History alone is not a reliable predictor of either tolerance or allergy to penicillin or other antibiotics
Penicillin allergy has been more in the medical news lately, partly at least because of the growing problem of antibiotic resistance and the concept of antibiotic stewardship.
In Australia, an average of 18% of adult patients report having an antibiotic allergy.1 Once this statement is made to a doctor, the patient is said to be “allergy labelled”, with alerts attached to all ensuing clinical documentation, warnings appearing with every script written and allergy-identifying wristbands being assigned on admission to hospital.
In hospitals, where often little effort has been made to question the label of penicillin allergy (for many reasons), the prevalence of the label “penicillin allergy” can be as high as 24% among patients admitted to general medical wards.3
The majority of patients will have the allergy labelled as being a reaction to a beta-lactam antibiotic, a group comprised of penicillins, cephalosporins, monobactams and carbapenems.1,4
It has been shown that patients who say they are allergic to an antibiotic such as penicillin overall have higher medical costs, experience longer hospital stays, are more likely to be readmitted and treated with alternative antibiotics (such as vancomycin, quinolones or macrolides).
They are also more likely to develop clinical complications such as severe infections with a vancomycin-resistant enterococcus, methicillin-resistant Staphylococcus aureus and Clostridium difficile.1,4-7
Although this procedure of creating an allergy label is designed to protect the patient from being prescribed a drug that will trigger a significant adverse reaction, studies have shown that up to 90% of patients reporting penicillin allergy can actually tolerate the drug on re-exposure.2
However, medical databases (and paper-based charts) often seem to encourage the reporting of all adverse reactions that appear associated with a particular drug as definite and as allergy.
And once that allergy is assigned to a patient, the process of assessing their true allergy status, also known as verification, is lengthy, often requires specialist referral and can seem too difficult so not pursued.
Commonly, when a patient is questioned about their allergy, the incident event is poorly recalled (“My mum/dad said I was allergic”) and there is little, if any, documentation, making it difficult to exclude allergy on the basis of history alone.8
Nonetheless, GPs can help to ease the burden of penicillin allergy by instigating the process of verification. In addition, immunology and allergy departments in public hospitals as well as private allergy clinics are keen to be involved in allergy assessment, especially for the large group of patients reporting seemingly mild reactions to the antibiotic, such as rashes without systemic symptoms.
Advantages in de-labelling 2
Access to penicillins which are safe, cheap and effective
Access to other beta-lactam antibiotics as no risk of cross-reactivity
Shorter hospital stays
Lower rates of readmission
Lower morbidity and mortality rates
Reduced use of broad spectrum antibiotics increasing the risk microbial resistance.
Practical guide to: “Is it allergy?” (or when to suspect a true allergy)
IgE mediated allergy (urticaria, anaphylaxis, asthma, angioedema) occurs within two hours of oral ingestion and usually within minutes of parenteral exposure.
Anaphylaxis to penicillin occurs at a frequency of one to four per 10,000 courses, with 10% of these being fatal.
Serum tryptase can be useful when IgE mediated allergy is not certain though it is only reliably elevated in patients with hypotension. It should be ideally measured at time zero (i.e. ASAP) and at its peak rise, two to four hours and commencement of reaction. If elevated, repeat testing is needed to show a return to normal. If levels remained raised, the person may have a systemic mast cell disorder in which drug allergy testing is best avoided. If there is a longer delay between exposure to the antibiotic and the reaction, the likelihood decreases that it is IgE mediated.
Delayed reactions, such as morbilliform eruptions, can occur from hours to days after penicillin use, and often occur through unknown mechanisms. The majority of these events are not allergic, but rather due to the underlying infection and therefore penicillin can be safely used.
As mentioned earlier, in the majority of cases, history alone is not a reliable predictor of either tolerance or allergy to an antibiotic. The only positive historical predictors of true allergy are a history of reactions that occur within five minutes of taking the drug or rashes that last for more than 14 days in children.9
There is an increasing number of studies of children and adults, which report that in a supervised environment with expertise to manage anaphylaxis, direct oral provocation testing of healthy patients with a history of rash alone is safe.
For patients with a history of rash alone, the rate of a reaction to the culprit antibiotic following an oral provocation test is reportedly low.9,10
However, a history of severe skin and systemic reactions should be considered a contraindication to testing, especially a history of Stevens-Johnson syndrome or toxic epidermal necrolysis. These patients should never be re-exposed to the drug, therefore both skin testing and desensitisation are contraindicated.11
Even in patients found to have a true penicillin allergy, cross-reactivity to other beta lactam antibiotics is very rare. Less than 2% of penicillin-allergy patients are also allergic to first and second generation cephalosporins, and even fewer are allergic to third and fourth generation agents. Carbapenems can cross-react, however monobactams (aztreonam) can safely be given to penicillin allergic patients.11
Who should be referred to an allergy specialist?
Any patient with a penicillin allergy label which has not been confirmed, and:
An oral provocation test in the GP surgery is not appropriate
Is also allergic to other antibiotics (especially different classes)
Is immunodeficient
Has a chronic disease requiring frequent antibiotics such as COPD, diabetes, or cystic fibrosis
Has a history of a severe allergic reaction
Is very young
Is an armed forces recruit (people with a drug allergy cannot join the armed forces)
If a referral is being considered, testing for specific IgE to penicillin (previously known as a RAST test) should be carried out .
These tests are very specific but only 30% sensitive, and best performed within three to six months after the reaction. A negative test does not exclude penicillin allergy.
If there is a definite history of anaphylaxis to penicillin, then discussion about medical identification jewellery is appropriate. Information for patients (and referrers) can be found at www.allergy.org.au. The provision of an adrenaline auto-injector is usually not recommended since the drug is avoidable and accidental exposure should not occur.
What occurs at the specialist?
Penicillin skin prick and intradermal testing will be considered if appropriate. If this testing is negative, an oral challenge will be performed.
The challenge is often graded with a 10% dose given first, followed by a full dose. This may then be followed by short course of the antibiotic after the challenge, more commonly performed in children, whereas extended courses in adults are currently not favoured due to concerns related to antimicrobial resistance.
In cases of proven penicillin IgE allergy, either through testing or a definite history of anaphylaxis, penicillin desensitisation may be carried out though this is only effective while the drug is continued. The desensitisation effect of immunotherapy, the induction of temporary tolerance, may be lost within 48 hours of cessation of the drug.
Summary
Self reported, but unconfirmed, penicillin allergy is common
True penicillin allergy is not common
More than 90% of those who state they are allergic to penicillin can, in fact, tolerate the drug
The high rate of unnecessary penicillin avoidance leads to increased healthcare costs, poorer patient outcomes and bacterial antibiotic resistance
Verification should be considered in all patients labelled as having a penicillin allergy
Immunologists and allergists are well-equipped to help de-label penicillin allergy where appropriate
Dr Daman Langguth is Clinical Immunologist, Sullivan Nicolaides Pathology, at Wesley Hospital, Brisbane
Professor Michaela Lucas is Immunologist at University of Western Australia and Sir Charles Gairdner Hospital, Perth
References:
1. KNEZEVIC, B., SPRIGG, D., SEET, J., TREVENEN, M., TRUBIANO, J., SMITH, W., JEELALL, Y., VALE, S., LOH, R., MCLEAN TOOKE, A. & LUCAS, M. 2016. The revolving door: antibiotic allergy labelling in a tertiary care centre. Internal Medicine Journal, 46, 1276-1283.
2. BOURKE, J., PAVLOS, R., JAMES, I. & PHILLIPS, E. 2015. Improving the Effectiveness of Penicillin Allergy De-labeling. J Allergy Clin Immunol Pract, 3, 365-34.e1.
3. TRUBIANO JA, MANGALORE RP, YI-WEI BAEY, DUY LE, GRAUDINS LV, CHARLES P, JOHNSON DF & AR KAR AUNG 2016. Old but not forgotten: Antibiotic allergies in General Medicine (the AGM Study). Medical Journal of Australia, 204.
4. TRUBIANO, J. A., CAIRNS, K. A., EVANS, J. A., DING, A., NGUYEN, T., DOOLEY, M. J. & CHENG, A. C. 2015a. The prevalence and impact of antimicrobial allergies and adverse drug reactions at an Australian tertiary centre. BMC Infect Dis, 15, 572
5. BLUMENTHAL, K. G., LU, N., ZHANG, Y. Q., LI, Y., WALENSKY, R. P. & CHOI, H. K. 2018b. Risk of meticillin resistant Staphylococcus aureus and Clostridium difficile in patients with a documented penicillin allergy: population based matched cohort study. Bmj-British Medical Journal, 361, 10.
6. CHARNESKI, L., DESHPANDE, G. & SMITH, S. W. 2011. Impact of an antimicrobial allergy label in the medical record on clinical outcomes in hospitalized patients. Pharmacotherapy, 31, 742-7
7. MACY, E. & CONTRERAS, R. 2014. Health care use and serious infection prevalence associated with penicillin “allergy” in hospitalized patients: A cohort study. J Allergy Clin Immunol, 133, 790-6.
8. LUCAS M, LOH RK, SMITH WB. Improving drug allergy management in Australia: education, communication and accurate information. Med J Aust. 2019 Feb; 210(2):62-64. Epub 2018 Dec 28.
9. MILL C, PRIMEAU MN, MEDOFF E, LEJTENYI C, O’KEEFE A, NETCHIPOROUK E, DERY A, BEN-SHOSHAN M. Assessing the Diagnostic Properties of a Graded Oral Provocation Challenge for the Diagnosis of Immediate and Nonimmediate Reactions to Amoxicillin in Children. JAMA Pediatr 2016; 170(6): e160033
10. IAMMATTEO M, ALVAREZ ARANGO S, FERASTRAOARU D, AKBAR N, LEE AY, COHEN HW, JERSCHOW E. Safety and Outcomes of Oral Graded Challenges to Amoxicillin without Prior Skin Testing. J Allergy Clin Immunol Pract 2019; 7(1): 236-43.
11. BLUMENTHAL KG, PETER JG, TRUBIANO JA, PHILLIPS EJ. Antibiotic allergy. Lancet. 2019 Jan 12;393(10167):183-198. doi: 10.1016/S0140-6736(18)32218-9. Epub 2018 Dec . Review.
