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PRE-PEN: A Skin Test for the Diagnosis of Penicillin Allergy

March 16, 2011 2:07 PM | Brad Miller (Administrator)

In the April WMSHP Newsletter, Juan Miretti, a PGY-1 Pharmacy Resident at Spectrum Health reviews PRE-PEN's use for penicillin allergy testing.

PRE-PEN: A skin test for the diagnosis of penicillin allergy

By Juan Miretti, PharmD, PGY1 Resident


Approximately 10% of patients report a penicillin allergy. When these individuals become ill with a serious bacterial infection, healthcare providers will often avoid using inexpensive first-line therapies over fear of a potential reaction. These patients must not only avoid penicillin antibiotics, but also the numerous other beta-lactam antibiotics available (i.e. cephalosporins, carbapenems). This forces healthcare providers to resort to other antibiotics that may limit effective antimicrobial stewardship and leads to about 30% higher costs for antibiotic treatment.

The most common hypersensitivity reaction to penicillin is an IgE-mediated reaction. IgE-mediated reactions, also known as type I hypersensitivity reactions, are life-threatening reactions characterized by systemic manifestations of anaphylaxis, which may include but not limited to erythema, urticaria, pruritis, angioedema, bronchospasm, and hypotension. Individuals having experienced such a reaction are diagnosed as having a penicillin allergy.

Patients may report an allergy to penicillin, but often the reaction experienced (i.e. nausea/vomiting) was an adverse drug reaction. There also exists the possibility that the reaction experienced (i.e. rash) was caused by the underlying infection and not by the penicillin. Of patients with a reported penicillin allergy, 80 to 90% do not have an IgE-mediated penicillin allergy when assessed by penicillin skin testing. Moreover, about 80% of patients that have had an IgE-mediated reaction to penicillin have negative skin tests after 10 years of avoidance. This indicates that many patients outgrow their allergy over time. It is also estimated that approximately 50% of penicillin allergic patients have outgrown their allergy after 5 years.

PRE-PEN is the only FDA approved commercially available skin test for the diagnosis of penicillin allergy. With the recent return of PRE-PEN to the market, healthcare providers are now able to accurately determine the risk of IgE-mediated reactions to penicillin antibiotics and related beta-lactam antibiotics in patients with a reported penicillin allergy. PRE-PEN was widely used for over 30 years but in 2004 it was withdrawn from the market due to the lack of a dedicated manufacturing facility. This significantly limited a healthcare provider’s ability to evaluate for penicillin hypersensitivity. Healthcare providers turned to penicillin desensitization, which was the only way to assure safe retreatment of patients with a documented penicillin allergy. Now with the availability of PRE-PEN, many patients who have been incorrectly labeled as allergic to penicillin will be able to receive inexpensive first-line antibiotic therapies. Appropriate use of PRE-PEN can reduce hospital costs and improve antimicrobial stewardship.


Candidates for PRE-PEN include any patient with a history of a reaction to a penicillin antibiotic that may have been IgE-mediated, or any patient who is currently denied access to beta-lactam antibiotics out of concern of such reactions. PRE-PEN is contraindicated in patients with clear histories of severe skin reactions (i.e. Stevens-Johnson syndrome, toxic epidermal necrolysis), patients known to be extremely hypersensitive to penicillin, and patients who have developed a systemic or marked local reaction to its previous administration.


Occasionally, patients may develop an intense local inflammatory response at the skin test site. Rarely, patients will develop a systemic allergic reaction characterized by manifestations of anaphylaxis. Skin testing should be performed under direct medical supervision and treatment for an anaphylactic reaction should be available.


A proper skin test involves 4 prick/puncture skin tests, and if these tests are negative, then 5 intradermal skin tests. The 4 prick/puncture tests include tests with PRE-PEN (major determinant), Penicillin G (minor determinant), histamine (positive control), and a diluent (negative control). The 5 intradermal tests include tests with PRE-PEN in duplicate, Penicillin G in duplicate, and a diluent (negative control).

Prick/puncture testing is performed first to decrease the risk of precipitating a systemic allergic reaction with intradermal testing. Most patients who have an IgE-mediated penicillin allergy will exhibit a negative prick/puncture skin test.

The reasoning for performing the intradermal skin test in duplicate is to prevent healthcare providers from making the wrong diagnosis due to ambiguous results. A false positive or false negative may be observed since the changes at the test site are relatively small.

To understand the rationale of using both major and minor determinants for the skin test, it is important to understand the immunochemistry of penicillin. When put into physiologic solution, penicillin spontaneously degrades into a number of intermediates, so called determinants. Penicillin mostly breaks down to penicilloyl, the major determinant, as well as other minor determinants that subsequently bind to host proteins. An allergic reaction occurs if the individual is sensitive to one or more of these determinants.

PRE-PEN is benzylpenicilloyl poly-L-lysine and is the major determinant. Skin testing with PRE-PEN should be done in conjunction with Penicillin G, which is the only commercially available minor determinant. Studies have shown that skin testing with PRE-PEN along with Penicillin G identifies up to 97% of patients who have an IgE-mediated penicillin allergy.


An important and underappreciated aspect of penicillin allergy is the unnecessary withholding of appropriate antibiotic therapy. This can lead to less effective antimicrobial stewardship and increased medical costs in patients who are labeled as penicillin allergic. Implementing skin testing with PRE-PEN at your institution can facilitate appropriate antibiotic therapy in patients with a reported penicillin allergy. Moreover, it will demonstrate the absence of penicillin allergy in many patients, will provide cost-effective antibiotic treatment options for healthcare providers and patients, and may help avoid the development of resistance to more powerful antibiotics.


  1. Park MA, Li JTC. Diagnosis and Management of Penicillin Allergy. Mayo Clin Proc. 2005; 80(3): 405-410. 
  2. PRE-PEN® [package insert]. Round Rock, Tex: ALK-Abelló, Inc. 2009.
  3. “PRE-PEN®, Penicillin Allergy Skin Test Antigen.” Fight the Cause Newsletter. Winter 2010. 1-5. Print. 
  4. PRE-PEN®, Penicillin Allergy Skin Testing Reference. Round Rock, Tex: ALK-Abelló, Inc. 2010. 
  5. PRE-PEN®. Round Rock, Tex: ALK-Abelló, Inc. 2010. DVD.
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