Safety and value of pre-transplant antibiotic allergy delabeling in a quaternary transplant center.

Abstract

Background

Self-reported antibiotic allergies, also known as antibiotic allergy labels, are common and may lead to worse patient outcomes. Within immunocompromised patients, antibiotic allergy labels can lead to inappropriate use of antimicrobials and may limit options for prophylactic and therapeutic options in the post-transplant period. While antibiotic allergy delabeling is considered an important aspect of antibiotic stewardship protocols, evidence and awareness of its application in transplant recipients is limited.

Methods

We describe our experience with an antibiotic allergy delabeling intervention in the pre-transplant evaluation period and its impact on post-transplant antimicrobial utilization. This was a retrospective analysis of patients with an antibiotic allergy label who underwent evaluation for solid organ or stem cell transplantation between 2015–2020. Patients included in this analysis were those who completed pre-transplant antibiotic allergy delabeling through our Drug Allergy Clinic and were retained in care for six months after transplant.

Results

Twenty-six of 27 patients underwent pre-transplant antibiotic allergy delabeling and safely received the delabeled antibiotic post-transplant. There were no reported side effects to the delabeled antibiotic within 6 months post-transplant. Specific examination of sulfonamide (sulfa)-antibiotic delabeling showed cost savings of $254 to $2,910 per patient in the post-transplant period compared to the use of alternative antibiotics for prophylaxis protocol.

Conclusion

Antibiotic allergy delabeling prior to transplant is safe, is of high value, and should be considered in the pre-transplant evaluation period. More resources are needed for the development of delabeling guidelines and support for broad implementation of pre-transplant antibiotic allergy delabeling programs.

Introduction

Recipients of solid organ transplant (SOT) and hematopoietic stem cell transplant (HSCT) are at a higher risk of infection-related complications due to their immunocompromised status. Due to multiple factors such as chronic morbidities and nosocomial exposures the transplant population is also susceptible to recurrent infections requiring antibiotics for treatment and prophylaxis. Antimicrobial therapy can also be limited by drug-drug interactions, especially with essential immunosuppressive therapy. Additionally, shifts in the microbiome due to antimicrobial exposure can lead to emergence of multi-drug resistant organisms.

Self-reported antibiotic allergies that end up in the patient’s electronic health record (EHR), also known as antibiotic allergy labels, are common and may lead to worse patient outcomes. Around 6% of patients with linkage to medical care are labelled as allergic to two or more antibiotics.¹ Antibiotic allergy labels have been associated with development of multi-drug resistant organisms such methicillin-resistant Staphylococcus aureus and vancomycin resistant Enterococci, increased incidence of Clostridioides difficile infection as well as increased rates of surgical site infection.² Within immunocompromised patients, it is known that antibiotic allergy labels lead to inappropriate use of antimicrobials with increased use of fluoroquinolones and glycopeptides.^3,4 Among SOT and HSCT patients, a history of antibiotic allergy may limit prophylactic and therapeutic options for antimicrobials in the post-transplant period, particularly sulfa and beta-lactam allergy labels.⁵ At Vanderbilt University Medical Center (VUMC) Drug Allergy Clinic, sulfa antibiotic allergy labels are prioritized for evaluation using established testing protocols^6,7 because sulfa antibiotics are routinely used for Pneumocystis jirovecii (PJP) prophylaxis and treatment and because alternatives are more expensive and less effective.

Antibiotic allergy delabeling can therefore be of value in antibiotic stewardship protocols for complex patient populations such as transplant recipients.⁸ Yet, while antibiotic allergy delableling is included in the Centers for Disease Control and Prevention Core Elements of Antibiotic Stewardship Programs⁹, Infectious Diseases Society of American Guidelines for Implementing an Antimicrobial Stewardship Program (ASP)¹⁰ and the recent white paper on antimicrobial stewardship in SOT from the American Society of Transplantation,¹¹ knowledge of its impact in transplant recipients is limited. In addition, although many transplant centers require antibiotic delabeling as a pre-requisite to transplantation, there are no published protocols to specifically guide transplant centers in how to establish such a program.

Here, we review the efficacy and safety of pre-transplant antibiotic allergy delabeling performed in the VUMC Drug Allergy Clinic. We provide support for a pre-transplant antibiotic delabeling program with a cost-based analysis to establish the value of antibiotic delabeling in transplant recipients. From these results, we will develop and implement a standardized protocol for antibiotic allergy delabeling to encourage institutional change.

Methodology

This study which involved retrospective analysis of the VUMC Drug Allergy clinic database was approved by the VUMC Institutional Review Board #161455 and was a collaboration between Allergy and Immunology, Transplant Infectious Diseases and Vanderbilt Antimicrobial Stewardship Program. Data was collected through a retrospective chart review of patients with a history of antibiotic allergy undergoing evaluation for transplant between 2015–2020. Inclusion criteria included those patients who completed pre-transplant evaluation of antibiotic allergy with the VUMC Drug Allergy Clinic, subsequently underwent transplant during the study window and were retained in care through six months post-transplant. Patients excluded from analysis were those not yet transplanted at the end of the study window and those who were evaluated by the VUMC Drug Allergy Clinic after their transplant. Relevant patient history included in our analysis includes type and timing of transplant, reported allergies to antibiotic(s) and their reaction and drug allergy testing if performed. Post-transplant use of antimicrobials in the 6 months following transplant was also reviewed for choice of antibiotic, duration of therapy, indication for use, adverse outcomes or side effects from antibiotics, and breakthrough infections if delabeled antibiotic was used for prophylaxis. Analysis was performed using Excel (Version 16.57) [Microsoft, Redmond, WA, USA]. In addition, a cost analysis of sulfa antibiotic delabeling was performed to determine if any cost savings could be achieved by avoiding use of alterative prophylaxis antibiotics. Cost estimates of sulfa antibiotics and their alternatives were obtained from publicly available data on www.drugs.com. Average duration of antibiotic use within our cohort was calculated based upon reported pharmacy fills and observed duration of treatment and prophylaxis within the EHR.

Results

A total of 70 patients were evaluated by VUMC Drug Allergy Clinic for antibiotic allergy delabeling during the pre-transplant window from 2015–2020. Of those, 27 met inclusion criteria for further review in this study. Patient characteristics are described in Table 1. Of the 27 patients, the majority were lung transplant recipients with the others having received heart transplant, liver transplant, dual heart and kidney transplant and HSCT. The most frequent antibiotic allergy labels were to beta-lactams and trimethoprim-sulfamethoxazole. Others reported included allergies to macrolides, vancomycin and fluoroquinolones. Eleven patients (40.7%) had more than one antibiotic allergy evaluated by VUMC Drug Allergy Clinic. Two of the lung transplant recipients had underlying cystic fibrosis and both were assessed for reported beta-lactam allergy. All 27 patients had at least one antibiotic allergy delabeled during their pre-transplant evaluation. One patient had a history of drug-induced liver injury related to trimethoprim-sulfamethoxazole and was instructed to avoid this class in the future. Otherwise, all twenty-six patients received a delabeled antibiotic in the six months following transplant with indications for antibiotic use including prophylaxis and treatment. One lung transplant recipient did not receive the delabeled macrolide antibiotic post-transplant as it was not indicated for either prophylaxis or treatment. Duration of delabeled antibiotic use ranged from 3 to 180 days, which was the endpoint of the retrospective review. Of the 26 patients that received a delabeled antibiotic, there were no reported adverse outcomes. Additionally, there were no reported breakthrough infections in patients receiving delabeled antibiotics used for prophylaxis.

Table 1.

Characteristics of transplant recipients who underwent antibiotic allergy delabeling during the study period.

Patient Characteristics	N
Transplant type	Number of Patients (N = 27)
Lung	19
Heart	3
Liver	1
Heart and Kidney	1
Hematopoietic Stem Cell	3
Self-reported Antibiotic Allergy Labels	Number of Labels (N = 37)
Beta-Lactam	19
Sulfa	12
Macrolide	3
Vancomycin	2
Fluoroquinolone	1
Delabeled Antibiotics	Number of Labels (N = 29)
Beta-Lactam	16
TMP-SMX	11
Vancomycin	1
Fluoroquinolone	1
Use of Delabeled Antibiotic	Number of Patients (N = 26)
Prophylaxis	16
Treatment	7
Prophylaxis and Treatment	2
Not Used	1
Average Duration of Use	Days
Beta-Lactam	18.5
TMP-SMX	142.8
Vancomycin	7
Fluoroquinolone	90

Cost analysis of sulfa antibiotic delabeling was calculated for 11 patients delabeled of this allergy during the study. The average duration of sulfa antibiotic use during six months of follow up among the 11 patients was 142.8 days or about five months. The calculated costs of trimethoprim-sulfamethoxazole¹², dapsone¹³, atovaquone¹⁴ and inhaled pentamidine¹⁵ for average duration of use and cost savings compared to use of trimethoprim-sulfamethoxazole are shown in Table 2. Using our estimates, total cost savings for the 11 study patients were between $3,244 to $32,460 while cost savings per patient was estimated at $254 to $2,910 with the use of pre-transplant sulfa antibiotic delabeling.

Table 2.

Cost analysis for Pneumocystis jiroveci prophylaxis agents used during study period. The cost of alternative agents is compared to first-line trimethoprim-sulfamethoxazole.

Drug	Unit Cost	Cost for average duration of use† per patient	Cost for average duration of use for study patients‡	Cost savings compared to TMP-SMX per patient	Cost savings compared to TMP-SMX for study patients‡
Trimethoprim-sulfamethoxazole (TMP-SMX)	$15 per 30 tablets	$75	$375	N/A	N/A
Dapsone	$70 per 30 tablets	$329	$3,619	$254	$3,244
Atovaquone	$439 per 210mL bottle	$2,985	$32,835	$2,910	$32,460
Inhaled Pentamidine	$163 per inhaled dose	$815	$8,965	$740	$8,590

^†Average duration of TMP-SMX use in study patients was 142.8 days. Cost estimate for TMP-SMX is based on daily dosing of a single strength tablet.

^‡11 patients received delabeled sulfa antibiotic in the six months following transplant.

Discussion

This single center retrospective review of 27 transplant recipients who underwent successful pre-transplant antibiotic allergy delabeling showed this practice to be safe and cost-effective through the first six months following transplant. All patients included in the review had at least one antibiotic allergy delabeled, suggesting that many self-reported antibiotic allergies are falsely labeled. This is consistent with prior studies^16,17 and occur for a variety of reasons including intolerance, viral exanthem or other interaction between a drug and an infection². It was encouraging that the patients who received a delabeled antibiotic after transplant had no immediate or delayed allergic, non-allergic adverse events or breakthrough infections when used for prophylaxis. And in the case of sulfa antibiotic delabeling, we found potential cost savings up to $2,910 per patient by avoiding use of expensive alternative agents for prophylaxis in the first six months following transplant. In the case of lung transplant recipients, cost savings would be even greater as they require lifelong prophylaxis against Pneumocystis.

This study highlights the value of identifying patients who report antibiotic allergies and referring them for evaluation in the pre-transplant period. The majority of patients included in our study were lung transplant recipients, likely because the lung transplant team is aware of the impact inaccurate antibiotic allergy labels can have on post-transplant outcomes and our Allergy section is integrated into the division of Pulmonary and Critical Care. Given the success shown in this small cohort, this practice should be incorporated into pre-transplant protocols across all organ transplants. However, this requires knowledge of the value and availability of this service by the organ transplant teams. While this service is easily accessed at our institution, less than 50% of Infectious Diseases specialists reported access to antibiotic allergy delabeling across the Emerging Infections Network.¹⁸

If allergy evaluation is not easily available, transplant centers should consider other means of antibiotic allergy testing. For instance, penicillin allergy testing can be performed by pharmacists and infectious diseases specialists and could be scaled up to include other antibiotic allergies.^19,20 Decision support tools to identify those with low risk allergies to drugs like penicillin who would be appropriate for direct oral challenge are available online.²¹ In addition, risk-stratified direct oral challenge of low-risk penicillin allergy labels as a delabeling procedure has been shown to be safe and effective even in critical care settings.^22,23 Direct oral challenge either in full dose one-step procedure (400/80 mg of TMP-SMX) or two-step graded challenge is also the procedure of choice and has been shown to be safe for delabeling the vast majority of reported sulfa antibiotic allergies.^6,7 Further, direct oral challenge can be performed without the use of specialty allergy services. Yet, there are still barriers to expansion of delabeling practices including access to high quality training on delabeling, resources for clinical space and materials, and accessible locations for patients who need drug challenge. Based upon the antimicrobial cost-savings we observed by enabling first-line sulfa prophylaxis and the potential for improved outcomes, we believe there is a strong rationale for committing the necessary resources to develop guidelines and programs for delabeling in transplant centers.

Additional gaps remain in the literature, including lack of a large-scale cost analysis of antibiotic allergy delabeling programs, limited awareness of delabeling as an ASP intervention and fear about implementation of such interventions in high-risk populations such as HSCT or SOT. There is also a gap between the literature supporting an intervention and the practical tool kit needed for implementation, but the barrier to remove low-risk allergy labels via direct challenge is low. While this was a small, single-center retrospective study in which lung transplant recipients were disproportionately represented, we find the results to be an encouraging step towards broader implementation of this practice.

Conclusions

Antibiotic allergy delabeling prior to transplant is safe, cost-effective and of high value in the care of transplant recipients. More guidance is needed to help transplant centers implement this practice routinely into their pre-transplant evaluation for all types of transplants, given the limited availability of allergy resources. Although at a minimum patients should be assessed for antibiotic delabeling pre-transplant, it should be considered that even earlier assessments before the immediate pre-transplant period may benefit antibiotic utilization and have other downstream benefits.

Abbreviations:

(SOT)

Solid organ transplant

(HSCT)

Hematopoietic stem cell transplant

(ASP)

Antimicrobial Stewardship Program

(TMP-SMX)

Trimethoprim-sulfamethoxazole

(EHR)

Electronic Health Record

(Sulfa)

Sulfonamide