Penicillin and Antibiotic Allergies

Detailed Course Handout

1 Learning Objectives

Upon completion of this handout, you should be able to:

1. Describe the different types of hypersensitivity reactions based on clinical presentation and immunological mechanisms
2. Recognise a patient history that will differentiate between immediate and delayed-type hypersensitivity reactions
3. Describe the risk of cross-reactions between various beta-lactam antibiotics
4. Describe the principles and contraindications for desensitisation
5. Describe the clinical manifestations, diagnosis and management of common non-beta-lactam antibiotic allergies

2 Introduction and Definitions

Antibiotic allergies are characterized by an underlying immunological response manifesting as immediate or delayed hypersensitivity reactions. Despite being the most commonly reported medication class to which an allergy is reported, antibiotic allergies are often inaccurate and rarely confirmed when investigated. Reported “allergy” may actually represent antibiotic intolerances, drug–infection interactions, or unrelated cutaneous eruptions.

The majority of adverse drug events are not immunologically mediated allergic reactions, but rather what are categorized as type A drug reactions, referring to predictable, dose-dependent events secondary to the pharmacologic action of the drug (on-target adverse drug reactions). Only 10% to 15% of reactions are defined as type B, which are seemingly random and unrelated to pharmacologic effects (off-target adverse drug reactions). Although antibiotics are the most important cause of reported allergic drug reactions for infectious disease specialists, only a small percentage of reported antibiotic allergies are truly immune-mediated (Macy et al., 2023).

2.1 On-target vs. Off-target Drug Effects

Figure 1: Classification of on-target versus off-target drug adverse effects (Macy et al., 2023). On-target effects are predictable and dose-dependent, while off-target effects include true immunological hypersensitivity reactions.

3 Pathophysiology: Gell and Coombs Classification

According to the Gell and Coombs classification, there are four main pathophysiologic mechanisms that result in allergic drug reactions:

• Type 1 (Immediate/IgE-mediated): IgE-mediated immediate reactions may present as urticaria, angioedema, or anaphylaxis. They usually occur within 1 hour of drug administration but may occur up to 6 hours later.
• Type 2 (Cytotoxic): Exemplified by drug-induced hemolytic anemia or thrombocytopenia; relatively uncommon with antimicrobial agents.
• Type 3 (Immune complex): Serum sickness–like reactions presenting with rashes, fever, and arthralgias, typically occurring several days after initiation of the culprit drug. True immune complex reactions (type 3) do not occur with antibiotics, but phenotypically similar serum sickness-like reactions do occur.
• Type 4 (Delayed/T-cell mediated): The most common manifestation of antimicrobial drug reactions, exemplified by morbilliform drug eruptions (MDE).

Four additional subclassifications have been introduced for type IV reactions that highlight the heterogeneous T-cell response:

• Type IVa: Th1-mediated reaction involving macrophage activation (exanthem)
• Type IVb: Th2 mediated with eosinophil-rich exanthems (e.g., DRESS)
• Type IVc: Cytotoxic reactions with bullous exanthems or pustular reactions (e.g., SJS/TEN)
• Type IVd: Neutrophil-rich pustular reactions (e.g., AGEP)

Figure 2: Modified Gell and Coombs Classification of hypersensitivity reactions, showing the four main types and the subclassifications of Type IV delayed reactions (Hausmann et al., 2010).

3.1 Immunological Mechanisms

Although the Gell and Coombs classification is still used today, many drug reactions do not neatly fit into this system. Type 1 immediate-onset endotypes have evolved beyond IgE-mediated mast cell activation alone to also include non–IgE-mediated causes, such as direct mast cell degranulation (previously termed anaphylactoid or pseudoallergic) and cytokine release. The human G protein–coupled receptor MRGPRX2 has been identified as a mast cell–specific receptor critical for direct mast cell activation (including degranulation) secondary to drugs such as vancomycin and ciprofloxacin (Castells et al., 2019).