Introduction
Beta-lactam class antibiotics are among the safest and most efficacious agents used in treating various bacterial infections.Reference Jones, Avramovski, Concepcion, Crosby and Bland1–Reference Kufel, Justo, Bookstaver and Avery4 However, beta-lactams account for the majority of inpatients’ self-reported medication allergies in the United States.Reference Jones, Avramovski, Concepcion, Crosby and Bland1 Published literature confirms that a majority of patients do not have an IgE-mediated reaction upon skin testing and can be safely transitioned to an appropriate, targeted beta-lactam.Reference Jones, Avramovski, Concepcion, Crosby and Bland1,Reference Bland, Bookstaver and Griffith2 Additionally, a significant number of patients with reported anaphylaxis to penicillins may lose their sensitivity over time.Reference Bland, Bookstaver and Griffith2
Allergy misclassification increases use of broad-spectrum, alternative antibiotics, potentiates antimicrobial resistance, and increases cost of care.Reference Jones, Avramovski, Concepcion, Crosby and Bland1–Reference Justo, Kufel, Avery and Bookstaver3,Reference Griffith, Justo, Winders, Al-Hasan, Mediwala and Bookstaver5–Reference Irawati, Hughes and Keen8 This can heighten the risk of suboptimal infection-related outcomes, prolonged hospital stays, and readmission.Reference Jones, Avramovski, Concepcion, Crosby and Bland1,Reference Taremi, Artau and Foolad6,Reference Macy9–Reference Trubiano, Chen and Cheng11 NBL prescribing likely stems from allergy documentation rather than microbiologic criteria in patients with a documented beta-lactam allergy.Reference Jones, Avramovski, Concepcion, Crosby and Bland1,Reference Taremi, Artau and Foolad6 Therefore, clarifying antibiotic allergy status is beneficial in both immediate and long-term antimicrobial stewardship efforts. Previous studies have also described an increase in direct antimicrobial treatment cost in patients with a documented penicillin allergy.Reference Macy and Contreras12,Reference Mattingly13 Trubiano and colleagues compared oncology patients with and without an antimicrobial allergy label (primarily beta-lactams, 65%).Reference Trubiano, Chen and Cheng11 Those with an allergy label experienced increased overall antibiotic use per admission, increased fluoroquinolone use, longer antibiotic courses, and higher readmission rates.
The Infectious Diseases Society of America and American Academy of Allergy, Asthma, and Immunology advocate for avoiding non-beta-lactam (NBL) antibiotic overuse without thorough allergy evaluations.Reference Barlam, Cosgrove and Abbo14,15 Comprehensive allergy management programs should include detailed allergy history-taking, risk stratification, and penicillin skin testing (PST) or direct drug challenge if needed.Reference Justo, Kufel, Avery and Bookstaver3,Reference Griffith, Justo, Winders, Al-Hasan, Mediwala and Bookstaver5 A thorough allergy history is often sufficient to rule out significant allergy and allows for beta-lactam use.Reference Griffith, Justo, Winders, Al-Hasan, Mediwala and Bookstaver5 PST additionally offers a >95% negative predictive value for ruling out IgE-mediated hypersensitivities and is an instrumental component of antimicrobial stewardship programs.Reference Bland, Bookstaver and Griffith2,Reference Justo, Kufel, Avery and Bookstaver3,Reference Cook, Barbara and Singh16–Reference Gadde, Spence and Wheeler20
Studies evaluating PST programs have demonstrated a reduction in NBL antibiotic days of therapy (DOT), length of hospital stay (LOS), hospital readmissions, and cost of care, by avoiding costly alternatives or combination therapy.Reference Jones, Avramovski, Concepcion, Crosby and Bland1,Reference Bland, Bookstaver and Griffith2,Reference Griffith, Justo, Winders, Al-Hasan, Mediwala and Bookstaver5,Reference Macy and Shu7,Reference Irawati, Hughes and Keen8,Reference Forrest, Schellenberg and Thien21 Heil and colleagues found a reduction in aztreonam use from 3.4 to 1.9 DOT/1000 PD after PST implementation.Reference Heil, Bork and Schmalzle22 This corresponded to approximately $26,000 in savings per year. However, there are limited studies assessing the financial and NBL use impact of a comprehensive allergy management program in such a large patient population, particularly in non-teaching, community medical centers without medical residents or ID fellows.
A multidisciplinary beta-lactam allergy management program was implemented at our institution to facilitate complete allergy documentation and increase use of targeted beta-lactams. The objective of the current study is to evaluate NBL utilization and financial outcomes associated with this program. To our knowledge, this study presents outcomes in one of the largest published inpatient PST cohorts.
Methods
This study was conducted at a non-teaching, urban, community medical center with a multidisciplinary allergy management program established in April 2019. As part of this existing program, pharmacists, infectious disease physicians, and an allergy and immunology physician identified inpatients with a beta-lactam allergy and collected detailed medication allergy histories. Patients were risk stratified as high, moderate, or low risk of IgE-mediated allergy based on the reaction history. Direct beta-lactam drug challenge was recommended for patients with low-risk histories. Moderate-risk patients were recommended to be further evaluated with PST. Beta-lactam avoidance was recommended in high-risk patients. For de-labeled patients, the pharmacist and allergist collaborated with hospitalists or ID consultants to optimize antimicrobial therapy and increase use of beta-lactams, as appropriate. We previously published details of this program.Reference Vyas, Raja and Morrison23
The electronic medical record (EMR) was queried for all inpatients who underwent PST at our institution from program initiation (April 11, 2019). Patients were excluded if not on inpatient antibiotic therapy or were under 18 years old. Patients were consecutively screened and enrolled. Patient demographics, allergy information, antimicrobial indications, laboratory and culture results, PST results, and antimicrobial therapy regimens were retrieved from the EMR. Patient’s actual antibiotic DOT was collected from the EMR. “Actual NBL DOT” included total NBL DOT that the patients received throughout the treatment course, before and after undergoing PST. We assumed that if no PST had been conducted, patients’ antibiotic therapy before PST would have remained unchanged for the remainder of the treatment course, termed “forecasted NBL DOT.” Treatment course was defined as antibiotic therapy for the current indication(s) and was censored at hospital discharge if needed. The difference between actual and forecasted DOT was deemed DOT avoided (DOT-A) for each patient. Although all antibiotic regimens were evaluated, this study focused on decreasing NBL use. Outcomes evaluated include total NBL DOT-A normalized per PST intervention and per 1000 days of inpatient antibiotic treatment (1000DT). The financial analysis evaluated the cumulative NBL cost avoided normalized per PST intervention and per 1000DT. The cost per day was calculated by multiplying the defined daily dose (DDD) of each antibiotic by the wholesale acquisition cost (WAC), as of April 2024, in USD. The DDD and WAC were used to allow for greater generalizability in various practice settings. Additional endpoints evaluated were PST outcomes and the average time into antimicrobial therapy that PST was conducted to uniquely frame the impact on our results. Outcomes were assessed with descriptive statistics, including measures of central tendency and dispersion.
Results
Between April 1, 2019 and July 8, 2024, there were 617 inpatients with a beta-lactam allergy who underwent PST at our institution. After excluding those without inpatient antimicrobial therapy or under 18 years old, 600 patients were included for study analysis (see Figure 1). Patients were an average of 67.4 ± 16.8 years old and a majority were female (69%). The average hospital length of stay was 11.2 ± 8.5 days and average duration of antibiotic therapy was 9.2 ± 7 days. Patients underwent PST an average of 3.7 ± 3.6 days into antimicrobial treatment.
Figure 1. Patient CONSORT diagram.
There were 613 distinct beta-lactam allergies and 669 antimicrobial indications in the study population, as some patients had more than one drug allergen or infection source documented. There were 554 patients with a penicillin class allergy (90.4%), 54 patients with a cephalosporin class allergy (8.8%), and 5 patients with a carbapenem class allergy (0.8%). Antimicrobial indications included acute bacterial skin and skin structure infections (23.9%), urinary tract infection (23.3%), pulmonary infection (21.5%), intra-abdominal infection (13.9%), and other infections (17.4%). Upon PST, 588 patients (98%) tested negative, 8 (1.3%) tested positive, and 4 (0.7%) were indeterminate due to recent antihistamine administration. There were two instances of antimicrobial intolerance after administration of optimized therapy after negative PST. All baseline characteristics are shown in Table 1.
Table 1. Baseline characteristics
Note. Some patients had multiple allergens documented and were treated for multiple infections; therefore, the total number of allergens and infections is greater than the total number of patients.
Amongst the 600 patients evaluated, total NBL DOT-A was 5,249 days and total associated cost savings were $206,458. This equated to NBL DOT-A of 952.7 per 1000DT or an average of 8.8 ± 12.3 DOT-A per PST intervention (see Figure 2). Total cost savings was $37,469.69 per 1000DT or an average of $344.10 ± $554.38 per PST intervention, driven primarily by aztreonam avoidance. NBL DOT and cost outcomes are shown in Table 2. Cost savings for each NBL agent is shown in Table 3.
Figure 2. Non-beta-lactam days of therapy per 1000 days of antibiotic therapy. Abbreviations: NBL, non-beta-lactam; DOT, days of therapy.
Table 2. Cost of NBL therapy
Abbreviations: NBL, non-beta-lactam; DOT, days of therapy; 1000DT, 1000 days of antibiotic therapy.
Table 3. Non-beta-lactam cost avoided
a Cost per day is calculated based on WHO DDD × WAC cost in USD (as of April 2024).
Discussion
This study evaluated a large inpatient PST cohort that demonstrated significant NBL DOT and cost avoidance per PST intervention, supporting program financial viability and sustainability. PST benefits likely extend beyond these study outcomes, contributing to reduced morbidity, mortality, and hospital LOS with targeted antimicrobial therapyReference Ramsey and Staicu25, likely secondary to greater effectiveness and/or lower adverse event rates.Reference Mattingly, Fulton and Lumish24,Reference Ramsey and Staicu25 Additionally, optimal inpatient management and stewardship positively impact outpatient antibiotic use and costs.Reference Ramsey and Staicu25,Reference Chen, Tarver and Alvarez26
There were 8.8 ± 12.3 NBL DOT-A per PST intervention or an average of 952.7 NBL DOT-A per 1000DT. Chen and colleagues evaluated 228 patients who underwent PST in a pharmacist-allergist collaboratively managed program, where 504 inpatient days (2.2 DOT-A per PST intervention) and 648 outpatient days of alternative antibiotic therapy were avoided.Reference Chen, Tarver and Alvarez26 Ramsey and colleagues described an PST program that avoided 982 days of combined inpatient and outpatient second-line antibiotic therapy.Reference Ramsey and Staicu25 Differences in DOT-A rate may be attributable to time into therapy PST was conducted, evaluation of inpatient-only compared to combined inpatient and outpatient data and baseline NBL prescribing rates. The significant avoidance of NBL DOT after PST intervention contributed to the total cost savings of $206,458 amongst the 600 patients in the 5-year study period. This equates to $37,469.69 per 1000DT and an average of $344.10 ± $554.38 per PST intervention. Other studies have identified similar results with an estimated cost savings of $225 to $350 per patient undergoing PST.Reference Jones, Avramovski, Concepcion, Crosby and Bland1,Reference Rimawi, Cook and Gooch19,Reference King, Challa and Curtin27,Reference Jones and Bland28
In our study, the expected NBL cost decreased by 54.2% after PST, from forecasted $380,609 to actual cost of $174,151 (see Table 2). Macy and colleagues evaluated 236 patients and found the average antibiotic cost per patient fell 30.6% from $71.17 to $49.63 if the subject had a negative PST.Reference Macy9 A PST program in North Carolina demonstrated an estimated cost savings of $82,000 in patients receiving antibiotic therapy changes as a result of PST.Reference Bland, Bookstaver and Griffith2
The cost savings in this study are largely driven by aztreonam avoidance. Staicu and colleagues evaluated aztreonam use after PST program implementation in 178 patients.Reference Staicu, Brundige and Ramsey29 They found a significant reduction in aztreonam DOT from 9.5 to 4.4 DOT/1000 patient days with an associated $60,000–$100,000 annualized projected cost avoidance compared to other first-line agents. Heil and colleagues evaluated 90 patients and conducted PST on 76. They found a reduction in aztreonam use from 3.4 to 1.9 DOT/1000PD after PST implementation, corresponding to approximately $26,000 in savings per year.Reference Heil, Bork and Schmalzle22 In our study of 600 patients undergoing PST, a total of 1,735 days of aztreonam therapy were avoided, which accounted for a cost savings of $159,620 for aztreonam alone during the study period. The total cost avoided for NBL agents was $206,458, making aztreonam responsible for over 75% of total cost savings.
A strength of the study is its strong internal validity, ensured by a consistent team managing the program, which limited practice variability. Furthermore, the study reflects a pragmatic view of program outcomes, as earlier identification, assessment, and intervention of candidates could magnify study results. Treatment durations were measured observationally, reflecting true clinical practice and thereby enhancing the external validity of findings. The rate of negative PST in previous studies has ranged from 94 to 100 percent, similar to the 98% of patients who tested negative upon PST in our study.Reference Ramsey and Staicu25,Reference Gugkaeva, Crago and Yasnogorodsky30–Reference Englert and Weeks34 Patients underwent PST on average 3.7 days into antibiotic treatment. Some patients had antibiotics discontinued or were discharged on the day of PST. The study period also includes the peak of the COVID-19 pandemic, which likely limited program workflow due to strict infection control measures. Additionally, some patients did not have changes to their NBL antimicrobial if it was considered drug of choice.
Cost savings were derived from NBL DOT-A during the acute treatment course, not including beta-lactam therapy costs or program implementation expenses. However, while not directly measured in this study, PST programs are likely cost-effective overall as previous studies estimate a cost of $256 [2020 USD] per PST, though variability exists.Reference Thao, Sharpe and Dholakia35,Reference Blumenthal, Li and Banerji36 Additionally, patients with antimicrobial allergy labels face higher healthcare burdens, including increased risk of hospital-acquired infections (eg Clostridioides difficile infection), adverse drug reactions, and hospital readmissions.Reference Macy and Contreras12,Reference Trubiano, Leung and Chu37,Reference MacFadden, LaDelfa and Leen38 Therefore, cost-effectiveness of PST encompasses factors beyond direct drug costs, demonstrates sustainability, and offers enduring value. Larger studies are needed to assess long-term clinical and economic outcomes and the impact of allergy re-labeling after PST. Cost evaluation was based on WAC of each drug as of April 2024 and DDD as per the World Health Organization. Actual cost savings may vary as per institutional contracted prices and daily dose as per indication or dose adjustment for hepatic or renal dysfunction.
Conclusion
This study presents the NBL use and financial impact in the largest identified cohort of inpatients undergoing PST in an urban, community, and non-teaching medical center. Results highlight significant avoidance of NBL DOT. Associated cost avoidance contributes to the sustainability and longevity of an allergy management program.
Financial support
None reported.
Competing interests
Dr. Donald Beggs was a former physician speaker for AbbVie Inc. The remaining authors report no conflicts of interest relevant to this article.
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