and identified a perioperative anaphylaxis prevalence of only 0.02%. Only one cefazolin-associated perioperative anaphylaxis case occurred in a patient with a penicillin allergy label, and there was no significant difference in cefazolin perioperative anaphylaxis between patients with and without penicillin allergy labels.

This provides additional real-world evidence supporting cefazolin use in many patients carrying a penicillin allergy label, rather than reflexively substituting clindamycin or vancomycin.

Caution remains essential: the specific reaction phenotype, the implicated drug, side-chain similarity, and institutional protocols must all be considered.

Pharmacists Are Well Positioned to Lead This Intervention

Penicillin allergy assessment fits naturally within antimicrobial stewardship.

Pharmacists already perform many of the skills required:

• Medication reconciliation
• Allergy-history interviews
• Antimicrobial optimization
• Renal and hepatic assessment
• Drug interaction review
• Patient counseling
• EHR documentation
• Communication with prescribers
• Monitoring for adverse drug reactions

Emerging 2026 research supports the feasibility of pharmacist-led models.

A Canadian prospective pilot used pharmacist-led PEN-FAST assessment in 155 hospitalized patients. Most patients were de-labeled through history alone, and the investigators concluded that PEN-FAST combined with direct oral challenge could be practically implemented by pharmacists.

In another 2026 pharmacist-driven program, 32 patients underwent full allergy reconciliation. The median PEN-FAST score was 0; 25 patients underwent direct oral challenge, and 28 patients ultimately had their allergy labels removed. The intervention was associated with antibiotic optimization, including 78 days of therapy saved, and estimated cost savings of $37,632.

These studies are small and largely single-center, so they should not be interpreted as definitive evidence for every healthcare setting. Nevertheless, they demonstrate that pharmacist-led beta-lactam allergy stewardship is increasingly feasible in real-world practice.

A Practical Pharmacist Workflow

A pharmacy or antimicrobial stewardship program can consider a workflow such as:

1. Identify

Find patients with a documented penicillin or beta-lactam allergy who are receiving or may benefit from beta-lactam therapy.

2. Interview

Obtain the actual allergy history directly from the patient whenever possible.

3. Classify

Determine whether the reported event represents:

• Intolerance
• Nonimmune adverse effect
• Low-risk hypersensitivity
• Immediate hypersensitivity
• Severe delayed hypersensitivity

4. Risk-stratify

Consider a validated tool such as PEN-FAST for appropriate adult patients.

5. Determine the pathway

Depending on the history and local protocol:

No convincing allergy → consider appropriate delabeling/documentation

Low-risk history → consider direct oral challenge when authorized and appropriately supervised

Higher-risk immediate reaction → consider allergy evaluation and/or skin testing

Severe delayed reaction → avoid routine challenge and refer for specialist evaluation

6. Optimize the antibiotic

If the allergy label is removed or an alternative beta-lactam is determined to be appropriate, reassess whether the patient can receive the preferred evidence-based antimicrobial.

7. Document

Record:

• Original reaction
• Risk assessment
• Testing/challenge performed
• Result
• Antibiotics subsequently tolerated
• Updated allergy status
• Patient counseling

Five Questions Every Pharmacist Should Ask

When you encounter a beta-lactam allergy label, start here:

1. What antibiotic caused the reaction?

“Penicillin” is not sufficiently specific.

2. What exactly happened?

Do not accept “allergic reaction” as the final answer.

3. How quickly did the reaction occur?

Timing helps distinguish immediate from delayed reactions.

4. How severe was the reaction?

Look specifically for anaphylaxis, angioedema, hypotension, respiratory compromise, mucosal involvement, blistering, organ injury, or hospitalization.

5. Has the patient tolerated a beta-lactam since then?

A documented subsequent exposure may be one of the most valuable pieces of information in the entire allergy history.

Three Stewardship Scenarios

Scenario 1: The “penicillin allergy” that isn’t an allergy

A patient reports:

“Penicillin gives me diarrhea.”

Stewardship approach:
This history is more consistent with intolerance than immune-mediated allergy. The allergy record should be clarified and updated according to institutional policy rather than automatically excluding penicillin therapy.

Scenario 2: Remote, mild reaction

A patient reports:

“I took amoxicillin about 15 years ago and developed a mild rash. I don’t remember any breathing problems, swelling, or hospitalization.”

Stewardship approach:
This history warrants structured risk assessment. If the patient meets criteria for a low-risk pathway, direct oral challenge may be considered under an appropriate protocol.

The PALACE trial provides strong randomized evidence supporting this approach in appropriately selected low-risk adults.

Scenario 3: Possible anaphylaxis

A patient reports:

“Within 30 minutes of penicillin, I developed hives, throat tightness, wheezing, and hypotension.”

Stewardship approach:
This is a high-risk immediate reaction history. Do not treat it as a routine low-risk de-labeling candidate. Specialist evaluation and appropriate allergy testing should be considered.

Where Antimicrobial Stewardship Meets Allergy Stewardship

Beta-lactam allergy management is increasingly recognized as a core antimicrobial stewardship activity.

The opportunity is not simply to prescribe more penicillins.

The goal is to ensure that patients receive the most appropriate antibiotic for their infection and their individual risk profile.

That may mean:

• Using amoxicillin instead of a broader alternative
• Using cefazolin rather than vancomycin or clindamycin for appropriate surgical prophylaxis
• Avoiding unnecessary fluoroquinolone exposure
• Preventing inappropriate carbapenem use
• Improving access to first-line therapy
• Reducing unnecessary antimicrobial toxicity and cost

The 2026 literature is moving the field further toward structured, risk-based, multidisciplinary allergy stewardship, including pharmacist participation.

Practice Pearls

Pearl #1

A documented allergy is a data point, not necessarily a diagnosis.

Pearl #2

The reaction phenotype matters more than the word “allergy.”

Pearl #3

Remote, mild reactions should not automatically eliminate all beta-lactam options.

Pearl #4

PEN-FAST can help identify adults who may be appropriate for low-risk evaluation.

Pearl #5

Direct oral challenge is evidence-supported for appropriately selected low-risk adults, but it requires a structured and supervised protocol.

Pearl #6

Penicillin allergy does not automatically equal cephalosporin allergy. Consider side-chain similarity.

Pearl #7

Cefazolin deserves special consideration in patients with penicillin allergy labels because its side-chain structure and accumulating clinical safety data support its use in many such patients.

Pearl #8

Delabeling is incomplete until the result is accurately documented and communicated.

The Bottom Line

Beta-lactam allergy labels can become invisible barriers to optimal antimicrobial therapy.

The solution is not to ignore the allergy label; and it is not to automatically avoid every beta-lactam.

The solution is better information.

A detailed history, structured risk assessment, appropriate testing or challenge, thoughtful interpretation of beta-lactam cross-reactivity, and careful EHR documentation can transform an ambiguous allergy label into a clinically useful assessment.

For pharmacists, this represents an important opportunity to expand antimicrobial stewardship beyond antibiotic selection and dosing into allergy stewardship.

Before replacing a beta-lactam with a broader-spectrum alternative, ask one more question: “What actually happened when this patient received the antibiotic?”

That question may be the first step toward safer, narrower, and more evidence-based antimicrobial therapy.

References

1. Trubiano JA, Vogrin S, Chua KYL, et al. Development and Validation of a Penicillin Allergy Clinical Decision Rule. JAMA Internal Medicine. 2020;180(5):745-752.
2. 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 Internal Medicine. 2023;183(9):944-952.
3. Fransson S, Boel JB, Mosbech H, Garvey LH. Penicillin allergy delabeling has a significant impact on subsequent antibiotic use in primary care. World Allergy Organization Journal. 2024;17(9):100958.
4. Murphy ZR, Muzaffar A, Massih SA, et al. Examining cefazolin utilization and perioperative anaphylaxis in patients with and without a penicillin allergy label: A cross-sectional study. Journal of Clinical Anesthesia. 2024;94:111377.
5. Kamaliddin C, Driver A, Druken R, et al. Feasibility and impact of pharmacist-led penicillin allergy de-labelling using the PEN-FAST scoring tool in a Canadian tertiary care hospital. Antimicrobial Stewardship & Healthcare Epidemiology. 2026;6(1).
6. Kaleo P, Patimavirujh N, Greene K, Piccicacco N, O’Neal M. Impact of a Pharmacist-Driven Penicillin Allergy De-Labeling Service (PADLS) on Hospitalized Patients. Pharmacy. 2026;14(1):33.
7. Li PH, Xu F, Shi W, et al. Prospective Multiregional Evaluation of Protocol-Based Penicillin Allergy De-labeling in China: Real-World Outcomes Challenge Mandatory Preemptive Skin Testing Policies. Journal of Allergy and Clinical Immunology: In Practice. 2026;14(2):445-452.e3.
8. Shi W, Wong KO, Li J, et al. Prospective outcomes of penicillin allergy evaluation: Quality of life and relabeling rates. Annals of Allergy, Asthma & Immunology. 2026;136(6):706-711.e2.
9. Khan DA, Banerji A, Blumenthal KG, et al. Drug Allergy: A 2022 Practice Parameter Update. Journal of Allergy and Clinical Immunology. 2022;150(6):1333-1393.

Editorial Disclaimer

This article is intended for professional education and general informational purposes. It does not replace patient-specific clinical assessment, institutional protocols, or consultation with allergy/immunology or other appropriate specialists. Direct oral challenges, skin testing, and de-labeling should be performed only within an appropriately established clinical protocol and by clinicians with the necessary training, monitoring capabilities, and emergency resources.