Penicillin allergy

Penicillin allergy occurs mainly through immune reactions, particularly involving Immunoglobulin E (IgE). Allergic reactions can be classified as immediate or non-immediate. Immediate reactions typically occur within minutes to hours after exposure and involve IgE antibodies, which cause the release of inflammatory substances like histamine. This can lead to symptoms such as hives, swelling, and anaphylaxis. Penicillin itself is too small to trigger an immune response directly. It binds to proteins in the body, forming larger complexes called neoantigens, which the immune system identifies as foreign, resulting in the production of IgE antibodies. These antibodies recognize specific penicillin metabolites, like penilloic acid, which can cause inflammation and vascular changes. There are also non-IgE-mediated allergic reactions. These include T-cell-mediated responses, which can occur hours to days after exposure and result in skin rashes or more severe conditions like drug reaction with eosinophilia and systemic symptoms (DRESS). Additionally, cross-reactivity between penicillin and other beta-lactam antibiotics, like cephalosporins, is common due to structural similarities, which can lead to similar immune responses.

Immediate Reactions:
These happen within minutes to a few hours after taking penicillin. They are driven by IgE antibodies that attach to mast cells and basophils, releasing histamine. This can lead to symptoms like hives, swelling, and even anaphylaxis.

Delayed Reactions:
These occur hours or days later and are usually driven by T cells rather than antibodies. They may cause skin rashes or more severe conditions like DRESS (Drug Reaction with Eosinophilia and Systemic Symptoms).

Clinical Aspect	Key Message / Details	Management / Recommendations
Epidemiology & Impact	Penicillin is implicated in up to 20% of drug-related anaphylaxis deaths in Europe and up to 75% in the US. It accounts for 0.7–10% of all anaphylaxis cases. Only 1–10% of self-reported penicillin allergies are confirmed as IgE-mediated on testing. Being labeled as penicillin allergic is associated with longer hospital stays, increased antibiotic resistance, and higher healthcare costs.	Confirm true allergy through specialist testing when appropriate. Avoid unnecessary labeling to reduce adverse outcomes and healthcare burden.
Risk Factors	Increased risk (↑) in patients aged 20–49 and in females. Concurrent infection and a past reaction (lower risk (↓) if the last reaction was >15 years ago).	Obtain a detailed history to assess individual risk profiles. Recognize high-risk groups to guide further evaluation and management.
Sensitization	Repeated courses of penicillin are more likely to cause sensitization than a single dose.	Consider the cumulative exposure history when evaluating a patient’s allergy status.
History Taking	A thorough history should document the specific drug, timing of onset, and resolution of symptoms.	Essential for differentiating between immediate and non-immediate reactions and for guiding subsequent investigations.
Immediate (IgE-mediated) Reactions	Typically occur within minutes to up to 6 hours (usually within 1 hour) after drug administration. Clinical features include anaphylaxis, urticaria, angioedema, wheezing, and laryngeal oedema. Can occur up to 4 days into the course.	Prompt recognition and urgent management of anaphylaxis. Detailed evaluation to confirm allergy and determine safe future use.
Non-Immediate Reactions	Occur 60 minutes to several days after the last dose. Can be mediated by non-IgE mechanisms, including cytotoxic reactions (blood disorders), immune complex reactions (serum sickness 3–4 weeks after treatment starts), and T cell–mediated delayed reactions (rashes).	Management strategies may differ from immediate reactions. Detailed history and specialized testing may help differentiate these reactions.
Maculopapular Rashes	Occur in up to 10% of patients exposed to aminopenicillins, with the incidence increasing in the presence of viral infections (notably 70–90% in patients with EBV or HPV).	Consider the role of viral infections in rash etiology; carefully evaluate before labeling a patient as allergic.
Cephalosporin Reactions & Cross-reactivity	Adverse reactions to cephalosporins are about 10 times lower than with penicillin. Cross-reactivity: up to 10% with first-generation cephalosporins and 2–3% with third-generation agents; approximately 2% of cephalosporin-allergic patients react to penicillin. Cross-reactivity is less frequent in non-immediate reactions.	Avoid cephalosporins in patients with a clear history of penicillin allergy (especially for immediate reactions). Consider alternative antibiotics or evaluate cross-reactivity risk based on cephalosporin generation and reaction type.
Indications for Specialist Testing	Indicated in patients with multiple drug allergies, those requiring frequent antibiotic courses (e.g., CF, diabetes, bronchiectasis, immunodeficiencies), when there is no suitable alternative antibiotic, or when anaphylaxis occurs under general anaesthesia with multiple drugs.	Refer to a drug allergy clinic for a detailed evaluation in an experienced hospital setting.
Allergy Investigations	Testing involves skin prick tests, intradermal tests, and occasionally patch testing with penicillin, amoxicillin, and the index drug. Approximately one-third of patients with a reported penicillin allergy have negative skin tests. Available IgE blood tests for beta‑lactams have low sensitivity and should be reserved for specific circumstances.	Use a graduated (incremental) drug challenge when skin tests are negative and it is deemed safe. Ensure testing is conducted under experienced supervision.
Current Recommendations & Patient Safety	In cases of a clear history of allergic reaction, current advice is to avoid all penicillins and cephalosporins. Patients should be aware of their allergy status.	Advise patients to wear an alert bracelet and ensure that drug allergy alerts are clearly documented in their medical records.

Clinical Aspect

Key Message / Details

Management / Recommendations

Epidemiology & Impact

Penicillin is implicated in up to 20% of drug-related anaphylaxis deaths in Europe and up to 75% in the US. It accounts for 0.7–10% of all anaphylaxis cases. Only 1–10% of self-reported penicillin allergies are confirmed as IgE-mediated on testing. Being labeled as penicillin allergic is associated with longer hospital stays, increased antibiotic resistance, and higher healthcare costs.

Confirm true allergy through specialist testing when appropriate. Avoid unnecessary labeling to reduce adverse outcomes and healthcare burden.

Risk Factors

Increased risk (↑) in patients aged 20–49 and in females. Concurrent infection and a past reaction (lower risk (↓) if the last reaction was >15 years ago).

Obtain a detailed history to assess individual risk profiles. Recognize high-risk groups to guide further evaluation and management.

Sensitization

Repeated courses of penicillin are more likely to cause sensitization than a single dose.

Consider the cumulative exposure history when evaluating a patient’s allergy status.

History Taking

A thorough history should document the specific drug, timing of onset, and resolution of symptoms.

Essential for differentiating between immediate and non-immediate reactions and for guiding subsequent investigations.

Immediate (IgE-mediated) Reactions

Typically occur within minutes to up to 6 hours (usually within 1 hour) after drug administration. Clinical features include anaphylaxis, urticaria, angioedema, wheezing, and laryngeal oedema. Can occur up to 4 days into the course.

Prompt recognition and urgent management of anaphylaxis. Detailed evaluation to confirm allergy and determine safe future use.

Non-Immediate Reactions

Occur 60 minutes to several days after the last dose. Can be mediated by non-IgE mechanisms, including cytotoxic reactions (blood disorders), immune complex reactions (serum sickness 3–4 weeks after treatment starts), and T cell–mediated delayed reactions (rashes).

Management strategies may differ from immediate reactions. Detailed history and specialized testing may help differentiate these reactions.

Maculopapular Rashes

Occur in up to 10% of patients exposed to aminopenicillins, with the incidence increasing in the presence of viral infections (notably 70–90% in patients with EBV or HPV).

Consider the role of viral infections in rash etiology; carefully evaluate before labeling a patient as allergic.

Cephalosporin Reactions & Cross-reactivity

Adverse reactions to cephalosporins are about 10 times lower than with penicillin. Cross-reactivity: up to 10% with first-generation cephalosporins and 2–3% with third-generation agents; approximately 2% of cephalosporin-allergic patients react to penicillin. Cross-reactivity is less frequent in non-immediate reactions.

Avoid cephalosporins in patients with a clear history of penicillin allergy (especially for immediate reactions). Consider alternative antibiotics or evaluate cross-reactivity risk based on cephalosporin generation and reaction type.

Indications for Specialist Testing

Indicated in patients with multiple drug allergies, those requiring frequent antibiotic courses (e.g., CF, diabetes, bronchiectasis, immunodeficiencies), when there is no suitable alternative antibiotic, or when anaphylaxis occurs under general anaesthesia with multiple drugs.

Refer to a drug allergy clinic for a detailed evaluation in an experienced hospital setting.

Allergy Investigations

Testing involves skin prick tests, intradermal tests, and occasionally patch testing with penicillin, amoxicillin, and the index drug. Approximately one-third of patients with a reported penicillin allergy have negative skin tests. Available IgE blood tests for beta‑lactams have low sensitivity and should be reserved for specific circumstances.

Use a graduated (incremental) drug challenge when skin tests are negative and it is deemed safe. Ensure testing is conducted under experienced supervision.

Current Recommendations & Patient Safety

In cases of a clear history of allergic reaction, current advice is to avoid all penicillins and cephalosporins. Patients should be aware of their allergy status.

Advise patients to wear an alert bracelet and ensure that drug allergy alerts are clearly documented in their medical records.