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Penicillin allergy and the use of beta-lactam antibiotics

► General information

  • Up to 20% of patients admitted to hospital report an “allergy” to penicillin; however, less than 2% of patients are truly allergic.
  • More than 95% of patients labeled as having a penicillin allergy are subsequently able to tolerate beta-lactam antibiotics since:
    • The most commonly reported reaction is a maculopapular rash which may or may not recur upon re-exposure to penicillin
    • IgE-mediated allergy declines over time rendering 80% of patients non-allergic after 10 years.
    • Patients may not have had an allergic reaction, but may have experienced an intolerance or adverse reaction (e.g., diarrhea) to the drug, a drug-infection interaction, or had a concomitant viral infection.
  • Patients with a penicillin allergy label are often prescribed alternative antibiotics that may be less effective, more toxic and associated with poorer outcomes including longer length of stay and increased cost to hospitals. Additionally, these alternative agents frequently have a broader antimicrobial spectrum and can contribute to the development and spread of antimicrobial resistance.

► Beta-lactam antibiotics

Penicillins, cephalosporins , carbapenems and monobactams are chemically related “beta-lactam” antibiotics. Below is a list of beta-lactam antibiotics.

Penicillins Cephalopsorins Carbapenems Monobactam
Amoxicillin, Ampicillin, Cloxacillin, Penicillin G, Penicillin V, Piperacillin

1stgeneration:
Cefadroxil, Cefazolin, Cephalexin

2ndgeneration:
Cefprozil, Cefuroxime, Cefoxitin, Cefaclor*

3rdgeneration:
Cefixime, Cefotaxime, Ceftazidime, Ceftriaxone

4thgeneration:
Cefepime

Ertapenem, Imipenem, Meropenem

Aztreonam (IV formulation only available through Special Access Program, Health Canada)
*no longer available in Canada

► Types of hypersensitivity reactions

Allergic or hypersensitivity reactions are those that have an immunologic component.

Drug hypersensitivity reactions are those that have an immunologic or allergic component:

  • “Immediate” reactions (IgE-mediated reactions) usually develop within 6 hours of starting drug therapy and may manifest as urticaria (hives), pruritus, and/or anaphylaxis (bronchospasm, hypotension, angioedema).
  • Delayed reactions without systemic involvement (e.g., maculopapular skin rash) usually appear 6-10 days after first drug exposure or within 3 days of second exposure.
  • Delayed reactions with systemic involvement (e.g., severe cutaneous adverse reactions [SCARs] such as Stevens-Johnson Syndrome [SJS], toxic epidermal necrolysis [TEN], Drug Reaction with Eosinophilia and Systemic Symptoms [DRESS], acute generalized exanthematous pustulosis [AGEP]) usually present 1-6 weeks after first drug exposure or within 3 days of second exposure.
  • Other reactions such as serum-sickness-like reactions, cytopenias, nephritis, drug fever have variable onset ranging from <72 hours to 4 weeks.

Note: Mild delayed skin rashes are often caused by an interaction between an aminopenicillin (amoxicillin or ampicillin) and a viral infection (e.g., infectious mononucleosis caused by Epstein-Barr virus).These are not true “allergic” reactions and thus it is not necessary to avoid use of any beta-lactam antibiotic.

► Management of patients with a beta-lactam allergy 

The management of patients designated allergic to a beta-lactam antibiotic is dependent on the initial reaction.

1. Non-allergic adverse reaction (diarrhea, nausea, vomiting, headache)

  • Use any beta-lactam antibiotic if preferred therapy.
  • Consider symptom management as appropriate (e.g., anti-nauseant, analgesic).

2. Unknown or vague reaction

  1. In patients with an unknown reaction to penicillin, especially occurring during childhood, cephalosporins and carbapenems can be considered.

3. Hypersensitivity reaction (see Figure 1)

Immediate hypersensitivity (IgE-mediated) reaction:

  • Hives (urticaria), pruritus, and/or anaphylaxis (bronchospasm, hypotension, angioedema) within 6 hours of starting therapy.
  • Patients with a history of a penicillin allergy may still receive non-cross reactive cephalosporins (see Table 1), which include cefazolin, ceftriaxone, ceftazidime.
  • These patients should only receive penicillins or cross-reactive cephalosporins after negative test results to beta-lactam allergy skin testing (BLAST), which is available through consultation with the Infectious Diseases Service.
  • Desensitization to a specific beta-lactam is another option for patients for whom BLAST testing is unavailable, or who have tested positive during BLAST testing.
  • In patients with a history of a cephalosporin allergy, a cephalosporin or penicillin with a different side chain can be considered

Delayed mild rash with no systemic involvement

  • Mild to moderate rash without fever and without involvement of internal organs or mucous membranes.
  • A beta-lactam antibiotic from a different class can be used (e.g., if the patient had a reaction to a penicillin, can use a cephalosporin).
  • Consult Dermatology, Clinical Pharmacology or Infectious Diseases as necessary.

Delayed reactions with systemic involvement

  • Reactions include SCARs (SJS/TEN, DRESS, AGEP) as well as serum sickness-like reaction, cytopenia, nephritis.
  • Avoid all beta-lactam antibiotics.
  • Consult infectious diseases and/or clinical pharmacology regarding appropriate and safe antibiotic options.

► Answers to commonly asked questions

1. Is there cross-reactivity between penicillins and cephalosporins?

  • In penicillin allergic patients, the incidence of allergic reactions to a cephalosporin was traditionally thought to be about 10-15%.
  • However, new evidence suggests that the risk of cross-reactivity is actually much lower, less than 2%. Cross-reactivity between penicillins and cephalosporins is dependent on the side chain structure of the beta-lactam antibiotic (see Table 1).
  • Cefazolin is not expected to cross-react with any penicillin or cephalosporin as it has unique side chains.
  • First generation cephalosporins (but not cefazolin) with a side chain similar to penicillins have the highest potential for cross-reactivity, with an attributable risk of about 0.5%. Second- and third-generation cephalosporins have negligible risks of cross-reaction with penicillins.
  • Data are lacking concerning cross-reactivity among beta-lactams with respect to delayed hypersensitivity reactions.

Recommendations for management (in the absence of diagnostic testing such as skin testing):

  • In patients who do not have evidence of an immediate hypersensitivity reaction to a penicillin (i.e., delayed reaction or unknown reaction), any cephalosporin can be used.
  • In patients who do have a history of an immediate hypersensitivity reaction to a penicillin, first-generation cephalosporins (notincluding cefazolin) and other penicillins should be avoided. However, non-cross-reactive second- or third generation cephalosporins (i.e., different side chains - see Table 1), cefazolin or carbapenems can be considered. Alternatively, if there is no suitable alternative antibiotic and a penicillin or a cephalosporin with a same/similar side chain is deemed necessary, the penicillin or cephalosporin may be used following successful desensitization.
  • In patients with a history of a severe hypersensitivity reaction including severe cutaneous adverse reaction (e.g., SJS/TEN, DRESS), hemolytic anemia, an organ-specific reaction (e.g., acute interstitial nephritis), drug fever or serum sickness-like reaction to a specific beta-lactam, all beta-lactams should be avoided.

2. Is there cross-reactivity between penicillins and carbapenems?

  • The incidence of cross-reactions between penicillins and carbapenems is less than 1%.

Recommendations for management (in the absence of diagnostic testing such as skin testing):

  • In patients who do not have evidence of an immediate hypersensitivity reaction to a penicillin (i.e., delayed reaction or unknown reaction), any carbapenem antibiotic can be used.
  • In patients who do have a history of an immediate hypersensitivity reaction to a penicillin, carbapenems can be considered.
  • In patients with a history of a severe hypersensitivity reaction including severe cutaneous adverse reaction (e.g., SJS/TEN, DRESS), hemolytic anemia, an organ-specific reaction (e.g., acute interstitial nephritis), drug fever or serum sickness-like reaction to a specific beta-lactam, all beta-lactams should be avoided.

3. Is there cross-reactivity among cephalosporins?

  • Even in patients with no penicillin allergy history, cephalosporins cause hypersensitivity reactions in 1-3% of patients.
  • Clinical cross-reactivity among cephalosporins relates to side chain similarity (see Table 1). The “generation” a cephalosporin belongs to should not be used to predict cross-reactivity to other cephalosporins.

Recommendations for management (in the absence of diagnostic testing such as skin testing):

  • In patients who do not have evidence of an immediate hypersensitivity reaction to a specific cephalosporin (i.e., delayed reaction or unknown reaction), any cephalosporin can be used, although avoidance of the specific cephalosporin that caused the reaction is suggested.
  • In patients who do have a history of an immediate hypersensitivity reaction to a specific cephalosporin, a cephalosporin or penicillin with different side chain can be used. If there is no suitable alternative antibiotic and the culprit cephalosporin or one with a same/similar side chain is deemed necessary, the cephalosporin may be used following successful desensitization.
  • In patients with a history of a severe hypersensitivity reaction including severe cutaneous adverse reaction (e.g., SJS/TEN, DRESS), hemolytic anemia, an organ-specific reaction (e.g., acute interstitial nephritis), drug fever or serum sickness-like reaction to a specific beta-lactam, all beta-lactams should be avoided.

4. Is skin testing or desensitization available in situations where a beta-lactam antibiotic appears to be the best therapeutic option for a seriously ill inpatient?

  • Beta-lactam allergy skin testing (BLAST) for select inpatients assessed by Infectious Diseases/Antimicrobial Stewardship teams is currently available on the inpatient units.
  • BLAST can also be arranged in follow up from hospital in the Drug Safety Clinic. Referrals should be faxed to x 5229. More information is available at drugsafety.sunnybrook.ca
  • For patients who are allergy test positive, desensitization is another alternative.Infectious Diseases and/or Clinical Pharmacology should be consulted to assess therapeutic alternatives and to arrange for desensitization if appropriate.

5. Does allergy to beta-lactam antibiotics run in families?

There is no evidence that IgE-mediated reactions are genetically mediated.Therefore, a history of penicillin allergy in one family member is not a contraindication to the use of a penicillin for another family member.

► References

  1.  Blumenthal KG, et al. Antibiotic allergy. Lancet 2019;393:183-98.
  2. Mirakian R, et al. Management of allergy to penicillins and other beta-lactams. Clin Exp Allergy 2015;45:300-27.
  3. NICE (National Institute for Health and Care Excellence). Drug allergy: diagnosis and management. www.org.uk/guidance/cg183 (Sept 3, 2014). Lagace-Wiens P, et al. Adverse reactions to beta-lactam antimicrobials. Expert Opin Drug Saf 2012;11:381-99.
  4. Shenoy ES, et al. Evaluation and management of penicillin allergy: a review. JAMA 2019;321:188-99.
  5. Trubiano JA, et al. The 3Cs of antibiotic allergy: classification, cross-reactivity and collaboration. J Allergy Clin Immunol Pract 2017;5:1532-42.

Last updated: June 2019

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