View / Download pdf version of this article
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
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
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
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.
What does a “sulfa allergy” really mean?
Patients commonly report, or are labelled with, an allergy to sulfa drugs, which can cause difficulty for clinicians
making prescribing decisions, and unnecessary anxiety for patients. Uncertainty about how this relates to the risks of
other medicines or foods that contain sulfur may lead to a patient being unnecessarily deprived of some treatment options
for other conditions, e.g. congestive heart failure or diabetes.
It is estimated that adverse reactions to sulfonamide antibiotics occur in 3–6 % of treatment courses, although only
a small proportion of these reactions are immune-mediated allergy.8 People with HIV and AIDS are reported
to have a higher incidence of hypersensitivity reactions with sulfonamide antibiotics.8 Cross-reactivity
between sulfonamide antibiotics and other drugs that contain sulfur is thought to be unlikely, as the chemical structure
of the sulfonamide is different to the sulfur structures present in other medicines (sulfhydryls in penicillamine and
captopril, sulfate salts of morphine, heparin and ferrous iron) and products (sulfates in soaps and cosmetics, sulfite
preservatives in foods) and other sulfonamide medicines (thiazide diuretics which do not contain the arylamine chemical group).
However, people who have experienced an allergic reaction to any antibiotic are at higher risk of reacting to a sulfonamide
It is therefore useful, when possible, to reconsider the basis of a “sulfa allergy” diagnosis using the principles discussed
in this article: is the reaction a non-immune related intolerance or adverse effect, a delayed immune reaction (T-cells-mediated),
or an allergy (IgE-related hypersensitivity)?
Specifying which particular medicine is implicated in a “sulfa” (or any other) allergy in the patient record, and educating
the patient about this, will assist in providing them with the best available treatment for infections, and other conditions.
For further information, see: “Appropriate
use of sulfonamide antibiotics”, BPJ 49 (Dec, 2012)
Thank you to Dr Miriam Hurst, Clinical Immunologist/Immunopathologist,
Labtests Auckland for expert review of this article.
- American College of Allergy, Asthma and Immunology (ACAAI). Allergy and immunology glossary. ACAAI, 2014. Available
http://acaai.org/resources/information/allergy-glossary (Accessed Jun, 2015).
- Smith W. Adverse drug reactions. Allergy? Side-effect? Intolerance? Aust Fam Phys 2013;42:12–6.
- Australian Society of Clinical Immunology and Allergy (ASCIA). Antibiotic allergy clinical update. ASCIA, 2014. Available
www.allergy.org.au/health-professionals/hp-information/asthma-and-allergy/allergic-reactions-to-antibiotics (Accessed Jun, 2015).
- Bhattacharya S. The facts about penicillin allergy: a review. J Adv Pharm Technol Res 2010;1:11–7.
- Macy E. Penicillin and beta-lactam allergy: epidemiology and diagnosis. Curr Allergy Asthma Rep 2014;14.
- Apter A, Schelleman H, Walker A, et al. Clinical and genetic risk factors of self-reported penicillin allergy. J
Allergy Clin Immunol 2008;122:152–8.
- Joint Task Force on Practice Parameters, American Academy of Allergy, Asthma and Immunology, American College of
Allergy, Asthma and Immunology, Joint Council of Allergy, Asthma and Immunology R (Ed). Drug allergy: an updated practice
parameter. Ann Allerg Asthma Immunol 2010;105:273.e1–78.
- DermNet NZ. Sulfa drugs and the skin. DermNet NZ, 2014. Available from:
www.dermnetnz.org/reactions/sulfa-drugs.html (Accessed Jun, 2015).