Deciphering Antibiotic Allergies via Penicillin Skin Testing

March 2021 - Vol.18 No. 3 - Page #16
Category: Penicillin Skin Testing

Drug allergies, including those to antibiotics, are a leading reason for patients to receive second line treatments (see SIDEBAR 1). One of the most common antibiotic classes to which patients report an allergy are beta-lactam antibiotics, specifically penicillins. Data has shown that approximately 10% of the population in the United States report having an allergy to an antibiotic in the penicillin class; however, many patients who report penicillin allergies do not have true immediate hypersensitivity, or IgE-mediated, reactions.1,2 With careful evaluation and questioning, it has been found that fewer than 1% of these patients are truly allergic to penicillin antibiotics.1,2 Additionally, close to 50% of patients with an IgE-mediated reaction to penicillins can lose this hypersensitivity within 5 years of the reaction; this number increases to almost 80% or higher by 10 years after the reaction.2,3

It is important that allergy clarification and investigation be done carefully, in conjunction with the patient, through direct conversation with specific questions, in addition to a thorough review of the medical chart for previous exposure and potential tolerance to similar medications. This requires clear and detailed documentation regarding allergy information obtained from the patient, which will be useful for future antimicrobial prescribing by medical providers. While many allergies may be inappropriately labeled in a patient’s medical chart, we must be diligent to not overlook documentation and/or evidence of true allergies.

Penicillin and beta-lactam antibiotics are not the only antimicrobials that can elicit a drug allergy. Fluoroquinolones, commonly prescribed to patients with and without a penicillin allergy, can cause allergies mainly through IgE-mediated (Type I) reactions or T-cell mediated (Type IV) delayed reactions.4 Likewise, vancomycin, which is commonly prescribed for patients with penicillin allergies, can elicit cutaneous erythema, flushing, and pruritis.1 Frequently referred to as Red Man Syndrome, this is due to a non-IgE-mediated histamine release. Many patients can tolerate the medication with infusion of the drug over an extra 1-2 hours and occasionally with the administration of diphenhydramine 30-60 minutes prior to each dose.

Risks of Inappropriate Allergy Labeling

Broad-spectrum antibiotics are often used as an alternative to penicillins. Patients labeled with a penicillin allergy may receive alternative antibiotics, such as vancomycin, clindamycin, fluoroquinolones, and aminoglycosides, which are broader in spectrum with lower efficacy or increased side effects.5 A 2014 retrospective matched cohort study found patients with a labeled penicillin allergy were likely to spend considerably more time in the hospital and were exposed to significantly more antibiotics, including fluoroquinolones, clindamycin, and vancomycin.6

Inappropriate penicillin allergy labeling can also result in higher health care costs and an increased risk for antibiotic resistance.1 Blumenthal and colleagues evaluated the impact of a reported penicillin allergy on the development of surgical site infections (SSIs) through a retrospective cohort study of 8385 patients who underwent 9004 procedures. Multivariate logistic regression found patients with a reported penicillin allergy had 50% increased odds of developing an SSI.7 Similar to other reports, patients with penicillin allergies in this study were given significantly less cefazolin and more clindamycin, gentamicin, and vancomycin.

Components of Appropriate Allergy Assessments

In order to ascertain the most accurate information on a patient’s allergy history, a direct conversation with the patient is necessary and vital. When evaluating a patient with a listed drug allergy, there are targeted questions that health care professionals should ask to obtain the most useful information2,8:

  • What medication were you taking when the reaction occurred (eg, drug name, dose, route)? Why were you given the medication?
  • How long ago did the reaction occur/How old were you when the reaction occurred?
  • What kind of reaction occurred? (eg, symptoms, timing, severity)
  • How long after taking the medication did the symptoms begin?
  • How was the reaction managed? Were you given anything that helped with the reaction? Did you seek medical care?
  • What was the outcome?
  • Were you taking any new medication(s) around the time that you developed the reaction?
  • Have you taken the medication or a similar medication since the reaction?
    • With this question, it may be useful to provide examples of medications that you would like to know if they have received and tolerated since the reaction. Patients may recognize brand names of medications instead of generic names, so you may have to provide both medication names.

The responses to these questions should be documented in the patient’s medical chart for other healthcare professionals to read and review, as needed. Any new information received from the patient interview should be used to update the allergy field of the electronic medical record (if applicable to your practice site) so that the most up-to-date information is available when medications are ordered and prescribed.

Benefits of Penicillin Skin Testing

Only after completing a thorough allergy assessment and determining that a patient has truly experienced an IgE-mediated hypersensitivity reaction, should the administration of a penicillin skin test (PST) be considered. A PST consisting of a major (benzylpenicilloyl polylysine) and minor (diluted penicillin G) determinant with an oral amoxicillin challenge has a negative predictive value of 97-99% for patients with a reported IgE-mediated penicillin allergic reaction.9 As with any medical test, these results will not completely exclude a patient from having an immediate or delayed allergic reaction after starting a penicillin-based antibiotic regimen.

A standard PST procedure consists of an initial percutaneous test, followed by an intradermal test, and then finally an optional, single oral penicillin challenge dose (see FIGURE 1). The percutaneous or scratch test involves lightly puncturing the patient’s epidermis with a few drops of each benzylpenicilloyl polylysine, diluted penicillin G, saline (negative control), and histamine (positive control). An accurate test requires that the patient have a positive reaction/skin wheal to the histamine and no reaction to the saline. If either of these two do not occur, the test should be considered indeterminate and the patient assessed to determine the reason for this inconsistent result. Another possible indeterminate result consists of the major and minor determinants not producing the same result. In this scenario, the percutaneous result would be considered positive and the patient should not advance to intradermal testing. A negative percutaneous test will produce no skin reaction/wheal for both the benzylpenicilloyl polylysine and diluted penicillin G sites after 15-20 minutes. Only patients with a negative percutaneous result should move on to the next step of intradermal testing.

Intradermal testing consists of producing five intradermal blebs (two with benzylpenicilloyl polylysine, two with diluted penicillin G, and one with saline/negative control) on the volar surface of the patient’s forearm or upper arm near the deltoid. A negative intradermal test will produce no skin wheals for both the benzylpenicilloyl polylysine and diluted penicillin G bleb sites after 15-20 minutes.

An indeterminate result consists of discordant results for the benzylpenicilloyl polylysine and diluted penicillin G sites. Only patients with a negative intradermal result should move on to the next step of an optional oral penicillin challenge dose or start treatment with a penicillin antibiotic. The entire process for completing a PST can take up to 45-60 minutes. If a penicillin oral challenge dose is administered, an additional 60 minutes of monitoring will be needed, which lengthens the overall test time to approximately 2 hours.

Benefits to performing inpatient PSTs include decreased use of non-beta lactam antibiotics (eg, fluoroquinolones, aztreonam, and clindamycin), improved antibiotic selection for future patient encounters, and direct antimicrobial cost savings.10-12 Most recently, Jones and colleagues observed that a negative skin test resulted in antibiotic cost savings of $557 per patient when patients were switched to a penicillin/beta-lactam agent.13

Another theoretical benefit of implementing a PST program at an institution is the ability to reduce the number of penicillin desensitizations performed. If a “labeled” penicillin allergic patient must receive a penicillin agent for a life-threatening infection, they will undergo a desensitization procedure. In most institutions, desensitizations require an intensive care unit admission, 1:1 patient-nursing ratio, and hours of slowly titrating a patient to a full treatment dose of the targeted medication. PST can mitigate the need for desensitizing a patient by ruling out those labeled allergic reaction that are not true allergies in an effective, safe, and time-efficient manner (See TABLE 1 for differences between desensitizations and PST).


Antibiotics—penicillins and beta-lactams in particular—remain the most commonly reported allergies in hospitalized patients. The ability to perform thorough allergy assessments to dispel inappropriate allergy designations can lead to a reduction in the use of second-line treatment agents; however, when patients have a true history of an IgE-mediated hypersensitivity reaction to penicillin, the only option to confirm or negate the allergy is by performing a PST.

Establishing a PST program can pose significant challenges. Thus, it is important to address program ownership, staffing assignments, and potential time constraints upfront. In addition, the facility must invest in thorough staff training to ensure an effective PST program. Ultimately, this investment will improve patient care, minimize the overuse of non-beta lactam antibiotics, abate the need for some ICU desensitizations of penicillin, and help expand the scope of pharmacy practice at our institution.


  1. Joint Task Force on Practice Parameters representing the American Academy of Allergy, Asthma and Immunology; American College of Allergy, Asthma and Immunology; Joint Council of Allergy, Asthma and Immunology. Drug allergy: an updated practice parameter. Ann Allergy Asthma Immunol. 2010;105(4):259-273.
  2. Evaluation and Diagnosis of Penicillin Allergy for Healthcare Professionals. Centers for Disease Control and Prevention website. Updated October 31, 2017. Accessed January 7, 2021.
  3. Weiss ME, Adkinson Jr NF. Beta-Lactam Allergy. In: Mandell GL, Bennett JE, Dolin R, ed. Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases. London, UK: Churchill Livingstone; 2000:299-305.
  4. McGee EU, Samuel E, Boronea B, et al. Quinolone Allergy. Pharmacy. 2019;7(3):97.
  5. Blumenthal KG, Peter JG, Trubiano JA, et al. Antibiotic Allergy. Lancet. 2019;393(10167):183-198.
  6. Macy E, Contreras R. Health care use and serious infection prevalence associated with penicillin ‘‘allergy’’ in hospitalized patients: A cohort study. J Allergy Clin ImmunolI. 2014;133(3):790-796.
  7. Blumenthal KG, Ryan EE, Li Y, et al. The Impact of a Reported Penicillin Allergy on Surgical Site Infection Risk. Clin Infect DisI. 2018;66(3):329-336.
  8. Gonzalez-Estrada A, Radojicic C. Penicillin allergy: a practical guide for clinicians. Cleve Clin J Med. 2015;82(5):295-300.
  9. Benzylpenicilloyl polylysine USP (PRE-PEN) injection [package insert]. Plainville, CT: AllerQuest LLC; 2013.
  10. King EA, Challa S, Curtin P, et al. Penicillin skin testing in hospitalized patients with β-lactam allergies: Effect on antibiotic selection and cost. Ann Allergy Asthma Immunol. 2016;117(1):67-71.
  11. Leis JA, Palmay L, Ho G, et al. Point-of-care β-lactam allergy skin testing by antimicrobial stewardship programs: a pragmatic multicenter prospective evaluation. Clin Infect DisI. 2017;65(7):1059-1065.
  12. 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.
  13. Jones BM, Avramovski N, Concepcion AM, et al. Clinical and economic outcomes of penicillin skin testing as an antimicrobial stewardship initiative in a community health system. Open Forum Infect DisI. 2019;6(4):ofz109.

Kristen Zeitler, BS, PharmD, BCPS, co-chair of the Tampa General Hospital (TGH) antimicrobial subcommittee, received a BS in chemistry from Fairfield University in Connecticut in 2007, followed by a doctor of pharmacy from the University at Buffalo in 2011. She then completed a pharmacy practice residency and an infectious diseases specialty residency at the hospital of the University of Pennsylvania in Philadelphia. Kristen joined TGH in 2013 to grow the antimicrobial stewardship program. Her practice interests include antimicrobial dosing and pharmacokinetics, antimicrobial stewardship, and fungal infections.

Nicholas Piccicacco, PharmD, BCIDP, AAHIVP, co-chair of the TGH antimicrobial subcommittee, received his Doctor of Pharmacy degree from the University of Florida in 2014. He then went on to complete a pharmacy practice residency at TGH and an Infectious Diseases specialty residency at Morton Plant Hospital – BayCare Health System in Clearwater, Florida.


In June 2018, Tampa General Hospital’s (TGH) Antimicrobial Stewardship (ASP) program embarked upon the process of implementing an inpatient penicillin skin test (PST) program. The first hurdle was finding the right individuals within the institution to conduct and administer the PST. Based on previous literature and experience, we offered this opportunity to our Infectious Diseases fellows, Infection Prevention, clinical ladder, and employee health nurses. Unfortunately, due to competing responsibilities, these groups were unable to commit to this program.

Given the stalemate in finding personnel to administer PST, the ASP pharmacists petitioned the Florida Board of Pharmacy (FLBOP) to allow ASP pharmacist-administered PST at TGH. With the help of legal counsel, we submitted a petition for declaratory statement and attended the June 2020 FLBOP meeting to present our case. The FLBOP concluded that our TGH-specific PST policy and procedures fit within the requirements of Florida Pharmacy Rule 64B16-27.830–Drug Therapy Management as a patient specific protocol, and we could move forward with trained ASP pharmacists administering PST at TGH.

Our planned process for conducting PST at TGH will consist of consultation by the ASP pharmacists to first conduct an allergy assessment with the patient, and then if deemed necessary, performance of a PST. Anecdotally, many inpatient PST consults can be mitigated by performing a thorough allergy assessment with the patient. The pharmacist will conduct both the percutaneous and intradermal tests in the patient’s room, with the supervising physician (the ASP medical director) reviewing each step and confirming a negative result. Based on the improved negative predictive value of the PST when added with an oral challenge, all patients will receive a post-PST amoxicillin dose to help elucidate any delayed hypersensitivity reactions. After confirmation by the supervising physician of a negative PST and amoxicillin challenge, the ASP pharmacist will then document a note in the patient’s chart of the PST results, remove the penicillin allergy (with consent from the patient), and add a “Penicillin Skin Test Negative” placeholder in the allergy field. The goal of the placeholder is to help prevent clinicians from later re-entering the penicillin allergy into the electronic medical record’s allergy field.

Due to the COVID-19 pandemic, our initial plan for initiating the PST program before the end of 2020 did not come to fruition. We are currently coordinating with our medicine colleagues in Allergy & Immunology to receive training on administering the PST and finalizing the EHR order set build with the penicillin skin test and rescue medications for potential anaphylactic reactions, with the goal of launching the program in the third quarter of 2021.


A drug allergy is defined as “an immunologically mediated response to a pharmaceutical and/or formulation (excipient) agent in a sensitized person.”1 The type of reaction or response a patient develops can be categorized according to the Gell and Coombs classification of hypersensitivity reactions.1,2,3 Type I, or immediate hypersensitivity reactions manifested as urticaria, angioedema or anaphylaxis, may occur within 1 hour of drug administration and are immunoglobulin E (IgE) mediated. Types II through IV are non-IgE-mediated reactions that typically have a delayed onset of action and manifest in different ways.


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