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Three Part Question

In what percent of [adult patients] who [self-report a penicillin allergy] have a [true allergy]?

Clinical Scenario

A 30-year-old male presents to the emergency department with cough, fever, and an infiltrate on chest x-ray. He is subsequently diagnosed with community-acquired pneumonia. You would typically prescribe him amoxicillin-clavulin as an outpatient but he is reporting a vague history of penicillin allergy. You wonder whether this is a true allergy.

Search Strategy

Medline was searched via the OVID interface (OVID Medline Epub Ahead of Print, In-Process & Other Non-Indexed Citations, Ovid MEDLINE(R) Daily and Ovid MEDLINE(R) 1946 to Present).

[({exp penicillins OR penicillin.mp} OR {exp amoxicillin-potassium clavulanate combination OR exp amoxicillin OR amoxicillin.mp} OR exp clavulanic acid OR amoxicillin clav.mp} OR {amox clav.mp} OR {amox clav.mp} OR {clavulin.mp} OR {clavulanate.mp} OR {piperacillin, tazobactam drug combination OR exp piperacillin OR piperacillin.mp} OR {piptazo.mp} OR {pip-tazo.mp} OR {exp cloxacillin OR cloxacillin.mp} OR {exp dicloxacillin or dicloxacillin.mp} OR {exp floxacillin OR flucloxacillin.mp} OR {exp amdinocillin OR mecillinam.mp} OR {exp amdinocillin pivoxil OR amdinocillin pivoxil.mp} OR {exp beta-lactams OR beta-lactam.mp}) AND ({exp self report or self report.mp} OR {self-report.mp}) AND ({exp hypersensitivity OR allergy.mp} OR exp hypersensitivity, immediate OR exp drug hypersensitivity syndrome OR exp hypersensitivity OR exp drug hypersensitivity OR exp hypersensitivity, delayed OR hypersensitivity.mp} OR {exp drug eruptions OR “exp drug-related side effects and adverse reactions” OR exp adverse drug reaction reporting systems OR drug reaction.mp} OR {exp drug eruptions OR drug eruption.mp} OR {exp anaphylaxis OR anaphylaxis.mp} OR {exp “drug-related side effects and adverse reactions”})]

Search Outcome

All relevant publications were reviewed. A total of 69 papers were found, of which 53 were irrelevant, 4 contained insufficient data for inclusion, 7 included pediatric patient data indistinguishable from the adult population, and 1 could not be located in the database. The remaining 4 papers are shown below.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Fooland F et al. 2019 USA	49 inpatients met the inclusion criteria, provided verbal consent, and underwent skin testing and/or oral challenge. Screening occurred on weekdays from Sept. 2017 to Jan. 2018.	Prospective, observational, single-centre clinical trial	Allergic reaction after PST (SPT and IDT) and oral challenge	46/49 (94%) of those who underwent PST were negative on PST and oral challenge. 1/49 (2%) tested negative on PST but developed a delayed maculopapular rash cutaneous reaction approximately 3 hours after the oral challenge. 2/49 (4%) were indeterminate after PST (due to negative histamine control responses). There were no documented reactions due to use of beta-lactams after a negative result on PST and oral challenge.	Screening only performed during weekdays. Cancer patients – possible alteration in a patient’s immune response. Single-centred. Small sample size. Only studied patients with likely IgE-mediated reactions, and low risk for reaction (excluded likely anaphylaxis).
Jones BM & Bland CM 2017 USA	46 inpatients enrolled from July 2014 to March 2015; 10 excluded as they did not undergo the entire PST.	Prospective, observational, single-centred	Allergic reaction after PST (SPT and IDT), with optional oral challenge	36/36 (100%) patients had a negative reaction to PST. 0/27(0%) patients transitioned to a beta-lactam had a documented reaction after administration (unclear if penicillin or cephalosporin).	Potential conflict of interest (authors received honoraria and grant funding from manufacturer). Single-centred. Small sample size. Only studied patients with likely IgE-mediated reactions, and low risk for reaction (excluded likely anaphylaxis).
Marwood et al. 2017 Australia	103 patients (19 to 69 years of age) met eligibility criteria and consented to testing, and 100 patient underwent testing (2011 to 2016).	Prospective, observational, single-centred	Allergic reaction after PST (SPT and IDT) and oral graded challenge	81/100 (81%) tolerated penicillins without evidence of allergy. 19/100 (19%) had true allergy. 17/100 (17%) had evidence of IgE hypersensitivity. 2/100 (2%) had delayed rash, likely caused by non-IgE-mediated mechanism.	9-day DPT protocol is problematic for compliance. Enrolment of 103/25,000 potential participants may suggest a risk of selections bias (significant motivation for the patient to partake in this study). Single-centred. Small sample size. Only studied patients with likely IgE-mediated reactions, and low risk for reaction (excluded likely anaphylaxis).
Raja AS et al. 2009 USA	150 ED patients (mean age 42 years) with a self-reported penicillin allergy.	Prospective, observational, single-centred	Allergic reaction after PST (SPT and IDT)	The false-positive rate for self-reported penicillin allergy was 137/150 (91.3%; 95% CI 85.3% to 95.1%).	Convenience sample so potential to miss important patients. Single-centred. Small sample size. Only studied patients with likely IgE-mediated reactions, and low risk for reaction (excluded likely anaphylaxis).

Comment(s)

¶The penicillin class of antibiotics are first-line therapies for a wide range of infections (Marwood et al., 2017). Despite this, penicillin allergies are widely self-reported by patients, reported by approximately 10% in the average population (Fooland et al., 2019; Marwood et al., 2017; Shenoy et al., 2019) and in even higher rates by older and hospitalized patients (Shenoy et al., 2019). A true allergy is typically defined as an immediate (type I) hypersensitivity reaction and is mediated by penicillin-specific IgE antibodies (Salkind et al., 2001). Delineating which patients have a true allergy is important for a number of reasons, such as improving the effectiveness of a therapy in the acute phase (Jones & Bland, 2017), decreasing the potential for microbial resistance, decreasing healthcare costs, reducing adverse side effects, and minimizing poor outcomes compared to patients without a penicillin allergy label (Fooland et al, 2019; Jones & Bland, 2017; Raja et al., 2009). ¶There are many protocols used for penicillin allergy testing. These typically all begin with an in-depth history to determine patients with likely IgE-mediated reactions, followed by one or more of the following: penicillin skin testing (PST), which combines skin prick testing (SPT) and intradermal testing (IDT), oral challenges, and serology testing for immunoglobulins. Each may use a different concentration of each reagent and have their own associated sensitivities and specificities, as demonstrated in the above articles (Fooland et al., 2019; Jones & Bland 2017; Marwood et al., 2017; Raja et al., 2009). ¶Every study encountered in this review was single-centred with small sample sizes, and a majority of studies with adequate data included pediatric patients (less than 18 years of age) resulting in their exclusion from this review. Only four studies were included, and not every study included an oral challenge as part of their study protocol. All studies used some form of PST protocol; Fooland et al. (2019) used a single-dose oral challenge, Jones & Bland (2017) incorporated an optional oral challenge, while Marwood et al. (2017) required patients to take a 9-day grade oral challenge while at home which requires compliance and accurate self-reporting of reactions. However, there is evidence that PST alone does not capture all patients with a true allergy (Silva et al., 2009). Furthermore, Fooland et al. (2019) enrolled patients with active cancer, which may limit their data around severe adverse reactions and testing validity. ¶Of note, the above studies only tested patients with likely IgE-mediated reactions but excluded those with the highest likelihood of history of anaphylaxis. As this overall group of patients are thought to have the highest risk of true allergy, the reported percentage of patients in these studies with true allergies is actually likely to be inflated since these numbers do not generally include patients who self-report a penicillin allergy but have low likelihood of having a true allergy. ¶While the data is suggestive that the prevalence of true penicillin allergies in adults is low (0%-19% of those with likely IgE-mediated reactions in the above studies), the small samples sizes and lack of consistent study protocol necessitate a deeper analysis in a wide variety of populations. The likely prevalence may then be known, and necessary protocols to implement accurate testing into clinical practice can then become standardized into a healthcare system. However, penicillin allergy testing is an effective means of determining which patients self-reporting allergies have a true allergy.

Editor Comment

PST, penicillin skin test; SPT, skin prick test; IDT, intradermal test.

Clinical Bottom Line

There is not enough high quality evidence to say what the true prevalence of penicillin allergies is in patients who self-report, but data does suggest that most adults who self-report a penicillin allergy are not allergic to penicillin antibiotics.

References

1. Fooland F et al. The Impact of Penicillin Skin Testing on Aztreonam Stewardship and Cost Savings in Immunocompromised Cancer Patients. Open forum infect. dis. 6(10):371, 2019 Oct.
2. Jones BM & Bland CM Penicillin skin testing as an antimicrobial stewardship initiative. Am J Health-Syst Pharm. 74(4):232-237, 2017 02 15.
3. Marwood J et al. De-labelling self-reported penicillin allergy within the emergency department through the use of skin tests and oral drug provocation testing. Emerg Med Australas . 29(5):509-515, 2017 Oct.
4. Raja AS et al. The use of penicillin skin testing to assess the prevalence of penicillin allergy in an emergency department setting. Ann Emerg Med. 54(1):72-7, 2009 Jul.
5. Silva R et al. Work up of patients with history of beta-lactam hypersensitivity. Allergol Immunopathol (Madr) 37(4):193-7, 2009 Jul-Aug.
6. Shenoy ES et al. Evaluation and management of penicillin allergy: a review. JAMA 321(2):188-199. 2019 Jan.
7. Salkind AR et al. Is this patient allergic to penicillin? An evidence-based analysis of the likelihood of penicillin allergy. JAMA 285(19):2498-2505, 2001 May.