A Comprehensive Review of Sulfonamide Hypersensitivity: Implications for Clinical Practice

Abstract

Sulfonamides, which are drugs commonly prescribed in hospital and outpatient settings, have historically been associated with a high incidence of hypersensitivity reactions. It is believed that there is an increased risk of cross-reactions with other drugs that contain this functional group in their structure. However, it has not been conclusively established that the sulfona-mide group is the sole cause of hypersensitivity reactions, as non-antibiotic sulfonamides do not share the same accessory groups with antibiotic sulfonamides. Therefore, cross-reactivity between different types of sulfonamides and sulfonamide-type antibiotics is not clearly demonstrated, and allergic reactions may involve other mechanisms. Misinformation about this topic can lead to inappropriate use of alternative antibiotics with lower efficacy or higher adverse effects, contributing to antibiotic resistance. It is crucial to individualize and monitor patients with a history of allergies to sulfonamide-type antibiotics when introducing a new drug containing sulfa and manage any adverse reactions promptly. Desensitization protocols may be a viable option for patients who specifically benefit from these antibiotics, particularly those who are immunosuppressed. This article provides a descriptive bibliographic review to update information on sulfa allergy, its prevalence, management, and recommendations to prevent such reactions and optimize pharmacotherapy, without underusing these drugs.

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Clinical Reviews in Allergy & Immunology
https://doi.org/10.1007/s12016-023-08978-w
REVIEW
A Comprehensive Review ofSulfonamide Hypersensitivity:
Implications forClinical Practice
BrunoSerrano‑Arias1 · AdrianaAraya‑Zúñiga2 · JohanWaterhouse‑Garbanzo3 · ZoeRojas‑Barrantes4 ·
SebastiánArguedas‑Chacón4 · EstebanZavaleta‑Monestel4
Accepted: 12 December 2023
© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2024
Abstract
Sulfonamides, which are drugs commonly prescribed in hospital and outpatient settings, have historically been associated
with a high incidence of hypersensitivity reactions. It is believed that there is an increased risk of cross-reactions with other
drugs that contain this functional group in their structure. However, it has not been conclusively established that the sulfona-
mide group is the sole cause of hypersensitivity reactions, as non-antibiotic sulfonamides do not share the same accessory
groups with antibiotic sulfonamides. Therefore, cross-reactivity between different types of sulfonamides and sulfonamide-
type antibiotics is not clearly demonstrated, and allergic reactions may involve other mechanisms. Misinformation about this
topic can lead to inappropriate use of alternative antibiotics with lower efficacy or higher adverse effects, contributing to
antibiotic resistance. It is crucial to individualize and monitor patients with a history of allergies to sulfonamide-type antibiot-
ics when introducing a new drug containing sulfa and manage any adverse reactions promptly. Desensitization protocols may
be a viable option for patients who specifically benefit from these antibiotics, particularly those who are immunosuppressed.
This article provides a descriptive bibliographic review to update information on sulfa allergy, its prevalence, management,
and recommendations to prevent such reactions and optimize pharmacotherapy, without underusing these drugs.
Keywords Sulfonamide· Allergy· Hypersensitivity· Cross-reaction· Desensitization
Introduction
As per the European Academy of Allergy and Clinical Immu-
nology, hypersensitivity reactions are defined as an unfavora-
ble, discomforting, or harmful reaction stemming from an
exaggerated response of the adaptive immune system. This
includes both allergic reactions, prompted by external stimuli,
and autoimmune responses, induced by internal factors [1].
Consequently, a drug allergy can be described as an atypical
or heightened response to a specific drug, involving diverse
hypersensitivity reactions that activate several immune cells
and mechanisms, that culminates in the manifestation of
diverse symptoms affecting respiratory, dermatological, ocu-
lar, gastrointestinal, and other systems [1].
Historically, sulfonamides are an extensively utilized group
of medications that have been associated with a high inci-
dence of allergic reactions [2]. These medications are char-
acterized by the presence of the sulfonamide functional group
(-SO2NH2) attached to a benzene ring, and they can generally
be classified into two groups: sulfonamide antibiotics (also
called sulfonylarylamine) and sulfonamide non-antibiotics.
* Esteban Zavaleta-Monestel
ezavaleta@clinicabiblica.com
Bruno Serrano-Arias
bserrano@cimcacr.com
Adriana Araya-Zúñiga
adriana.arayazuniga@ucr.ac.cr
Johan Waterhouse-Garbanzo
johan.waterhouse@ucr.ac.cr
Zoe Rojas-Barrantes
zrojas@ClinicaBiblica.com
Sebastián Arguedas-Chacón
sarguedas@clinicabiblica.com
1 Pharmacy Department, Centro de Investigación y Manejo de
Càncer, SanJosé, CostaRica
2 Medicine Department, Hospital Calderón Guardia, SanJosé,
CostaRica
3 Medicine Department, HospitalMéxico, SanJosé,
CostaRica
4 Pharmacy Department, Hospital Clínica Bíblica, SanJosé,
CostaRica

Clinical Reviews in Allergy & Immunology
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The chemical structure of a sulfonamide antibiotic is unique,
as it includes an arylamine (aromatic amine) side chain linked
to the N4 position and a 5 or 6-member aromatic heterocy-
clic ring at the N1 position (Fig.1). On the other hand, non-
antibiotic sulfonamides, although these contain sulfur, have a
different chemical structure [3–5].
The intricate mechanisms behind immune-mediated drug
reactions involving sulfonamides remain incompletely elu-
cidated and described. Consequently, there is a prevailing
belief that individuals diagnosed with a sulfonamide antibi-
otic allergy may display cross-reactivity to other medications
containing sulfur, including loop diuretics like furosemide,
cyclooxygenase inhibitors such as celecoxib, clopidogrel,
captopril, omeprazole, ranitidine, spironolactone, and sulin-
dac, and various others. This perception has resulted in the
underutilization of potentially beneficial pharmacological
therapies, posing a challenge to the management of many
patients. Moreover, it can lead to the inappropriate use of
alternative antibiotics with either reduced efficacy or height-
ened adverse effects and potentially contributing to antibi-
otic resistance [6–10].
This review aims to comprehensively analyze current
information regarding sulfonamide allergies, with the goal
of enhancing the pharmacotherapy of sulfonamide medica-
tions and mitigating their underutilization, spanning both
antibiotics and non-antibiotics, by providing insights into
effective strategies for managing patients with these aller-
gies. Additionally, the review will explore potential cross-
reactions between antimicrobial and non-antimicrobial sul-
fonamides, considering their chemical structures.
Materials andMethods
This study constitutes a descriptive bibliographic review
aimed at presenting updated information on hypersensitiv-
ity reactions to sulfonamides, including their prevalence,
clinical management, and recommendations for prevention.
To compile this publication, a bibliographic search was
conducted across different databases such as PubMed, Clini-
cal Key, ScienceDirect, Springer, and Ovid. The primary
focus of the article search was on publications between 2013
and 2023, utilizing keywords such as “drug allergy,” “hyper-
sensitivity,” “antibiotic,” “sulfonamides,” “cross-reactivity,”
and “desensitization.” A total of 43 articles were selected for
inclusion in the review. Articles falling outside the specified
time frame were excluded, as were those lacking full content
accessibility and those published in languages other than
Spanish and English.
Discussion
Epidemiology
It is estimated that around 3–6% of the global population has
an allergy to sulfonamide antibiotics, which can manifest
as either immediate or delayed hypersensitivity reactions
[5–12]. Among children, the self-reported prevalence of
antibiotic allergy ranges from 0.2 to 0.5% to 2.2 to 2.7% [1,
13]. Also, it has been observed that the incidence of antibi-
otic allergies is higher in immunocompromised patients, par-
ticularly those with human immunodeficiency virus (HIV),
with reported antibiotic allergies in up to 1 in 4 immuno-
compromised hosts [11, 12, 14]. Approximately 3% of the
general population is estimated to experience reactions to tri-
methoprim-sulfamethoxazole (TMP-SMX). The prevalence
increases to 12–40% among individuals with hematological
malignancies and reaches 30–70% among patients diagnosed
with acquired immunodeficiency syndrome (AIDS) [15].
The most common manifestation of sulfonamide hypersen-
sitivity is skin rash, happening in approximately 2–3% of hos-
pitalized patients [16]. A rare manifestation of hypersensitivity
reaction to sulfas is the Drug Reaction with Eosinophilia and
Systemic Symptoms (DRESS). Published case series identi-
fied that 15–37% of the DRESS syndromes could be attributed
to antibiotics. According to an electronic health record review
in the USA conducted in 2019, 3% of the antibiotic-induced
DRESS syndrome cases were caused by sulfonamides [17].
Cases of acute eosinophilic pneumonia have been reported in
healthy patients with a history of sulfonamides use [18].
Steven Johnson syndrome (SJS) and toxic epidermal
necrolysis (TEN) are also rare presentations of hypersensi-
tivity reactions, occurring in approximately 10 people per
million population [11, 12]. The most frequent cause of SJS
and TEN are drug-induced, and sulfamethoxazole is the drug
most associated with these serious adverse events [19, 20].
Etiology andPathogenesis
As previously stated, sulfonamide antibiotics possess two
unique structural features that distinguish them from other
Fig. 1 Chemical structure of sulfonylarylamine showcasing its princi-
pal components

Clinical Reviews in Allergy & Immunology
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non-antibiotic sulfonamide drugs: the arylamine group at
the N4 position and a heterocyclic ring attached to the N1
position of the sulfonamide group (Fig.1). These distinct
characteristics at N4 and N1 positions are strong indicators
of an immune response and are believed to be necessary
for the development of hypersensitivity reactions [3–5, 15].
Different risk factors contribute to the occurrence of hyper-
sensitivity reactions to sulfonamides. These include drug and
host-related factors, concomitant and chronic illnesses, genetic
elements, immunogenetic associations, and other relevant vari-
ables [21]. Also, another identified risk factors for hypersensi-
tivity reactions to sulfas are HIV immunodeficiency possibly
due to impaired glutathione metabolism and the presence of
sulfonamide-specific IgE and genetic susceptibility, especially
in the presence of the HLA-B*15:02, HLA-C*8:01, and HLA-
C*6:02 alleles, which have been implicated in reactions such as
SJS and TEN [22, 23].
On the most commonly prescribed sulfonamide antibiotics
is TMP-SMX. The metabolism of sulfamethoxazole, consisting
of an acetylation process, by either cytochrome P450 (CYP) in
the liver or myeloperoxidase (MPO), leads to the corresponding
hydroxylamine (SMX-HA); if there is further oxidation, SMX
N-nitrosamine (SMX-NO) is produced. It can also be metabolized
by CYP2C9 [7, 20]. Both of these reactive metabolites (SMX-HA
and SMX-NO) bind covalently to many endogenous proteins and
peptides. This exposure indicates a potential role for oxidative
stress in development of drug hypersensitivity reactions [7, 20].
In addition, patients with individual characteristics such as
“slow acetylator” phenotypes could have more risk of suffering a
hypersensitivity reaction (primarily skin side effects) because of
an incorrect detoxification of the aniline portion of the sulfona-
mide [7]. On the contrary, the auto-oxidation of SMX-HA cre-
ated the highly reactive metabolite SMX-NO, which can result
in an immune-related reaction by the haptenization of a pro-
tein. Also, SMX-NO can bind to cellular protein, causing tissue
damage by direct cytotoxicity and may also interact directly
with antibodies or T-cells without haptenation, by forming
strong enough non-covalent bonds with T-cell MHC receptors
to induce an immune response [2, 7, 20]. This describes the pos-
sible mechanism of hypersensitivity reactions to sulfonamides
not mediated by IgE.
In the case of IgE-mediated hypersensitivity reactions,
the interaction between sulfonamide group and IgE immu-
noglobulins has been shown to be highly stereospecific and
mediated by specific parts of the antibiotic structure [9]. In
this type of reactions, there are two epitopes that can trig-
ger allergic processes: the single methyl group attached to
the heterocyclic ring N4 in the beta carbon atom and the
aromatic amine structure at the N1 sulfonamide position.
These groups act as immunogens that are recognized by the
IgE [2, 7, 12, 20].
The most frequent hypersensitivity reactions caused by
sulfonamides are types IVc and IVd and, to a lesser extent,
type I. Table1 shows the differences in the pathophysiology
and clinical manifestations for each type of hypersensitivity
reaction [6, 9, 12, 24].
Manifestations ofHypersensitivity Reactions
toSulfonamide Antibiotics
As previously mentioned, hypersensitivity reactions related
to sulfonamide use are variable, ranging from immediate
type I reactions which are less frequent, to type IV late-onset
reactions that are the most common [12].
Within the immediate effects, anaphylaxis can affect
multiple organs or systems in the body and, therefore,
is considered a life-threatening condition in its acute
manifestation. Cases of this type of allergic reactions to
sulfonamides are rare; nonetheless, cases involving both
oral and topical sulfonamides have been reported, and
Table 1 Pathophysiology of hypersensitivity reactions
Type of
hypersensitivity
reaction
Mediator of the immune response Physiopathology Clinical manifestations
IIgE Mass release of IgE Anaphylactic shock, hives, and angioedema
II IgG and complement IgG and complement-dependent
cytotoxicity
Cytopenia 1–2weeks post-exposure (PE)
III IgM, IgG, and complement Deposition of immune complexes Serum sickness 7 to 8days PE, or urticaria
1week PE, or vasculitis 1–3weeks PE
IVa Th1 Monocyte-mediated inflammation Eczema, contact dermatitis 1–3weeks PE
IVb Th2 Eosinophil-mediated inflammation DRESS 2–6weeks PE and/or
maculopapular rash 4–7days PE
IVc Cytotoxic T lymphocytes CD4- and/or CD8-mediated keratinocyte
apoptosis
SJS/TEN 4–28days PE. Maculopapular or
pustular rash 1–2days PE
IVd T lymphocytes Neutrophil-mediated inflammation Generalized exanthematic pustulosis days
PE

Clinical Reviews in Allergy & Immunology
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treatment in these cases consists of immediate adminis-
tration of intramuscular adrenaline, as well as mandatory
evaluation of the patient’s airway, circulation, breathing,
and consciousness [25–27]. On the other hand, more fre-
quently described are urticarias or angioedema that are not
usually fatal [2, 7, 28].
Late reactions of type IV hypersensitivity mainly involve
cutaneous manifestations, although they may also present
symptoms in other organs and systems. Skin reactions are
the most reported and include urticaria, erythema, maculo-
papular lesions, and pruritus. These reactions are typically
dose-dependent and occur within 72h to 13days after treat-
ment [12].
SJS and TEN are rare presentations of type IV hyper-
sensitivity reaction to sulfonamide drugs, and most of
these reactions are caused by antimicrobial-type sulfona-
mides. These are characterized by the appearance of blis-
ters, Nikolsky’s sign, leukopenia, thrombocytopenia, target
lesions, erosion of the mucous membranes, and compromise
of renal function. In the case of SJS, the skin involvement
is < 10% of the total surface, whereas in TEN, the involve-
ment is > 30%; both syndromes can overlap [12, 19, 29].
When encountering these cases, it is crucial to accurately
distinguish them from other types of skin conditions, includ-
ing non-allergic adverse effects, chronic urticaria, gastroen-
teritis, contact dermatitis, vasculitis, infections, post-viral
rashes, and other similar dermatoses, through a process of
differential diagnosis [11].
Management Recommendations
Early allergic-type hypersensitivity reactions may include
mild reactions (skin rashes, angioedema, and urticaria).
In these cases, it is recommended to immediately discon-
tinue the medication, use an alternative drug, and consider
expectant management, and if necessary, the administration
of first- or second-generation antihistamines or corticoster-
oids to alleviate symptoms. If sulfonamide must be used as
it is the only suitable drug, desensitization or oral challenge
(OC) should be considered [11, 30].
Regarding the delayed hypersensitivity reactions, such as
SSJ/TEN and DRESS syndrome, it is imperative to discon-
tinue the medication immediately, admit the patient to the
hospital for careful monitoring, initiate systemic corticos-
teroid therapy, administer antihistamines for urticaria, main-
tain IV fluid therapy to prevent dehydration and electrolyte
imbalances, and take measures to prevent hypothermia [12].
Desensitization andOral Challenge
Drug desensitization is a technique used to build tolerance
to a medication following a previous adverse reaction. It
consists of starting with very low doses of the drug and
continuously increasing the dosage until the desired dos-
age is achieved. This process is particularly beneficial for
TMP-SMX as this drug is commonly used for several indi-
cations, such as treatment of urinary tract and upper res-
piratory infections, and methicillin-resistant Staphylococcus
aureus (MRSA) infections. It is also the preferred choice
for prophylaxis against Pneumocystis jirovecii pneumonia
in immunocompromised patients, including HIV and trans-
planted patients [8, 20].
In these situations, it is advised to wait for a minimum
of 1month after the initial hypersensitivity reaction before
initiating desensitization. It is important to note that this
procedure is not recommended for patients with a medical
history of SJS or TEN, acute generalized pustulosis, serum
sickness, nephritis, hepatitis, or a history of DRESS syn-
drome following the use of TMP-SMX [12, 31, 32].
The desensitization process follows a protocol that can
be prepared depending on the patient’s needs. Figure2
shows an example of a 1-day protocol that consists of 13
to 14 doses administered within 15min each, doubling
the amount of TMP/SMX every time, and a protocol that
is performed in 10days, also doubling the dose each day
[22, 33]. It is important to emphasize that whether any of
the established desensitization protocols truly induce drug
tolerance is unknown [2].
Despite being effective for patients, desensitization can
be time-consuming and may require repeating each time
the drug has to be administered to the patient. As a result,
the oral challenge (OC) with TMP-SMX is now considered
as the preferred method in current practice, and it is used
to prove if the patient truly has a sulfa allergy. The OC is
a 1- or 2-step procedure that has demonstrated in several
trials to be clinically equivalent to the desensitization pro-
cess [4, 10, 34].
Several studies have conducted a comparison and evalu-
ation of the OC and desensitization processes. A Cochrane
review, which analyzed these, concluded that desensitiza-
tion resulted in fewer discontinuations compared to the
OC method. Based on the results of each study, it remains
unclear whether desensitization procedures are simply pro-
longed OC methods that may not be necessary for most
patients [35–37].
The 1-step OC consists of a single administration of
TMP-SMX at a dose of 80–400mg, followed by a 2-h
observation period in a clinic after the full dose is given.
Similarly, the 2-step OC follows the same approach, but
initially administers a lower dose of 8–40mg, and care-
fully monitors the patient for 1h. If the results are posi-
tive after the hour, the second dose of 80–400mg is then
administered [4]. Table2 shows a risk stratification based
of prior reactions to the administration of TMP-SMX and
recommendations on which process would be better in
each case [36].

Clinical Reviews in Allergy & Immunology
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In case that a patient cannot undergo a desensitization
or OC due to the development of severe delayed symptoms
at any point in the past, such as SJS, TEN, DRESS, or any
drug-induced nephritis or hepatitis, dapsone is an option
that can be considered in HIV-infected patients since it has
been proven that is tolerated when there is a TMP-SMX
hypersensitivity or intolerance [2, 35, 36].
Cross‑Reactivity
Cross-reactivity occurs when an individual exhibits
a reaction to drugs that are structurally similar, and
this reaction can be mediated by the recognition of a
shared epitope, metabolite, or hapten-carrier molecule,
leading to an immune response [12]. Figure3 shows a
15 30 45 60 75 90 105 120 135 150 165 180195 210
Dose TMP (mg) 0.08 0.16 0.32 0.64 1.28 2.56 510204080160 320 440
Dose SMX (mg) 0.0160.032 0.0640.128 0.2560.512 124816 32 64 88
0
50
100
150
200
250
300
350
400
450
500
Dose (mg)
Time (minutes)
1-day TMP-SMX desensitization protocol
12345678
91
0
Dose TMP (mg) 248164080160 320 400 800
Dose SMX (mg) 0.40.8 1.63.2 816326484160
0
100
200
300
400
500
600
700
800
900
Dose (mg)
Time (days)
10-day TMP-SMX desensitization protocol
Fig. 2 One-day and 10-day TMP-SMX desensitization protocols. Adapted from Chow TG etal. and Dorn JM etal

Clinical Reviews in Allergy & Immunology
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sulfonamide categorization divided in antibiotic and non-
antibiotic sulfonamide.
As mentioned above, antibiotic sulfonamide IgE-
mediated hypersensitivity is caused by the interaction of IgE
with specific substituents (N1 substituent or N4 aromatic
amine), which are not found in non-antibiotic sulfonamides,
indicating that there should be no cross-reactivity between
these groups of drugs, theoretically [12]. Based on the
same criteria, since non-IgE hypersensitivity reactions are
typically associated with the metabolism of the aromatic
amine moiety, cross-reactivity in these cases should not be
expected either [12].
While it may seem that reactions in a patient occur due
to cross-reactivity when two structurally similar drugs
are administered together, it is not appropriate to make
assumptions solely based on this. A large retrospective
cohort study conducted by Apter, A. etal. in 2006 demon-
strated that patients who had a history of reactions to penicil-
lin were at a higher risk of experiencing adverse reactions
when given cephalosporins and antibiotic sulfonamides,
even though these drugs (antibiotic sulfonamides) do not
share a similar structure with penicillin [2, 12].
Furthermore, an additional study demonstrated that
patients who had experienced reactions to antimicrobial
sulfonamides had a high odds ratio reaction for non-anti-
biotic sulfonamides but an even greater likelihood of reac-
tion to penicillin [22]. This implies that cross-reactivity is
improbable to be the leading cause of the heightened risk of
reaction [12, 38]. This could be explained because sensitiv-
ity to sulfonamide antibiotics may heighten the likelihood
Table 2 Risk stratification based of prior reactions to the administration of TMP-SMX
Adapted from Rose etal. [36]
Risk Characteristics Preferred process
High risk Patient with recent anaphylaxis (< 5years) TMP-SMX skin test or 2-dose TMP-SMX OC (depending on the
severity of the anaphylaxis presented) TMP-SMX desensitization
for HIV-positive patients
HIV-positive patients with detectable viral load
and/or CD4 + lymphocytopenia
Moderate risk Recent immediate symptoms (< 5years) 2-dose TMP-SMX oral challenge
Remote anaphylaxis (> 5years)
Low risk Delayed non-severe symptoms 1-dose TMP-SMX oral challenge
Remote immediate symptoms (> 5years)
Fig. 3 List of medicinal products belonging to the group of sulfonamides categorized by antibiotic and non-antibiotic drugs

Clinical Reviews in Allergy & Immunology
1 3
of reacting to non-antibiotic sulfonamides, and this can be
attributed to a pre-existing predisposition to drug reactions
rather than immunologic cross-reactivity.
A systematic review of the literature spanning from 1966
to 2011 to examine cross-reactivity among sulfonamides
identified nine case reports that indicated potential cross-
reactivity between antibiotic and non-antibiotic sulfona-
mides. Nonetheless, the authors noted that in several of these
cases, diagnostic testing to ascertain the underlying cause
of the allergic reactions was not carried out, thus raising the
possibility that the reactions may have been coincidental [2,
12, 22, 38].
Based on the available information, patients with history
of reactions to antibiotic sulfonamides should not necessar-
ily avoid the use of non-antibiotic sulfonamides due to a
contraindication for an “increased risk of hypersensitivity
reaction.” However, it may be reasonable to avoid any antibi-
otic sulfonamide in patients with a previous history of severe
hypersensitivity reactions to this class of medication, regard-
less of the route of administration. Additionally, TMP should
be avoided in patients with previous reactions to TMP-SMX
since it cannot be confirmed with certainty that the reaction
was solely caused by the sulfonamide component [2, 3, 12,
22, 38–40].
It should be emphasized that drug monographs may be
a source of misinformation on this topic, as many of them
recommend avoiding sulfonamide groups as warnings, pre-
cautions, or even contraindications. Nevertheless, in several
cases, these recommendations may lack scientific evidence
to support them. Therefore, clinicians should not solely rely
on drug monographs when making decisions, but should
consider the complete patient history, including any known
hypersensitivity reactions to sulfonamides and non-sulfon-
amide medication [12, 22, 41].
TMP‑SMX andOther Antibiotic Sulfonamides, COX‑2
Inhibitors, andDiuretics
TMP-SMX (Fig.4A) is the second antibiotic with the high-
est number of reported hypersensitivity reactions. In case a
patient presents a severe allergic reaction, any other sulfon-
amide-type antibiotic should be avoided. However, because
it is highly effective against MRSA and is also the first-line
treatment and prophylaxis for pneumocystis pneumonia in
immunosuppressed patients, desensitization is highly recom-
mended in this group of patients [12, 22].
Other antimicrobial agents implicated in this type of cross-
reactivity include sulfasalazine, which is metabolized into
Fig. 4 Chemical structures of
A TMP-SMX, B celecoxib, C
furosemide, D torsemide, and E
bumetanide

Clinical Reviews in Allergy & Immunology
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sulphapyridine, acting as a sulfonamide-type antibiotic, as well
as silver sulfadiazine and sodium sulfacetamide, which are used
as antimicrobials in ophthalmic applications [2].
Celecoxib (Fig.4B) is a non-antibiotic sulfonamide
drug that is commonly used as an anti-inflammatory.
Cross-reactions with celecoxib in patients with a his-
tory of antibiotic sulfonamide hypersensitivity are not
frequently reported, probably because celecoxib lacks the
heterocyclic ring at the N1 position. Several meta-analy-
ses have also shown that a history of sulfonamide allergy
does not significantly increase the risk of developing
allergies to celecoxib, as patients with such a history
have a similar risk to the general population [11, 42].
Diuretics
A series of publications have demonstrated the risk of cross-
reactive drugs between sulfonamide antibiotics and furosem-
ide (Fig.4C). These studies have concluded that sulfonamide
allergy associations are not caused by cross-reactivity, but
rather by a general predisposition to allergic reactions, as bio-
chemical and clinical studies have shown no evidence of sul-
fonamide cross-reactivity. In cases where there is a documented
allergy to furosemide, bumetanide and torsemide (Fig.4D, E,
respectively) may be considered as potential alternative drugs
for patients who are allergic to furosemide [43].
There are other drugs that have been associated with
cross-reactivity; Table3 shows in detail the risk of reaction
that each one presents [22, 41].
Prevention andRecommendations
Antibiotic Sulfonamides
In patients who report hypersensitivity to sulfonamide anti-
biotics, antibiotic replacement is the best option to avoid
the risk of a hypersensitivity reaction. Sulfonamides should
only be administered when there is no other acceptable and
effective treatment and with the prior medical advice of an
immunologist or allergist to individualize each patient [12].
Non‑Antibiotic Sulfonamides
Based on information obtained from meta-analysis and case
presentations, sulfonamide drugs have been categorized, as
shown in Table3. There are no contraindicated drugs; how-
ever, some have a high risk of reactions, so the individual
benefit-risk should be evaluated for each patient, taking into
consideration the patient’s complete medical history to fully
assess each case [41].
Conclusions
Hypersensitivity reactions to sulfonamides are a significant rea-
son why antibiotic sulfonamides are avoided in everyday clini-
cal practice. The sulfonamide group itself has not been proven
to be the primary cause of these reactions, but rather they are
attributed to the accessory groups attached to the sulfonamide
molecule. Because non-antimicrobial sulfonamides do not pos-
sess these accessory groups, it has not been conclusively dem-
onstrated that there is cross-reactivity between these drugs and
sulfonamide-type antibiotics. Therefore, allergic reactions to
this group of drugs may involve other mechanisms. Although
cross-reactions have been observed and are common among
antibiotics, desensitization protocols and oral challenges may
be a promising option for patients who require such medica-
tions, particularly those who are immunocompromised. Despite
this, it is important to always follow management guidelines by
individualizing care and closely monitoring individuals with a
history of allergies to sulfonamide-type antibiotics when intro-
ducing a new drug containing sulfonamide, to promptly manage
any adverse reactions.
Table 3 Classification of
sulfonamides according to
cross-reaction risk [38]
Description Drugs
Contraindicated due to cross-reactivity -
Possible cross-reactivity Sulfasalazine
Low likelihood of cross-reactivity Dapsone
Unlikely cross-reactivity Loop diuretics (furosemide)
Thiazide diuretics (hydrochlorothiazide)
Protease inhibitors (darunavir)
Carbonic anhydrase inhibitors (acetazolamide)
COX-2 inhibitors that contain sulfur (celecoxib)
5-HT agonists (sumatriptan)
Sulfonylureas (glipizide)
Other classification (tamsulosin, sotalol, topiramate, etc.)
Unable to draw conclusions B-Raf enzyme inhibitors (vemurafenib)

Clinical Reviews in Allergy & Immunology
1 3
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Technologies intheWriting Process
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ChatGPT to improve readability of translated sentences.
After using this tool/service, the authors reviewed and edited
the content as needed and take full responsibility for the
content of the publication.
Author Contributions The authors proudly take ownership of the entire
research journey, from conceiving and designing the study to meticu-
lously collecting, analyzing, and interpreting the data. Their dedication
extends to the meticulous preparation of the manuscript, showcasing
their commitment to every facet of this intellectual exploration.
Declarations
The omission of statements pertaining to ethics approval, consent,
and the availability of dataand/or materials is deliberate, as they were
deemed unnecessary for the present study.
Competing Interests The authors declare no competing interests.
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