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\begin{document}

\title{Addressing Beta-lactam Allergy: A Time for action}



\author[1]{Elizabeth Philips}%
\author[2]{Pascal Demoly}%
\author[3]{Maria  Torres}%
\affil[1]{Vanderbilt University Department of Medicine}%
\affil[2]{Montpellier Universite d'Excellence}%
\affil[3]{Universidad de Malaga Facultad de Medicina}%


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  \date{May 18, 2024}


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\textbf{Addressing Beta-lactam Allergy: A Time for action}

Elizabeth J. Phillips, MD, FIDSA, FAAAAI, Pascal Demoly, MD, PhD, Maria
J Torres, MD, PhD

\textsuperscript{1} Department of Medicine, Center for Drug Safety and
Immunology, Vanderbilt University Medical Center, Nashville Tennessee
USA, \textsuperscript{2}Institute for Immunology \& Infectious Diseases,
Murdoch University, Murdoch Australia, \textsuperscript{3}Division of
Allergy, Department of Pulmonology, University Hospital of Montepellier,
and IDESP, Univ. Montpellier -- Inserm, Montpellier
France,\textsuperscript{4}Allergy Unit, Hospital Regional Universitario
de Malaga-IBIMA-BIONAND-ARADyAL, and Departmento de Medicina,
Universidad de Malaga, Malaga, Spain

Correspondence:

Elizabeth J. Phillips, MD, FIDSA, FAAAAI

Center for Drug Safety and Immunology

Vanderbilt University Medical Center

1161 -- 21\textsuperscript{st} Avenue South

Nashville, TN 37232

(615) 322-9174 (tel)

Elizabeth.j.phillips@vumc.org

It is now 93 years since the discovery of penicillins, and over 75 years
since the first use of penicillin. We have entered yet another wave of
challenges plagued with antibiotic resistance accelerating at a rate
that well exceeds that of new antibiotic development. In the face of
these uphill battles, 8-15\% of a global population who has had access
to care is labeled as penicillin allergic.\textsuperscript{1} In the
United States (US) there are at maximum 6000 specialists who practice
allergy out of a total of 700,000 practicing physicians, and not all
allergists are proficient in and practice drug allergy. Conservatively
out of 30,000,000 who are labeled as penicillin allergic at any one time
in the US, this would mean that each allergist would need to delabel a
minimum of 6000 patients. In Europe and the United Kingdom, the figures
are proportionately identical, with some differences between countries.
Even if all patients had equal access to care, this type of scalability
remains impossible. This overwhelming burden that threatens to
negatively impact healthcare through delays in treatment, higher
healthcare utilization and cost, less effective treatment and increased
antibiotic resistance and Clostridioides difficile infection, demands a
risk-based approach that simplifies the penicillin allergy delabeling
process and establishes bridges with non-allergists.\textsuperscript{1,
2}

What have we learned that now makes the population level goal of
penicillin delabeling achievable? First off, prevention is better than
cure. We should critically examine pediatric populations for antibiotic
use to address over-prescription of antibiotics including penicillins
for viral infections. We should avoid labeling children with benign
delayed exanthems that occur in the setting of a likely viral infection
as penicillin allergic. When continued treatment is necessary we should
in fact encourage ``treating through'' such reactions. When a label of
penicillin allergy seems inevitable in a child we should address this
label early and pay particular attention to antibiotic stewardship. New
data on serum sickness-like reaction suggests that many of these are
likely virally mediated and do not reproduce on ingestion
challenge.\textsuperscript{3} Community based education programs can
help disseminate timely information on penicillin allergy to dispel
myths and alleviate fears. A label of penicillin allergy should be both
viewed and approached as a threat to both individual and public health.
On a public health level addressing penicillin allergy should be seen as
a broad stewardship tool that provides a level of herd protectiveness
against antibiotic resistance. On an individual level a label of
penicillin allergy should be approached with the same routineness as any
other preventative health check, and primary care physicians and
providers should be trained to understand and manage low-risk penicillin
allergy labels.\textsuperscript{4} Patients should regularly discuss
their drug allergy passport with their healthcare providers such as
pharmacists and physicians. Allergy passports should enable
interoperability, high traceability and time-stamped information solving
the problem of frequent unavailability and inaccuracy of drug allergy
information.\textsuperscript{5} Risk stratification should occur and if
in a low-risk category a patient should be given the option of direct
oral challenge and delabeling. Risk stratification to identify by
clinical history the low-risk penicillin allergic patients who would be
appropriate for simple procedures is key. Several mechanisms now exist
to risk stratify those labeled as penicillin allergic in routine
clinical practice. These clinical prediction rules provide an evidence
base to identify the majority of low-risk penicillin allergy labeled
patients who are at low risk for rechallenge
reactions.\textsuperscript{6, 7} In current practice it is likely that
less than 1\% of such low-risk patients will be at risk for a reaction
on ingestion challenge.\textsuperscript{1, 8}

To make widespread penicillin allergy delabeling an achievable and
scalable goal we must be convinced of the safety of direct ingestion
challenges. A randomized study allocated children 5 years or older with
low-risk cutaneous reaction to penicillin skin testing followed by
amoxicillin challenge versus 2 step direct oral challenge with
amoxicillin with tolerance of amoxicillin of 96\% of those with direct
challenge and only minor reactions in the
remainder.\textsuperscript{9}These results have recently been confirmed
in an European population of children.\textsuperscript{10} Aside from
the inconvenience and potential need for specialty assessment, for very
low-risk patients, the use of skin testing would be expected to perform
poorly considering their low pre-test probability of a reaction. Several
other studies have demonstrated that a single or two-step direct
ingestion challenge with penicillins such as amoxicillin is a safe and
practical strategy to remove a label of penicillin
allergy.\textsuperscript{11} Although there is evidence to support the
use of risk stratification tools to delabel penicillin allergy under
allergist guidance, we require an educational program on drug allergy
for primary care physicians as well validation of these risk
stratification tools, to show that low-risk penicillin delabeling can be
achieved in this setting.

Even in the face of risk stratification and safety of direct ingestion
challenge, populations are not equal in terms of their medical risk or
antibiotic needs. Intuitively populations that serve to benefit from
penicillins and other beta lactams have been shown to have inferior
outcomes when labeled as penicillin allergic that would benefit from a
delabeling intervention. This includes the association of penicillin
allergy label and use of an alternative antibiotic with post-operative
surgical site infections.\textsuperscript{12} Other settings where
research has shown feasibility in delabeling include children in the
emergency department, critically ill populations with high antibiotic
needs, and pregnant women where the high rates of surgical delivery and
group B Streptococcal colonization in pregnancy create a high demand for
penicillin and cephalosporins as safe firstline
drugs.\textsuperscript{1, 13, 14} Increasingly, assessment of unverified
penicillin allergy has been recognized as an antibiotic stewardship
intervention in immunocompromised states such as transplant and cancer
where populations have much to gain by being
delabeled.\textsuperscript{15}

There is a ``time for action'' for removal of penicillin allergy labels
on a population level but how do we achieve widespread implementation
(Figure 1)? Policy changes should be driven by collaboration with
Infectious diseases specialists and allergists who should join forces to
pair antibiotic allergy management with antibiotic stewardship. In the
community we need to educate parents and pediatricians to make them
aware of the hazards of both unnecessary antibiotics and penicillin
allergy labels for mild rashes that are often related to a viral
infection and unlikely to recur. Primary healthcare providers should be
given greater incentives to delabel penicillin allergic patients at the
point-of-care and armed with decision support tools to facilitate risk
stratification. For those whose history is not consistent with allergy
this could include direct delabeling without testing. In the future,
evidence may support that routine direct ingestion challenge with a
penicillin and delabeling is safe in the primary care setting. Finally,
by off-loading low-risk reactions to primary care providers we can then
prioritize care of the patients with a higher-risk allergy and/or
medical history by engagement with specialists who can provide more
in-depth assessments and give them the best antibiotic options.

\emph{Figure 1:} Addressing Beta-lactam Allergy: An Implementation
Roadmap: There are currently many missed opportunities for community
members and healthcare providers to take action forward on the
``penicillin allergy delabeling'' movement. This includes not only
active measures to delabel patients by history and direct oral challenge
and to identify high risk patients for prioritized penicillin allergy
delabeling but also preventive measures to avoid unnecessary use and
exposure to antibiotics and avoidance of unnecessary labeling in those
with mild rashes of likely viral origin.

\emph{References}

1. Castells M, Khan DA, Phillips EJ. Penicillin Allergy. \emph{N Engl J
Med} . Dec 12 2019;381(24):2338-2351. doi:10.1056/NEJMra1807761

2. Blumenthal KG, Phillips EJ. Positioning Drug Allergy Delabeling as a
Critical Tool for Precision Medicine, Quality Improvement, and Public
Health. \emph{J Allergy Clin Immunol Pract} . Oct 2020;8(9):2916-2919.
doi:10.1016/j.jaip.2020.07.046

3. Delli Colli L, Gabrielli S, Abrams EM, et al. Differentiating Between
beta-Lactam-Induced Serum Sickness-Like Reactions and Viral Exanthem in
Children Using a Graded Oral Challenge. \emph{J Allergy Clin Immunol
Pract} . Feb 2021;9(2):916-921. doi:10.1016/j.jaip.2020.08.047

4. Dona I, Caubet JC, Brockow K, et al. An EAACI task force report:
recognising the potential of the primary care physician in the diagnosis
and management of drug hypersensitivity. \emph{Clin Transl Allergy} .
2018;8:16. doi:10.1186/s13601-018-0202-2

5. Brockow K, Aberer W, Atanaskovic-Markovic M, et al. Drug allergy
passport and other documentation for patients with drug hypersensitivity
- An ENDA/EAACI Drug Allergy Interest Group Position
Paper.\emph{Allergy} . Nov 2016;71(11):1533-1539. doi:10.1111/all.12929

6. Trubiano JA, Vogrin S, Chua KYL, et al. Development and Validation of
a Penicillin Allergy Clinical Decision Rule. \emph{JAMA Intern Med} .
Mar 16 2020;doi:10.1001/jamainternmed.2020.0403

7. Plager J, Judd A, Blumenthal K. Role of clinical history in
beta-lactam hypersensitivity. \emph{Curr Opin Allergy Clin Immunol} .
Aug 1 2021;21(4):320-326. doi:10.1097/ACI.0000000000000758

8. Romano A, Atanaskovic-Markovic M, Barbaud A, et al. Towards a more
precise diagnosis of hypersensitivity to beta-lactams - an EAACI
position paper. \emph{Allergy} . Jun 2020;75(6):1300-1315.
doi:10.1111/all.14122

9. Mustafa SS, Conn K, Ramsey A. Comparing Direct Challenge to
Penicillin Skin Testing for the Outpatient Evaluation of Penicillin
Allergy: A Randomized Controlled Trial. \emph{J Allergy Clin Immunol
Pract} . Sep - Oct 2019;7(7):2163-2170. doi:10.1016/j.jaip.2019.05.037

10. Prieto A, Munoz C, Bogas G, et al. Single-dose prolonged drug
provocation test, without previous skin testing, is safe for diagnosing
children with mild non-immediate reactions to
beta-lactams.\emph{Allergy} . Aug 2021;76(8):2544-2554.
doi:10.1111/all.14800

11. Cooper L, Harbour J, Sneddon J, Seaton RA. Safety and efficacy of
de-labelling penicillin allergy in adults using direct oral challenge: a
systematic review. \emph{JAC Antimicrob Resist} . Mar 2021;3(1):dlaa123.
doi:10.1093/jacamr/dlaa123

12. Boston BCDSP. Drug-induced anaphylaxis: a cooperative
study.\emph{JAMA} . 1973;224:613-615.

13. Staicu ML, Vyles D, Shenoy ES, et al. Penicillin Allergy Delabeling:
A Multidisciplinary Opportunity. \emph{J Allergy Clin Immunol Pract} .
Oct 2020;8(9):2858-2868 e16. doi:10.1016/j.jaip.2020.04.059

14. Stone CA, Jr., Stollings JL, Lindsell CJ, et al. Risk-stratified
Management to Remove Low-Risk Penicillin Allergy Labels in the
ICU.\emph{Am J Respir Crit Care Med} . Jun 15 2020;201(12):1572-1575.
doi:10.1164/rccm.202001-0089LE

15. Trubiano JA, Thursky KA, Stewardson AJ, et al. Impact of an
Integrated Antibiotic Allergy Testing Program on Antimicrobial
Stewardship: A Multicenter Evaluation. \emph{Clin Infect Dis} . Jul 1
2017;65(1):166-174. doi:10.1093/cid/cix244\selectlanguage{english}
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