When is an allergy to an antibiotic really an allergy?

If the history of allergy is not definitive, the starting point is to consider whether the details of the reported allergic event give any clues as to the true nature of the reaction:

• Was it an allergy, an adverse effect or an intolerance (see below)?
• Could the symptoms have been caused by the illness, another medicine (including medicine interaction) or other factor rather than the antibiotic?
• Has the patient subsequently tolerated the same or a similar antibiotic?

The answers to these questions will help in the risk-benefit analysis of whether the antibiotic can be prescribed again.

Allergy is an immunological reaction (IgE-mediated hypersensitivity) to a medicine. It is when the immune system produces an exaggerated or inappropriate response that does not normally in occur in most other people.¹ It can be severe, is usually reproducible and may also occur with other structurally related medicines.² Allergies can attenuate over time or may persist for a lifetime. Symptoms and signs are usually rapid in onset, i.e. within one to two hours of taking the medicine, and include:³

• Urticaria
• Angioedema
• Bronchospasm
• Anaphylaxis

Delayed immune reactions can occur several days after antibiotic treatment is begun, and are generally mediated by T-cells (IgG-mediated).^{3, 4} Macular, papular or morbilliform rash is a common example of a delayed reaction to antibiotics, and it is often difficult to tell whether this rash is caused by the infection or the treatment.³ Delayed reactions to antibiotics (especially amoxicillin) are more often seen in patients with intercurrent infections of Epstein-Barr virus or HIV.³ Patients will usually not experience the reaction again if re-exposed to the antibiotic when well.³

More serious delayed immune reactions generally involve rash in conjunction with systemic symptoms, including:³

• Serum sickness-like reaction – onset several days after treatment and characterised by vasculitic rash, arthralgia, flu-like symptoms and sometimes proteinuria. This is most commonly seen in patients taking cephalosporins, particularly cefaclor, and sulfonamides.
• Stevens-Johnson syndrome – a form of toxic epidermal necrolysis, characterised by a red-purple rash and blistering of skin and mucous membranes. This is most commonly associated with the use of sulfonamides.
• Aseptic meningitis – can be induced with use of antibiotics such as trimethoprim or co-trimoxazole. The exact mechanism for this reaction is unknown.

Adverse effects are the undesirable but predictable symptoms and signs associated with the pharmacological action of a medicine, e.g. diarrhoea, nausea and vomiting with amoxicillin, Clostridium difficile infection as the cause of post-antibiotic diarrhoea.²

Intolerance is a sensitivity reaction to a medicine that does not involve the immune system. It is dependent on both the pharmacological action of the medicine and patient susceptibility factors.² It can be loosely defined as an unusually low threshold for experiencing the adverse effects of a medicine or an exaggerated expression of the adverse effects of a medicine, e.g. severe diarrhoea resulting in colitis with amoxicillin.² Intolerance can also be characterised by the development of an adverse effect that is not usually associated with that medicine, e.g. tinnitus with amoxicillin.²

Viral infection is a common cause of rash, particularly in children, e.g. roseola infantum.³ Rash caused by viral infection is often mistaken for an allergic reaction to antibiotics, e.g. in a patient given an antibiotic for an infection that is subsequently found to be viral rather than bacterial.

Who is most susceptible to antibiotic allergy?

Allergy to an antibiotic occurs after a person has had an initial exposure (which can include in utero exposure) and has become sensitised. Therefore prior tolerance of an antibiotic does not provide evidence that a person is not allergic.² Once a person has had a clinically significant IgE-mediated allergic reaction to an antibiotic, e.g. urticarial rash, it is likely, but not inevitable, that upon re-exposure to the antibiotic they will experience this reaction again, and in some cases the reaction will be more severe, e.g. anaphylaxis.² It has been estimated that up to 60% of patients with confirmed penicillin allergy will have an allergic reaction if re-exposed to penicillin, however, estimates vary considerably.⁴

Penicillin is the most frequent antibiotic class allergy (and penicillin G [benzylpenicillin] the most frequent allergy among penicillins), followed by sulfonamides and tetracylines.^{3, 4} Most people who report a “penicillin allergy” will not have a true allergy.⁵ In the United States, it is estimated that 8% of patients have a penicillin allergy noted in their clinical record.⁵ However, less than one in 20 of these people have a clinically significant IgE-mediated reaction on oral re-challenge of penicillin.⁵ It is estimated that anaphylaxis occurs in one to four people per 10 000 courses of penicillin, and 10% of these anaphylactic reactions are fatal.³

Parenteral administration of an antibiotic is associated with a higher risk of allergic reaction than oral administration. Allergy to antibiotics most commonly occurs between age 20 – 49 years.³ Beta-lactam antibiotic allergy is reported twice as frequently in females than in males,⁵ although this may be explained by higher antibiotic use by females in this age group. It is uncertain whether a history of atopy or a family history of antibiotic allergy increases a person’s risk of antibiotic allergy. A small study analysed risk factors in 62 patients who attended allergy clinics in the United States, of whom 23 had documented penicillin allergy and 39 were age, gender and ethnicity matched controls who had tolerated penicillin. Multivariate analysis showed that a history of penicillin allergy in a first-degree relative and a history of allergy to other medicines were significant risk factors for penicillin allergy. Penicillin allergy was associated with a history of atopy, but this was not statistically significant in the multivariate model.⁶ Limitations of this study included the sample size and whether patients attending an allergy clinic were a representative population. Further research is needed in this area to provide definitive answers.

Can you test for an antibiotic allergy?

If a patient has a convincing history of an allergic reaction to an antibiotic, there is no need for laboratory investigation; allergy is established and laboratory confirmation of this would not change management.

If the patient has an uncertain history, it is in theory possible to test for antibiotic allergy, however, testing is not available for all antibiotics and when it is available, results need to be interpreted appropriately.

Blood tests for serum specific IgE (EAST/RAST) to penicillin can be requested by any primary care practitioner. Most patients who are allergic to penicillin are not allergic to the whole molecule; instead, their reaction is to degradation products of penicillin bound to self-carrier proteins.³ Serum specific IgE testing to penicillin includes the major antigens but does not include the “minor determinants”. A positive result is therefore useful but a negative result does not exclude a significant allergy, and sensitivity may be as low as 45%.⁷ Skin prick and intradermal testing to penicillin, which includes the major and minor determinants, is a specialist procedure, only offered at certain hospitals. The negative predictive value of this test is very high, with no serious reactions reported in patients who were negative on testing who then underwent penicillin challenge. Some hospitals will perform supervised antibiotic challenges on all patients with negative skin prick or intradermal tests.

Some providers may offer skin prick or intradermal testing for cephalosporin allergy. Testing for other antibiotics is not usually available.

If laboratory testing for antibiotic allergy is being considered, it is strongly recommended to discuss an appropriate approach to testing with the local laboratory or relevant specialist.

Can antibiotics be safely administered after an adverse reaction?

If the patient has a history of an acute IgE-mediated hypersensitivity reaction after taking an antibiotic, it can be assumed that this reaction is likely to occur again on re-exposure.² Deliberate re-exposure to the antibiotic is not recommended unless the benefits of treatment outweigh the risks. In most cases alternative classes of antibiotics will be available and can be used instead. Desensitisation protocols can be carried out under specialist supervision in a hospital setting to induce temporary tolerance to an antibiotic if it is required for treating a serious infection, e.g. neurosyphilis in a patient with penicillin allergy.

People with an allergy to one antibiotic may react to structurally similar antibiotics. It is sometimes possible to predict cross-reactivity on the basis of the structure of the drug and, if known, what the person is specifically allergic to, e.g. people with penicillin allergy have a different likelihood of cross-reactivity if their reaction is due to sensitisation on the side chain of one specific penicillin than if their reaction is due to the common beta lactam ring.⁷ This is best discussed with an allergy specialist. Cross-reactivity to cephalosporins in patients allergic to penicillin does occur, but it is thought that this risk is very low.⁴ Carbapenems are usually tolerated by people who are allergic to penicillin, but are rarely used outside the hospital setting.

If the patient has a history of a delayed hypersensitivity reaction after taking an antibiotic, re-challenge may be possible, depending on the nature of the reaction.³ Delayed rashes, in particular following the use of aminopenicillins (e.g. amoxicillin), are common and the subsequent use of beta lactam antibiotics is not necessarily contraindicated in these patients, although the rash may reoccur.³ Re-exposure to the antibiotic is not recommended if the patient has experienced a severe delayed reaction, e.g. serum sickness-like reaction, drug-rash with eosinophilia and systemic symptoms (DRESS) or Stevens-Johnson syndrome.³

Any adverse reactions to an antibiotic should be reported to the Centre for Adverse Reactions Monitoring (CARM), which will ensure that a warning is placed on the patients NHI record. Patients with an IgE-mediated drug allergy or a serious non-IgE-mediated reaction should be encouraged to wear a medic alert emblem.

If the patient has a history of intolerance or adverse effects after taking an antibiotic, it depends on the nature of the symptoms or signs as to whether this is a contraindication for taking the medicine in the future. Patients who have experienced a serious adverse effect after taking an antibiotic, e.g. cholestatic jaundice after taking amoxicillin clavulanate, are unlikely to be willing to risk experiencing this effect again. Conversely, the benefits of treatment with a particular antibiotic (and lack of availability of other suitable options) may outweigh the risk of recurrence of adverse effects in patients who have experienced less severe adverse effects, e.g. vomiting and diarrhoea with an antibiotic.