Seven-year-old Eoin presents to the emergency department (ED) with right forearm cellulitis.
He has no comorbidities but is said to have a penicillin allergy after developing a maculopapular rash on day three of amoxicillin treatment for an upper respiratory tract infection at three years of age. Because of his penicillin allergy, the GP treated the cellulitis with erythromycin, but the swelling had not improved despite a few days of antibiotics.
You feel flucloxacillin would be a more appropriate antibiotic, but Eoin’s “penicillin allergy” needs exploring.
Adverse drug reaction versus antibiotic allergy
An adverse drug reaction (ADR) is an unwanted or harmful reaction suspected to be related to the administration of a drug or combination of drugs under normal conditions of use.
Generally, ADRs are clinically classified as either Type A (on-target reactions) or Type B (off-target reactions). Type A reactions comprise over 80% of all ADRs and are dose-dependent. From a pharmacological perspective, the type of reaction is predictable based on the drug’s therapeutic effect. Type B reactions, on the other hand, are not predictable based on the known therapeutic effects of the drug. Hypersensitivity reactions fall under Type B reactions. They comprise 20% of ADRs, making cutaneous reactions the most common. The problem is that all ADRs are often erroneously referred to as allergies.
Antibiotic allergy is an immunologically mediated response to an antibiotic in a sensitised individual. It is mediated by IgE, IgG, or T lymphocytes. Immediate reactions are usually induced by an IgE-mediated mechanism within the first hour of drug administration. Delayed reactions develop more than an hour after drug exposure and are often induced by a T-lymphocyte-dependent reaction. These typically manifest as a maculopapular exanthem.
Penicillin allergy (PenA) is the most commonly reported antibiotic allergy in paediatrics; amoxicillin is the most agent. Studies in the United Kingdom (UK), United States (US), and Australia estimate the prevalence of PenA carriage to be somewhere between 8–25%.
The question is, how do we differentiate between the two?
How do I take an allergy-focused history?
The clinical interview is a powerful tool to identify patients with low-risk symptoms (more about these in the next section) who may safely proceed to direct challenge with the antibiotic in question. An Australian study showed over 20% of adults with a reported antibiotic allergy could be safely de-labelled with an allergy-focussed history alone.
Why is it so important? The Centre for Disease Prevention and Control identified allergy history taking as a vital tool to improve the quality of antibiotic prescribing. Simply put, an excellent allergy history can improve the management of infectious diseases.
In a 2017 study of inpatient practitioners (doctors, pharmacists, physician assistants and nurse practitioners), 95% of practitioners always asked the name of the offending medication, and 86% explored the specific allergy symptoms. Pharmacists more frequently asked how long ago the reaction occurred than other HCPs (p = 0.02).
Pertinent allergy symptoms include:
- When did the reaction occur?
- How old was the child?
- Symptom(s) of the reaction?
- Time between ingestion of antibiotic and symptom?
- Any concurrent medications?
- Was medical intervention sought?
- Has penicillin been tolerated before the reported reaction?
- Has any penicillin-based antibiotic been ingested after the reported reaction?
- Was the allergy confirmed by any form of testing?
What symptoms do parents report as penicillin allergy?
In the vast majority of cases, applying a PenA label results from low-risk events for allergy.
Although penicillin is the class of antibiotics most associated with anaphylaxis, life-threatening reactions are extremely rare. A review from the United Kingdom found that over 100 million amoxicillin courses were administered over 35 years, resulting in just one fatality.
Benign childhood rashes are typically urticarial and onset more than six hours after the first dose of penicillin. They are non-immediate mild exanthemata without systemic symptoms or mucosal or organ involvement. Most of the symptoms of PenA reported by families have a low likelihood of true allergy.
Risk stratification of reported PenA symptoms.
| High-risk symptoms | Low-risk symptoms | Not immune-mediated |
|---|---|---|
| Immediate cutaneous symptoms (within 6 hours of ingestion; typically 1 hour) Anaphylaxis Orofacial Swelling Severe cutaneous adverse reactions | Delayed cutaneous symptoms (maculopapular exanthem, urticaria, pruritus) Poor recollection of events** No hospital intervention | Isolated gastrointestinal symptoms (nausea, vomiting, diarrhoea) Neurological symptoms (headache, mood disorders) Family history of PenA |
**More uncommon in the paediatric than the adult population
But a delayed onset doesn’t necessarily mean a benign rash. Some severe cutaneous adverse reactions also have a delayed onset.
Steven Johnson Syndrome (SJS)
Toxic Epidermal Necrolysis (TEN)
Drug Hypersensitivity Syndrome (DHS)
Drug Rash with Eosinophilia and Systemic Symptoms (DRESS)
Acute Generalised Exanthematous Pustulosis (AGEP)
Severe cutaneous adverse reactions
| Reaction | Onset | Clinical Features |
|---|---|---|
| TEN & SJS | Usually within 7-14 days of first drug exposure or within 3 days of a second exposure. | Painful rash and fever, mucosal or cutaneous erosions, vesicles, blistering or epidermal detachment, red purpuric macules, or erythema multiforme. |
| DHS & DRESS | Usually 2-6 weeks after first drug exposure or within 3 days of a second exposure. | Widespread red macules, papules or erythroderma, fever, lymphadenopathy, liver dysfunction and eosinophilia. |
| AGEP | Usually within 3-5 days after first drug exposure. | Widespread pustules, fever, and neutrophilia. |
The PenA conundrum: is this rash allergic or viral?
The most common symptom of drug reaction, drug-viral infection or non-IgE-mediated mast cell activation is urticaria.
Delayed rashes, occurring several hours to days after drug administration, are often non-IgE mediated. During viral infections, the underlying cause of cutaneous drug reactions may be a viral-induced polyclonal activation of lymphocytes, stimulation of cellular immunity, or changes in drug metabolism. These reactions are misinterpreted as an allergy when a penicillin-based antibiotic (PBA) is concurrently administered, but they are more likely to be viral-induced or due to a drug-virus interaction.
Caubet et al. studied children presenting to the ED with delayed-onset urticarial or maculopapular rashes following beta-lactam antibiotic therapy. They explored the causes of these rashes and determined the risk of developing a similar rash on re-exposure. An oral drug challenge was performed on 88 patients, with a reproducible reaction in six (immediate in 1). None of the six patients developed a rash perceived to be more severe than the index reaction. Viruses (mostly Enteroviruses) were isolated in 54 of the 82 patients with an oral drug challenge.
A note on beta-lactams
There’s often confusion around what is and isn’t a penicillin-based antibiotic. Simply put, a beta-lactam antibiotic has a beta-lactam ring in its molecular structure. Penicillins are beta-lactams, as are cephalosporins of all generations (cefalexin, ceftriaxone, cefotaxime, and more) and the similarly structured cephamycins (e.g., cefoxitin), monobactams (such as aztreonam), and carbapenems (you may be familiar with meropenem).
There are many penicillin-based antibiotics. The list is long, but some of the more common ones include amoxicillin (which is also combined with clavulanate in Co-Amoxiclav), ampicillin, flucloxacillin, methicillin, oxacillin, penicillin G and V and piperacillin (combined with Tazocin to make PizTazobactam).
Does a false PenA label have consequences?
The short answer is yes. Most antibiotic allergy labels acquired in childhood are carried into adulthood and are responsible for increased hospitalisation stays, inappropriate antibiotic prescriptions, and healthcare costs.
PenA labels are insufficiently reconciled in acute paediatric settings, and prescribers choose an alternative antibiotic that may be inappropriately broad-spectrum, potentially less efficacious with greater adverse effects and more costly. Therefore, PenA labels are not benign and should not be ignored.
A penicillin allergy label is like a snowflake waiting to become an avalanche.
1. Impact on patients’ care
Patients with a reported PenA history have a significantly longer length of hospital stay and are exposed to significantly more antibiotics associated with Clostridium difficile. Blumenthal et al. discovered that PenA labels exposed patients to a higher risk of postoperative surgical site infections enhanced by the use of alternative, non-penicillin antibiotics. A 2018 Portuguese study by Sousa-Pinto et al. showed that children with PenA labels had significantly longer hospital stays than those without such labels.
2. Impact on antimicrobial stewardship
Studies have shown that patients with antibiotic allergy labels are more likely to receive inappropriately broader spectrum, less effective antibiotics with more toxic profiles. A large US study by Blumenthal showed a 1.69-fold increase in MRSA (methicillin-resistant staphylococcus aureus) infection risk associated with PenA. A meta-analysis by Wu et al. demonstrated significant reductions in antibiotic appropriateness and antibiotic guideline consistency associated with antibiotic allergy labels.
3. Economic and cost implications
A 4-year-old with community-acquired pneumonia would need one bottle of amoxicillin (250mg/5ml), which costs £1.99 (Alliance Healthcare). In an unverified PenA, macrolide is likely to be prescribed: one bottle of clarithromycin or erythromycin (125mg/5ml) costs £5.22 or £5.81 respectively (Alliance Healthcare).
Prescription costs (of broad-spectrum antibiotics) are 30-40% higher in patients with reported PenA. A UK study by Powell et al. in 2020 estimated savings of £5,501 in antibiotic drug costs and a huge £503,932 in reduced excess bed days annually after de-labelling 50% of patients with a self-reported PenA. Similar cost analyses by Vyles have shown cost savings in a US paediatric ED.
How is PenA confirmed?
Testing for beta-lactam allergy not only helps to remove false labels but also to identify true allergies. Testing includes skin prick testing, intradermal testing, patch testing, and oral challenge.
The International Consensus on Drug Allergy Guidelines recommends skin testing as the first-line test for immediate reactions. If skin prick testing is negative, an oral challenge is performed to exclude or confirm an immune-mediated reaction. Children requiring regular medical assessments or frequent hospitalisations are at high risk of having multiple antibiotic allergy labels. Skin testing and/or challenge tests are useful in these children.
However, the diagnostic value of skin testing has been controversial for non-immediate reactions because of the high rates of false-negative or false-positive results. This leads to overdiagnosis of allergy, particularly in children with low-risk symptoms of PenA. Inaccessibility, allergy specialist input, and cost are also barriers to skin testing, and so many would not consider skin prick testing a particularly useful investigation in non-immediate PenA reactions.
An oral challenge, or drug provocation testing, is the gold standard for evaluating penicillin allergy. The therapeutic dose of the culprit drug is administered under medical observation to exclude IgE-mediated hypersensitivity reactions. This can take either of two forms: single dose or multiple doses. Less than 7% develop allergic rashes on re-exposure, possibly due to T-cell-mediated drug eruptions. These reactions are close to their baseline incidence in the general population. Iammatteo et al. recently reviewed various direct oral challenge protocols to explore benign non-immediate rashes in children. They found eight studies performed in allergy clinics and daycare units. Severe immediate reactions are rare; therefore, performing these challenges under strict observation is not cost-effective. A study by Mill et al. provided the largest sample size (n = 818), demonstrating the safety and accuracy of direct oral amoxicillin challenge in children with reported benign skin rashes.
There is a lack of consensus concerning the optimal duration of oral challenge to assess benign non-immediate reactions in children. No studies have compared one protocol to another. A single-day direct oral challenge seems appropriate for diagnosis, as reactions occurring on re-exposure are mild in the majority of cases. However, if the antibiotic is indicated, the patient should expect to complete the prescribed therapy.
The key is that IgE-mediated reactions to beta-lactams can wane over time. Therefore, initial immunological reactions might not recur on a subsequent challenge.
How can non-allergy specialists tackle false PenA labels?
About 10% of UK patients carry PenA labels; hence, it is impractical for all patients with low-risk symptoms to undergo formal allergy testing. Relying on allergy services means that a significant portion of paediatric patients with lower-risk reactions who have no access to speciality services will be missed. Removing false labels is an integral part of antimicrobial stewardship.
No validated symptom risk stratification tool exists in paediatrics. Devchand et al. recently validated a tool designed by Australian non-specialist clinicians to risk-stratify patients and potentially de-label patients with clearly non-immune mediated reactions. Studies have utilised similar tools in Paediatric ED and outpatient clinics. Application of a risk stratification tool results in 1 of 3 possible outcomes: removal of spurious PenA label, referral to specialist allergy assessment services for those deemed high risk, or confirmation of PenA status.
*The British Society of Allergy and Clinical Immunology recommends at least two hours of hospital observation after the first dose of penicillin. Upon discharge, information should be given to seek medical care if any severe symptoms occur.
The paradox is that a PenA label attached to a patient’s record with the intent of improving patient safety and reducing adverse events is now recognized to adversely impact antimicrobial appropriateness, antimicrobial resistance, and medication safety.
Considering safety and feasibility, direct oral challenges may be performed with a single therapeutic dose or with 2-step challenges – 10% of the therapeutic dose, followed by 90% 20-30 minutes later. Following a negative oral challenge, families should be educated and reassured that their children can tolerate penicillin.
What are the anticipated barriers in tackling PenA?
1. Clinicians’ apprehension of severe allergic reaction
A good understanding of antibiotic allergy will surmount this barrier. Interventions to improve allergy knowledge may include appropriate local pathways, multi-dimensional education on the importance of PenA verification, drug allergy history taking, testing indications and methods, and the implications of negative testing.
It may be more difficult to remove labels in adulthood; these labels have been fortified for decades with avoidance of PBA. Earlier intervention during childhood years is needed.
2. Limited time to verify PenA in acute settings
Confirming PenA in low-risk reported symptoms is the best service paediatric clinicians can offer to promote antimicrobial stewardship in such children. Even in the busy emergency department, it takes priority over time constraints, given the long-term consequences of spurious allergy labels.
3. Presumed resistance to de-labelling by parents
Clinicians with good allergy knowledge can initiate a shared decision-making process with parents of children with reported PenA. Patient education should focus on the harms of unverified penicillin allergies
4. Parental fear of using penicillin-based antibiotics even after de-labelling
Parents may refuse penicillin-based antibiotics for their children because they continue to fear a penicillin reaction despite a negative PenA evaluation. Educating parents can potentially affect the uptake and effectiveness of any PenA evaluation programme. Multimedia educational materials might also alleviate the anxiety of future reactions in those who are not allergic. Part of this education package should include that although a negative oral challenge excludes IgE-mediated reactions, children may experience other benign rashes at a similar incidence to the general population.
What alternative antibiotics are safe in true PenA?
The literature reports cross-reactivity with cephalosporin in between 2% and 8% of cases of PenA. This is particularly seen in aminocephalosporins containing shared chemical side chains with penicillin. These cephalosporin-penicillin allergy cross-reactions appear due to similarity in R1 side chains rather than the beta-lactam structure. Therefore, patients with a history of immediate hypersensitivity reactions to a particular cephalosporin should also avoid all cephalosporins with a similar R-group side chain. Cross-reactivity between penicillins and carbapenems is less than 1%, while none exists between penicillins and monobactams.
Notably, if oral challenge with amoxicillin shows no evidence of PenA, the chance of cross-reactivity is deemed clinically irrelevant.
Pertinent allergy-focussed history can identify patients with low-risk symptoms.
There is good evidence that children with low-risk symptoms can safely proceed with direct oral challenge.
Nonallergy specialists can carry out direct oral challenges in all acute paediatric settings.
It is vital to verify the accuracy of a PenA label to prevent unnecessary penicillin avoidance and inappropriate use of alternative antibiotics, which may be less effective.
But what happened to Eoin? The ED doctor had recently attended a webinar on false PenA labels. After deeming Eoin at low risk of PenA, the doctor explained the benefit of prescribing flucloxacillin for Eoin’s cellulitis and the low risk of reaction. Eoin received a dose of flucloxacillin in ED and was observed for two hours after antibiotic administration. With no reaction, Eoin was discharged on a 7-day course of flucloxacillin with advice to return if he had any reactions. The discharge letter to GP stated, “Eoin is not allergic to penicillin”. He did not reattend.
References
Blumenthal KG, Lu N, Zhang Y, et al. Risk of methicillin-resistant Staphylococcus aureus and Clostridium difficile in patients with a documented penicillin allergy: population-based matched cohort study. BMJ. 2018; 361:k2400
Blumenthal K, Ryan E, Li Y, et al. The impact of a reported penicillin allergy on surgical site infection risk. Clin Infect Dis. 2018; 66(3):329‐36
Caubet JC, Kaiser L, Lemaitre B, et al. The role of penicillin in benign skin rashes in childhood: a prospective study based on drug rechallenge. J Allergy Clin Immunol Pract. 2011; 127:218-22
Demoly P, Adkinson NF, Brockow K, et al. International Consensus on drug allergy. Allergy. 2014 ;69(4):420-37
Devchand M, Kirkpatrick CMJ, Stevenson W, et al. Evaluation of a pharmacist-led penicillin allergy de-labelling ward round: a novel antimicrobial stewardship intervention, Journal of Antimicrobial Chemotherapy. 2019; 74(6):1725-30
Iammatteo M, Lezmi G, Confino-Cohen R, et al. Direct Challenges for the Evaluation of Beta-Lactam Allergy: Evidence and Conditions for Not Performing Skin Testing. J Allergy Clin Immunol Pract. 2021 ;9(8):2947-2956.
Kerr J Penicillin allergy: a study of incidence as reported by patients. The British journal of clinical practice. 1994;48(1):5–7
Lee P, Shanson D. Results of a UK survey of fatal anaphylaxis after oral amoxicillin. J Antimicrob Chemother. 2007; 60:1172–9.
Macy E. Penicillin and beta-lactam allergy: epidemiology and diagnosis. Current allergy and asthma reports. 2014;14(11):476
Macy E, Blumenthal KG. Are cephalosporins safe for use in penicillin allergy without prior allergy evaluation? J Allergy Clin Immunol Pract. 2018; 6(1):82-9.
Mill C, Primeau MN, Medoff E, et al. 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
Norton AE, Konvinse K, Phillips EJ, et al. Antibiotic Allergy in Pediatrics. Pediatrics. 2018; 141(5):e20172497
Powell N, Honeyford K, Sandoe J. Impact of penicillin allergy records on antibiotic costs and length of hospital stay: a single-centre observational retrospective cohort. J Hosp Infect. 2020 Sep;106(1):35-42.
Shenoy ES, Macy E, Rowe T et al. Evaluation and management of penicillin allergy: a review. JAMA 2019; 321:188–99.
Sousa-Pinto B, Araujo L, Freitas A, et al. Hospitalizations in children with a penicillin allergy label: An Assessment of Healthcare Impact. Int. Arch. Allergy Immunol. 2018; 76(3-4):234-238
Staicu ML, Soni D, Conn K, et al. A survey of inpatient prescriber knowledge of penicillin allergy at 2 community teaching hospitals. Ann Allergy Asthma Immunol. 2017; 119:42-7
Stone CA Jr, Trubiano J, Coleman DT, Rukasin CRF, Phillips EJ. The challenge of de-labeling penicillin allergy. Allergy. 2020 Feb;75(2):273-288.
Torda A, Chan V. Antibiotic allergy labels—the impact of taking a clinical history. Int J Clin Pract. 2018; 72:e13058
Torres MJ, Blanca M, Fernandez J, et al. Diagnosis of immediate allergic reactions to beta-lactam antibiotics. Allergy 2003; 58:961-72.
Trubiano J, Cairns K, Evans J, et al. The prevalence and impact of antimicrobial allergies and adverse drug reactions at an Australian tertiary centre. BMC infectious diseases. 2015; 15:572
Trubiano JA, Chen C, Cheng AC, et al. Antimicrobial allergy ‘labels’ drive inappropriate antimicrobial prescribing: lessons for stewardship. J Antimicrob Chemother. 2016; 71:1715‐22
Vyles D, Antoon JW, Norton A, et al. Children with reported penicillin allergy: Public health impact and safety of delabeling. Ann Allergy Asthma Immunol. 2020; 124(6):558-565.
Vyles D, Chiu A, Simpson P, et al. Parent reported penicillin allergy symptoms in the pediatric emergency department. Acad Pediatr. 2017; 17(3):251–55
Wu JH, Langford BJ, Schwartz KL, et al. Potential negative effects of antimicrobial allergy labelling on patient care: a systematic review. Can J Hosp Pharm. 2018; 71(1):29–35
