Summary

Amoxicillin is a semi-synthetic, broad-spectrum, penicillinase-sensitive aminopenicillin with a beta-lactam ring and side chain as sites for immunological recognition. Amoxicilloyl is the major allergenic determinant of amoxicillin, produced when its β-lactam ring opens and covalently attaches to proteins, forming a stable hapten-protein conjugate. Most common manifestations of allergy to the penicillin family are benign immediate and delayed cutaneous reactions, however, penicillin allergy is also the leading cause of fatal drug anaphylaxis. Clinical history alone is not reliable for the diagnosis of penicillin allergy, hence one or more among skin and blood tests for penicillin sensitization and penicillin provocation tests are required. Penicillin skin testing and penicillin-specific IgE determination are highly specific but lack diagnostic sensitivity for immediate allergic reactions. A clearly positive IgE test to penicillin has been proposed by international guidelines as a criterion for sparing drug provocation tests for penicillin allergy diagnosis.

Despite a reported global prevalence of 6%-25% for penicillin allergy, fewer than 10% of suspected cases are truly allergic to penicillin. The burden of penicillin allergy overdiagnosis has personal and public health implications. Factors predictive of genuine allergy to penicillins include frequent antibiotic use, female gender, older age, a family history of allergies, and atopic conditions. Cross-reactivity between aminopenicillins and benzylpenicillins and between aminopenicillins and other beta-lactams, such as cephalosporins, is variable, depending on the similarity in chemical structures.

Epidemiology

Worldwide distribution

Penicillin allergy, with an estimated prevalence of 6%-25%, is the most reported drug allergy globally. In keeping with other penicillins, the estimated incidence of allergy to amoxicillin was found to range between 1% and 10 %. It is estimated that allergological work-up could delabel beta-lactam allergy in 90% of patients.

Indeed, <10% of people labeled as penicillin allergic have a true immunoglobulin (Ig)E-mediated hypersensitivity to penicillin, while most of these could safely tolerate penicillin. This is possibly due to two reasons: inaccurate diagnosis and the gradual loss of sensitization with time.

In a prospective Spanish study conducted in 510 pediatric patients (< 16 years) with a clinical history of reactions to beta-lactam drugs, amoxicillin involvement was suspected in 349 cases (68.5%) based on the clinical history, but confirmed in only 39 cases (11%). Overall, allergological workup confirmed genuine beta-lactam allergy in only 54 cases (10.6%) from this cohort.

Among 221 patients labeled as having amoxicillin hypersensitivity, only 37 (16.7%) had confirmed amoxicillin allergy after SPT and drug provocation test (DPT) in a UK-based retrospective study from 2013-2019. Among 100 patients exposed to amoxicillin-clavulanic acid as index drug, amoxicillin allergy was confirmed in 47.

A retrospective study conducted on drug-induced anaphylaxis reports (January 2004 – December 2014) from the Beijing Pharmacovigilance Database retrieved 1189 cases (mean age 47.6 years) with 39.3% (467/1189) attributed to antibiotics. Among the antibiotics, beta-lactams were suspected in most cases (58.9%; 275/467), and among these, amoxicillin was suspected in 8 cases, either alone or in combination with clavulanic acid.

In a Thailand-based cross-sectional study on 13,959 patients who had received at least one treatment course with penicillins and/or cephalosporins, adverse drug reactions were documented in 99 patients of whom 29 (29.3%) had received amoxicillin and 19 (19.2%) had received the amoxicillin – clavulanic acid combination.

A surveillance-based study was conducted on 6542 children in US emergency departments between 2011-2015 to evaluate antibiotic adverse drug events (ADEs) leading to emergency visits. ADEs comprised allergic reactions, but also other adverse effects, effects of excess dose, and others. Amoxicillin was found to be the leading cause of ADE in children ≤9 years; however, ADE proportion decreased with age (≤2 years [67.6%], 3-4 years [54.5%], and 5-9 years [44.7%]).

Using 2013 - 2023 data in the FDA Adverse Event Reporting System, adverse reactions to penicillins were reported as anaphylaxis more often than other medications (6.5% compared to 0.23%). Among 3176 penicillin-related anaphylaxis reports, 2373 (74.7%) concerned amoxicillin, either alone (1353 cases) or in combination with clavulanic acid (1,020 cases). Thus, anaphylaxis to amoxicillin-containing drugs had a reporting odd risk of 1.97 (95%CI 1.82-2.14) compared with all other penicillins.

Risk factors

Risk and predictive factors contribute to the stratification of patients’ risk of having genuine beta-lactam allergy, and thus to the choice of the diagnostic strategy.

A study identified antibiotic overuse to be significantly associated with the risk of allergic diseases in both adults and children. Penicillin allergy has also been found to be more prevalent in females and older individuals. The presence of atopic diseases like asthma, family history of drug-induced allergy, and higher age at reactions may be considered risk factors for true amoxicillin allergy in children. Severe systemic reactions (anaphylaxis) are consistently more frequently reported in association with parenteral administration than with oral intake of penicillins (.

Pediatric issues

Beta-lactam antibiotics are the most prevalent medications that trigger allergic reactions in children. Approximately 5% of the pediatric population globally is diagnosed with a penicillin allergy but upon careful diagnostic testing, <5% of these cases are confirmed. Conversely, delayed rashes occurring during amoxicillin or ampicillin treatment in children with acute Epstein-Barr primoinfection (infectious mononucleosis) may be due to an allergic mechanism more often than previously suspected, since 5 of 10 children investigated in a case series exhibited T-lymphocyte activation to amoxicillin and ampicillin.

Among different penicillin antibiotics, amoxicillin is one of the most frequently prescribed antibiotics in children for the treatment of bacterial infections (community-acquired) and allergic and non-allergic reactions to amoxicillin are common in children.

Pregnancy

The evaluation of 222 pregnant women labeled as penicillin-allergic with clinical history, appropriate skin tests and if necessary a drug challenge test which was performed with amoxicillin resulted in the delabeling of 209 (95%) of these patients, confirming the overestimation of penicillin allergy diagnosis.

Route Of Exposure

Main

Exposure to amoxicillin mainly occurs during amoxicillin treatment via two routes: orally in the form of a solution, suspension, or tablets, and parenterally via injections of amoxicillin sodium salt. Occupational exposure occurs via direct skin contact and potentially via inhalation in healthcare and pharmaceutical workers.

Clinical Relevance

Penicillin allergies are divided into two categories: immediate and delayed, each stemming from different immune responses. Immediate reactions happen within 1 to 6 hours of taking the drug, with symptom onset taking place during the first 15 minutes in 85% of patients and can range from urticaria to life-threatening anaphylaxis. Delayed reactions occur at least 6 hours after dosing, with a majority taking place 1 to 2 weeks after intake, and may present as benign maculopapular exanthema but severe, life-threatening presentations are also reported, such as DRESS (Drug Reaction with Eosinophilia and Systemic Symptoms) syndrome, Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis.

In particular, amoxicillin and other aminopenicillins present with a higher risk for benign drug-induced delayed exanthema, typically described during acute Epstein-Barr virus infection.

A study evaluating hypersensitivity reactions to beta-lactams in children reported that the most prevalent presentations of immediate hypersensitivity to amoxicillin were mild to moderate, ranging from urticaria and exanthema to angioedema and asthma. A similar type of mild immediate reaction of urticaria and angioedema was observed in another study involving adult patients allergic to amoxicillin or penicillin.

Risk stratification is vital for healthcare providers in diagnosing and managing penicillin allergies, affecting decisions regarding beta-lactam therapy or alternatives. High-risk patients may show severe immediate reactions such as anaphylaxis, low blood pressure, laryngeal edema, bronchospasm in association with urticaria, angioedema, and generalized exanthema. Conversely, low-risk patients are reported to have milder immediate reactions like isolated pruritus, gastrointestinal symptoms, contact dermatitis, or mild maculopapular exanthema.

Diagnostics

Clinical predictors for true beta-lactam allergies are lacking, hence suspected allergy cases need to be confirmed by specific IgE testing and if necessary, by an in vivo DCT.

Skin testing for amoxicillin is performed with the water soluble formulation. Serum specific IgE testing is safe, is not influenced by ongoing antihistamine medication and can be performed in primary care settings. Both skin tests and IgE tests for penicillin allergy display high specificity but insufficient sensitivity, with a systematic review and meta-analysis finding 96.8% and 97.4%, and 30.7% and 19.4%, respectively. However, a novel chemiluminescence immunoassay (CLIA) with synthetic sIgE was found to exhibit 100% clinical specificity and 73% sensitivity in diagnosing amoxicillin allergic reactions in patients.

Similar to other penicillins, the interpretation of amoxicillin-specific IgE should ideally consider the level of total IgE. Low levels of penicillin-specific IgE display lower diagnostic specificity in the context of elevated total IgE levels. Penicillin sensitization decreases over time and may become undetectable with both skin tests and serum specific IgE. The half-life of serum specific IgE was found to be 1 year in most patients,. Accordingly, penicillin allergy work-up is recommended 4-6 weeks after the drug-induced reaction and no later than one year after the index reaction. Early investigation can be performed with specific IgE determination in acute samples obtained at the time of an immediate reaction. Specific IgE testing is recommended as the first-line investigation in high-risk patients, e.g. having experienced severe immediate reactions to penicillin. A clearly positive IgE test can be considered sufficient for the diagnosis of beta-lactam allergy in patients with an evocative clinical history, especially anaphylaxis

If specific IgE tests are negative, additional examinations with skin and drug provocation test become necessary.

Conversely, USA practice parameter recommends skin testing over blood IgE testing due to lower diagnostic sensitivity of the latter.

Prevention And Therapy

Prevention strategies

Avoidance

It is considered that patients with confirmed amoxicillin allergy must not be administered the trigger and cross-reactive molecules, based on similar side chains, particularly those belonging to the same subclass, such as other aminopenicillins and aminocephalosporins: ampicillin, cefaclor, cephalexine. However, the rate of real-world cross-reactivity might be lower than inferred from chemical structures. In addition, a majority of selective reactors to amoxicillin with IgE targeting the side chain tolerate other penicillins. The allergological work-up of patients reporting reactions to a combination of amoxicillin and clavulanic acid may result in the latter being the trigger, and amoxicillin can be safely administered.

Cross-Reactivity

Partial cross-reactivity within the penicillin family is reported, due to shared structural features such as side chains and the beta-lactam ring. Aminopenicillins (such as amoxicillin and ampicillin) have a side chain identical or similar to that of several first and second generation cephalosporins, explaining their cross-reactivity. However, cefazolin and cefuroxime do not exhibit structure similarity with amoxicillin. Cross reactivity has also been found between aminopenicillins and benzylpenicillin. In a study conducted in the UK (2013-2019), 15/36 (42%) of patients with confirmed amoxicillin hypersensitivity were found to cross-react with other penicillins, especially with benzylpenicillin (87%).

Explained Results

Allergen information

Amoxicillin is a commonly prescribed semi-synthetic, broad-spectrum, penicillinase-sensitive BL antibiotic of the aminopenicillin group. Its allergenic properties require haptenization with carrier proteins such as serum albumin. IgE to amoxicillin can target the side chain, the thiazolidine ring, or to the conjugate formed by the beta-lactam ring and the carrier protein.

Clinical information

Amoxicillin hypersensitivity reactions with a demonstrated adaptive immune mechanism are termed amoxicillin allergy. Immediate amoxicillin allergy (1-6 hours after administration) is mostly IgE-dependent, while delayed amoxicillin allergy (>6hours after administration) is mostly T cell-dependent. Urticaria and exanthema are the most common symptoms. Similar to other penicillins, confirmed amoxicillin allergy represents around 10% of patients with a label of amoxicillin allergy, prompting recommendations for proactive amoxicillin allergy delabeling after risk stratification.

Cross-reactivity

Clinical reactivity to amoxicillin may be selective if IgE is directed to the side chain, or cross-reactive with other penicillins if IgE is directed to the beta-lactam ring. The side chain of amoxicillin is identical or similar to that of several first- and second-generation cephalosporins, resulting in partial cross-reactivity with potential clinical relevance.