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World Allergy Organ J
World Allergy Organ J
The World Allergy Organization Journal
1939-4551
World Allergy Organization

S1939-4551(24)00089-9
10.1016/j.waojou.2024.100958
100958
Brief Research Report
Penicillin allergy delabeling has a significant impact on subsequent antibiotic use in primary care☆
Fransson Sara MD, PhD a
Boel Jonas B. Msc.Pharm, PhD bc
Mosbech Holger F. MD, DMSc a
Garvey Lene H. MD, PhD Professor Lene.Heise.Garvey@regionh.dk
ad⁎
a Allergy Clinic, Department of Dermatology and Allergy, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark
b Department of Clinical Microbiology, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark
c Copenhagen University Hospital, The Hospital Pharmacy, Copenhagen, Denmark
d Department of Clinical Medicine, Copenhagen University, Copenhagen, Denmark
⁎ Corresponding author. Allergy Clinic, Department of Dermatology and Allergy, Herlev and Gentofte Hospital, University of Copenhagen, Gentofte Hospitalsvej 8, 1. floor, DK-2900 Hellerup, Denmark. Lene.Heise.Garvey@regionh.dk
22 8 2024
9 2024
22 8 2024
17 9 10095817 5 2024
18 7 2024
31 7 2024
© 2024 The Authors
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Efforts to delabel penicillin allergic patients are important as the majority of suspected penicillin allergy can be ruled out by relevant allergy testing. The aim is to change the antibiotic pattern in delabeled patients to minimize use of unnecessary broad-spectrum antibiotics, reducing the risk of antimicrobial resistance and making treatment more cost effective. However, published information on subsequent antibiotic use is scarce.

To evaluate the effect of delabeling on subsequent antibiotic use in primary care, a cohort of 2911 patients tested for penicillin allergy was compared to a matched control group of 14,522 individuals from the background population. In total 86.4% of the tested patients were delabeled.

For delabeled patients, penicillin use increased from 0.07 prescriptions per patient year before allergy investigation, to 0.53 prescriptions per patient year post investigation (p < 0.001). The use of fluoroquinolones and macrolides was reduced and reached a level comparable to the background population.

This study shows that penicillin allergy delabeling has significant positive impact on subsequent antibiotic use in primary care, and that penicillin use increases to levels similar to the background population. Penicillin allergy delabeling should be prioritized as an important and efficient element in antimicrobial stewardship initiatives.

Keywords

Penicillin allergy
Delabeling
Drug provocation
Antibiotic prescriptions
Primary care
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pmcThe World Health Organization (WHO) has identified antimicrobial resistance as a major threat to global public health. The threat is driven by extensive use of broad-spectrum antibiotics. Patients with a suspected penicillin allergy are often treated with broad-spectrum antibiotics. About 10% of hospital inpatients have a registered penicillin allergy, but about 90% of these can be delabeled (have their allergy label removed) after allergy testing1,2 to allow penicillin use and reduce the need for alternative broad-spectrum antibiotics.

Patients with a penicillin allergy label receive suboptimal treatment and have more prolonged hospital admissions and higher hospital mortality.2,3 Previous studies have indicated that penicillin allergy testing is cost-effective, as a penicillin allergy leads to increased health care costs due to longer hospital stays, higher re-admission rate, and use of more expensive antibiotics, which also increases the risk of antimicrobial resistance.4, 5, 6, 7 Most studies investigating antibiotic use after penicillin allergy testing address antibiotic use during hospital admission1,8 and only few studies cover the antibiotic use in primary care.4,7,9

The aim of this large, matched cohort study was to evaluate the effect of penicillin provocation testing on antibiotic use by comparing the antibiotic use among patients with disproved and confirmed penicillin allergy respectively, with the antibiotic use among the background population in Denmark, where 90% of antibiotics are prescribed in primary care.10

Cases were identified from the department's drug allergy database and data from 2911 patients were included. All were ≥18 years old and had undergone at least 1 drug provocation test (DPT) with a penicillin in an allergy clinic at a university hospital, in the period 2010–2018. Penicillin allergy was confirmed in 396 patients (13.6%) (confirmed allergy) and disproved in 2515 patients (86.4%) (delabeled). For patients with several DPTs with the same drug, results from the last DPT were included. The control group consisted of 14,522 individuals selected from the background population. They were matched 1:5 to cases with selection criteria being the nearest neighbor propensity score on sex, age, days of hospital admission 2 years before inclusion and comorbidity which could affect antibiotic use, see Supplemental Table 1.

Data were collected from the following Danish national health registers: “The Register of Pharmaceutical Sales”, which contains data on all dispensed antibiotics from primary care, “The National Patient Register”, which contains comorbidities and days of hospital admission, and “The Civil Registration System”.

Antibiotic prescriptions before allergy investigation (pre-period) were examined from 2005 (or from index reaction if occurring later) to the date of DPT, referred to as the day of inclusion. Prescriptions after DPT (post-period) were examined from date of DPT (day of inclusion) to June 2020 or death, or emigration. Prescriptions were examined as prescriptions per patient year.

The prescription rate in the pre- and post-period were compared by calculating the rate ratio and corresponding 95% confidence interval using unconditional maximum likelihood estimation (Wald). For the comparison of time to first antibiotic or penicillin prescription, we used Cox proportional hazard regression, adjusting for age group and sex. All analyses were performed using R 4.3.1.

Descriptive data on cases and controls can be found in Table 1 and Supplemental Table 1. In the pre-period, delabeled and confirmed allergic patients had a comparable antibiotic prescription pattern while the antibiotic prescription patterns changed in the post-period, especially for penicillin use (Fig. 1). For delabeled patients, the penicillin use increased from 0.07 prescriptions per patient year in the pre-period to 0.53 prescriptions per patient year in the post-period (p-value <0.001), see Supplemental Table 2. The use of fluoroquinolones and macrolides was reduced and reached a level comparable to the background population (controls). For patients with a confirmed allergy the antibiotic use was similar in the pre and post period, although a small increase in penicillin use was seen.Table 1 Descriptive data on cases and controls

Table 1Characteristic	Confirmed allergya
N = 396	Delabeleda
N = 2515	Casesa
N = 2911	Controlsa
N = 14,522	p-valueb	
Age at inclusion	48 (35, 64)	48 (35, 62)	48 (35, 62)	48 (35, 62)	>0.9	
Female	321 (81%)	1855 (74%)	2176 (75%)	10,867 (75%)	>0.9	
Time to first antibiotic in post-period (years)	1.11 (0.36, 2.82)	1.31 (0.43, 3.13)	1.27 (0.42, 3.07)	1.55 (0.50, 3.48)	<0.001	
Received penicillin in pre-period	82 (21%)	543 (22%)	625 (21%)	9018 (62%)	<0.001	
Received penicillin in post-period	108 (27%)	1809 (72%)	1917 (66%)	10,036 (69%)	<0.001	
Received any antibiotics in pre-period	264 (67%)	1983 (79%)	2247 (77%)	10,157 (70%)	<0.001	
Received any antibiotics in post-period	321 (81%)	2026 (81%)	2347 (81%)	11,210 (77%)	<0.001	
Median time in pre-period (years)	1.6 (0.8, 7.5)	7.0 (1.2, 9.5)	6.6 (1.1, 9.4)	6.6 (1.1, 9.4)	0.7	
Median time in post-period (years)	5.52 (4.54, 7.30)	5.93 (4.66, 7.36)	5.84 (4.65, 7.35)	5.78 (4.57, 7.31)	0.10	
a Median (IQR); n (%).

b Wilcoxon rank sum test; Pearson's Chi-squared test on cases vs. controls.

Fig. 1 Antibiotic prescription per patient year in pre- and post-period. See Supplemental Table 2 for detailed data

Fig. 1

This large, matched cohort study shows that penicillin allergy delabeling results in significant positive changes in the antibiotic prescription pattern. Due to the design of the study, we were able to demonstrate that the use of penicillin increased after delabeling to levels comparable to the background population. In addition, the use of broad-spectrum alternative antibiotics decreased, which confirms that penicillin allergy delabeling makes an important and efficient contribution to the fight against antimicrobial resistance.

Several studies with different designs have shown that penicillin use increases after allergy has been disproved; however, only a few smaller studies have measured the long-term effect on antibiotic use in primary care, without using direct comparison to the background population.1,4,8,9

As seen in Fig. 1, the use of penicillin increases in the post period in all 3 groups, including patients with a confirmed penicillin allergy. Use of penicillin among patients with a confirmed allergy has been reported before.4 In our study, this could be explained by the fact that patients who tested positive for one type of penicillin, eg, with delayed reactions to amoxicillin, in many cases had an additional DPT with phenoxymethylpenicillin, which was tolerated and could be used subsequently. Allergy to penicillins and other beta-lactam antibiotics is primarily directed against specific sidechains and is rarely caused by the beta lactam ring,11 which means that testing with individual penicillins is needed to elucidate cross reactivity patterns.

The strength of this study is the large, matched control group representing the background population and well-defined cases who all underwent DPT to confirm or disprove allergy. A limitation is that it only identifies antibiotics that have been dispensed, and we cannot be sure that drugs were in fact taken by patients. Also, data were not detailed enough to allow an estimate of the economic perspectives.

In conclusion, this study shows that penicillin allergy delabeling has a significant positive impact on subsequent antibiotic prescription and should be prioritized as an important and efficient element in antimicrobial stewardship initiatives.

Abbreviations

DPT: Drug provocation test.

Declaration of all sources of funding

This work was supported by Harboefonden [Grant number 20172 to S.F.].

Authorship

L.H.G., H.F.M., J.B.B. and S.F. took initiative to the study with regard to the conception and design. S.F. and J.B.B acquired and analyzed the data. S.F. drafted the first draft. All authors helped with interpretation of data and provided critical comments on the intellectual content of the article. All authors have approved the final version.

Ethics

The study was approved by the Danish Patient Safety Authority (nr. 31-1521-463), The Danish Health Data Authority (FSEID-00005488) and The Danish Data Protection Agency (P-2020-910).

Submission declaration

The manuscript is original, has not been published before and is not currently being considered for publication elsewhere.

Declaration of competing interest

The authors report no competing interests.

Appendix A Supplementary data

The following are the Supplementary data to this article:Multimedia component 1

Multimedia component 1

Multimedia component 2

Multimedia component 2

☆ Full list of author information is available at the end of the article

Appendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.waojou.2024.100958.
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