Condition

Penicillin Allergy

Editors: James M. Fernandez MD, PhD; Roxana I. Siles MD, FACAAI, FAAAAI; Zbigniew Fedorowicz PhD, MSc, DPH, BDS, LDSRCS; Dan Randall MD, MPH, FACP

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Background Information

Description

  • Penicillin allergy is an immune-mediated reaction to penicillins, their derivatives, or their metabolic products.
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  • Penicillins are beta-lactam antibiotics.
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  • Other beta-lactam antibiotics include cephalosporins, monobactams, and carbapenems.
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    • All beta-lactams have a beta-lactam ring.
    • Side chains differ among the beta-lactams.
    • Penicillins and monobactams (aztreonam) have an R1 side chain.
    • Cephalosporins have both an R1 and R2 side chain.

Also Called

  • Penicillin allergic reaction
  • Allergy to penicillin
  • Adverse reaction to penicillin

Types of Hypersensitivity Reactions

  • Hypersensitivity reactions to penicillins can fall into any category depending on underlying immunologic response (based on the Gell-Coombs classification).
    • Type I: immediate (IgE-mediated) reactions
    • Type II: cytotoxic (IgG- and/or IgM-mediated) reactions
    • Type III: IgG/IgM immune complex-mediated reactions
    • Type IV: delayed-type hypersensitivity (T-cell-mediated) reactions, which are subdivided into 4 types:
      • Type IVa: T-helper 1 (Th1) cell-mediated reactions
      • Type IVb: Th2 cell-mediated reactions
      • Type IVc: cytotoxic T-cell-mediated reactions
      • Type IVd: T-cell-mediated neutrophilic inflammation
    • Reference -
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      , J Allergy Clin Immunol Pract 2020 Oct;8(9S):S3
  • Immune-mediated reactions may also be classified based on timing of symptoms into immediate reactions and nonimmediate (also called delayed) reactions.
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    • Immediate reactions:
      • Typically occur within 1 hour after administration of the drug, but can occur up to 6 hours after administration.
      • Are usually IgE-mediated, type I reactions.
    • Nonimmediate or delayed reactions:
      • Typically occur > 1 hour after administration of the drug, but often occur many hours to days after therapy.
      • Are usually T-cell-mediated types II, III, or IV reactions.

Incidence/Prevalence

  • Hypersensitivity reactions are reported to occur with 0.5%-2% of penicillin administrations.
    • The most commonly reported reaction is skin rash.
    • The rate of immediate, IgE-mediated reactions appears to be decreasing.
    • Reference - JAMA 2019 Jan 15;321(2):188
  • Maculopapular (morbilliform) rashes associated with penicillins:
    • Maculopapular (morbilliform) rashes are reported in up to 10% of patients taking ampicillin or amoxicillin.
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    • 30%-100% of patients with Epstein-Barr virus or herpes virus infection who are given aminopenicillins report developing maculopapular (morbilliform) rashes.
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  • About 10% of patients report a history of allergic reactions to penicillin; however, after evaluation, ≥ 90% of these patients can tolerate penicillin.
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    • Reasons for the discrepancy between reported and actual penicillin allergy include:
      • Mislabeling an adverse effect (such as gastrointestinal disturbances or vaginitis) as a penicillin allergy
      • Mislabeling a manifestation of an underlying viral or bacterial infection or an interaction of the infection with the antibiotic (such as a rash) as a penicillin allergy
      • Waning of penicillin IgE antibodies over time, considering that:
        • Sensitization to penicillin is reported to decrease over time
        • After 20 years, most patients with initial symptoms consistent with penicillin allergy are able to tolerate penicillin
      • Reference - J Allergy Clin Immunol Pract 2020 Oct;8(9S):S3
    • Frequency of different types of reaction to penicillin (in patients reporting penicillin allergy) in electronic health records include:
      • Rash in 38%
      • Unknown in 26%
      • Hives in 18%
      • Angioedema in 9%
      • Gastrointestinal upset in 6%
      • Anaphylaxis in 5%
      • Itching in 5%
      • PubMed30644987JAMAJAMA201901153212188-199188Reference - JAMA 2019 Jan 15;321(2):188
  • In a large medical database, rates of 0.7% for allergic-like events and about 0.005% for anaphylaxis were reported within 30 days of receiving penicillin.
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  • STUDY SUMMARY
    94% of children and adults with self-reported history of penicillin allergy reported to tolerate penicillin challenge without adverse hypersensitivity response
    SYSTEMATIC REVIEW: Am J Med 2020 Apr;133(4):452

Risk Factors

  • Risk factors for allergic reactions to penicillin include:
    • Concurrent viral infections, as some delayed hypersensitivity reactions occur more often in the presence of a viral infection, particularly Epstein-Barr virus.
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      • 30%-100% of patients with Epstein-Barr infection who are treated with amoxicillin or ampicillin are reported to develop a nonpruritic maculopapular (morbilliform) rash.
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      • Aminopenicillins are associated with maculopapular (morbilliform) rash in ≤ 7% of patients while penicillin VK is associated with maculopapular (morbilliform) rash in about 2% of patients.
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      • Other viral infections that have been implicated in hypersensitivity reactions to penicillin and other drugs include Humanherpes virus (HHV-6) and cytomegalovirus (CMV). Reactivation can even mimic or exacerbate symptoms of drug reaction with eosinophilia and systemic symptoms (DRESS) (J Allergy Clin Immunol Pract 2022 May;10(5):1155-1167.e5full-text).
    • Topical and parenteral administration
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    • History of reaction to other drugs (multiple drug allergy syndrome) or previous reactions to penicillin
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    • Repetitive penicillin exposure
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  • Allergic reactions to penicillin may be reported more commonly in female patients and in patients aged 20-49 years or > 80 years old.
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  • Certain disease states, such as cystic fibrosis, Ebstein-Barr viral infection, and HIV infection may predispose patients to penicillin allergy.
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Etiology and Pathogenesis

Causes

  • Penicillin allergy is caused by exposure of sensitive patients to penicillins and penicillin derivatives, including:
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  • Some reactions, particularly delayed maculopapular (morbilliform) rashes, may be triggered by penicillins acting as co-factors with viral infections to stimulate a T-cell response that manifests as the skin rash.
    • Epstein Barr Virus (EBV) or Humanherpes virus 6 (HHV-6) are most commonly associated with the development of rashes when penicillins are given to patients during these infections (World Allergy Organ J 2024 Mar;17(3):100877).
    • 30%-100% of patients with Epstein-Barr virus or herpes virus infection who are given aminopenicillins report developing maculopapular (morbilliform) rashes.
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  • Some patients may have selective allergy to specific penicillins.
    • For example patients may have positive skin testing with amoxicillin or ampicillin but negative testing to penicillin G or other forms of penicillin.
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    • This selectivity may be due to R-group side chains of aminopenicillins.
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    • Selective hypersensitivity to piperacillin/tazobactam has also been reported in a retrospective cohort study of 87 patients after skin testing with piperacillin/tazobactam plus other penicillin determinants. 48 patients (55%) were diagnosed with piperacillin/tazobactam hypersensitivity, including 26 patients (54%) with immediate reactions and 22 patients (45%) with nonimmediate hypersensitivity (J Allergy Clin Immunol Pract 2021 May;9(5):2001).

Pathogenesis

  • Penicillin and penicillin metabolites are thought to trigger an immune response through the following mechanism.
    • Penicillin is metabolized into benzylpenicilloyl (major determinant) and other byproducts (minor determinants), both of which play a role in immune response.
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      • The beta-lactam ring opens to form benzylpenicilloyl, which is the chemical entity thought to be responsible for about 60%-85% of allergic reactions to penicillin.
      • Penicillin can also isomerize to penilloate, penicilloate, and benzyl-n-propylamine. These are also called minor determinants and are thought to be responsible for about 10%-20% of reactions.
    • Penicillin binds to carrier proteins to form haptens, inducing an immune response.
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      • The formation of haptens is a necessary step, as the penicillin molecule is too small to induce an immune response.
      • Carrier proteins for penicillin have not been identified.
  • Immunologic mechanisms involved for each allergy type:
    • Type I reactions are immediate and IgE-mediated:
      • Penicillin hapten formation leads to production of IgE antibodies through T-cell and B-cell initiated mechanisms.
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      • Sensitization after initial exposure to penicillin often takes weeks to develop, but clinical symptoms typically manifest < 1 hour after penicillin reexposure because specific IgE antibodies are activated quickly.
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      • IgE antibodies bind to mast cells and basophils, activating release of histamine and other inflammatory mediators.
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      • Angioedema and urticaria are fairly common features of IgE-mediated reactions, but immediate reactions can also present with hypotension, bronchospasm, or (rarely) anaphylaxis. Anaphylaxis is more often reported with reactions to minor penicillin determinants than major determinants.
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      • Anaphylaxis usually presents with acute onset of skin manifestations (such as hives, pruritus, flushing, or swelling of lips/tongue/throat) and bronchospasm or hypotension, but can also be defined as the involvement of 2 or more organ systems OR a drop in blood pressure alone after allergen exposure. See Anaphylaxis for additional information.
    • Type II-IV reactions are considered nonimmediate and involve other mechanisms.
      • Type II reactions are caused by antibody-mediated cell destruction and related mechanisms.
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        • Penicillin metabolites bind to circulating proteins and form haptens/antigens on cell surfaces (such as white or red blood cells, neutrophils, or platelets) to which IgG and IgM bind leading to antibody-dependent, cell-mediated cytotoxicity, complement-dependent cytotoxicity, and phagocytosis.
        • Clinical manifestations of these processes can include hemolytic anemia, thrombocytopenia, and cytopenia.
        • Clinical symptoms typically manifest < 72 hours (but can be days) after penicillin exposure.
      • Type III reactions are mediated by formation of immune complexes.
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        • Penicillin metabolites bind to circulating proteins and form complexes with IgG or IgM (or aggregates) that deposit into tissues of the kidneys, joints, and/or skin, and activate the complement system.
        • Clinical manifestations depend on the site of deposition and include fever, vasculitis, serum sickness, interstitial nephritis, arthralgia, lymphadenopathy, splenomegaly, and/or erythema multiforme.
        • Clinical symptoms typically manifest days to weeks after penicillin exposure.
      • Type IV reactions are cell-mediated:
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        • There are 4 subtypes which include Type IVa (mediated by Th1 helper T cells and macrophage activation), Type IVb (mediated by (mediated by Th2 cells and eosinophils), Type IVc (mediated by cytotoxic CD8 T cells leading to cell death), and Type IVd (mediated by cytotoxic CD8 T cells, Th17 helper T cells, and neutrophils).
        • Type IV reactions are thought to involve T-cell-mediated responses.
          • In the hapten model, penicillin protein-hapten complexes are taken up and processed by antigen presenting cells. Presentation of the fragments on major histocompatibility complexes (MHC) activates T-cell responses.
          • In the P-i concept model (pharmacologic interaction with immune receptor), a drug binds directly (noncovalently) to T-cell receptors and interactions with major histocompatibility complexes then activate an immune response.
          • T-cell responses include activation of CD4 T cells that stimulate white blood cells, causing tissue damage and/or activation of CD8 T cells, resulting in cell apoptosis.
        • Notable clinical manifestations include contact dermatitis (Type IVa), maculopapular exanthems and drug rash with eosinophilia and systemic symptoms (DRESS) syndrome (Type IVb), Stevens-Johnson syndrome/toxic epidermal necrolysis (Type IVc), and acute generalized exanthematous pustulosis (Type IVd).
        • Symptoms typically develop > 48 hours and within a few days after exposure, but reactions such as DRESS syndrome and Stevens-Johnson syndrome/toxic epidermal necrolysis may be delayed up to several weeks.
        • Reference - Allergy Asthma Proc 2019 Nov 1;40(6):470
Pathogenesis and clinical presentation of hypersensitivity reactions to penicillin

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Pathogenesis and clinical presentation of hypersensitivity reactions to penicillin

Abbreviations: AGEP, acute generalized exanthematous pustulosis; DRESS, drug rash with eosinophilia and systemic symptoms; GM-CSF, granulocyte-macrophage colony-stimulating factor; HLA, human leukocyte antigen; MHC-II, major histocompatibility complex class II; SJS, Stevens-Johnson syndrome; TCR, T-cell receptor; TEN, toxic epidermal necrolysis; Th2 cell, type 2 helper T cell.

The structure of penicillin, the major and minor allergic epitopes of penicillin and beta-lactams

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The structure of penicillin, the major and minor allergic epitopes of penicillin and beta-lactams

Panel A- The structure of penicillin and beta- lactams showing the consistent beta-lactam ring (shaded pink). Panel B- Penicillin metabolizes into benzyl penicilloyl (major determinant) and other byproducts -parent penicillin, penicilloate, and penilloate (minor determinants), which trigger an allergic response.

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