Beta lactam hypersensitivity

Beta-lactam
Hypersensitivity
• Topic Review
• 22nd November 2019
• Rapisa Nantanee, M.D.
• Pediatric Allergy and Immunology Unit
• King Chulalongkorn Memorial Hospital

Outline
Introduction
Epidemiology
Classification
Immunological Mechanisms
• β-Lactam Determinants
• Carrier Proteins
• Pharmacogenetics
Diagnosis
Investigation
Cross Reactivity
Management
Conclusions

Introduction
• β-Lactams, which include penicillins, cephalosporins, carbapenems,
and monobactams, are the most widely used antibiotics and the first-
choice drugs to control several bacterial infections.
• Cephalosporins are among the most commonly used antibiotics for
hospitalized patients in the United States and the most common
antibiotic class patients receive at discharge.
• All beta-lactam use is associated with a certain rate of adverse
reactions. Many of these adverse reactions result in an allergy to the
beta-lactam being entered into the patient’s medical record.
Baggs, J, et al. Estimating National Trends in Inpatient Antibiotic Use
Among US Hospitals From 2006 to 2012. JAMA Intern Med. 2016.
Torres, MJ, et al. Controversies in Drug Allergy: Beta-Lactam
Hypersensitivity Testing. J Allergy Clin Immunol Pract. 2019.

Introduction
• An unconfirmed allergy to beta-lactams is a significant public health
risk.
• Because patients so labeled typically do not receive narrow-spectrum
penicillins and cephalosporins when clinically indicated.
• The alternative antibiotics they receive result in poorer clinical outcomes,
increased incidence of serious antibiotic-resistant infections, prolonged
hospitalizations, and greater health care utilization.

Introduction
• Unfortunately, only a small minority of these recorded allergies are
clinically significant immunologically mediated drug hypersensitivity.
• Only 17.4% of Thai children with a history of β-lactam hypersensitivity
had true drug hypersensitivity.
• Only 33.3% of Thai children with a history of anaphylaxis were
confirmed to have true drug hypersensitivity.
• Performance of penicillin allergy testing has shown that
approximately 90% of patients with a reported history of penicillin are
not allergic to penicillin.
Manuyakorn, W, et al. Skin testing with β-lactam antibiotics for diagnosis of
β-lactam hypersensitivity in children. Asian Pac J Allergy Immunol. 2016.
Zagursky, RJ, et al. Cross-reactivity in b-Lactam Allergy. J Allergy Clin
Immunol Pract. 2018.

Epidemiology
• In Denmark, the prevalence of alleged penicillin allergy, by history, in
a hospital population was 5.0%.
• 15/43 (34.8%) patients received penicillins during the current hospitalisation
despite of their history of penicillin allergy. No one experienced adverse
reactions to the administration of penicillin.
• Penicillin-induced anaphylaxis is relatively rare, with several studies
suggesting a rate of approximately 0.02% of treated patients.
Borch, JE, et al. The Prevalence of Suspected and Challenge-
Verified Penicillin Allergy in a University Hospital Population.
Basic & Clinical Pharmacology & Toxicology. 2006.
Napoli, DC, et al. Pediatric Asthma, Allergy & Immunology.
2000.

Classification
• Adverse drug reactions (ADRs) and hypersensitivity reactions (HSRs)
• On-target and off-target reactions
• Gell and Coombs hypersensitivity mechanisms (eg, types I through IV
HSRs)
• Reaction chronology and onset (immediate vs delayed)
Blumenthal, KG, et al. Antibiotic allergy. Lancet. 2019.

Classification
Adverse drug
reactions (ADRs)
On-target ADRs
Off-target ADRs
Immunologically-
mediated: antibody-
mediated and T-cell-
mediated
Non-immunologically-
mediated
Hypersensitivity
reactions (HSRs):
immunologically-
mediated ADRs.
Drug Hypersensitivity
Any untoward medication
effect experienced at
normal therapeutic doses
of the drug
Due to an augmentation of the
known therapeutic and
pharmacological action of a
drug, such as antibiotic-
associated diarrhoea or
Clostridioides difficile infection
Without immunological memory might
have an immunological phenotype,
such as non-IgE-mediated mast-cell
activation seen with the use of
fluoroquinolones.
Associated with immunological
memory of varied duration

Blumenthal, KG,
et al. Antibiotic
allergy. Lancet.
2019.

Classification
Khan, DA, et al. Cephalosporin Allergy: Current Understanding
and Future Challenges. J Allergy Clin Immunol Pract. 2019.

Classification
Adverse drug
reactions (ADR)
Type A
Including overdoses and
pharmacological reactions,
are dose dependent and
predictable
Type B: Drug
hypersensitivity
reactions (DHRs)
dose-independent,
unpredictable, noxious, and
unintended response to a
drug taken at a dose
normally used in humans
Demoly, P, et al. International Consensus on drug allergy. Allergy. 2014.

Demoly, P, et al. International Consensus on drug allergy. Allergy. 2014.

Classification
• Drugs can also be implicated as the cause through coincidential association
with a viral exanthem or through drug-infection interactions
• A drug-infection interaction is the rash observed with Epstein-Barr virus and
aminopenicillin treatment, present in at least 30% of such patients.
• Bacterial (eg, rash and mucositis associated with Mycoplasma pneumoniae) and viral
(eg, herpes simplex virus) infections are directly linked to the onset of erythema
multiforme mimicking Stevens-Johnson syndrome.
• A more traditional illness that resembles Stevens-Johnson syndrome and toxic
epidermal necrolysis has also been associated with viruses such as Coxsackie A6.
• Viral reactivation to human herpesvirus (HHV) 6 and 7, cytomegalovirus, and Epstein-
Barr virus has been described and thought to occur as a consequence of regulatory
T-cell expansion and the immune dysregulation associated with DRESS, rather than
as a trigger of DRESS syndrome.

Zagursky, RJ, et al. Cross-reactivity in b-Lactam Allergy. J Allergy Clin Immunol Pract. 2018.

Ariza A, et al. Hypersensitivity Reactions to ß-Lactams: Relevance of
Hapten-Protein Conjugates. J Investig Allergol Clin Immunol. 2015.

Oxazolidine ring
Dihydropyrrole ring

• BLs are small molecules (<1000 Da) whose interaction with the
immune system can be explained by 3 major working hypotheses:
• The hapten hypothesis
• The danger hypothesis
• The pharmacological interaction (PI) hypothesis

IgE-mediated mechanism
Drug-specific IgE binds to high-affinity receptors (FcεRI) on
the surface of tissue mast cells and circulating basophils.
The binding of drug-carrier molecule adducts (multivalent
antigen) to at least 2 adjacent IgE molecules.
Induces degranulation of mast cells and basophils, leading
to the release of inflammatory mediators, including
histamine, leukotrienes, and cytokines.
The whole structure (including the
BL and the protein carrier) is
necessary for the formation of the
complete antigenic determinant

Ariza A, et al. Hypersensitivity Reactions to ß-Lactams: Relevance of Hapten-Protein Conjugates. J Investig Allergol Clin Immunol. 2015.
Small molecules did not
induce an immune response
unless they were covalently
bound to a protein.
Cell damage induces production of
danger signals that interact with the
immune system, thus activating antigen
presenting cells. Drugs themselves or
concomitant substances originating from
viral infections can induce danger signals
and thus initiate allergic reactions.
A reversible interaction between the drug and
the T-cell receptor major histocompatibility
complex (MHC) could take place. This would
induce activation of T lymphocytes and thus
initiate an immune response against the drug
in an MHC-restricted and processing-
independent pathway.

β-Lactam
Determinants
• Benzylpenicillin
• Amoxicillin
Penicillins
Cephalosporins
Carbapenems
Monobactams
Clavams

Benzylpenicillin Determinants
• The major determinant is benzylpenicilloyl (BPO), which
results from the conjugation of BP with amino groups from
carriers.
• The stability of BPO has enabled its chemical
characterization and its use as BPO acid or BPO amide in
diagnostic studies.
• At least 3 epitopes have been recognized in the BPO
molecule.
• The side chain, the whole molecule bound to a carrier by ring
opening, and the bicyclic nuclear structure
• The BPO amide structure is also included in immunoassays.
• ImmunoCAP-FEIA: the specificity ranged from 83.3% to 100% and
the sensitivity from 12.5% to 25%
• RAST: specificity ranged from 66.7% to 83.3% and sensitivity from
42.9% to 75% Ariza A, et al. Hypersensitivity Reactions to ß-Lactams: Relevance of
Urticaria

Benzylpenicillin Determinants
• The generation of BP metabolites with different
possibilities for conjugation led researchers to
seek other determinants.
• Current skin testing determinants are purer and
more stable products, consisting of
• Benzylpenicilloyl octa-L-lysine as the major
determinant
• Benzylpenilloate (penilloate) as the minor
determinant
• sensitivity of 61.36% and specificity of 100%
Anaphylaxis

Amoxicillin Determinants
• The major antigenic determinant of AX is the amoxicilloyl (AXO) amide.
• Results from the opening of BL by amino groups, in much the same way as BP
• The AXO structure is included in in vitro tests (ImmunoCAP).
• In skin testing, the free BL, AX itself, is used with the assumption that it will be
conjugated to a carrier protein after application on the skin.
• The addition of AX to the panel of haptens for skin testing in patients with
suspected reaction to penicillins is currently recommended for routine skin
testing by the European Network for Drug Allergy.
• The lack of commercialized AX diagnostic reagents meant that the injectable
sodium salt was used in many countries, with several studies proving the validity
of this approach for diagnosing immediate hypersensitivity to penicillins.
• Since 2010, AX specifically designed for skin testing has been commercialized by
Diater.

Cephalosporins Determinants
• The antigenic determinants of cephalosporins
are not yet completely elucidated.
• A study of RAST inhibition with monomer
structures consisting of this conjugation
concludes that the R1 side chain, rather than
the BL structure, seems to play a dominant
role in determining the specificity of
immunologic reactions to cephalosporins.
• The results indicate
that the percentage
of cross-reactivity
between BLs with an
identical side chain is
high (38%) and that
this critical part of
the molecule seems
to play a key role in
these results.

Cephalosporins Determinants
• Determinants have not been reliably defined for cephalosporins and the
speed and efficiency by which cephalosporins form hapten-protein
conjugates is comparatively inferior to those of penicillins.
• Cephalosporins differ from penicillins by both their 6-membered
dihydrothiazine ring and the presence of an R2 group.
• Some evidence supports that the opening of the beta-lactam ring destroys
the R2 side chain and leads to unstable conjugates and fragmented poorly
identified determinants.
• Although IgE antibodies can theoretically bind to the beta-lactam ring, the
protein carrier, molecule, and side chains, it may be that the R1 side chain
and the remaining beta-lactam moiety covalently linking to host proteins is
central to immunogenicity.

Carbapenems Determinants
• Reactions between carbapenems and proteins have been described.
These reactions result in a stable structure consisting of the open BL
ring bound to the carrier proteins through an amide linkage.
• The specificity of the response to carbapenems is likely to be related
to the relatively stable dihydropyrrole ring.
• The incidence of cross-reactivity between penicillin and carbapenem
in skin tests to be around 1%.

Monobactams Determinants
• Monobactams are BL compounds in which the BL ring is alone.
• The only commercially available monobactam is aztreonam, whose R
substituent consists of the same side chain as ceftazidime.
• This molecule might be expected to form relatively stable
homogeneous conjugates.
• Three cell lines of hybridoma that produce antibodies recognizing
aztreonam have been established.
• Two of the monoclonal antibodies recognize aztreonam and ceftazidime,
indicating that the same acyl side chain is a relevant part of the determinant.
• The monoclonal antibody from the third line recognized a new antigenic
determinant and displays broad cross-reactivity with several BLs.

Clavams Determinants
• Clavulanic acid is the only BL included in this group.
• A CLV skin test (DAP Clavulanic, Diater SA) was recently patented and
commercialized for diagnostic purposes.
• Skin testing results indicate that selective immediate reactions to CLV do
occur and account for around 30% of immediate allergic reactions to the
combination of AX-CLV. Ariza A, et al. Hypersensitivity Reactions to ß-Lactams: Relevance of

Candidate Carrier Proteins
• The immune response to BLs is determined not only by the chemical
structures of the metabolites, but also by the nature of the adduct
itself and the characteristics of its uptake, processing, and
presentation by antigen-presenting cells.
• Human serum albumin (HSA) was traditionally considered the main
target protein in the haptenation process for penicillins.
• The grade of HSA modification is dependent on the drug concentration
and the incubation time used for the in vitro modification, with BLs
showing a preference for some HSA-specific residues.
• The factors that determine which amino acids are modified by BLs are
not known, binding to lysine residues may be favored by the presence
of a serine close to the polypeptide chain or the tertiary configuration
of the protein.

Candidate Carrier Proteins
• Serum proteins other than HSA could be involved in the haptenation
process and in the induction of an immune response; however, very
little is known about their nature or their role in the development of a
hypersensitivity reaction.
• A study observed that serum proteins other than HSA, such as
transferrin and immunoglobulin (light and heavy chains), were also
modified by AX.
• The fact that other relatively abundant serum proteins did not form
detectable adducts under the experimental conditions used suggests
that factors other than plasma protein concentration could determine
which serum proteins were targets for BL antibiotics.

Cellular Proteins
• Formation of these antigenic determinants is slower with cellular proteins than
with serum proteins.
• BP derivatives have the ability to bind to the cellular membranes of macrophages
and monocytes.
• A recent study carried out using piperacillin and T-cell culture revealed no cellular
adducts.
• Covalent binding of AX to HLA class I molecules on the surface of B cells has been
reported to cause overexpression of these molecules.
• Moreover, we recently showed that confocal fluorescence microscopy with a
biotinylated AX analog (AX-B) revealed the presence of intracellular protein
adducts and modified proteins in extracts from AX-B–treated cell lines
(monocytes, B-lymphoma cells, and macrophages) with different patterns,
showing that the haptenation process may be cell type–dependent.

Pharmacogenetics
• HLA may be necessary but not sufficient and subject to other ecologic and epigenetic
factors.
• The most significant associations to date have been described between penicillins and
drug-induced liver disease.
• HLA-B*57:01 (flucloxacillin)
• HLA-A*02:01; HLADRB1* 15:01; HLADQB1* 06:02 (amoxicillin–clavulanate)
• An association between the haplotype HLADQA1*01:04/DQB1*05:03/DRB1*14:05 and
drug and non-drug-induced interstitial nephritis. The specific relevance of this haplotype
for beta-lactam-associated acute interstitial nephritis is not known.
• Candidate gene studies for beta-lactam allergy have demonstrated the strongest
associations with genetic variation in HLA class II antigen presenting genes, NOD2 genes
affecting class II expression, genes involved in IgE synthesis (STAT6, IL4RA, IL13),
expression of preformed mediators (LGALS3), and cytokines (IL-4, IL-10, IL-18).
• For beta-lactams, a genome-wide association study showing a signal in the class II HLA
region did not reach genome-wide significance.
Lucena MI, et al. Susceptibility to amoxicillin-clavulanate-induced liver injury
is influenced by multiple HLA class I and II alleles. Gastroenterology. 2011.
Khan, DA, et al. Cephalosporin Allergy: Current Understanding and Future
Challenges. J Allergy Clin Immunol Pract. 2019.

Diagnosis
History
Skin testing
In vitro tests
Drug challenge

Patient-reported history
for risk stratification
• What were the symptoms?
• What was the timing of the reaction
after taking penicillin? Was it after the
first dose or after multiple doses?
• How long ago did the reaction happen?
• How was the reaction treated? Was
there a need for urgent care or was
epinephrine administered?
• Has the patient tolerated similar
medications, such as ampicillin,
amoxicillin, or cephalexin since the
penicillin reaction?

Blumenthal, KG, et al. Antibiotic
allergy. Lancet. 2019.

Penicillin skin testing
• Penicillin skin testing is the most reliable method for evaluating IgE-
mediated penicillin allergy. (B)
• Ideally, penicillin skin testing should be performed with both major and
minor determinants. The negative predictive value of penicillin skin testing
for immediate reactions approaches 100%, whereas the positive predictive
value is between 40% and 100%. (B)
• Skin testing with the major determinant and penicillin G only (without
penicilloate or penilloate) may miss up to 20% of allergic patients, but data
on this are conflicting. (C)
• Resensitization after treatment with parenteral penicillin appears to be
higher than for oral treatment, and therefore repeat penicillin skin testing
may be considered in patients with a history of penicillin allergy who have
tolerated a course of parenteral penicillin. (C)
Solensky, R, et al. Drug Allergy: An Updated Practice Parameter.
Annals Of Allergy, Asthma & Immunology. 2010.
Macy, E, et al. Adverse Reactions Associated with Therapeutic
Antibiotic Use after Penicillin Skin Testing. Perm J. 2011.
A penicillin skin test result is considered
positive if a greater than or equal to 5 mm
wheal surrounded by erythema is observed.

Solensky, R, Et Al. Drug Allergy: An Updated Practice
Parameter. Annals Of Allergy, Asthma & Immunology. 2010.
Brockow, K, et al. Skin test concentrations for systemically
administered drugs – an ENDA/EAACI Drug Allergy Interest
Group position paper. Allergy. 2013.

Quantitation of Specific IgE
• Immunoassay is the most widely used method for the quantitation of
specific IgE to BLs.
• In ImmunoCAP-FEIA (Phadia), commercial fluoroimmunoassay platform,
haptens are bound to spacers on a solid phase with high surface capacity.
• Specificity is 83.3%-100% and sensitivity 12.5%-45%, depending on the clinical
manifestations and skin test results.
• Noncommercial radioimmunoassay
• Radioallergosorbent test (RAST): a hapten-carrier conjugate is anchored to
a functionalized cellulose solid phase.
• The sensitivity of RAST with BL-PLL is around 50%, with a specificity of around 80-
95%.

Basophil Activation Test by Flow Cytometry
• The basophil activation test has been used as a diagnostic test for IgE-
mediated reactions to drugs and is based on the in vitro stimulation
of basophils by the culprit drug in peripheral blood.
• Sensitivity 49% and specificity 93%.
• It has been observed that the sensitivity of this assay is higher when
haptens (drugs) not previously conjugated to a carrier molecule are
used.

Non-immediate reactions
• For non-SCAR T-cell-mediated hypersensitivity, re-challenge is safe and
cross-reactivity is less defined.
• For severe T-cell-mediated reactions, such as Stevens-Johnson syndrome
and toxic epidermal necrolysis, DRESS, and organ-specific reactions, there
are few long-term antibiotic re-challenge or cross-reactivity data to guide
future therapy.
• However, since ex-vivo and invitro studies have demonstrated long-lived
immune responses, patients with severe T-cell-mediated allergies
associated with antibiotics should refrain from re-exposure to the same
drug and, ideally, all potentially cross-reactive drugs.
• The exception to this is when SCAR occurs in the setting of multiple drug therapy for
tuberculosis.

Lymphocyte Transformation Test by Flow
Cytometry
• The lymphocyte transformation test is an in vitro test based on the
measurement of T-cell proliferation in cell culture in the presence of
the drug of interest.
• In vitro proliferation suggests a previous in vivo reaction due to
sensitization.
• This test can be used for the in vitro diagnosis of T cell–mediated
reactions to BLs, although it is not routinely recommended and is still
considered a research tool.

Drug challenge
• Direct DPT may be recommended, without STs, in children with a
history of delayed-onset benign cutaneous BL-associated adverse
drug reactions.
• Several recent studies have demonstrated the safety of this approach
in those children in whom there is no anaphylactic signs and no signs
of SCARs.
• This is especially true in small children in whom viral infections are
mostly responsible for skin exanthemas.
• This approach is cost-effective and is now incorporated in clinical
guidelines.

Drug challenge
• Drug challenges are contraindicated in
• antibiotic-induced lupus, vasculitis, organ-specific drug reactions causing
cytopenias, hepatitis, nephritis, or pneumonitis and severe cutaneous adverse
reactions including SJS and DRESS.
• Drug challenges are generally avoided in patients with SSLR.
• However, there are some data suggesting that children with SSLR to
amoxicillin may tolerate amoxicillin challenges.
• SSLRs to cefaclor are typically cefaclor-specific and these patients tolerate
other cephalosporins with no greater risk than average patients.
Macy, E, et al. Practical Management of Antibiotic
Hypersensitivity in 2017. J Allergy Clin Immunol Pract. 2017.

Drug challenge
5–15–30–50% of daily therapeutic dose
N.B.: with the above mentioned additional steps
for index reactions of anaphylaxis
A surveillance period of 2 h after the last
administered dose, and a prolonged surveillance
after discharge of 48 h
1-day protocol for immediate and mild
nonimmediate reactors
A. Full dose challenge
B. Graded challenge (1/10th and then a full dose)
C. Graded challenge (1/100th, 1/10th, and then a
full dose)
Depends on Low/High-probability, possibility of
anaphylaxis, comorbid disease
1/2 h of observation after the first 2 doses and
1/2-1 h of observation after the final dose
For delayed reactions, a single therapeutic dose
with 2 to 5 days of home follow-up is generally
sufficient.
Chiriac A-M, et al. Optimal step doses for drug provocation
tests to prove beta-lactam hypersensitivity. Allergy. 2017.
The reference standard test to determine a clinically significant
DHR is a reaction occurring within the expected time period
after the first dose of a full therapeutic dose of the BL, less
than 6 hours for IRs and greater than 6 hours for NIRs.
Torres, MJ, et al. Controversies in Drug Allergy: Beta-Lactam Hypersensitivity
Testing. J Allergy Clin Immunol Pract. 2019.

Cross Reactivity: Penicillins & Cephalosporins
• The R1 side-chain structure of cephalosporins usually remains intact and is
the major factor for cross-reactivity between cephalosporins and
penicillins.
• Skin testing predicts only IgE reactions and shows cross-reactivity in some
patients between penicillins and early generation cephalosporins that
share side-chain identity, namely, between ampicillin/amoxicillin and
cephalexin/cefadroxil.
• In cases where a patient may react in tests to both penicillin and
cephalosporin with dissimilar structures, it is not clear whether there is
true cross-reactivity or natural coexisting sensitivity to both drugs.
• There is debate as to the involvement of R1 and/or R2 as antigenic
determinants that cause type I hypersensitivity for various cephalosporins.
Zagursky, RJ, et al. Cross-reactivity in β-Lactam
Allergy. J Allergy Clin Immunol Pract. 2018.

• Early dogma that cephalosporin allergy occurs in approximately 10%
of penicillin-allergic patients has been shown to be incorrect because
• (1) 90% to 99% of patients reporting being allergic to penicillin can tolerate
penicillins due to misclassification of reaction and natural waning of type I
allergy, and
• (2) most of the reported cases of penicillin-allergic patients who did
experience an adverse reaction to a cephalosporin were given an early
generation cephalosporin drug.
• In the latter case, reactivity was most likely the result of structurally similar
antigenic R1 groups of the cephalosporin and penicillin drugs, or contamination
of early generation cephalosporins by penicillin.
• The actual rate of cross-reactivity is probably less than 1%.

• Compounds with dissimilar structures yet similar bioisostere
properties (similar 3-dimensional electronic and steric properties)
might result in cross-reactivity.
• An example of this is the benzyl group of penicillin G and the thiophene side
chain of cephalothin.
• The cross-reactivity between penicillin G and cephalothin may be due to the
common methylene group within the side chains.
• Cephalothin is a special case in the debate about cephalosporin cross-
reactivity with penicillin because cephalothin was the first cephalosporin
marketed in the United States (in 1964) and it was contaminated with
benzylpenicillin and that alone would explain the reports of cross-reactivity.

Zagursky, RJ, et al.
Cross-reactivity in
β-Lactam Allergy. J
Allergy Clin
Immunol Pract.
2018.

Zagursky, RJ,
et al. Cross-
reactivity in
β-Lactam
Allergy. J
Allergy Clin
Immunol
Pract. 2018.

Cross Reactivity: Others
• Prospective studies of carbapenems suggest that attributable cross-
reactivity is very unlikely or absent between these β-lactams and
penicillins/cephalosporins.
• The low rate of cross-reactivity (0.8%-1%) between penicillins and
carbapenems could be attributable to unique separate sensitivities to the 2
antibiotic classes in the same patients. These results are consistent with
studies of penicillin-allergic patients where skin and in vitro tests established
that the IgE response was directed toward the R1 side chain of structurally-
related penicillins.
• Monobactams do not have cross-allergy with penicillins or most
cephalosporins, with the exception of ceftazidime, which shares an
identical R1 side chain as aztreonam.

Zagursky, RJ, et al. Cross-reactivity in β-Lactam Allergy. J Allergy Clin Immunol Pract. 2018.

Management
• Virtually every patient reporting a history of or who is skin test
positive to penicillins may receive a cephalosporin antibiotic as a
replacement with the exception of those showing R1 side-chain
similarity.
• Choose a drug with dissimilar R side-chain groups
• However, we did not take into account possible cross-reactivity due to
bioisosteric structures such as the methyl-substituted isoxazole R1 of
oxacillin with the methoxyimino R1 of cefuroxime, ceftriaxone,
cefepime, and cefotaxime, or the postulated benzene and thiophene
ring bioisosterism of benzylpenicillin and cephalothin that may be due
to contamination and not bioisosterism.

Management
• Based on a clearer understanding of penicillin, cephalosporin, and β-
lactam allergy, it is now known that an allergy diagnosis based on skin
testing and oral/parenteral challenge rather than a patient’s reported
history will permit more than 95% of patients labeled as allergic to be
delabeled.
• Clinical evaluation of patients reporting a penicillin antibiotic allergy should
include skin testing and oral challenge if the drug is orally available. A
negative penicillin test result removes a patient as being labeled as penicillin
allergic with reasonable medical certainty and allows one to prescribe
penicillins. This procedure should be considered electively rather than
urgently.

Management
• Clinical evaluation of patients reporting a cephalosporin allergy
should include cephalosporin skin testing with the native molecule
and oral challenge if the drug is orally available.
• The notion that penicillin-allergic patients must avoid all
cephalosporins because of potential cross-reactivity among the
molecules should be dismissed as a myth. Cross-reactivity between
penicillins and cephalosporins occurs rarely and when it occurs it is
due to similarity in the R1 side chain of the molecules.

Management
• The notion that a patient allergic to a specific cephalosporin must avoid all
cephalosporins because of potential cross-reactivity among the molecules
should be dismissed as a myth.
• Cross-reactivity between cephalosporins occurs rarely and when it occurs it is due to
similarity in the R1 or R2 side chain of the molecules.
• The important take-home message that is evidence based is the need to perform a
skin test to confirm the safety of any drug if a patient has been labeled as allergic and
then an oral provocation test under physician supervision. This may occur in an
outpatient setting as long as there is preparedness for treatment of anaphylaxis.
Similarly, in the hospital setting after skin testing, if negative, parenteral drugs
provocation testing may be used to permit the use of a test β-lactam and delabeling.
• It should be recognized that patients with a bona fide allergy to a β-lactam
antibiotic may experience an allergic reaction to a different β-lactam
antibiotic as an independent hypersensitivity reaction that is not related by
cross-allergy.

Management: Desensitization
• Immunologic IgE induction of drug tolerance (drug desensitization) is the
progressive administration of an allergenic substance to render effector
cells less reactive.
• The resulting state is temporary, and its maintenance requires continued
administration of the offending drug.
• When a penicillin is the drug of choice, in patients with ST-confirmed IgE-
mediated penicillin allergy, desensitization can be recommended after
considering risks and benefits.
• It is not possible to desensitize an individual with any clinically significant T-
cell mediated BL-associated NIR, and attempted desensitization is
absolutely contraindicated in all SCARs.
Solensky, R, et al. Drug Allergy: An Updated Practice

Management: Desensitization
• In penicillin induction of drug tolerance, the initial dose is typically
approximately 1/10,000 of the full therapeutic dose. Further dosage
increases are typically twice the previous dose and are administered
at 15- to 30-minute intervals until therapeutic levels are achieved.
The duration of the procedure varies, depending on the drug and
route of administration, but, in most cases, can be accomplished
within 4 to 12 hours.
• Induction of drug tolerance should be performed in an appropriate
setting, supervised by physicians familiar with the procedure, with
continual monitoring of the patient and readiness to treat reactions,
including anaphylaxis, should it occur.

Wurpts, G, et al. Guideline on
diagnostic procedures for
suspected hypersensitivity to
beta-lactam antibiotics.
Allergo J Int. 2019.

Management: Graded Challenge
• Graded challenge (also known as test dosing): to introduce a medication
cautiously so as not to induce a severe reaction.
• does not modify an individual’s immune response to a given drug.
• The procedure is intended for patients who, after a full evaluation, are unlikely to
be allergic to the given drug.
• The starting dose for a graded challenge is higher than for induction of drug
tolerance, and the number of steps in the procedure may be 2 or several.
• It is possible that a “graded challenge” consisting of more than 4 or 5 steps may
induce modifications of immune effector cells and therefore induce drug
tolerance in the patient. For that reason, future administrations of the drug
should be given cautiously.
• Example: In penicillin skin test–positive patients who require treatment with
cephalosporins.

Beta-lactam Allergy Pathways: Penicillin
Chiriac, AM, et al.
Controversies in Drug
Allergy: Drug Allergy
Pathways. J Allergy Clin

Beta-lactam Allergy Pathways: Cephalosporins
Chiriac, AM, et al.
Controversies in Drug
Allergy: Drug Allergy
Pathways. J Allergy Clin

Conclusions
• Differentiation between adverse drug reactions and DHRs is essential.
• A misdiagnosis of allergy to BLs results in dramatically poorer clinical
outcomes for patients and is not acceptable any longer.
• All individuals with a history of DHRs to BLs should be evaluated and
tested, if possible, to confirm current hypersensitivity or tolerance. An
interval of 4 to 6 weeks after a systemic reaction may be advised
before performing diagnostic tests.
• The role of in vitro testing for diagnosing DHRs to BLs has not been
established.

Beta lactam hypersensitivity

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