c2 Penicilloyl V

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.

Nature

Penicillin V (phenoxymethylpenicillin) is a molecule characterized by the presence of a phenoxy-methyl side chain attached to the β-lactam penicillin ring (Pubchem 2021). The β-lactam ring is the four-member chemical structure that is responsible for the antimicrobial properties of penicillin (De Rosa 2021).  All classes of penicillins share the β-lactam ring and a thiazolidine ring, with differing side chains (Patterson 2021). IgE-mediated allergic reactions appear to be directed at different parts of the penicillin molecule; some bind to side chains (thus determining cross-reactivities), some bind to the thiazolidine or β-lactam ring, other IgE bind to the molecule as a whole, and any combinations in between (Baldo 1999). When the ring structure is metabolized, it forms minor (penicillin, penicilloate and penilloate) and major (penicilloyl) allergenic components (Baldo 1999, Patterson 2021). It is estimated that around 95% of penicillin molecules that bind to proteins under physiological conditions form penicilloyl groups, hence “major” stands for “larger amount” rather than other antigenic qualities (Baldo 1999). 

Penicillium chrysogenum is the organism used to industrially produce penicillin V (Castle 2007).

Worldwide distribution

Penicillin allergy appears to be the most common drug allergy reported in the USA, with a prevalence between 8-12% (Albin 2014). True allergy is estimated to be up to 20% of reported suspect cases (BMJ Bulletin 2017). A study by Ponvert et al (Ponvert 2011) reported that, following diagnostic workups, true allergy was confirmed in 12–60% of children with suspected β-lactam hypersensitivity. In a review by Bhattacharya (Bhattacharya 2010), 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% (Bhattacharya 2010, Patterson 2021). Oral administration, which is the route employed for penicillin V, is less likely to cause severe reactions such as anaphylaxis compared to parenteral administration (ScienceDirect 2021).

Risk factors

A history of previous allergic reaction to penicillins, gender bias (female) and increasing age may all be risk factors for penicillin allergy (Albin 2014, BMJ Bulletin 2017). People of Asian race may have lower rates of penicillin allergy (Albin 2014).

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 (Kwok 2023). 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 (Piccorossi 2020). 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 (D'Netto 2022).

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 (Wolfson 2021).  

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 (Montelius 2005).

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 (Bousquet 2007, Bhattacharya 2010, Castells 2019, Khan 2022, Kopač 2012).

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 (Bousquet 2007, Bhattacharya 2010). The severity of the symptoms also greatly varies between patients, from mild skin rash to severe anaphylactic shock (Patterson 2021).

Symptoms of immediate allergic reactions include urticaria, angioedema, rhinitis, bronchospasm, anaphylaxis (with or without shock) and maculopapular exanthema (Bhattacharya 2010, Bousquet 2007, Romano 2003). 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 (Albin 2014).

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 (Siew 2019).

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 (Sousa-Pinto 2021). 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 (Zidarn 2009).

The interpretation of penicillin-specific IgE should ideally consider the level of total IgE (Garvey 2019). Low levels of penicillin-specific IgE display lower diagnostic specificity in the context of elevated total IgE levels  (Vultaggio 2009, Zidarn 2009, Lendal 2025). 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% (Vultaggio 2015).

Penicillin sensitization decreases over time and may become undetectable with both skin tests and serum specific IgE (Hjortlund 2014, Lendal 2025). The half-life of serum specific IgE was found to be 1 year in most patients (Hjortlund 2014). Accordingly, penicillin allergy work-up is recommended 4-6 weeks after the drug-induced reaction (Demoly 2014) and no later than one year after the index reaction (Hjortlund 2014, Lendal 2025). Early investigation can be performed with specific IgE determination in acute samples obtained at the time of an immediate reaction (Garvey 2019). Specific IgE testing is recommended as the first-line investigation in high-risk patients, e.g. having experienced severe immediate reactions to penicillin (Demoly 2014, Dona 2025). 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 (Garvey 2019, Romano 2020, Dona 2025)

If specific IgE tests are negative, additional examinations with skin and drug provocation test become necessary (Lendal 2023, Dona 2025).

Conversely, USA practice parameter recommends skin testing over blood IgE testing due to lower diagnostic sensitivity of the latter (Khan 2022).

Cross-reactivity

Cross reactions between different penicillins are described (Antunez 2006; Bhattacharya 2010).

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 (Bhattacharya 2010, Patterson 2021, Antunez 2006). 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 (Sanchez-Morillas 2014). Meng et al. (Meng 2016) 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 (Meng 2016).

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 (BMJ Bulletin 2017, Novalbos 2001).

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.

Author: RubyDuke Communications

Reviewer: Dr. Joana Vitte

Last reviewed: September 2025