Drs Shuaib Nasser (pictured) and Jane Queen discuss current advice on the management of allergy to penicillins and other beta-lactams
Read this article to learn more about:
- available guidance from NICE and BSACI
- essential information to record when someone presents with a possible penicillin allergy
- distinguishing allergy from intolerant reactions.
Almost 1 million people admitted to NHS hospitals each year have a diagnostic ‘label’ of drug allergy, with the most common being penicillin allergy.1 Hospital Episode Statistics from 1996 to 2000 reported that each year drug allergies and adverse drug reactions accounted for approximately 62,000 hospital admissions in England.2 Beta-lactam antibiotics are recognised as one of the most frequent causes of drug reactions,3,4 with about 10% of the general population claiming to have a penicillin allergy.2 Penicillin is estimated to cause between 0.7% and 10% of all cases of anaphylaxis,5 and amoxicillin and ampicillin are associated with delayed maculopapular rashes in 5–10% of patients, particularly in the presence of a viral infection.6–9 Among the non-penicillin beta-lactams, allergy is reported less often; for example, allergic reactions with cephalosporins are at least 10 times less frequent compared with penicillin.10
Attaching a label of penicillin allergy
It is easy to attach a label of penicillin allergy, but difficult to remove it from a patient record. Any rash occurring during or soon after a course of penicillin is assumed to be due to penicillin allergy. Time pressures in primary care or the Accident and Emergency Department often lead to inadequate recording of clinical detail or severity and an alternative drug is readily prescribed. In most cases, with the passage of time, details of the original reaction are forgotten even by the patient or carer. The effect is a limitation of future antibiotic choice and inability to assess whether any beta-lactam, including a cephalosporin, can be prescribed even in urgent clinical need. This lack of clinical information also delays specialist investigation of penicillin allergy. The fact that 90% of those individuals with a label of penicillin allergy are no longer allergic or may never have been allergic in the first place2 makes it even more vital to record clinical detail in a structured format at first presentation of drug allergy.
In some cases a beta-lactam may need to be prescribed without prior specialist investigation, but this can only be considered with knowledge of the presenting features and severity of the original reaction. Both the BSACI11 and the NICE2 drug allergy guidelines recommend a structured approach to documenting drug allergy at first presentation in all new cases of possible beta-lactam allergy. NICE recommends that the clinical detail listed in Box 1 (see below) should be recorded as a minimum.2
Box 1: Essential structured document when a person presents with suspected drug allergy2
You should include:
- the generic and proprietary name of the drug or drugs suspected to have caused the reaction, including dose and formulation
- a description of the reaction
- the indication for the drug being taken (if there is no clinical diagnosis, describe the illness)
- date and time of the reaction
- the number of doses taken or number of days on the drug before onset of the reaction
- the route of administration
- a list of drug or drug classes to avoid in future.
- Adapted from NICE CG183
Health economic consequences
It has been shown that people with a label of penicillin allergy are more likely to be treated with broad-spectrum antibiotics, such as quinolones, vancomycin, and third-generation cephalosporins.12 Each of these antibiotics is associated with an increased rate of clinical complications, such as antibiotic resistance and Clostridium difficile infection, leading to increased hospital stay.13 In a matched cohort of hospitalised patients in the US, those with a history of penicillin ‘allergy’ had 0.59 more hospital days during 20 months follow up compared with controls. These patients had 23.4% more C. difficile infections and 30.1% more vancomycin-resistant Enterococcus infections.13
Antibiotic costs in hospital patients labelled as penicillin allergic were estimated to be 63 times greater than for those not marked as allergic to penicillin.14 Therefore, an unconfirmed label of penicillin allergy may lead to inappropriate use of non-penicillin broad-spectrum antibiotics and could potentially lead to antibiotic resistance, suboptimal therapy, secondary infection, and increased cost. In a UK survey of in-patients with a history of penicillin allergy, the additional cost per patient was £89.29.15 These studies emphasise the vigilance required when attaching a label of penicillin allergy.
Death from penicillin anaphylaxis
The risk of fatal anaphylaxis with penicillin has been estimated at 0.0015% to 0.002% of treated patients.16 In a study of 151 fatalities, 70% had received penicillin previously and one-third of them had already experienced rapid-onset allergic reactions. Death occurred within 15 minutes in most of these cases.16
In one study from Denmark from 1968 to 1990, 20% of drug-related deaths from anaphylaxis were caused by penicillins;17 and studies in the USA have shown up to 75% of deaths from anaphylaxis in the USA were caused by penicillin.5,18 A UK study of drug-induced fatal anaphylaxis between 1992 and 1997 reported 12 deaths attributable to antibiotic use, of which six were due to the first dose of a cephalosporin.19 Three of these patients were known to be allergic to amoxicillin and one had a history of penicillin allergy, thus emphasising the close structural relationship between amino-penicillins and early generation cephalosporins.
Clinical features of beta-lactam allergy
Hypersensitivity or ‘allergic’ reactions to penicillin and other beta-lactam antibiotics can be broadly classified as ‘immediate’ or ‘non-immediate’ based on the temporal association of onset of symptoms following drug administration. Patient risk factors for immediate responses to penicillin are listed in Box 2 (see below).
Immediate responses are IgE-mediated and generally occur within minutes to 1 h following exposure to the last dose. Non-immediate reactions are usually non-IgE-mediated and manifest from >1 h up to several days after last dose administration.20 The NICE drug allergy guideline has listed common patterns of presentation and has provided a useful guide to symptoms and signs of drug allergy with timing of onset after exposure to drug based on underlying mechanism.2 This should help with differentiation of drug allergy from intolerant reactions. Table 1 (see below) should be used as a guide when deciding whether drug allergy has occurred.
Box 2: Patient risk factors for immediate responses to penicillin10
- A clinical history of penicillin allergy in the distant past (>15 years) associated with a low risk (0.4%) of reacting on drug challenge
- Women are more likely to report a history of drug allergy including penicillin ‘allergy’ than men (11.0% vs 6.5%, respectively)
- Topically applied penicillin is highly immunogenic and therefore no longer used
- Frequent courses are more likely to sensitize, for example in patients with cystic fibrosis receiving repeated courses of intravenous antibiotics
- Increasing antibiotic allergy with increasing age, with 20% of those over 80 years old reporting penicillin allergy
- Older age is more likely to predispose to a fatal outcome because of cardiovascular or respiratory comorbidity or use of beta-blockers.
- Adapted from BSACI guideline: managemnt of allergy to penicinlln and other beta-lactams
|Immediate reaction||Anaphylaxis—a severe multi-system reaction usually with erythema, urticaria or angioedema in combination with hypotension and/or bronchospasm||Onset usually under 1 hour, previous exposure not always confirmed|
|Urticaria or angioedema without systemic features|
|Non-immediate reactions||without systemic involvement||Widespread red macules or papules (exanthem-like)||Onset usually on day 6–10 of first drug exposure (reaction to first exposure may be more prolonged), or day 1–3 of second exposure|
|Fixed drug eruption (localised inflamed skin)|
|with systemic involvement||Widespread red macules, papules or erythroderma with systemic involvement. For example, drug reaction with eosinophilia and systemic symptoms (DRESS) or drug hypersensitivity syndrome (DHS)—characterised by fever, lymphadenopathy, liver dysfunction and low platelets||Onset usually 2–6 weeks after first drug exposure, or 24–48 hours after second exposure|
|Toxic epidermal necrolysis or Stevens–Johnson syndrome—characterised by mucosal or cutaneous erosions, vesicles, blistering or epidermal detachment, and red purpuric macules or erythema multiforme. Painful rash and fever are often early signs||Onset usually 7–14 days after first drug exposure, or 24–48 hours after second exposure|
|Acute generalised exanthematous pustulosis (AGEP)—widespread pustules, usually with a fever and neutrophilia||Onset 3–5 days after first drug exposure|
|Common disorders caused, rarely, by drug allergy:
||Time of onset variable|
Cross-reactivity with cephalosporins
First-generation and some second-generation cephalosporins have the potential for cross-reactivity with the penicillins. Cross-sensitisation can be due to the beta-lactam core chemical structure, but in practice is more usually due to side-chain homology. The aminopenicillins, ampicillin, and amoxicillin are likely to have cross-sensitisation with early generation cephalosporins; for example, amoxicillin has an identical side-chain to cefadroxil, and ampicillin has a side-chain also found in cefaclor, cephalexin, and cephradine. Therefore the much quoted figure of 8% cross-reactivity between penicillins and cephalosporins21 is in reality much higher between these specific cephalosporins and the aminopenicillins.
Late second-generation cephalosporins, such as cefuroxime, and third-generation cephalosporins, such as ceftriaxone, cefotaxime, and ceftazidime, are less likely to be associated with cross-reactivity as they have different side-chains to penicillins with a risk closer to 0.5%.22 These can be prescribed in penicillin allergy provided the original reaction was not life threatening.
Testing for drug allergies
IgE tests for beta-lactams, although specific, are not sensitive and therefore serum-specific IgE testing should be considered only in patients undergoing specialist investigation and in conjunction with skin tests.2,11 Blood tests cannot reliably confirm or exclude a diagnosis of beta-lactam allergy and should not be undertaken in primary care.
Referral for specialist drug allergy testing
Testing for allergy to penicillin or other beta-lactams is a specialist procedure, undertaken in drug allergy clinics. One US study has estimated that even if testing all patients with a label of penicillin allergy could only save 50% of the additional hospital days, this would still save about four times the cost of undertaking penicillin allergy tests.13 In the UK, referral criteria for allergy testing to penicillin are limited to those types of patient listed in Box 3 (see below).
Testing may not be helpful and is therefore not indicated in patients:11,20
- who have suffered from symptoms consistent with IgG or IgM-mediated reactions. These patients should not receive penicillin again
- with a family history but no personal history of allergy to penicillin
- with a history of beta-lactam allergy, but who subsequently tolerated the same penicillin.
The referral letter should provide as much of the information listed in Box 1 (see above) as available, including the name of the implicated drug and details relating to the allergic reaction.2
Testing for drug allergy is a balance between patient safety and the necessity for diagnosis. Systemic and even fatal reactions during testing can occur. Skin prick testing is undertaken with: penicillins; individual allergenic determinants of penicillins; and, if indicated from the clinical history, other penicillins, such as amoxicillin, co-amoxiclav, and flucloxicillin, and other beta-lactams, such as cephalosporins. If skin prick testing is negative, intradermal tests are undertaken, which are more sensitive but also require a larger dose of allergen to be injected into the skin, which adds to the risk of a systemic reaction. If both sets of skin tests are negative, then oral challenge with the original implicated drug is required to confirm or exclude drug allergy. As with all drug allergy testing, this is conducted in an environment with the facilities and expertise to reverse a drug-related allergic reaction. The patient is monitored for at least 2 hours after drug challenge and will often be asked to continue a 3-day course of treatment at home to exclude the possibility of a delayed reaction.
In the majority of cases, drug challenge is negative and the label of penicillin allergy can be removed from the patient record, allowing unhindered future prescription of penicillin or other beta-lactams. If testing confirms penicillin allergy, the choice lies between either excluding all penicillins and first-generation or second-generation cephalosporins or undertaking further testing to delineate whether the allergy is specific to a single beta-lactam or applies to a broader range of compounds.
Once testing is complete, a drug allergy notification is sent to the patient and copied to their GP. The notification contains details of drugs to avoid in future and crucially a list of alternative drugs that can be taken safely.10
Box 3: Referral criteria to a drug allergy service for patients with suspected allergy to penicillin or a cephalosporin11,20
- Patients with a label of ‘multiple antibiotic allergy’
- Patients with a history of immediate or non-immediate* reaction to penicillin/s and/or cephalosporin/s with a requirement for frequent antibiotics, for example patients with bronchiectasis, or diabetes
- Patients with a history of immediate or non-immediate* reaction to penicillin/s and/or cephalosporin/s requiring specific treatment with a beta-lactam.
- Delayed-onset urticaria, maculopapular and morbilliform exanthemata.
The high proportion of patients with a label of drug allergy and especially penicillin allergy is unacceptable. This leads to increased costs associated with the use of alternative and less effective drugs and contributes to antibiotic resistance. The NICE guideline on drug allergy published in 2014 provides sensible and practical advice on how to recognise drug allergy and what to record when the patient presents acutely. This should reduce the likelihood of ‘mislabelling’ and allow details of the original reaction to be revisited when the same drug is required in future.
Medical records with drug allergy information should be updated regularly and the patient made aware of their own drug allergy with the provision of written information. All clinical correspondence should now include drug allergy information as this should reduce the likelihood of inadvertent drug allergy reactions. Guidance has been provided on who should be referred to a specialist drug allergy service.
- Documentation of drug allergy should follow a structured approach and should be undertaken in all newly diagnosed cases of beta-lactam allergy to determine severity and whether the mechanism of allergy was consistent with IgE-mediated or delayed allergy
- Patients who do not have evidence of IgE mediated allergy are more likely to tolerate cephalosporins
- Providers of primary care electronic systems should ensure that the minimum dataset in Box 1 (see above) is captured in a convenient and structured manner
- Personalised written information about a patient’s drug allergy should be provided to them immediately or soon after the original reaction has occurred, and is necessary to reduce the likelihood of inadvertent prescription or administration of a drug to which they are allergic. This information will include details on which drugs or drug classes to avoid in future
- Everyone with a drug allergy is advised to carry personalised written information about their drug allergy and to share it whenever they visit a healthcare professional or are prescribed, dispensed, or are about to be administered a new drug
- The pharmacist is expected to check drug allergy status before dispensing any drug even if over the counter
- All communication about a patient should include drug allergy status in order to reduce drug errors that continue to occur in the health service. This includes:
- GP referral letters
- hospital discharge letters
- prescriptions issued in any healthcare setting
- Recent NICE guidance recommends that ‘Prescriptions (paper or electronic) issued in any healthcare setting should be standardised and redesigned to record information on which drugs or drug classes to avoid to reduce the risk of drug allergy.’ This would mean a redesign of the current FP10 standard prescription form to include information on drug allergy
- Patients with a family history, but no personal history, of penicillin allergy do not require investigation.
GP commissioning messages
written by Dr David Jenner, NHS Alliance GMS contract/PBC Lead
- CCGs should review their commissioned services for clinical allergy as these are often inconsistent across the country
- CCGs working with local specialist allergy services should ensure there are local care pathways for the identification, treatment, and investigation of patients presenting with possible beta-lactam (and other) allergies
- There should be a clearly defined route for referral for investigation of suspected beta-lactam allergy where future antibiotic prescribing is likely to be significantly restricted e.g. bronchiectasis or where multiple potential sensitivities are suspected
- GPs should be aware that they may face questioning over the accuracy of recording of allergies to medicines from 1 April 2015, when a contractual requirement for patients to have online access to a summary of their care record came into force
- GPs should encourage patients with definite and severe reactions to beta-lactams (or other drugs) to carry patient alert cards or bracelets to inform health professionals attending in emergency or where access to the care record is not possible.
- Health and Social Care Information Centre. Hospital Episode Statistics, Admitted Patient Care, England - 2012-13: Diagnosis. HSCIC, 2013. Available at: www.hscic.gov.uk/catalogue/PUB12566/hosp-epis-stat-admi-diag-2012-13-tab.xlsx
- NICE. Drug allergy: diagnosis and management of drug allergy in adults children and young people. Clinical Guideline 183. NICE, 2014. Available at: www.nice.org.uk/guidance/CG183
- Gomez M, Torres M, Mayorga C et al. Immediate allergic reactions to betalactams: facts and controversies. Curr Opin Allergy Clin Immunol 2004; 4: 261–266.
- Torres M, Blanca M. The complex clinical picture of beta-lactam hypersensitivity: penicillins, cephalosporins, monobactams, carbapenems, and clavams. Med Clin North Am 2010; 94: 805–820.
- Neugut A, Ghatak A, Miller R. Anaphylaxis in the United States: an investigation into its epidemiology. Arch Intern Med 2001; 161: 15–21.
- Shapiro S, Siskind V, Slone D et al. Drug rash with ampicillin and other penicillins. Lancet 1969; 2: 969–972.
- Kerns D, Shira J, Go S et al. Ampicillin rash in children: relationship to penicillin allergy and infectious mononucleosis. Am J Dis Child 1973; 125 (2): 187–190.
- Patel B. Skin rash with infectious mononucleosis and ampicillin. Pediatrics 1967; 40 (5): 910–911.
- Schiavino D, Nucera E, De Pasquale T et al. Delayed allergy to aminopenicillins: clinical and immunological findings. Int J Immunopathol Pharmacol 2006; 19 (4): 831–840.
- Mirakian R, Leech S, Krishna M, et al. BSACI guideline: managemnt of allergy to penicinlln and other beta-lactams. Clin Exp Allergy. 2015; 45 (2):300–327.
- Mirakian R, Ewan P, Durham S et al. BSACI guidelines for the management of drug allergy. Clin Exp Allergy 2009; 39: 43–61.
- Lee C, Zembower T, Fotis M et al. The incidence of antimicrobial allergies in hospitalized patients: implications regarding prescribing patterns and emerging bacterial resistance. Arch Intern Med 2000; 160 (18): 2819–2822.
- Macy E, Contreras R. Health care use and serious infection prevalence associated with penicillin ‘allergy’ in hospitalized patients: a cohort study. J Allergy Clin Immunol 2014; 133 (3): 790–796.
- Sade K, Holtzer I, Levo Y, Kivity S. The economic burden of antibiotic treatment of penicillin-allergic patients in internal medicine wards of a general tertiary care hospital. Clin Exp Allergy 2003; 33: 501–506.
- Satta G, Hill V, Lanzman M, Balakrishnan I. β-lactam allergy: clinical implications and costs. Clin Mol Allergy 2013; 11: 2.
- Idsoe O, Guthe T, Willcox R, De Weck A. Nature and extent of penicillin side-reactions, with particular reference to fatalities from anaphylactic shock. Bull World Health Org Geneva 1968; 38: 159–188.
- Lenler-Petersen P, Hansen D, Andersen M et al. Drug-related fatal anaphylactic shock in Denmark 1968–1990. A study based on notifications to the Committee on Adverse Drug Reactions. J Clin Epidemiol 1995; 48 (9): 1185–1188.
- Delage C, Irey N. Anaphylactic deaths: a clinicopathologic study of 43 cases. J Forensic Sci 1972; 17: 525–540.
- Pumphrey R, Davis S. Under-reporting of antibiotic anaphylaxis may put patients at risk. Lancet 1999; 353: 1157–1158.
- Dworzynski K, Ardern-Jones M, Nasser S. Diagnosis and management of drug allergy in adults, children and young people: summary of NICE guidance. BMJ 2014; 349: g4852.
- Pichichero M. A review of evidence supporting the American Academy of Pediatrics recommendation for prescribing cephalosporin antibiotics for penicillin-allergic patients. Pediatrics 2005; 115: 1048–1057.
- Atanasković M, Velicković T, Gavrović- Jankulović M et al. Immediate allergic reactions to cephalosporins and penicillins and their cross-reactivity in children. Pediatr Allergy Immunol, 2005; 16 (4) 341–347.