Summary

Penicilloyl V (phenoxymethylpenicilloyl) is the major allergenic determinant of penicillin V, formed when the beta-lactam ring of this antibiotic is opened and binds to lysine residues in proteins during the process of haptenisation. Penicilloyl V can elicit mild to severe local and/or systemic allergic reactions. Immediate hypersensitivity reactions are IgE-mediated and tend to occur within one hour of administration, whereas delayed reactions may take up to several days to appear. The type of symptoms observed are variable, including but not limited to skin rashes, gastrointestinal signs, and anaphylactic shock. 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.

The true extent of penicillin allergy in the wider population is likely to be overestimated. Cross reactions between different types of β-lactam antibiotics (defined by the change of side chain attached to the β-lactam ring) are commonly observed, though specific sensitization to Penicillin V (with tolerance to other β-lactams) has also been observed.

Epidemiology

Worldwide distribution

Penicillin allergy appears to be the most common drug allergy reported in the USA, with a prevalence between 8-12%. True allergy is estimated to be up to 20% of reported suspect cases. A study by Ponvert et al reported that, following diagnostic workups, true allergy was confirmed in 12–60% of children with suspected β-lactam hypersensitivity. In a review by Bhattacharya, the adverse reactions associated with penicillin administration ranked as common (experienced by >1% of patients) were diarrhea, nausea, rash, urticaria, neurotoxicity, superinfections. Infrequent adverse reactions (0.1–1% of patients) fever, vomiting, erythema, dermatitis, angioedema, seizures and pseudo-membranous colitis. True anaphylaxis (presenting with hypotension, angioedema, bronchospasm and urticaria were estimated around 0.02–0.04%. Oral administration, which is the route employed for penicillin V, is less likely to cause severe reactions such as anaphylaxis compared to parenteral administration.

Risk factors

A history of previous allergic reaction to penicillins, gender bias (female) and increasing age may all be risk factors for penicillin allergy. People of Asian race may have lower rates of penicillin allergy.

Pediatric issues

In the pediatric population, approximately 5% are diagnosed with a penicillin allergy, making it a prevalent medication allergy worldwide. Upon rigorous diagnostic testing, less than 5% of these cases are validated as clinically significant immediate (IgE-dependent) or delayed (T cell-dependent) allergy to penicillin. Additionally, the differentiation between an allergic rash and a viral exanthema in children poses a differential diagnostic challenge for penicillin allergy. It was shown that about 10% of pediatric drug reaction cases are initially reported positive, but only a few are verified through detailed allergy assessments. In pediatric patients, skin tests using major and minor determinants, along with amoxicillin, without a follow-up penicillin antibiotic dose challenge, was proposed as a safe and effective method for assessing IgE-mediated penicillin hypersensitivity.

Pregnancy

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

Route Of Exposure

Main

Penicillin V is only available in formulations for oral use.

Secondary

Hypersensitivity reactions can occur following exposure in the workplace. Production staff, healthcare workers and people handling veterinary medicines appeared to be most at risk of exposure.

Clinical Relevance

Clinical Relevance

Penicillin allergies can present as immediate or delayed reactions. Immediate reactions are IgE-mediated occurring within 1 to 6 hours of administration, albeit symptom onset takes place during the first 15 minutes in 85% of patients and range from urticaria to life-threatening anaphylaxis. Delayed reactions rely on a T-lymphocyte mechanism, occur at least 6 hours after administration, with a majority taking place after 1 to 2 weeks 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, and toxic epidermal necrolysis.

The clinical presentation of allergic reactions to penicillin V (broadly speaking, β-lactam antibiotics) is greatly varied in terms of type (systemic versus local reactions), body system affected and timing of appearance of the symptoms. The severity of the symptoms also greatly varies between patients, from mild skin rash to severe anaphylactic shock.

Symptoms of immediate allergic reactions include urticaria, angioedema, rhinitis, bronchospasm, anaphylaxis (with or without shock) and maculopapular exanthema. In a retrospective study of patients who had previously reported a suspected penicillin allergy, the type of reactions were ranked from most common to least: skin rash, unspecified reaction, swelling or angioedema, anaphylaxis, other, itching, shortness of breath or dyspnea, nausea and/or vomiting, diarrhea, palpitations, headache and ocular toxicity. It is worth noting that many patients experienced more than one reaction.

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.

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. Technical improvements in penicillin reagents for in vitro diagnosis, introduced in 2006, resulted in a reported 82% reduction of false positive penicillin-specific IgE results.

The interpretation of penicillin-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. A study in 171 patients with immediate reactions to penicillins and positive allergy work-up found that a ratio of specific IgE to penicillins (sum of specific IgE to a panel including benzylpenicillins and aminopenicillins) to total IgE greater than 0.002 had a positive predictive value of 92.5%.

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.

Cross-Reactivity

Cross reactions between different penicillins are described.

IgE-mediated responses tend to recognize the same side chain within different groups of β-lactams, rather than the β-lactam ring, therefore side chain similarity is more often involved in cross-reactivity. However, it is also possible to become selectively sensitized to penicillin V. In an isolated case of a 34-year-old man receiving treatment for an infection, generalized urticaria without pruritus was noted. However, upon allergy workup, the results were negative, and the patient could still tolerate other β-lactams. Meng et al. carried out the diagnostic workup on a number of patients to identify whether a reported specific penicillin allergy was cross-reactive with other β-lactams. In one patient who was allergic to flucloxacillin, specific IgE testing and skin test were positive for a number of other β-lactams, including penicillin V.

Cephalosporins do not need to be ruled out to treat a patient with proven penicillin allergy, provided that the side chain is different from the penicillin causing allergic reactions.

Explained Results

Allergen Information

Penicillin V or phenoxymethylpenicillin is a commonly prescribed beta-lactam antibiotic. Its allergenic properties require haptenization with carrier proteins such as serum albumin, followed by the generation of major and minor allergenic determinants.

Clinical information

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

Cross-reactivity

Different types of penicillin and cephalosporins exhibit partial cross-reactivity, mainly due to shared beta-lactam rings and similar side chains. The rate of cross-reactivity varies, being higher with aminocephalosporins due to their similar R1 side chains, while cephalosporins like cefazolin show much lower cross-reactivity due to distinct side chains.