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Penicillin allergy—getting the label right

Abstract

Penicillini allergy is a potentially serious adverse reaction that impacts on antibacterial treatment options. Although it is commonly reported and recorded in medical records, only a minority of patients with a label of penicillin allergy actually have the condition confirmed. The term ‘allergy’ may be incorrectly applied to adverse reactions that do not have an immunological basis and inappropriate labelling of penicillin allergy can lead to the unnecessary avoidance of penicillins and other beta-lactam antibacterials. Here, we discuss key features that help to distinguish patients at low or high risk of having a true penicillin allergy, summarise what is known about the risk of allergic reactions to other beta-lactam antibacterials in patients with penicillin allergy and discuss the steps to consider when assessing a label of penicillin allergy.

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Background

Penicillin allergy is an immunologically mediated hypersensitivity reaction that can be life-threatening.1 It is the most commonly reported drug allergy in the UK, reported by about 10% of the population.2,3 However, it has been estimated that between less than 10% and up to 20% of those reporting penicillin allergy are truly allergic.2,4 It is important that the term penicillin allergy is correctly applied in order to avoid adverse effects or inappropriate treatment.

National guidelines highlight the need to check for hypersensitivity and outline treatment options for people with penicillin allergy.2,5,6 Prescription of a penicillin to patients with a previous allergy-like event following penicillin treatment is common and could result in a severe allergic reaction if there is a true penicillin allergy.2,7 People with suspected but unverified penicillin allergy are likely to be treated with alternative antibacterials that have a broader spectrum of activity, which may impact on microbial resistance patterns.8–10 In addition, alternative antibiotics may have more adverse effects and be more expensive.

In case-control studies, people with a history of suspected penicillin allergy spent more time in hospital and had poorer clinical outcomes than controls without such a history.11,12 In a retrospective study of patients in hospital in the USA, those with a label of penicillin allergy were exposed to significantly more fluoroquinolones, clindamycin and vancomycin (p<0.0001) and had higher rates of Clostridium difficile, MRSA and vancomycin-resistant enterococcus infections than matched controls.11

Strategies aimed at reducing incorrectly labelled penicillin allergy are important given the growing concern about the emergence of multi-resistant pathogens and the importance of antimicrobial stewardship programmes to preserve the effectiveness of antibacterials. Preliminary studies suggest that appropriate allergy testing and removal of incorrect labelling of penicillin allergy can decrease broad-spectrum antibacterial use and reduce length of inpatient stay, mortality and treatment costs.13,14

Basic immunology of penicillin allergy

Penicillins belong to a large group of antibacterials that share a four-membered beta-lactam ring in their molecular structure but differ in their side chains.1 Other beta-lactams include cephalosporins, carbapenems (e.g. imipenem, meropenem) and monobactams (e.g. aztreonam). Both the beta-lactam core and side chains in the molecule may be immunogenic.1,15 Degradation products of the beta-lactam core form the major allergenic determinants and those from the rest of the molecule form minor determinants. Both are included in preparations for allergy testing (see later).1

Reactions can be classified as immediate or non-immediate based on the timing of appearance of symptoms.1,15

Immediate reactions have their onset in 1 to 6 hours (generally within 60 minutes) after exposure to a dose of an antibacterial and often involve symptoms of an IgE-mediated allergic reaction, ranging from urticaria or pruritus to angioedema and anaphylaxis.1,16

Non-immediate reactions, occurring more than 60 minutes (commonly several days) after exposure to penicillin, mainly result from the release of specific cytokines by activated T-cell subsets. The most common non-immediate reactions are maculopapular/morbilliform and urticarial rashes.1,16

Less commonly, severe reactions may occur, including Stevens-Johnson syndrome, toxic epidermal necrolysis, serum sickness, drug reaction with eosinophilia and systemic symptoms (DRESS) and acute generalised exanthematous pustulosis.

Who is at risk of penicillin allergy?

Repeated exposure to antibacterials, for example in medical conditions that require frequent antibacterial use such as cystic fibrosis, is recognised as a clinical risk factor for penicillin allergy.1 Overall, evidence suggests that the risk of penicillin allergy is exposure-related, with those at highest risk of repeat exposure being at greatest risk. Female sex has been identified as a risk factor in adults for both self-reported and confirmed penicillin allergy,17,18 possibly related to greater antibacterial use in women.18 The prevalence of penicillin allergy appears to increase with age and may be partly explained by higher rates of antibacterial exposure in older age groups.18

Although a family history of penicillin allergy has been found to be associated with self-reported penicillin allergy, the issue of genetics and family history remains unresolved.1,19 There does not appear to be a major relationship between atopy and the incidence of penicillin allergy.1,19 However, the British National Formulary (BNF) advises that people with atopic allergies may be at greater risk from anaphylactic reactions to penicillins.20

No specific risk factors have been identified in children.1 In a study of children (average age 3.5 years, range 6 months to 14.5 years) in whom delayed-onset urticarial or maculopapular rash after penicillin administration had been reported, the rash recurred in only 6.8% on re-challenge.21 Viral infections were detected in the majority of children with a negative re-challenge result and it has been suggested that many rashes attributed to penicillin allergy may be viral in origin.21,22

Management issues

For some people, the label of penicillin allergy may have few clinical consequences if their need for antibacterials is infrequent. However, a full diagnostic work-up by specialist allergy services is recommended for people with specific anticipated treatment requirements (see Box 1).1,2

Box 1

Indications for investigation of people with suspected penicillin allergy (immediate or non-immediate reactions)1

  • a label of ‘multiple antibacterial allergy’, or

  • a personal history of beta-lactam hypersensitivity in people who require frequent antibacterial treatment (e.g. people with cystic fibrosis, diabetes, immunodeficiencies), or

  • a personal history of beta-lactam hypersensitivity in people who require treatment with a specific beta-lactam, or

  • a history of an anaphylactic reaction during general anaesthesia when penicillin was one of a number of drugs administered.

There is no single validated test to diagnose or exclude beta-lactam hypersensitivity and a combination of tests is required.23 The protocol in the European Network for Drug Allergy (ENDA)ii guidelines (published in 2003) includes clinical history, skin tests, in-vitro testing and, when required, drug provocation tests.24 In a study of 1,779 people with suspected immediate hypersensitivity to penicillin, diagnosis was confirmed in 509 (28.6%) using the ENDA short diagnostic algorithm.25

A survey of consultants involved with allergy testing in the UK found considerable variation in the investigation and management of beta-lactam hypersensitivity and low adherence with the European guidelines.23 Among the reasons identified were the time and resources required to undertake the full ENDA protocol, which takes 2 to 5 days to complete. The need for a UK guideline was highlighted.

UK-specific guidelines have been produced by the British Society for Allergy and Clinical Immunology (BSACI), which omit the routine use of in-vitro testing (see Box 2).1

Box 2

BSACI guidelines—steps for verifying suspected penicillin allergy

  • Detailed clinical history

  • Skin tests*

  • If skin tests are negative, oral provocation test*

*If results are positive, avoid penicillins in future; if both skin tests and oral provocation tests are negative, patient is regarded as tolerant.

Clinical history

Although clinical history alone is an unreliable basis for diagnosing penicillin allergy, it forms an essential first step in assessing the diagnosis.1,2 When a patient presents with suspected penicillin allergy, the following data should be collected:1,2

  • name and route of administration of penicillin given, and indication;

  • date and time of the reaction;

  • time between last dose administered and onset of symptoms;

  • description of the reaction: nature and severity of symptoms;

  • resolution of symptoms.

In addition, written medical and nursing records, photographs and eye-witness accounts should be sought.1 It is important to distinguish immediate from non-immediate reactions, based on the time of onset of symptoms in relation to the last dose of drug received and to distinguish mild symptoms from moderate to severe reactions.

However, complete records may be unavailable, especially if the reaction occurred many years previously.

Skin testing

Skin testing provides useful diagnostic information for both IgE-mediated and T-cell-mediated reactions, and should be the first line of investigation in adults.1 It should be carried out in specialist allergy centres, as experience is required to interpret the results and to manage any potential adverse systemic reactions. Testing should be performed shortly after a reaction has occurred, as positive responses are less likely after a long interval.26 Testing should include major and minor determinants for penicillin hypersensitivity (commercially available as a standard preparation), benzylpenicillin, amoxicillin and the specific beta-lactam under suspicion.1

Skin tests for non-immediate reactions are not standardised, but typically either patch tests or late reading of intradermal tests at intervals up to 72 hours are used for T-cell mediated reactions.1 Patch tests are likely to be safe and helpful in people with other severe cutaneous reactions, but the safety of intradermal testing is uncertain and should only be considered in selected cases after careful risk assessment.1

Skin tests are not used to identify reactions mediated by IgG or IgM. Patients who have symptoms consistent with IgG- or IgM-mediated reactions (such as blood disorders or serum sickness) should not receive penicillin again.1

Skin testing for penicillin allergy is useful in children with a history of anaphylaxis.1 The diagnostic value of skin testing is lower in non-immediate reactions.1,22,27 The authors of a study in children with a history of delayed-onset urticarial or maculopapular rashes concluded that painful and time-consuming skin tests would have predicted a positive response in only 4 of 88 children and that an oral challenge was the best diagnostic test in these children.21 Skin tests are not considered to be useful in reactions such as erythema multiforme, which are not mediated by IgE or T cells.1

In-vitro testing

The sensitivity of bioassays for IgE in penicillin allergy is low.1 In the UK, IgE testing should be considered only for selected patients undergoing specialist investigation. In-vitro tests for other biomarkers are not currently used in clinical practice in the UK.

Oral provocation testing

For people with negative skin test results, drug challenge is required to confirm or exclude both immediate or non-immediate drug allergy.1 Oral provocation testing is not used in people with a positive skin test and is not recommended for people at high risk of delayed life-threatening reactions (e.g. those who have had a severe cutaneous systemic reaction) or for people with unstable asthma or those taking beta-blockers. Oral provocation tests should only be undertaken by specialist centres and typically involve administering incremental doses of the suspect drug under supervision.

Cross-reactivity

For both IgE-mediated and T-cell-mediated hypersensitivity, cross-reactivity between different penicillins, and between penicillins and other beta-lactam antibacterials appears to be mainly due to similar chemical side chain structures.28 Cross-reactivity related to the core beta-lactam ring structure and conferring cross-sensitivity to all beta-lactams appears to be rare.

Penicillin and cephalosporin cross-reactivity appears to have been overestimated, in part because first-generation cephalosporins were contaminated with penicillin.1 In penicillin-allergic patients, cross-reactivity between penicillin and first- and early second-generation cephalosporins has been reported to occur in up to 10% of patients, and between penicillin and third-generation cephalosporins in 2–3% patients. A meta-analysis reported an increase in allergic reactions to first-generation cephalosporins (e.g. cefadroxil, cefalexin, cefradine) in penicillin-allergic patients, but any increase was found to be negligible with second- and third-generation cephalosporins.29

Cefadroxil, cefradine, cefaclor, cefalexin and ceftaroline should be avoided in patients who have a confirmed reaction to a penicillin, as cross-reactivity can result from similarities in the side chains of the molecules.1,20 Other second- and third-generation cephalosporins with a different side-chain to the reacting penicillin may be considered, under specialist management, for life-threatening infections when non-cephalosporin antibacterials would be suboptimal.30 The BSACI guideline for patients with a history of penicillin allergy requiring cephalosporin treatment recommends skin tests for both penicillin and cephalosporin followed, depending on the results, by oral provocation and, if necessary, desensitisation.1

The BNF advises that patients with a history of immediate hypersensitivity to penicillin should not receive a cephalosporin.20 If a cephalosporin is essential in these patients because a suitable alternative antibacterial is not available, then cefixime, cefotaxime, ceftazidime, ceftriaxone or cefuroxime can be used with caution.20

Antibacterial choices for people with a label of penicillin allergy

Individuals with a history of anaphylaxis, urticaria, or rash immediately after penicillin administration are at risk of immediate hypersensitivity to a penicillin; these individuals should not receive a penicillin.20 People with a positive skin test should avoid penicillins and be prescribed alternative antibacterials for subsequent infections.1 People with severe non-immediate reactions to penicillin (e.g. toxic epidermal necrosis or Stevens-Johnson syndrome) should be advised to avoid penicillins under all circumstances, due to the potential severity of such reactions.

If there is a specific or regular requirement for treatment with penicillin, people with suspected IgE-mediated allergy should be formally re-evaluated for penicillin allergy in a drug allergy clinic (see above).1 For patients with confirmed IgE-mediated penicillin allergy, drug desensitisation under expert supervision leads to a temporary tolerance of a single course of penicillin but should only be carried out if this is felt to be clinically important and no alternative drug is available.1 However, expertise in drug desensitisation is limited to a relatively small number of specialist allergy centres in the UK.

For people with allergy to a particular penicillin side chain, it may be possible to select a beta-lactam with a different side chain.1,28

For patients in whom all beta-lactams are contra-indicated, alternative non-beta-lactam antibacterials include tetracyclines, metronidazole, macrolides, aminoglycosides, quinolones and glycopeptides.31 National antimicrobial prescribing guidelines include suggested alternatives for people with penicillin allergy.5,6

The BNF suggests that patients with a history of a minor rash (i.e. non-confluent, non-pruritic rash restricted to a small area of the body) or a rash that occurs more than 72 hours after penicillin administration are probably not allergic to penicillin.20 In these individuals, a penicillin should not be withheld unnecessarily for serious infections; the possibility of an allergic reaction should, however, be borne in mind. Other beta-lactam antibiotics (including cephalosporins) can be used in these patients.20

Drug allergy notification

Penicillin allergy notification is important for the prevention of further episodes. People with suspected or confirmed penicillin allergy should have their allergic status documented in their medical records and in all correspondence between primary and secondary care (and other healthcare providers).2 This information should be disseminated to other healthcare professionals to reduce the risk of re-exposure. If the suspected allergy has been excluded by allergy testing, details should be added to the medical record and all interested parties informed in writing.

Information for patients

People with suspected or confirmed penicillin allergy and their carers should be given verbal and written information about the allergy and the drugs and drug classes to be avoided.1,2 The information should be carried at all times (e.g. using a MedicAlert product) and be shared with healthcare professionals. Adrenaline auto-injectors are not usually prescribed for people with a drug allergy on the basis that the likelihood of an acute severe allergic reaction occurring outside of a medical setting is low.32

Conclusion

Penicillin allergy is an immunologically mediated hypersensitivity reaction that can be life-threatening. However, many patients who have been labelled as penicillin-allergic may have had a non-immunological adverse effect (e.g. vomiting, diarrhoea and non-specific rash), an idiopathic reaction or other temporally-related adverse reaction that was inappropriately attributed to the drug.

Ensuring that a label of penicillin allergy is correctly used has benefits for patients and may reduce healthcare costs and antibacterial resistance. Penicillins should be withheld from people with a label of penicillin allergy. Patients who are likely to require frequent treatment with a penicillin or treatment with a specific penicillin in the future should be considered for referal to specialist allergy clinics for confirmation or exclusion of penicillin allergy. Cross-reactivity to other beta-lactams (e.g. cephalosporins that have the same or similar side chains in their molecular structure) can occur. People who have experienced minor reactions to penicillins that have been incorrectly labelled as an allergic response may be able to tolerate second and third generation cephalosporins, carbapenems or monobactams. Non-beta-lactam antibacterials are an alternative in those with proven penicillin allergy or those at high risk of severe or life-threatening reactions.

For patients with a label of penicillin allergy, clear communication between healthcare professionals and across healthcare organisations is required to avoid the adverse consequences of allergic reactions or unnecessary use of alternative antibacterials.

Reference

Footnotes

  • i Penicillins are part of the beta-lactam family of antibacterials, which include cephalosporins, carbapenems and monobactams. In this article we use the term penicillin to refer to penicillin antibacterials and not to other beta-lactams.

  • ii A subgroup of the European Academy of Allergy and Clinical Immunology that includes individuals with a research interest in the epidemiological, clinical or fundamental aspects of drug hypersensitivity.

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