Penicillin allergy testing: benefits for patients, institutions, and public health

They say they’re allergic to penicillin. But are they?

They say they’re allergic to penicillin. But are they?

Patients may mistake adverse events or symptoms of an infection for an allergic reaction.1

A history of penicillin allergy alone is not reliable in predicting immediate allergic reactions to the drug. Some patients who are labeled “penicillin allergic” may have experienced nonallergic reactions to the drug (eg, gastrointestinal upset, or headache). Indeed, many patients are erroneously labeled as “penicillin allergic” after the occurrence of a penicillin adverse event, when in reality they could safely be readministered a penicillin or related antibiotic. Also, some patients mistake the signs and symptoms of the infection for which they are being treated—or unrelated symptoms—as an allergic reaction to the drug.

10% of people in the United States—or 33 million Americans—report that they have a penicillin allergy2,3

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Patients may grow out of their allergy over time.2

In fact, 80% of patients lose their sensitivity after 10 years. Retesting them may indicate that they can now safely receive penicillin antibiotics.

Penicillin allergy testing may help improve patient outcomes

Correctly identifying patients who are not allergic to penicillin can help them:

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Receive first-line antibiotic therapy recommended by guidelines4

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Decrease exposure to broad-spectrum antibiotics, which can reduce incidence of adverse events and antibiotic resistance4

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Reduce their length of inpatient hospital stay by 33%5


Penicillin allergy testing can open up new or additional treatment options for patients

Antibiotic resistance is a clinical and public health crisis.6 Using narrow-spectrum antibiotics—like penicillin—over broad-spectrum antibiotics helps slow the development of antibiotic resistance and reduces healthcare costs.7

Annual impact of antibiotic-resistant infections in the United States

35,000 deaths6

2.8 million infections6

$20 billion increase in medical costs8

Implementing penicillin allergy skin testing helps achieve multiple AMS goals:


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CHOOSE the most appropriate antibiotic therapy with the correct dose, indication, and duration9

63% of patients who were skin tested received a narrower-spectrum antibiotic10


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PREVENT antimicrobial misuse and abuse9

After a negative skin test, 55% of patients were switched to a penicillin, 40% to a cephalosporin, and 5% to a carbapenem10


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MINIMIZE the development of resistance9

Exposure to carbapenems and cephalosporins has been shown to result in a 10- to 20-fold increase in gram-negative resistance to these broad-spectrum antibiotics9

Guidelines from multiple national organizations—the CDC, AAAAI, ACAAI, and IDSA—recommend using penicillin allergy testing to enhance patient care.2,11-13


AAAAI=American Academy of Allergy, Asthma & Immunology; ACAAI=American College of Allergy, Asthma & Immunology; AMS=antimicrobial stewardship; CDC=Centers for Disease Control and Prevention; CMS=Centers for Medicare & Medicaid Services; IDSA=Infectious Diseases Society of America; MRSA=methicillin-resistant Staphylococcus aureus; VRE=vancomycin-resistant Enterococci.

References: 1. Penicillin allergy. Mayo Clinic. Published December 5, 2019. Accessed June 24, 2021. 2. Evaluation and diagnosis of penicillin allergy for healthcare professionals. Centers for Disease Control and Prevention. Updated October 31, 2017. Accessed June 24, 2021. 3. U.S. and world population clock. Accessed June 24, 2021. 4. Blumenthal KG, Peter JG, Trubiano JA, Phillips EJ. Antibiotic allergy. Lancet. 2019;393(10167):183-198. doi:10.1016/S0140-6736(18)32218-9 5. du Plessis T, Walls G, Jordan A, Holland DJ. Implementation of a pharmacist-led penicillin allergy de-labelling service in a public hospital. J Antimicrob Chemother. 2019;74(5):1438-1446. doi:10.1093/jac/dky575 6. Antibiotic resistance threats in the United States, 2019. Centers for Disease Control and Prevention. Accessed March 10, 2021. 7. Antibiotic treatment in the hospital: sometimes it can be stopped. American Board of Internal Medicine Foundation. Published February 2016. Accessed June 24, 2021. 8. Carter RR, Sun J, Jump RL. A survey and analysis of the American public’s perceptions and knowledge about antibiotic resistance. Open Forum Infect Dis. 2016;3(3):ofw112. doi:10.1093/ofid/ofw112 9. Doron S, Davidson LE. Antimicrobial stewardship. Mayo Clin Proc. 2011;86(11):1113-1123. doi:10.4065/mcp.2011.0358 10. Heil EL, Bork JT, Schmalzle SA, et al. Implementation of an infectious disease fellow–managed penicillin allergy skin testing service. Open Forum Infect Dis. 2016;3(3):ofw155. doi:10.1093/ofid/ofw155 11. Sexually transmitted diseases treatment guidelines, 2006. Centers for Disease Control and Prevention. MMWR Recomm Rep. 2006;55(RR-11);1-94. 12. Antibiotic stewardship: the need for penicillin allergy testing. American Academy of Allergy, Asthma & Immunology. Accessed March 5, 2021. 13. Barlam TF, Cosgrove SE, Abbo LM, et al. Implementing an antibiotic stewardship program: guidelines by the Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America. Clin Infect Dis. 2016;62(10):e51-e77. doi:10.1093/cid/ciw118


PRE-PEN is indicated for the assessment of sensitization to penicillin (benzylpenicillin or penicillin G) in patients suspected to have clinical penicillin hypersensitivity. A negative skin test to PRE-PEN is associated with an incidence of immediate allergic reactions of less than 5% after the administration of therapeutic penicillin, whereas the incidence may be more than 50% in a history-positive patient with a positive skin test to PRE-PEN. These allergic reactions are predominantly dermatologic. Whether a negative skin test to PRE-PEN predicts a lower risk of anaphylaxis is not established. Similarly, when deciding the risk of proposed penicillin treatment, there are not enough data at present to permit relative weighing in individual cases of a history of clinical penicillin hypersensitivity as compared to positive skin tests to PRE-PEN and/or minor penicillin determinants.


The risk of sensitization to repeated skin testing with PRE-PEN is not established. Rarely, a systemic allergic reaction including anaphylaxis (see below) may follow a skin test with PRE-PEN. To decrease the risk of a systemic allergic reaction, puncture skin testing should be performed first. Intradermal skin testing should be performed only if the puncture test is entirely negative.

PRE-PEN is contraindicated in those patients who have exhibited either a systemic or marked local reaction to its previous administration. Patients known to be extremely hypersensitive to penicillin should not be skin tested.

No reagent, test, or combination of tests will completely assure that a reaction to penicillin therapy will not occur. The value of the PRE-PEN skin test alone as a means of assessing the risk of administering therapeutic penicillin (when penicillin is the preferred drug of choice) in the following situations is not established:

  • Adult patients who give no history of clinical penicillin hypersensitivity.
  • Pediatric patients.

In addition, the clinical value of PRE-PEN where exposure to penicillin is suspected as a cause of a current drug reaction or in patients who are undergoing routine allergy evaluation is not known. Likewise, the clinical value of PRE-PEN skin tests alone in determining the risk of administering semisynthetic penicillins (phenoxymethylpenicillin, ampicillin, carbenicillin, dicloxacillin, methicillin, nafcillin, oxacillin, amoxicillin), cephalosporin-derived antibiotics, and penem antibiotics is not known.

In addition to the results of the PRE-PEN skin test, the decision to administer or not administer penicillin should take into account individual patient factors. Healthcare professionals should keep in mind the following:

  • A serious allergic reaction to therapeutic penicillin may occur in a patient with a negative skin test to PRE-PEN.
  • It is possible for a patient to have an anaphylactic reaction to therapeutic penicillin in the presence of a negative PRE-PEN skin test and a negative history of clinical penicillin hypersensitivity.
  • If penicillin is the drug of choice for a life-threatening infection, successful desensitization with therapeutic penicillin may be possible irrespective of a positive skin test and/or a positive history of clinical penicillin hypersensitivity.

Occasionally, patients may develop an intense local inflammatory response at the skin test site. Rarely, patients will develop a systemic allergic reaction, manifested by generalized erythema, pruritus, angioedema, urticaria, dyspnea, hypotension, and anaphylaxis. The usual methods of treating a skin test antigen-induced reaction—the applications of a venous occlusion tourniquet proximal to the skin test site and administration of epinephrine—are recommended. The patient should be kept under observation for several hours.

Pregnancy Category C: Animal reproduction studies have not been conducted with PRE-PEN. It is not known whether PRE-PEN can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. The hazards of skin testing in such patients should be weighed against the hazard of penicillin therapy without skin testing.

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit or call 1-800-FDA-1088. Please see full Prescribing Information for additional Important Safety Information.