c2 Penicilloyl V

Penicillin V (phenoxymethylpenicillin) is a commonly prescribed β-lactam antibiotic which 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 is variable, including but not limited to skin rashes, gastrointestinal signs, and anaphylactic shock. 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 (1). attached to the β-lactam penicillin ring. The β-lactam ring is the four-member chemical structure that is responsible for the antimicrobial properties of penicillin (2).  All classes of penicillins share the β-lactam ring and a thiazolidine ring, with differing side chains (3). 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 (4). When the ring structure is metabolized, it forms minor (penicillin, penicilloate and penilloate) and major (penilloyl) allergenic components  (3, 4). 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 (4). 

Taxonomy

Penicillium chrysogenum is the organism used to industrially produce penicillin V (5).

Worldwide distribution

(Penicillin allergy appears to be the most common drug allergy reported in the USA, with a prevalence between 8-12% (6). True allergy is estimated to be up to 20% of reported suspect cases (7). A study by Ponvert et al (8) reported that, following diagnostic workups, true allergy was confirmed in 12–60% of children with suspected β-lactam hypersensitivity. In a review by Bhattacharya (9), 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% (3, 9). Anaphylaxis is more likely to occur following parenteral administration, compared to oral (10).

Risk factors

A history of previous allergic reaction to penicillins, gender bias (female) and increasing age may all be risk factors for penicillin allergy (6, 7). People of Asian race may have lower rates of penicillin allergy; therefore, this characteristic might be protective (6).

Main 

Individuals are most likely to come into contact with penicillins by oral or parenteral administration during the therapeutic course of common infections, although penicillin V is only available in formulations for oral use (10).

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 (11).

Penicillin allergies can present as immediate, IgE-mediated hypersensitivity reactions within one hour of administration, or delayed IgG-mediated reactions which may take several days to become apparent (9, 12).

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 (9, 12). The severity of the symptoms also greatly varies between patients, from mild skin rash to severe anaphylactic shock (3).

Symptoms of immediate allergic reactions include urticaria, angioedema, rhinitis, bronchospasm, anaphylaxis (with or without shock) and maculopapular exanthema (9, 12, 13). 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 (6).

Other topics 

Care should be taken by the prescribing medical professional regarding potential allergic cross-reaction to other components of a drug, such as excipients. In a 2015 case report, an 11-year old patient presented with a delayed skin reaction following administration of a penicillin-based antibiotic. The diagnostic workup confirmed that the delayed allergic reaction observed was due soy contamination (14).

Provocation tests such as Skin Prick Test (SPT) and Intra Dermal Tests (IDT) are considered the “gold standard” to diagnose a true hypersensitivity, but these are often not carried out due to ethical and safety concerns. As an alternative, a Basophil Activation Test (BAT) and measuring the total/specific IgE tests (15) can be used for the diagnosis of penicillin allergy.

However, as the agreement between the two tests is minimal and sensitivity is only marginally increased by performing both, the authors suggest that SPT and total IgE ratio might be more useful in improving the diagnosis of penicillin allergy (15). 

Cross-reactivity

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

IgE-mediated responses tend to be specific to the same side chain within different groups of β-lactams, rather than the β-lactam ring, therefore it is similarities of the side chains that determine cross-reactivity (3, 9, 16). However, it is also possible to become sensitized to penicillin V alone. 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 (17). Meng et al. (18) 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 (18).

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 (7, 19).

Author: RubyDuke Communications

Reviewer: Dr. Christian  Fischer

Last reviewed: December  2021