VOLUME 42 : NUMBER 6 : DECEMBER 2019 ARTICLE Penicillin allergy: a practical approach to assessment and prescribing Misha Devchand Infectious diseases SUMMARY antimicrobial stewardship pharmacist1,2 Penicillin allergies are not always lifelong. Approximately 50% are lost over five years. Jason A Trubiano A reaction to penicillin during a childhood infection is unlikely to be a true allergy. Director1 Postdoctoral fellow 3 Only 1–2% of patients with a confirmed penicillin allergy have an allergy to cephalosporins. Research fellow4 In patients with a low risk of severe allergic reactions, cephalosporins are a relatively safe treatment option. 1 Antimicrobial Stewardship, Drug and Antibiotic Allergy Patients with a history of delayed non-severe reactions, such as mild childhood rashes that Service and Centre for occurred over 10 years ago, may be suitable for an oral rechallenge with low-dose penicillin. This Antibiotic Allergy and should be done in a supervised hospital environment. Research, Austin Health 2 Pharmacy Department, In many cases, with appropriate assessment and allergy testing, it may be possible to remove the Austin Health penicillin allergy label. 3 The National Centre for Infections in Cancer, Peter 3 10 MacCallum Cancer Centre Introduction stay, hospital readmission rates, surgical site infections,14 and admissions to intensive care units.15 4 Department of Medicine, Most patients who say they have a penicillin allergy Austin Health, University of are not allergic to penicillins. While 10% of the Similarly in general practice, penicillin allergy labels Melbourne population will report a penicillin allergy, less than 1% are associated with an increased risk of death and 16 Melbourne will be truly allergic.1,2 They have been erroneously MRSA infection or colonisation. labelled as penicillin-allergic. Impermanent allergy Keywords In the USA, penicillin allergies are the most commonly It has been demonstrated that more than 90% of beta-lactams, documented drug allergy, with up to 20% of cephalosporins, patients labelled as having a penicillin allergy would hypersensitivity hospitalised patients having a recorded penicillin be able to tolerate penicillins following appropriate 3,4 allergy. In Australian hospitals, national point assessment and allergy testing.17-19 Even penicillin prevalence data (2013–14) show that 8.9% of patients allergies confirmed by skin tests can wane over time. Aust Prescr 2019;42:192–9 5 have a penicillin allergy label on their medical record. A Half the patients who have a positive skin test for https://doi.org/10.18773/ high proportion of these labels are likely to be incorrect. 13,20 austprescr.2019.065 penicillins will lose that reactivity after five years. The patient may have had a non-immune-mediated There is therefore interest in penicillin allergy reaction such as nausea and vomiting, an exanthema ‘de-labelling’. This is the removal of the allergy label (e.g. after taking amoxicillin during an Epstein-Barr following either allergy history reconciliation or testing 6,7 virus infection) or an injection-site reaction. (oral provocation or skin testing). Impact of allergy labels What is true penicillin allergy? Patient-reported penicillin allergies alter antibiotic The classification of a patient-reported penicillin management and may result in the use of suboptimal allergy label is the first important step in appropriate or broader spectrum drugs such as fluoroquinolones, care (Table 1). Before prescribing, ask patients about 6,8-11 macrolides, glycopeptides and cephalosporins. their allergies, as not all allergies may have been Having a penicillin allergy label has been associated documented in their medical records. Conversely, with an increased risk of Clostridium difficile, some reactions labelled as allergic may be other types methicillin-resistant Staphylococcus aureus (MRSA), of adverse events. Ask about the clinical features of and vancomycin-resistant enterococci infections and suspected reactions. colonisation.3 The increased use of broad-spectrum drugs in hospitalised patients with penicillin allergies Allergic cross-reactivity also contributes to the growing global problem of The beta-lactam antibiotics include penicillins, antimicrobial resistance.6,9,12,13 Antibiotic allergy labels cephalosporins, carbapenems and monobactams. are correlated with increases in length of hospital Previously it was thought that patients with penicillin 192 Full text free online at nps.org.au/australian-prescriber © 2019 NPS MedicineWise VOLUME 42 : NUMBER 6 : DECEMBER 2019 ARTICLE Table 1 Antibiotic allergy classifications Type Mechanism Clinical examples Common antibiotic examples Antibiotic recommendation Type A adverse drug reactions – non-immune-mediated Non-severe Nausea, vomiting, diarrhoea, pruritis Beta-lactams Use all antibiotics (without rash), headache Pharmacologically predictable reactions Severe Encephalitis, renal impairment, Cefepime, aminoglycosides, Only avoid the implicated drug tendinopathy fluoroquinolones or dose Type B adverse drug reactions – immune-mediated 1 IgE-mediated Urticaria, angioedema, Penicillins, cephalosporins bronchospasm, anaphylaxis 2 Antibody (usually Haemolytic anaemia, Penicillins, cephalosporins Avoid implicated drug. Caution IgG)-mediated cell thrombocytopenia, vasculitis with drugs in the same class destruction and structurally related drugs 3 IgG or IgM and Fever, rash, arthralgia Penicillin, amoxicillin, cefaclor complement 4 T-cell mediated Maculopapular exanthema, drug Beta-lactams, glycopeptides, Avoid implicated drug, reaction with eosinophilia and sulfonamides drugs in the same class and systemic symptoms (DRESS), structurally related drugs Stevens-Johnson syndrome, toxic epidermal necrolysis, acute generalised exanthematous pustulosis Anaphylactoid reactions – non-immune-mediated Non-IgE- Direct mast-cell Flushing, itching, urticaria, Vancomycin, macrolides, Manage the reaction, mediated stimulation or angioedema fluoroquinolones either by slowing the basophil activation infusion or premedication (with antihistamines or corticosteroids) allergies had a 10% risk of cross-reactivity with patients reporting a severe-immediate cefalexin cephalosporins and carbapenems.21 However, reviews hypersensitivity, intradermal tests determined that six have reported that the risk of cross-reactivity between (40%) would not be able to tolerate ampicillin.5,28 cephalosporins, carbapenems and penicillins may be While the data regarding cross-reactivity have as low as 1%.21-24 primarily been about immediate hypersensitivities, The cross-reactivity between beta-lactam antibiotics similar patterns have been reported in non-severe 29,30 [Author: is Ref 28 may be due to the beta-lactam ring itself, an delayed penicillin allergies. There are limited published?] adjacent thiazolidine or dihydrothiazine ring, or data regarding cross-reactivity in severe delayed from the side chains (R1 in penicillins or R1 and R2 in reactions, such as Stevens-Johnson syndrome, toxic cephalosporins) – see Fig. 1. True cross-reactivity is epidermal necrolysis, drug reaction with eosinophilia largely due to the R1 side chains, with the highest risk and systemic symptoms, and acute generalised being in beta-lactams with identical side chains. exanthematous pustulosis. For these severe delayed reactions, information regarding cross-reactivity is not Cross-reactivity is particularly seen with a reliable guide for empirical prescribing. aminopenicillins (amoxicillin, ampicillin) and aminocephalosporins (cefalexin, cefaclor, cefadroxil, Assessing penicillin allergies ceprozil).24 The rate of cross-reactivity between The key to both prescribing and de-labelling for aminopenicillins and aminocephalosporins has been patients with a history of penicillin allergy is an reported to be as high as 30–40% in predominately accurate assessment. This involves an understanding European studies.23,25-27 At the antibiotic allergy of the allergy particularly the severity, timing and testing centres of Austin Health and the Peter tolerance. Therapeutic Guidelines: Antibiotic contains MacCallum Cancer Centre in Melbourne, out of 15 a guide for this assessment (Fig. 2).31 Full text free online at nps.org.au/australian-prescriber 193 VOLUME 42 : NUMBER 6 : DECEMBER 2019 ARTICLE Penicillin allergy Fig. 1 Rates of cross-reactivity between beta-lactam antibiotics Basic structures Beta-lactam structures and rates of cross-reactivity Clinically relevant cross-reactivity <2%* Beta-lactam ring Penicillins Cephalosporins Similar side chains – penicillins (R1): 0 H 0 H • penicillin VK and NH penicillin G R R C 0 1 C N S CH3 1 N S Shared side chains – CH 3 penicillins and N N R cephalosporins (R1): Penicillin structure 0 0 0 2 ‡ HO • amoxicillin , Acyl side chain ‡ Thiazolidine ampicillin , cefalexin, 0 H ring cefaclor None R1 <1% <1% Shared side chains – C N S CH3 cephalosporins (R1): CH 3 • cefalexin, cefaclor N 0 0 • cefepime, ceftriaxone, cefotaxime Beta-lactam ring HO Monobactams† Carbapenems None • ceftazidime, aztreonam 0 H R Cephalosporin structure 2 R1 No shared side chains – R1 C N R3 Acyl side chain penicillins and cephalosporins (R1): Dihydrothiazine N 0 H N 0 ring 0 0 • cefazolin R 0 S 1 C N HO S 0 OH N R 0 2 Beta-lactam ring Beta-lactam antibiotics include penicillins, cephalosporins, carbapenems and monobactams. The left panel shows basic structures of beta-lactam antibiotics. Cross-reactivity is possible through the core beta-lactam ring, adjacent thiazolidine (penicillin) or dihydrothiazine