Penicillin allergy: A practical guide for clinicians

Author and Disclosure Information

ABSTRACTPenicillin allergy is the most commonly reported drug allergy in the United States. However, after undergoing a complete evaluation by a board-certified allergist, including skin testing, 90% of patients labeled as “penicillin-allergic” are able to tolerate penicillin. Clinical presentation is key in classifying reactions as either mediated by or not mediated by immunoglobulin E (IgE), and in determining which patients may benefit from penicillin skin testing, graded-dose challenge, or desensitization. Cross-reactivity between penicillin and other beta-lactams is less common than previously thought.


  • The prevalence of reported penicillin allergy is 10% in the general population. However, more than 90% of these patients are found not to be allergic to penicillin after skin testing.
  • In patients found to have penicillin allergy, the frequency of positive results on skin testing decreases by 10% per year of avoidance. Therefore, 80% to 100% of patients are expected to test negative for penicillin allergy by 10 years after their reaction.
  • Skin testing for penicillin allergy is only useful for type 1 IgE-mediated reactions. However, in properly selected patients, the negative predictive value of penicillin skin testing is nearly 97%.
  • The rate of cross-reactivity between penicillin and cephalosporins is approximately 3%.



Most patients who report that they are allergic to penicillin can ultimately receive penicillin or a penicillin-type antibiotic again after an appropriate evaluation and, possibly, treatment. This course of action decreases the need for broad-spectrum antibiotics,1–4 reduces health care costs, and prevents the development of multidrug-resistant pathogens.5

About 10% of the general population say that they are allergic to penicillin.1,6,7 Although the prevalence of life-threatening anaphylactic reactions to penicillin has been estimated to be between 0.02% and 0.04%,6 the most common reaction is a cutaneous eruption. Since anaphylactic reactions are mediated by immunoglobulin E (IgE), evaluation of patients with a history of penicillin allergy by penicillin skin testing is recommended to rule out IgE-mediated reactions.

This review outlines a practical approach to evaluating a suspected IgE-mediated reaction to penicillin, with key points in the history and diagnostic testing. We also review subsequent management and cross-reactivity with other beta-lactam-containing antibiotics.


Evaluation of patients with a history of penicillin allergy can be improved with an understanding of the classification of drug reactions, risk factors for allergy, and the pathophysiology of penicillin allergy.

Classification of drug reactions

Adverse drug reactions include all unintended pharmacologic effects of a drug and can be classified as predictable (type A) or unpredictable (type B). Predictable reactions are dose-dependent, are related to the known pharmacologic actions of the medication, and occur in otherwise healthy individuals. Unpredictable reactions are further classified into drug intolerance, drug idiosyncrasy, drug allergy, and pseudoallergic reactions.8,9

Penicillin allergy can manifest as any hypersensitivity reaction of the Gell and Coombs classification (Table 1).9 Type I (immediate) and type IV (delayed) reactions are the most common types of reactions that occur with antibiotics and should be classified based on the onset of symptoms as immediate (within 1 hour) or delayed (days or weeks).8

Risk factors for IgE-mediated reaction

Risk factors for a hypersensitivity reaction include frequent or repetitive courses of penicillin10 and high-dose parenteral (rather than oral) administration.

Age and atopy are not risk factors for penicillin allergy.7 However, atopy increases the risk of a more severe anaphylactic reaction to penicillin, and anaphylactic reactions are most commonly reported between the ages of 20 and 49.6

Pathophysiology of penicillin allergy

Figure 1. In a penicillin molecule, metabolites of the core ring structure, ie, the beta-lactam ring and the thiazolidine ring, can trigger immediate immunoglobulin E-mediated reactions. Reactions to the side chain may be responsible for cross-reactivity with other antibiotics.

All penicillins share a common core ring structure (beta-lactam and thiazolidine rings) but differ in their side chains (R group) (Figure 1).

Under physiologic conditions, the core ring structure is metabolized into major (penicilloyl) and minor (penicillin itself, penicilloate and penilloate) antigenic determinants that may trigger an immediate IgE-dependent response.9 In the United States, commercial forms of antigenic determinates for skin testing exist in the form of penicillin G (minor determinant) and penicilloyl-polylysine, better known as Prepen (major determinant).

Immediate-type reactions to similar antibiotics such as aminopenicillins and cephalosporins may be caused by IgE antibodies against the R-group side chain rather than the core penicillin major and minor determinants.11

Questions to ask patients who have a history of penicillin allergy

Figure 2. Clinical decision algorithm for penicillin allergy.

Patients should be questioned closely about previous and current reactions to penicillin and should undergo skin-prick and intradermal testing, followed by graded-dose challenge or drug tolerance desensitization (Figure 2).

Questions to ask patients who have a history of penicillin allergy (Table 2)9,12 include the following:

Do you remember the details of the reaction? These include the route of administration, the time between the dose of penicillin and the appearance of symptoms, and how the reaction was managed.

Immediate reactions (ie, IgE-mediated, or Gell and Coombs type I) usually occur within the first hour after the first dose of the antibiotic, although they occasionally take up to 2 hours to occur, especially if the medication is taken orally and is taken with food. Symptoms consistent with IgE-mediated reactions include urticaria (most common), pruritus, angioedema, laryngeal edema, wheezing, shortness of breath, presyncope or syncope, hypotension, and cardiorespiratory collapse.

In contrast, symptoms of a non–IgE-mediated reaction are delayed in onset, occurring after days of treatment. They include nonpruritic maculopapular eruptions, hemolytic anemia, serum sickness, Stevens-Johnson syndrome, drug rash with eosinophilia and systemic symptoms, acute interstitial nephritis, and toxic epidermal necrolysis.9

Ask about previous and current reactions to penicillin

If the patient has had severe non–IgE-mediated reactions to penicillin (eg, Stevens-Johnson syndrome, toxic epidermal necrolysis, acute interstitial nephritis, hemolytic anemia, or serum sickness) in the past, skin testing, graded-dose challenge, and desensitization are contraindicated.

How many years ago did the reaction occur? Most patients lose their sensitivity to penicillin over time.7,13–15 Nearly 50% of patients with IgE-mediated penicillin allergy lose their sensitivity within 5 years of the reaction,15 increasing to 80% or more by 10 years.13

How was the reaction managed? What was the outcome? Use of and positive response to epinephrine and histamine 1 receptor antagonists (antihistamines) with resolution or significant improvement of symptoms within a few hours may indicate an IgE-mediated reaction.

What was the indication for penicillin? Many cutaneous reactions are a result of an underlying viral or bacterial infection. For example, up to 90% of patients with Epstein-Barr virus infection develop a maculopapular rash when given penicillin.16

Have you tolerated other forms of penicillin since the reaction? Sometimes the patient has already tolerated other beta-lactams such as aminopenicillins, cephalosporins, and semisynthetic penicillins (piperacillin-tazobactam). Patients who tolerate other beta-lactams without adverse reactions are not allergic to beta-lactams.

Next Article:

A 57-year-old woman with abdominal pain

Related Articles