Penicillin Antibiotics and Allergy Reaction

Penicillin Antibiotics

In 1928 the bacteriologist Alexander Fleming discovered that Penicillium notatum can secrete an antimicrobial molecule that can inhibit bacterial growth in vitro and named it penicillin. The discovery of penicillin changed the course of history and set the stage for the antibiotic era and the subsequent development of other, more effective antibiotics. The original molecule extracted from P. notatum was originally called benzylpenicillin (penicillin G), and today penicillin refers to different molecules that has the structure of a β-lactam and has the same antimicrobial activity as penicillin G. Penicillin has saved millions of lives since its discovery, including children, pregnant women, patients with sepsis, meningitis or endocarditis, and other life-threatening infections, and today penicillin G remains the only recommended treatment for preventing mother-to-child transmission of syphilis.

To address the problem of penicillin resistance, pharmacologic research has begun to develop a new generation of penicillins. The second generation of penicillins are semisynthetic β-lactamase-resistant penicillins such as oxacillin, methicillin, and dicloxacillin, which resist the enzyme penicillinase in staphylococci, and are therefore also known as antistaphylococcal penicillins. The spectrum of activity of this class of antibiotics is relatively narrow, and in order to provide wider coverage of Gram-negative bacteria, a third generation of broad-spectrum penicillins (also known as aminopenicillins) was introduced, with amoxicillin and ampicillin being the main representatives of this class of penicillins. Third-generation penicillins are more effective against a wider range of Gram-negative bacteria because they are more stable to penicillinase. The last generation of penicillins, carboxypenicillins and ureidopenicillins, further extended the range of penicillin action against Gram-negative bacteria and showed potent activity against Pseudomonas aeruginosa.

Figure 1. Chemical structures of different classes of penicillins
(Source: Lobanovska M, et al. 2017)

Penicillin Allergy

Penicillin is the most common drug allergy found in medical records, with prevalence rates varying across regions and populations treated. Penicillin has been the most common cause of fatal and nonfatal allergic reactions to drugs in the United States and the United Kingdom. Benign skin reactions such as urticaria and delayed maculopapular rash are the most common types of reactions. The lowest incidence of anaphylaxis is associated with oral penicillins, and aminopenicillins are one of the drugs at high risk for causing a benign delayed rash, usually in the context of an acute EBV infection. In addition, aminopenicillins are considered the most common cause of acute generalized exanthematous pustulosis (AGEP). The administration of penicillins may also cause severe skin reactions in some patients, such as drug reactions with eosinophilia and systemic symptoms (DRESS).

Penicillin is a semi-antigen, and the β-lactam ring binds to lysine residues in serum proteins, and when bound to the polylysine substrate, it produces the major antigenic determinant, penicillamide polylysine. Clinical immune-mediated responses associated with penicillins are primarily antibody-mediated or T-cell-mediated. Immune responses mediated by antibodies can be divided into three categories, of which type I hypersensitivity is mediated by IgE. Dendritic cells bind and internalize penicillin-binding proteins for presentation to naive CD4⁺ T cells (type 0 helper T cells). In the presence of interleukin-4 (IL-4), naive T cells develop as penicillin-specific type 2 helper T (Th2) cells. The latter produce IL-4 and IL-13, which induce B cells to differentiate into penicillin-specific IgE-secreting plasma cells. IgE binds to Fc epsilon receptors on the surface of basophils and mast cells, and on re-exposure, polyvalent penicillin cross-links the Fc epsilon receptor bound to the IgE antibody, inducing degranulation of mast cells and the release of soluble inflammatory mediators such as histamine, prostaglandins, and leukotrienes, which leads to the clinical manifestations of anaphylaxis. In type II reactions, antibodies or immune complexes target the cell membrane structure of red blood cells, white blood cells, or platelets, leading to cell destruction or sequestration and ultimately hemolytic anemia and thrombocytopenia. In type III reactions, antibodies formed within 4 to 10 days react with the penicillin protein carrier to form soluble immune complexes. Activation and deposition of complement in small vessels leads to recruitment of neutrophils by Fc-IgG receptors, which releases protein hydrolases leading to tissue damage and localized vascular inflammation such as small vessel (hypersensitivity) vasculitis and serum sickness.

Figure 3. Antibody-mediated mechanisms of adverse reactions to penicillins
(Source: Castells M, et al. 2019)

T-cell-mediated reactions usually occur more than 6 hours after penicillin administration or during treatment with multiple exposures to penicillin. Delayed responses are usually associated with models involving non-covalent binding, such as models of pharmacological interactions or alterations in HLA peptide presentation specificity. Antigen-presenting cells process drug-modified peptides and present them to the antigen-binding groove of the HLA for recognition by T-cell receptors (TCRs) on CD4⁺ or CD8⁺ T-cells, leading to T-cell activation and release of cytokines and chemokines. Common phenotypes include reactions within 1 to 6 hours after exposure (urticaria and anaphylactic reactions), and reactions occurring more than 6 hours after a single or multiple administrations (macular papules). Delayed T-cell-mediated responses with systemic involvement include severe cutaneous reactions (SJS-TEN, DRESS, and AGEP).

Figure 4. T cell mediated mechanisms of adverse reactions to penicillins
(Source: Castells M, et al. 2019)

A thorough history evaluation of patients reporting penicillin allergy is necessary, and in some cases, allergists are readily available to perform penicillin allergy evaluations and to assist in the development of protocols, pathways, and referral processes to maximize the safety and efficiency of these evaluations. However, most patients reporting penicillin allergy may be evaluated by a non-specialist. Based on allergy history, patients can be risk-stratified, which helps clinicians decide whether a penicillin skin test or drug challenge is appropriate.

Table 1. Risk Stratification for Penicillin Allergy Evaluation

(Source: Shenoy ES, et al. 2019)

Penicillin ELISA Kits

Penicillin Antigens

Penicillin Antibodies