Evaluation of Pharmacist-Driven Penicillin Allergy Reconciliation

Abstract

Objectives

Prior studies have shown that direct challenge of penicillin allergies is safe and noninferior to penicillin skin testing. The aim of the study was to assess the feasibility and impact of pharmacist-led penicillin allergy reconciliation using a direct challenge approach in an urban area’s community hospital.

Image Credit: Walter Cichetti | stock.adobe.com

Study Design

Retrospective cohort study.

Methods

Data were collected using the electronic medical record on patients who underwent penicillin allergy reconciliation between October 2023 and May 2024 at a community hospital. The primary objective was to evaluate the percentage of patients who were delabeled using the reconciliation protocol. Secondary objectives included method of direct challenge, percentage of
patients whose antibiotic therapy was optimized, 30-day readmission rates, and cost savings.

Results

Fifty-three total patients with a documented penicillin allergy underwent an allergy evaluation. Eight patients were not suitable for the challenge due to their high-risk reaction history. Among the remaining 45 patients, 34 underwent a direct challenge per the algorithm, and 11 were delabeled based on history alone. Nearly all patients eligible for reconciliation were successfully delabeled (97.8%). For secondary outcomes, 16 of the 18 patients (88.9%) requiring antibiotics at the time of reconciliation had their regimen optimized. Seven patients were readmitted within 30 days of discharge; of these, 4 of the 5 patients requiring antibiotics were treated with a penicillin-class antibiotic. Approximately $17 per patient was saved on antibiotic therapy when optimized to a penicillin-class medication while hospitalized.

Conclusion

A pharmacist-driven direct challenge approach is a feasible, effective, and potentially cost-saving method of penicillin allergy evaluation in a community hospital setting.

Introduction

Approximately 10% of patients admitted to the hospital report an allergy to penicillin.^1-4 This percentage increases to an estimated 20% when factoring in those who require antibiotic therapy.^1,3 Despite the overwhelming number of reported penicillin allergies, roughly 1% of the population has a true IgE-mediated allergy,^2-5 and more than 80% of patients with true IgE-mediated penicillin allergies will lose the reaction after 10 years.^2,4 Limiting the use of preferred β-lactam agents has undermined stewardship efforts by forcing the use of more broad-spectrum antibiotics; this leads not only to increased adverse drug events, such as Clostridioides difficile infections, but also to increased antimicrobial resistance, increased costs, treatment failure, and mortality risk.^2,4,5

The American Academy of Allergy, Asthma & Immunology, the CDC, and the Infectious Diseases Society of America all recommend penicillin allergy delabeling for patients with reported allergies and consider the practice a vital component of antimicrobial stewardship programs nationwide.^1-3 Direct oral challenge, penicillin skin testing, and delabeling based on patient history are current interventions used to reconcile penicillin allergies.^5,6 However, because penicillin skin testing is costly and requires trained personnel, it is not always available, particularly in community hospital settings or facilities without dedicated allergists. In recent years, data show that direct challenge without prior skin testing is safe and may increase the rate of penicillin allergy delabeling in areas where access to skin testing is unavailable. Cooper et al. performed a systematic review to assess the safety and efficacy of direct oral challenge in adult patients. Of the 1202 patients challenged, only 3.4% reported reactions, and 96.5% of challenged patients were delabeled.⁷

There is a paucity of literature describing pharmacist-led penicillin delabeling programs, despite pharmacists often having the training and expertise to make an impact in this area of patient care. Our study aimed to assess the feasibility of implementing a pharmacist-led penicillin allergy delabeling process in a community hospital. To evaluate the impact of the process, we looked at delabeling rates, antibiotic optimization, and adverse reactions associated with the direct challenge approach.

Methods

This was an institutional review board–exempt, retrospective cohort analysis of a quality improvement penicillin allergy reconciliation initiative performed at a 203-bed community hospital in middle Tennessee between October 2023 and May 2024. Although this analysis did not have exclusion criteria, the antimicrobial stewardship pharmacist excluded those who received corticosteroids or antihistamines within 24 hours of the evaluation for reconciliation. The hospital’s clinical surveillance software (VigiLanz Pharmacy Surveillance; Inovalon) was used to retrospectively identify patients who had undergone the reconciliation process, which was defined as conducting both the allergy evaluation and the direct challenge process. Data were collected using the electronic medical record (EMR) and included baseline characteristics (sex, age, race, comorbidities, type and quantity of other documented antibiotic allergies), allergic reaction history characteristics (causative medication, allergy presentation, time in years since initial reaction), medication given for the challenge, time in hours to reaction after challenge, use of rescue medications, and antibiotic therapy before and after the challenge, including duration of alternative and penicillin-based antibiotic therapy.

The primary end point of the study was the percentage of patients who were delabeled using the penicillin allergy reconciliation protocol. The protocol used by the antimicrobial stewardship pharmacist was designed based on the algorithm utilized in a randomized, controlled trial comparing direct challenge with penicillin skin testing protocols.⁸ Secondary end points included method of direct challenge, percentage of patients whose antibiotic therapy was optimized as a result of the challenge, 30-day readmission rates, and cost savings from patients whose antibiotic therapy was optimized as a result. Direct cost savings were calculated by comparing non–penicillin-class regimens with penicillin-class regimens while the patient was admitted to the hospital; the calculation began on the day the patient was transitioned to a penicillin-class medication. The price of the medications was determined using their average wholesale price. Safety end points included the incidence of adverse or allergic reaction to the direct challenge dose and the incidence of adverse drug events related to any antibiotic therapy. All data obtained and presented were analyzed using descriptive statistics and reported as percentages.

Penicillin allergy reconciliation protocol

An antimicrobial stewardship pharmacist identified patients with a documented penicillin allergy in the EMR and performed an allergy reconciliation evaluation. This pharmacist assessed patients’ allergy histories using a penicillin allergy reconciliation algorithm to determine eligibility for a direct challenge and coordinated care with the primary care team or infectious disease consult service to initiate the challenge. The direct challenge was performed using 1 dose of an oral or intravenous (IV) penicillin-class medication, determined by the overseeing physician based on the patient’s clinical status. The patient was monitored by nursing staff every 15 minutes for an hour after administration. After the monitoring period, the antimicrobial stewardship pharmacist counseled the patient about the results of the challenge and the removal of their allergy designation, if appropriate.

Adapted from the algorithm used by Mustafa et al.⁸

The patients who were identified by the stewardship pharmacist underwent a reconciliation interview to determine the severity of their allergy history. As noted previously, the algorithm used at our facility was adapted from the one utilized by Mustafa et al. (Figure).⁸ Patients who reported moderate to severe IgE-mediated type I (i.e., immediate hypersensitivity) reactions, including anaphylaxis and angioedema, were ineligible because those reactions are considered high risk. If appropriate, these patients were advised to seek a penicillin skin test or allergist evaluation to delabel their allergy. Low-risk allergies, such as isolated cutaneous events or unknown reactions occurring more than 5 or 10 years prior, respectively, were eligible for a direct challenge. A report of isolated gastrointestinal symptoms or a family history without a personal history of reaction negated the need for a formal challenge, and the patient’s allergy was delabeled.

Results

A total of 53 patients who underwent a penicillin allergy reconciliation evaluation were identified and retrospectively reviewed. The baseline characteristics of the included patients are shown in Table 1. The distribution of race, sex, and age is typical of the patient population seen at our institution.

Primary End Point

Of the 53 patients evaluated using the penicillin allergy reconciliation protocol, 8 were deemed by the antimicrobial stewardship pharmacist to have a serious reaction history and not eligible for the challenge. Among the severe reactions, anaphylaxis was the most common (49.1%), followed by angioedema (24.5%). Of the original 53 patients, 34 (64.2%) were given a direct challenge dose, and 11 (20.8%) did not require a challenge dose based on their allergy history and were delabeled (Table 2). Forty-four of the 45 patients (97.8%) who did not require an allergist referral or penicillin skin testing were successfully delabeled.

Secondary End Points

As illustrated in Table 2, the majority of patients received an oral dose of a penicillin-class antibiotic. Amoxicillin was the most commonly used challenge medication (56.6%); the remainder received amoxicillin and clavulanate potassium (Augmentin; USAntibiotics, LLC), ampicillin, ampicillin sodium/sulbactam sodium (Unasyn; Pfizer Inc), or piperacillin and tazobactam (Zosyn; Pfizer Inc). A total of 37 patients were receiving antibiotic therapy at the time of the direct challenge; of those, 34 patients had their penicillin allergy delabeled. The other 3 patients required a penicillin skin test for evaluation. Of the 34 patients who were delabeled, 18 required antibiotic therapy post challenge, and 16 (88.9%) were able to have their therapy optimized to a first-line penicillin antibiotic. First-line penicillin antibiotic therapy was defined as any of the following antibiotics: amoxicillin, amoxicillin-clavulanate, ampicillin, ampicillin/sulbactam, and piperacillintazobactam. Seven of the 53 patients evaluated were readmitted within 30 days, but none for an allergy-related reaction, and all 7 had undergone delabeling during their previous admission (ie, the reconciliation process). Five of the 53 patients were readmitted with an infectious diagnosis requiring antibiotic therapy, and all but 1 were able to use a penicillin-class medication. Thirteen patients were included in the cost analysis because they were switched to a penicillin agent while inpatient rather than at discharge. A total of $225 was saved among the 13 patients, averaging approximately $17 per patient.

IV, intravenous; NA, not applicable.
^aIn the past 90 days.
^bMacrolides, nitrofurans, nitroimidazoles, and lincosamides.

Safety End Points

One patient (2.9%) reported an adverse/allergic reaction after the administration of the challenge dose. The reaction was reported to be itching that began within 1 hour of administration; a dose of antihistamine was given, and the itching subsided. No severe adverse or allergic reactions were reported. Additionally, no adverse reactions were noted with the use of the alternative broad-spectrum therapy in any of the 37 patients receiving non–penicillinclass antibiotics during their hospitalization.

Discussion

It is widely known that penicillin allergies are overreported, resulting in the use of inferior antibiotic therapy and suboptimal patient outcomes.^2,4,5 Although penicillin skin testing has traditionally been considered the gold standard of penicillin allergy reconciliation, its benefit is often limited by its time- and cost-prohibitive nature. In addition, allergy skin testing has historically been performed by allergists in either inpatient or outpatient allergy clinics, significantly limiting its application in centers without an allergy service. In this study, we demonstrated feasibility and impact of a pharmacistdriven penicillin allergy reconciliation without the use of penicillin skin testing, lending further support to existing literature using similar protocols for penicillin allergy direct challenges, especially in patients with low-risk allergy histories.^8-13 As evidenced in this study—with more than 80% of patients eligible for or not requiring a direct challenge—this method can increase access to penicillin allergy reconciliation, especially in smaller community hospitals without access to allergists and penicillin skin testing.

Although the protocol used in this study is not a validated clinical tool to identify low-risk penicillin allergies that do not require formal allergy testing, such as the PENFAST decision rule (penicillin allergy, ≤ 5 years since the reaction, anaphylaxis/angioedema or severe cutaneous reaction, treatment required for the reaction) utilized by Copaescu et al,¹² its portability allows for widespread use by health care providers. The singular patient who experienced a reaction to the challenge—representing 2.9% of the 34 patients challenged—had only mild, allergic-type, subjective symptoms; this rate was similar to the 2.6% mild allergic reaction rate to a direct challenge dose of amoxicillin reported by Iammatteo et al.⁹ It was also similar to the rate reported by Mustafa et al, which speaks to the utility of the risk stratification tool adapted from that study.⁸ However, due to the small sample size of patients
receiving a challenge dose, the true safety risk cannot be
reliably estimated.

In addition to the previously mentioned organizations that support penicillin allergy reconciliation, the Emerging Infections Network has conducted member surveys that support the positive effect of penicillin allergy delabeling on antimicrobial stewardship efforts.^14,15 It is common for infectious disease physicians to be consulted to evaluate reported penicillin allergies in patients requiring antibiotic therapy. However, collaboration with other health care professionals in these protocols, such as pharmacists, can increase access to allergy reconciliation and improved antimicrobial stewardship. Evidence that a pharmacist-led model is feasible could prove to be invaluable in places where an allergy service is not available. This model also offers cost-savings potential by effectively utilizing resources a hospital already has, enabling the use of cost-effective antibiotic therapy, and avoiding expensive delabeling techniques when they are not necessary. Moreover, reconciliation of antibiotic allergies, especially penicillin, can lead to safer and more appropriate antibiotic usage.¹⁶

PST, Penicillin Skin Test

To our knowledge, no other studies have assessed the safety of IV penicillin class agents for direct challenge, which appear to be a safe and viable option in patients with low-risk allergy histories. Including IV medications into a reconciliation protocol expands access to patients who cannot take oral medications at the time of the challenge. Although our study population did not include critically ill patients, it would be valuable to expand future studies of IV penicillin direct challenge to patient populations in the intensive care unit, such as those requiring total parenteral nutrition or with other conditions limiting oral absorption of antibiotics.¹⁷

The optimization of antimicrobial therapy to include the use of a penicillin-class medication is the ultimate goal of penicillin allergy reconciliation. A systematic review and meta-analysis of 24 studies by Sacco et al found that penicillin allergy reconciliation led to increased prescribing of both penicillin and cephalosporin class medications and decreased prescribing of vancomycin and fluoroquinolones.¹⁸ It was suggested that the increase in cephalosporin agents secondary to allergy delabeling could be attributed to physicians concerned about cross-reactivity in patients with a penicillin allergy history.¹⁸ Our study further validates the results of Sacco et al, with almost 50% of patients in our analysis being able to transition to a penicillin-class antibiotic.

An additional benefit of transitioning to these preferred agents is a reduced risk of adverse events compared with the use of broad-spectrum antibiotics such as vancomycin and fluoroquinolones. Although patients in our analysis who received alternative antibiotics did not demonstrate any adverse events, these antibiotics are known to be associated with adverse outcomes such as acute kidney injury, C difficile infections, and cardiac events. Penicillin delabeling protocols aim to curtail the use of overly broad antibiotic therapy and reduce the risk of prolonged hospital stays, treatment failure, and readmission.¹⁹

Penicillin-class medications are preferred first-line therapy for many infectious diseases¹⁹ and are generally associated with a lower cost compared with other antibiotics. A study by Jones et al of 98 patients showed that changes to the antimicrobial regimen after a negative penicillin skin test (n = 70) saved the average patient $353.03 vs the pretest regimen.20 Although this cost savings seems substantially higher than the savings shown in our study, it is important to note that Jones et al did not indicate whether the cost difference included antibiotics prescribed at discharge, which we did not include in our cost-savings analysis. Moreover, we calculated the cost savings in our study using the cost to the hospital, not the patient, as done by Jones et al.²⁰ There also was no reliable way to predict future cost savings that will likely be observed upon future hospitalizations.

Penicillin allergy reconciliation is associated with decreased costs to both the hospital and the patient and indirect cost savings that should be considered when assessing the benefit of penicillin allergy delabeling. As previously mentioned, a documented penicillin allergy is associated with increased risk of treatment failure, hospital readmissions, and adverse patient outcomes, resulting in increased costs.^2,4,5 Therefore, our study likely underestimates the true value of penicillin allergy reconciliation for the health care system from a cost perspective.

Limitations

This study had several limitations, including its retrospective cohort design and small sample size of predominantly female and White patients, which may limit generalizability to more diverse patient populations and the ability to draw definitive conclusions on efficacy and safety. Nevertheless, our study offers further data and provides insight about practices in the Southeast United States from a community hospital perspective. The algorithm used by the stewardship pharmacist has not been formally validated and does not have a known negative predictive value proving its utility; however, it was based on the same criteria and principles as previously validated allergy reconciliation tools.⁸ Considerations for future research would be to conduct a prospective study using a larger sample size in a more diverse patient population. Not only would this make the results more generalizable, but conclusions of efficacy and safety could also be drawn to further validate this pharmacist-led model for allergy reconciliation.

One limitation to the long-term success of penicillin allergy reconciliation in general is the challenge of ensuring appropriate documentation within the EMR.

It is imperative to communicate the results of the penicillin challenge to the patient and, if possible, to future providers and across medical systems via such methods as wallet cards or discharge paperwork. Upon delabeling of the allergy, our facility includes documentation in the primary care team’s note stating the results of the challenge to (hopefully) avoid the allergy being reinstated during future admissions. We also talk with the patient post challenge and encourage them to inform their primary care providers and pharmacy of their updated allergy status. Regardless, patients seen outside our facility for future medical care may still receive suboptimal antibiotic therapy because communication between medical systems is lacking. Shared access to EMRs would provide a better option for transitions of care in the future.¹⁶ However, we acknowledge the limitations and practicality of this suggestion.

Conclusions

Our findings add to the overwhelmingly positive evidence for the safety, efficacy, and feasibility of direct challenge protocols as an alternative to penicillin skin testing for allergy reconciliation in low-risk patients. The pharmacist-driven protocol increases access to penicillin allergy reconciliation in a variety of settings, including community hospitals. It leads to high rates of delabeling, with nearly 98% of eligible patients in our study successfully delabeled. Although the availability of onsite penicillin skin testing would further increase access, it may not be necessary for an effective protocol, and it would likely add time and cost to allergy reconciliation. Patients who undergo allergy reconciliation also can often have their antibiotic therapy optimized to preferred narrow-spectrum regimens containing penicillin class medications, limiting the risks of treatment failure and antimicrobial resistance and reducing costs. Pharmacist-led antibiotic allergy reconciliation highlights the significance of antimicrobial stewardship teams within inpatient settings and during transitions of care. It offers future opportunities for refinement and broader implementation of these protocols across health care settings, helping to optimize antibiotic use, improve patient outcomes, and support the broader goals of antimicrobial stewardship.

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