Penicillin Allergy - Assessment and Management of a Patient presenting with a History of

Publication: 22/01/2013  
Next review: 18/11/2024  
Clinical Protocol
ID: 3226 
Approved By: Improving Antimicrobial Prescribing Group 
Copyright© Leeds Teaching Hospitals NHS Trust 2021  


This Clinical Protocol is intended for use by healthcare professionals within Leeds unless otherwise stated.
For healthcare professionals in other trusts, please ensure that you consult relevant local and national guidance.

Assessment and Management of a Patient presenting with a History of Penicillin Allergy

Penicillin Allergy - Assessment and Management of a Patient presenting with a History of

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This document is a guide and should be used as a tool to assist healthcare workers faced with patients claiming an allergy to penicillin in making safe decisions. If there is doubt, the healthcare workers should err on the side of caution and avoid penicillin-containing antibiotics. If unclear, the healthcare worker should escalate the decision to the senior member of the medical team who can discuss the decision with a Microbiologist.

Allergic reactions to B-Lactam antibiotics are the most frequently encountered immunologically mediated adverse drug reaction 3. Up to 17% of the population report an allergic reaction to penicillin the nature and severity of which may be difficult to determine 5. Studies have shown patients labelled as penicillin allergic are more likely to receive drugs that are more costly, broader spectrum and have the potential for more adverse reactions (including Clostridium difficile infection) and induction of antimicrobial resistance 5 7. Treatment with such agents may be inferior to their B-lactam alternative and associated with greater treatment failure. The in-patient antibiotic cost of managing a patient with an allergy to penicillin is reported to be 63% higher than that of a patient who can tolerate penicillin 8. Only 10% of those alleging allergy to penicillin have a genuine allergy 9 with 50% of reactions being non-immune modulated or side effects of the drug (for example rash when taking amoxicillin for viral infection, diarrhoea and vomiting etc.) 5.
Assessment of the reaction is essential to determining the nature of the reaction and informing future antibiotic choices.

This guideline will instruct on how to make that assessment and discuss the management options available following such an assessment.

Basic Immunology of Penicillin Allergy

Understanding the classification systems of allergic reaction, their underlying mechanisms and clinical presentations aids the healthcare provider in assessing the likelihood and nature of a reaction to a given antibiotic when faced with a patient reporting an allergy. It informs the healthcare provider when making the choice of antibiotic in order to treat the infection most effectively by the safest means.

Table 1. Definitions of terms relating to allergy

Adverse Drug Reaction is a response to a drug which is noxious and unintended and which occurs at doses normally used in man for prophylaxis, diagnosis, or therapy of disease or for the modification of physiologic function 1

Drug Allergy is an immunologically mediated reaction that exhibits specificity and recurrence on re­exposure to the offending drug. A Drug Allergy is a form of Adverse Drug Reaction 2

Anaphylaxis is a severe, potentially fatal, systemic allergic reaction that occurs suddenly after contact with an allergy-causing substance4

Immediate Onset Reactions occur within 1 hour of administration of the drug. These are IgE mediated reactions and may progress to Anaphylaxis 6

Accelerated Onset Reactions occur between 1 and 72 hours of administration of the drug. These are almost always IgE mediated reactions 6

Early Onset Reactions is a collective term used to describe Immediate and Accelerated Onset reactions 6

Late Onset Reactions occur beyond 72 hours of administration of the drug. These are either Gell and Coombs classification 2-4 and idiopathic reactions or new onset IgE-mediated reactions (very unusual) 6

Allergic adverse drug reactions may be classified by immune mechanism 10 or by time of onset of reaction 11.

Immediate or Type 1 reactions are often associated with systemic manifestations of anaphylaxis (such as diffuse urticaria/wheals, erythema, pruritis, hypotension, cardiac dysrhythmias, bronchospasm, laryngeal oedema, angioedema either alone or in combination). Anaphylactic reactions occur in 4-15 of every 100,000 courses of penicillin and are seen predominantly in the young adult age group (ages 20-49 years). Atopy does not predispose to anaphylaxis but may result in a more severe reaction 12. There is generally no hereditary mechanism for anaphylaxis to penicillin and as such a family history should not influence the clinician.

Type I reactions result from penicillin or its metabolites binding with preformed specific IgE antibodies bound to tissue mast cells and/or circulating basophils. This complex formation causes the release (de-granulation) of the inflammatory mediators, including histamine, contained within these cells.

Reactions to penicillin occurring between 1-72 hours are known as accelerated reactions and may also be IgE mediated. These reactions are also characterized by urticaria, laryngeal oedema, angioedema and/or bronchospasm but rarely life threatening.

Late reactions occur more than 72 hours after administration of the drug and are rarely life threatening. The mechanism behind such reactions is heterogeneous. The most common reaction is a rash. The combined frequency of rash to penicillin has been estimated at 1-4% of treatment courses with maculo-papular or morbiliform rash being then most common occurring in 5.2-9.5% of treatment courses of ampicillin. These are usually symmetrical, confluent macules or papules. They generally originate on the extremities of ambulatory patients and tend to spare the soles and palms. In non-ambulatory patients the pressure areas are frequently affected.

Late reactions are not assessable by Skin Testing as they are not mediated by IgE antibodies 12.

Salkind, A. R. et al. JAMA 2001;285:2498-2505 [11] (based on classification scheme described by Gell and Coombs)

The immunochemistry of β-lactam antibiotics is complex and has not been fully elucidated. Penicillins comprise a β-lactam ring, to which it owes its antimicrobial activity, and a 5-membered thiazolidine ring. On degradation the β-lactam ring is opened and binds avidly to protein and the thiazolidine ring is preserved.

In contrast cephalosporin antibiotics have their 5-membered thiazolidine ring replaced with a 6-membered dihydrothiazine ring and undergo fragmentation of both the β-lactam and dihydrothiazine rings on degradation. It has been postulated that these differences account for the differences in immunogenicity 6.

Side chain similarity is now thought to relate more closely with cross- reactivity of penicillin and cephalosporins: the closer the side chain homology the greater the probability of cross reaction although both side chain and nuclear haptens may be involved 6 13 14. First generation cephalosporins (such as cephalexin, cephradine) have a much greater probability of cross reaction in patients with a history of penicillin allergy. This is discussed in more detail in the section on Cross Reactivity.

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Clinical Diagnosis

Clinical Assessment of a patient giving a History of Penicillin Allergy

The clinician assessing a patient giving a history of allergy to penicillin (or any other antibiotic) should attempt to define the type of reaction 12 15-19. Information should be sought from the patient or patients’ carers, the medical notes and the patients General Practitioner. The aim is to determine the nature of the adverse reaction in order to assess the risk of further exposure to the agent or related drugs. Published tools exist for the assessment of drug hypersensitivity 20 however, as most patients report reactions in the past, a detailed assessment of the reaction can be difficult.

The assessment questions in Box 1 should assist in determining the nature of the reaction.

Box 1- Taking a History of Penicillin Allergy: What to ask

  1. What antibiotics has the patient reacted to in the past?
  2. What antibiotics has the patient taken and tolerated since the allergy diagnosis (in particular penicillins or cephalosporins)?
  3. When did the reaction take place (estimated date)?
  4. What was the nature of the reaction (eg. diarrhoea, rash, swelling, difficulties breathing etc.)?
  5. If rash then:
    • Describe nature of rash (eg. maculo-papular, pustular, bullous, urticarial etc.)
    • Could this rash be related to the underlying condition (eg. viral rash, meningicoccal sepsis etc.)?
    • Could the rash be related to interaction with other medication?
    • How long after commencing the antibiotic did the rash appear?
  6. Why was the patient taking the antibiotic?
  7. Did this reaction result in hospitalisation or movement to a High Dependency Unit/Intensive Care Unit if already an in-patient?
  8. Did the reaction resolve on cessation of the antibiotic?

To find this information speak to the patient or carer, the GP and look in the patients notes.

Management of the patient with a history of allergy to penicillin

Management of the patient with a penicillin allergy is dependent on their clinical requirements. The questions below should be answered

  • What type of allergy does the patient have (type 1, unknown or non-type 1) (see section “Clinical Assessment of a patient giving a History of Penicillin Allergy”
  • Does the patient require an antibiotic at this time?
  • If yes, according to Trust Antibiotic Guidelines and the assessment of the patients’ allergy can the patient take the first line antibiotic without risk (See Box 2 and Box 3)?
  • Is it essential the patient has this antibiotic or does an alternative with comparable efficacy exist (a discussion with a Microbiologist or Infectious Disease Physician may be required to determine this)?

This risk assessment should be made by the most senior member of the clinical team and should be documented in the patients notes. It is important to note that the balance of risks may change for each infection and should be repeated before every course of antibiotic is initiated.

Cross-reactivity of other classes of antimicrobials in patients with penicillin allergy

Carbapenems (meropenem, imipenem, ertapenem)

Historically, there was believed to be a cross reactivity rate of almost 50% with carbapenems in patients with penicillin allergy. This was based on a single study with few patients 21. More recent prospective studies have shown the rate to be much lower: When skin testing patients with confirmed penicillin allergy and a clinical history of type 1 reaction to penicillin, only 1% of patients reacted to imipenem and meropenem 22-25. Retrospective studies reviewing the case notes of patients reported to have allergy to penicillin found rates of cross-reactivity of up to 9.8% for meropenem and 12.2% for imipenem 26 27 when including all reaction types. This implies a cross reaction rate of 1% when using carbapenems in patients who have previously suffered IgE-mediated reactions to penicillins. The risk of a life threatening reaction in patients who have suffered non-IgE mediated reaction to penicillin should be no greater than that of the normal population.

Monobactams (aztreonam)

Patients who have experienced a type 1 hypersensitivity reaction to ceftazidime should avoid aztreonam due to the risk of cross-reactivity due to side chain similarity of the two drugs 28 29.

Box 3- Can the patient tolerate first line drug safely?

Nature of penicillin allergy



Immediate (IgE mediated) reaction

Avoid penicillins and related classes demonstrating cross reactivity


Non-Immediate reaction (Mild)
eg. “Morbiliform” exanthems (non-urticarial, non-pruritic rash)

If certain reaction is non-IgE mediated then can be given the same antibiotic again by graded challenge:

Using the preferred antibiotic and route of administration, give the patient 10% of dose followed by 50% of dose followed by the remaining dose, each at 20 minute intervals with continuous observation. For this the patient requires consenting and needs to be fully co-operative.

If uncertain then chose a safe alternative and consider elective skin testing if likely to require prolonged or recurrent courses of antibiotics

6 9

Non-Immediate reaction (Severe)
eg. Stevens-Johnson Syndrome (SJS)
Toxic Epidermal Necrolysis (TEN)
Drug reaction with Eosinophilia and Systemic Symptoms (DRESS)
Acute Generalised Exanthematous Pustulosis (AGEP)
Interstitial Nephritis
Delayed angioedema/urticaria
Serum Sickness

Drug specific response

Avoid precipitating drug

Safe to use drugs of same class


Studies in the non-Cystic Fibrosis patient group found evidence of cross-reactive skin tests (3.4%) but no evidence of clinical cross-reactivity to aztreonam in the patients with skin test confirmed penicillin allergy when challenged with the drug 28 30-32.

In studies looking at Cystic Fibrosis patients, skin test cross reactivity was demonstrated in 5.3% of patients with clinical evidence of cross reactivity on challenge 29 33 34. The research did not look specifically at penicillin allergy and ceftazidime cross reactivity may account for a proportion of these cases. The findings in the Cystic Fibrosis patient group cannot be extrapolated to the general population as there is greater degree of hypersensitivity and sensitization to antibiotics in this group than in the general population. This degree of sensitization is demonstrated in the studies.


As discussed earlier, the commonly held belief that 10% of patients with allergy to penicillin will cross react when given cephalosporins is a myth. This myth is based on historical data and it is hypothesized that an explanation could be that cephalosporins and penicillins were manufactured on the same fermentation production line; hence some cephalosporins contained trace amounts of penicillin.

The true rate of cross reaction is dependent on the generation of cephalosporin. For first generation cephalosporins (cefalexin in this case), patients reporting allergy to penicillins demonstrated a cross-reaction rate of 6.5-7% 35 36 however this rate is shown to be higher (14%) when studying patients whose allergy is confirmed by skin testing 37.

Box 4- Table of Cross Reactions to drugs when patient has history of an Immediate-Type (Type 1) Hypersensitivity to Penicillin


Risk of Cross-Reaction




Antibiotics where cross-reaction HIGHLY LIKELY



All contain penicillin and have been associated with accidental administration to patients with Penicillin Allergy

Penicillin, Benzyl-penicillin, amoxicillin, ampicillin, piperacillin/tazobactam, co-amoxiclav, co-fluampicil, ticarcillin (timentin), pivmecillinam, temocillin




Antibiotics where cross-reaction POSSIBLE



1st generation



Also in this class:



¥ Including all reactions (type 1 and non-type 1) based on history of penicillin allergy only
+ Demonstrated by skin test in patients with type 1 reaction to penicillin

2nd Generation



Also in this class:



Cefuroxime studied only. These rates describe anaphylaxis in those patients given cefuroxime who had a history of penicillin/amoxicillin allergy (higher number) and those with a history of allergy confirmed by skin testing (lower number)

3rd Generation



Also in this class:
Cefotaxime, Ceftriaxone



$Ceftazidime studied only. Based on history of penicillin/amoxicillin allergy alone. Reaction rate 1.7% in control group with no reported allergy to penicillin/amoxicillin





0.9%+ - 9.8%#

22 24 26 27

+ Demonstrated by skin test in patients with type 1 reaction to penicillin


0.8%+ - 12.2%#

23 25-27

# Including all reactions (type 1 and non-type 1) from case note review


Insufficient Data


Antibiotics where cross-reaction UNLIKELY



Ciprofloxacin, Levofloxacin



No Cross-reactivity demonstrated




0% § - 5.3% *


§ Non- CF patient group only. Some cross reactivity documented in the CF patient group
* Cross reactivity with patients allergic to ceftazidime is well documented- avoid in this patient group




No Cross-reactivity demonstrated

Co-trimoxazole (Septrin)






Erythromycin, Clarithromycin



Tetracycline, Doxycycline






Vancomycin, Teicoplanin



Regarding second generation cephalosporins, Pichichero et. al. reviewed the relative risk of giving cefuroxime to patients who had a history of allergy to penicillin or amoxicillin compared to those who had no such history. Eight of 428 patients (1.9%) with a history and 89 of 5410 patients (1.7%) with no history reacted to cefuroxime. When the groups were separated by history of allergy confirmed by skin testing the rates were similar: 2 of 283 patients (1.6%) with and 5 of 397 patients (1.3%) without a history confirmed by skin testing reacted when given the drug. The relative risk was not significantly different for either group (-0.3%; CI -0.7-1.5% for the “history of allergy” group and -0.3%; CI -2.1-0.9% for the “history confirmed by skin testing” group)14.

Ceftazidime, a third generation cephalosporin with anti-Pseudomonal activity, showed a similar pattern. Of 538 patients giving a history of penicillin allergy, only 3 (0.06%) reacted when administered ceftazidime whereas 57 of the 3427 (1.7%) patients with no history of allergy to penicillin or amoxicillin reacted. Nil patients of a group of 30 who had their allergy confirmed by skin testing reacted to ceftazidime when challenged. Similarly there were no recorded reactions to ceftriaxone of 142 patients with history of penicillin/amoxicillin confirmed with skin testing 14.

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Record: 3226
  • To ensure patients receive safe and effective care when they require antibiotic management
  • To standardise and optimise the assessment and management of a patient presenting with a history of penicillin allergy
  • To reduce the inappropriate prescription of harmful antibiotics to patients with a history of penicillin allergy
  • To optimize the management of infection in patients with a history of penicillin allergy
Clinical condition:

Assessment and Management of a Patient presenting with a History of Penicillin Allergy

Target patient group: Patients presenting with a History of Penicillin Allergy
Target professional group(s): Secondary Care Doctors
Adapted from:

Evidence base

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  2. Vervloet D, Durham S. ABC of allergies: Adverse reactions to drugs. British Medical journal 1998;316(1511-4).
  3. Rodriguez-Pena R, Antunez C, Martin E, Blanca-Lopez N, Mayorga C, Torres MJ. Allergic reactions to β-lactams. Expert Opinion on Drug Safety 2006;5(1):31-48.
  4. Sampson HA, Munoz-Furlong A, Campbell RL. Second symposium on the definition and management of anaphylaxis: Summary report—Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network symposium. Journal of Allergy and Clinical Immunology 2006;117:391-7.
  5. Borch JE, Andersen KE, Bindslev-Jensen C. The Prevalence of Suspected and Challenge-Verified Penicillin Allergy in a University Hospital Population. Basic & Clinical Pharmacology & Toxicology 2006;98(357-362).
  6. Pichichero ME. A Review of Evidence Supporting the American Academy of Pediatrics Recommendation for Prescribing Cephalosporin Antibiotics for Penicillin-Allergic Patients.
    Pediatrics 2005;115(4):1048.
  7. MacLaughlin EJ, Saseen JJ, Malone DC. Costs of b-Lactam Allergies: Selection and Costs of Antibiotics for Patients With a Reported b-Lactam Allergy. Archives of Family Medicine 2000;9:722-26.
  8. 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(4):501-6.
  9. Yates AB. Management of Patients with a History of Allergy to Beta-Lactam Antibiotics. The American Journal of Medicine 2008;121(7):572-76.
  10. Gell PGH, Coombs RRA. Classiification of allergic reactions responsible for clinical hypersensitivity and disease. Oxford: Blackwell Scientific Publications, 1975.
  11. Levine BB. Immunologic Mechanisms of Penicillin Allergy- A Haptenic Model System for the Study of Allergic Diseases of Man. New England Journal of Medicine 1966;275:1115-25.
  12. Salkind AR, Cuddy PG, Foxworth JW. Is This Patient Allergic to Penicillin? An Evidence-Based Analysis of the Likelihood of Penicillin Allergy. JAMA 2001;285(19):2498-505.
  13. Kelkar PS, Li JT. Cephalosporin allergy. N Engl J Med 2001;345(11):804-9.
  14. Pichichero ME. Cephalosporins can be prescribed safely for penicillin-allergic patients. J Fam Pract 2006;55(2):106-12.
  15. Torres MJ, Blanca M, Fernandez J, Romano A, Weck A, Aberer W, et al. Diagnosis of immediate allergic reactions to beta-lactam antibiotics. Allergy 2003;58(10):961-72.
  16. Romano A, Blanca M, Torres MJ, Bircher A, Aberer W, Brockow K, et al. Diagnosis of nonimmediate reactions to beta-lactam antibiotics. Allergy 2004;59(11):1153-60.
  17. Gruchalla RS. Clinical assessment of drug-induced disease. Lancet 2000;356(9240):1505-11.
  18. Gruchalla RS. 10. Drug allergy. J Allergy Clin Immunol 2003;111(2 Suppl):S548-59.
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  20. Demoly P, Kropf R, Bircher A, Pichler WJ. Drug hypersensitivity: questionnaire. EAACI interest group on drug hypersensitivity. Allergy 1999;54(9):999-1003.
  21. Saxon A, Adelman DC, Patel A, Hajdu R, Calandra GB. Imipenem cross-reactivity with penicillin in humans. J Allergy Clin Immunol 1988;82(2):213-7.
  22. Atanaskovic-Markovic M, Gaeta F, Medjo B, Viola M, Nestorovic B, Romano A. Tolerability of meropenem in children with IgE-mediated hypersensitivity to penicillins. Allergy 2008;63(2):237-40.
  23. Romano A, Viola M, Gueant-Rodriguez RM, Gaeta F, Pettinato R, Gueant JL. Imipenem in patients with immediate hypersensitivity to penicillins. N Engl J Med 2006;354(26):2835-7.
  24. Romano A, Viola M, Gueant-Rodriguez RM, Gaeta F, Valluzzi R, Gueant JL. Brief communication: tolerability of meropenem in patients with IgE-mediated hypersensitivity to penicillins. Ann Intern Med 2007;146(4):266-9.
  25. Atanaskovic-Markovic M, Gaeta F, Gavrovic-Jankulovic M, Velickovic TC, Valluzzi RL, Romano A. Tolerability of imipenem in children with IgE-mediated hypersensitivity to penicillins. J Allergy Clin Immunol 2009;124(1):167-9.
  26. Prescott WA, Jr., DePestel DD, Ellis JJ, Regal RE. Incidence of carbapenem-associated allergic-type reactions among patients with versus patients without a reported penicillin allergy. Clin Infect Dis 2004;38(8):1102-7.
  27. Sodhi M, Axtell SS, Callahan J, Shekar R. Is it safe to use carbapenems in patients with a history of allergy to penicillin? J Antimicrob Chemother 2004;54(6):1155-7.
  28. Frumin J, Gallagher JC. Allergic cross-sensitivity between penicillin, carbapenem, and monobactam antibiotics: what are the chances? Ann Pharmacother 2009;43(2):304-15.
  29. Moss RB, McClelland E, Williams RR, Hilman BC, Rubio T, Adkinson NF. Evaluation of the immunologic cross-reactivity of aztreonam in patients with cystic fibrosis who are allergic to penicillin and/or cephalosporin antibiotics. Rev Infect Dis 1991;13 Suppl 7:S598-607.
    30. Adkinson NF, Jr. Immunogenicity and cross-allergenicity of aztreonam. Am J Med 1990;88(3C):12S-15S; discussion 38S-42S.
    31. Saxon A, Hassner A, Swabb EA, Wheeler B, Adkinson NF, Jr. Lack of cross-reactivity between aztreonam , a monobactam antibiotic, and penicillin in penicillin-allergic subjects. J Infect Dis 1984;149(1):16-22.
    32. Vega JM, Blanca M, Garcia JJ, Miranda A, Carmona MJ, Garcia A, et al. Tolerance to aztreonam in patients allergic to beta-lactam antibiotics. Allergy 1991;46(3):196-202.
    33. Jensen T, Koch C, Pedersen SS, Hoiby N. Aztreonam for cystic fibrosis patients who are hypersensitive to other beta-lactams. Lancet 1987;1(8545):1319-20.
    34. Jensen T, Pedersen SS, Hoiby N, Koch C. Safety of aztreonam in patients with cystic fibrosis and allergy to beta-lactam antibiotics. Rev Infect Dis 1991;13 Suppl 7:S594-7.
    35. Petz LD. Immunologic cross-reactivity between penicillins and cephalosporins: a review. J Infect Dis 1978;137 Suppl:S74-S79.
    36. Dash CH. Penicillin allergy and the cephalosporins. J Antimicrob Chemother 1975;1(3 Suppl):107-18.
    37. Audicana M, Bernaola G, Urrutia I, Echechipia S, Gastaminza G, Munoz D, et al. Allergic reactions to betalactams: studies in a group of patients allergic to penicillin and evaluation of cross-reactivity with cephalosporin. Allergy 1994;49(2):108-13.
    38. Lin RY. A perspective on penicillin allergy. Arch Intern Med 1992;152(5):930-7.

A. Meta-analyses, randomised controlled trials/systematic reviews of RCTs
B. Robust experimental or observational studies
C. Expert consensus.
D. Leeds consensus. (where no national guidance exists or there is wide disagreement with a level C recommendation or where national guidance documents contradict each other)

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