Summary

Ampicillin is a semi-synthetic, broad-spectrum penicillinase-sensitive aminopenicillin with a beta-lactam ring and side chain as sites for immunological recognition. Ampicilloyl is the major allergenic determinant of ampicillin, formed when the β-lactam ring opens and covalently binds to proteins, creating a stable hapten-protein complex. 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. However, 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.

A study conducted in Belgium on 1,009,598 patients (2010-2018), of whom 28,147 (3%) were labeled with antibiotic allergy, found that penicillin allergy labels had the highest prevalence, at 2% (22,824/1,009,598 patients). Aminopenicillins (ampicillin, amoxicillin and combinations) accounted for 0.12% (1208 patients). Among 1233 aminopenicillin labels, 42 were attributed to ampicillin.

A US-California-based retrospective chart review was conducted on 80 pediatric patients (mean age 7.3 years, mean time interval since the initial reaction 3.3 years) with an alleged penicillin drug allergy. Intradermal skin tests were performed in 73 patients, revealing sensitization to penicillin G, the major determinant of penicillin (benzylpenicilloyl-polylysine), and ampicillin in 19.2%, 8.3%, and 13.7% of patients, while 4.1% reacted to ampicillin only of.

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 6 (6.1%) had received ampicillin.

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.

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.

A study in Turkey with 81 children (median age 9 years, median time since index reaction 6 months) suspected of beta-lactam allergy, with aminopenicillins (amoxicillin, ampicillin and combinations) incriminated in 49 (60.5%) patients, found that upon allergological work-up, only 10 (12.3%) of patients received a confirmed diagnosis of beta-lactam allergy. Ampicillin was suspected in 8 patients prior to the investigations and confirmed in only 1 patient.

Pregnancy

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

Route Of Exposure

Main

Exposure to ampicillin mainly occurs during ampicillin treatment via two routes: orally in the form of a suspension, or tablets, and parenterally via injections of ampicillin.

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

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 drug challenge test.

Skin testing for ampicillin is performed with the injectable 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.

Similar to other penicillins, the interpretation of ampicillin-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

It is considered that patients with confirmed ampicillin 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: amoxicillin, cefaclor, cephalexine. However, the rate of real-world cross-reactivity might be lower than inferred from chemical structures.

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. A study throughout 2014 – 2018 identified 328 patients with cephalosporin allergy labels. Among them, 4.8% (16/328) had positive skin tests for ampicillin, and cross-reactivities were found between ampicillin and cephalexin, cefuroxime, ceftriaxone, and amoxicillin. Cross-reactivity between carbapenems and penicillins or cephalosporins is reportedly less than 1% with monobactams.

Explained Results

Allergen information

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

Clinical information

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

Cross-reactivity

Clinical reactivity to ampicillin 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.