Getting It Right: Delabeling Penicillin Allergy

Background

About 10% of US patients report having an allergic reaction to a penicillin-class antibiotic in the past (listed in chart as an allergy).

Many patients who report penicillin allergies do not have true IgE-mediated reactions.

  • 9 out of 10 who report an allergy are not truly allergic (in total, <1% of the population)
  • About 80% of patients with IgE-mediated reactions lose sensitivity after 10 years

Approximately 50% of all hospitalized patients receive antibiotics. For those with a listed penicillin allergy, alternative antibiotics are often used (typically broad-spectrum) → more expensive, less effective, more toxic, and facilitate antibiotic resistance

  • Patients with documented PCN allergy are 5x more likely to receive clindamycin (associated with C.diff infections)
  • Patients with documented PCN allergy are 18x more likely to receive aztreonam

Correctly identifying patients who are not truly penicillin-allergic can decrease unnecessary use of broad-spectrum antibiotics.


What is considered a true allergy?

Characteristics of an IgE-mediated (Type 1, or immediate hypersensitivity) reaction:

  • Occurs immediately or within ~1 hr
  • Urticaria (hives)
  • Angioedema – localized edema affecting the abdomen, face, extremities, genitalia, oropharynx, or larynx
  • Wheezing and shortness of breath (bronchospasm)

Anaphylaxis – requires involvement of at least 2 systems:

  • Skin: hives, flushing, itching, angioedema
  • Respiratory: cough, nasal congestion, shortness of breath, chest tightness, wheeze, sensation of throat closure or choking, change in voice-quality
  • Cardiovascular: hypotension, lightheadedness, tachycardia (or bradycardia), chest pain
  • Neuro: sense of impending doom, loss of consciousness
  • GI: nausea, vomiting, abdominal cramping, diarrhea

Other hypersensitivity reactions (non-IgE mediated)

  • Stevens-Johnson syndrome
  • Toxic epidermal necrolysis (TEN)
  • Serum sickness
  • Acute interstitial nephritis
  • Hemolytic anemia
  • Drug rash with eosinophilia and systemic symptoms (DRESS)
  • Acute generalized exanthematous pustulosis (AGEP)

Common adverse reactions

On the other hand, there are lots of common adverse reactions to penicillins that are not true allergies and should not be considered contraindications to use.

  • Diarrhea
  • Nausea/vomiting
  • Yeast vaginitis
  • Mild drug eruptions
  • Remember that morbilliform rash with EBV infection??
  • Family history*

*Penicillin allergy is not considered an inheritable trait, so family history DOES NOT preclude you from getting penicillin-based antibiotics.

History taking is very important in differentiating types of reactions!

In order to determine what someone’s reaction was, it is important to ask the patient very specific questions about the type and location of symptoms, exactly what medication was used and if they’ve had similar meds since then, the timing of the reaction compared to med administration, how long ago it was, and how it was ultimately treated. 


What should we do about it?

Knowing that many people are incorrectly labeled as having a penicillin allergy (didn’t have a true hypersensitivity reaction, family history, grew out of it), we’re left with a couple questions: 

  • Do we keep avoiding penicillins forever?
  • What about other beta lactams?

Several recent studies have informed efforts to “delabel” patients who are incorrectly documented as penicillin allergic – to decrease cost, resistance, and treat with optimal drug. 

“Delabeling” is also supported by the American Academy of Allergy, Asthma, and Immunology; IDSA; and CDC. 


Penicillin skin testing (PST)

PST is the standard approach to evaluate an allergy history suggestive of an IgE-mediated reaction or to rule out an IgE-mediated reaction if the history is unclear. 

  • More than 90% of patients are not truly allergic after testing
  • High negative predictive value (number of true negatives out of all people who test negative)
  • NPV allows you to assess the likelihood of NOT having a disease with a negative test

Cannot use PST for other types of hypersensitivity reactions (e.g. SJS/TEN, DRESS, serum sickness, etc.) As such, in anyone with these conditions, future use of penicillins (and related meds such as cephalosporins and carbapenems) should be entirely avoided.

Only 0.1% with a labeled penicillin allergy currently undergo testing. 

Downsides of PST:

  • Not widely available – requires referral
  • High false positive rate
  • Expensive

Can we skip PST?

Given that getting a PST can be a challenge, new studies have looked at whether or not a direct challenge (DC) with a penicillin drug followed by observation is a safe alternative to skin testing. This would allow the testing to be done in a wider variety of settings and potentially at a lower cost.

Recent evidence shows that DC is a safe alternative to PST in low risk patients. In a 2019 randomized controlled trial comparing PST to 2-step DC, Mustafa et al (J Allergy Clin Immunol Pract) looked at 2 groups: individuals aged 5-18yo with history of cutaneous-only reaction >1 year ago and adults >18yo with cutaneous-only reaction >10 years ago. These groups were randomized 1:1 to PST followed by oral challenge to amoxicillin or 2-step DC.

  • PST group: 10/80 (12.5%) had positive PST
  • DC group: 3/79 (3.8%) positive DC – only cutaneous manifestations treated with oral antihistamines
  • 8.7% fewer positive results with DC (p = .079), DC costs $340 less per patient, took less time by about 6 minutes, and eliminates need for needles

Other notable studies:


But what is “low risk”?

A study by Stevenson et al (J Allergy Clin Immunol Pract, 2020) sought to determine an optimal definition for “low risk” penicillin allergy. Such a definition would enable non-specialists to safely perform oral challenges to penicillin when appropriate and to identify high-risk individuals to refer for PST. 

  • 447 patients with penicillin-allergy testing outcomes – retrospectively looked at statistical models of these outcomes for 8 different definitions of “low-risk”
  • Optimal definition (thought to be safest in clinical practice – highest NPV and high sensitivity): 
    • Benign rash (urticarial, maculopapular rash) >1 year ago without angioedema, mucosal ulceration, or systemic involvement
    • 54.6% of the patients met this definition – 97.1% of these tolerated a 1 or 2 dose DC (and those who reacted did not have anaphylaxis)


Validation of a Clinical Decision Making Tool (PEN-FAST)

Trubiano et al (JAMA 2020) validated the penicillin allergy clinical decision rule “PEN-FAST” for point-of-care risk assessment. PEN-FAST identifies individuals who can safely use penicillin-family drugs without the need for confirmatory testing.

  • 622 patients with reported penicillin allergy underwent testing via skin prick, intradermal injections, patch testing, or oral challenge
  • 4 factors were found to be associated with a positive allergy test – in patients reporting a PENicillin allergy
    • Five years or less since reaction (2 points)
    • Anaphylaxis, Angioedema OR Severe cutaneous adverse reaction (2 points)
    • Treatment required for reaction (1 point)

External validation of the PEN-FAST decision aid remained clinically relevant in a retrospective cohort of 945 patients from 3 centers in Sydney and Perth, Australia and Nashville, TN.

If a patient is “low risk” based on this calculator in the office, you can encourage either safe use of beta lactams or an oral challenge program in the office.


And where do we stand with cephalosporins??

Recent literature has shown that the major determinant in the cross-reactivity between penicillins and cephalosporins is the similarity between the side chain of first generation cephalosporins and penicillins (rather than the ß-lactam structure)

Risk of an allergic reaction to cephalosporins in those with an established IgE-mediated allergy to penicillin is low as long as the side chains between the drugs are not similar.

  • Cross-reactivity = 1-10% in people with TRUE penicillin allergy, higher in general with earlier generation cephalosporins

Common cross-reactors:

  • Cephalexin (1st gen)
  • Ceftriaxone (3rd gen)
  • Cefpodoxime (3rd gen)

Safer options:

  • Cefazolin (1st gen)
  • Cefuroxime (2nd gen)
  • Cefdinir (3rd gen)
  • Cefixime (3rd gen)

Blog post based on Med-Peds Forum talk by Lindsey Mahoney, PGY3