Sulfonamide allergy

Sulfonamide allergy
PORNSIRI SAE-LIM , MD
PEDIATRIC ALLERGY AND IMMUNOLOGY
DEPARTMENT KING CHULALONGKORN MEMORIAL HOSPITAL

Overview
Introduction
Epidemiology
Classification
Clinical presentation
Diagnosis
Investigation
Management

IIntroductionion
Sulfa allergy = sulfonamide antibiotic allergy
In the general population : 3–8% of patients are reported to experience a sulfonamide allergy
Sulfonamide antibiotics allergy reported range from
◦ minor types : maculopapular eruption, fixed drug eruption
◦ major life-threatening types : Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and
anaphylactic reaction
Rash is reported as the most frequently observed reaction
◦ Immunocompetent : 1.5–3% of patients
◦ human immunodeficiency virus (HIV) : high as 30% in patients

Sulfonamide Structure
Contain an NH2-SO2 moiety
◦ Sulfur atom double bonded to two oxygens along with nitrogen
and a functional R1 group
Two main groups
◦ According to chemical structure and therapeutic action
◦ Sulfonamide antibiotics
◦ An aryl-amine (-Ar-NH2) at the N4 position
◦ A five or six membered, nitrogen-containing ring at the N1 position
◦ Sulfonamide nonantibiotics
N1 and N4 positions are the primary determinants of drug allergy instead of the common sulfonamide moiety

Sulfonamide antibiotics
Sulfamethoxazole (Bactrim®, Comox®, Spectrim®)
Sulfadiazine
Sulfasalazine (Salazopyrin EN®, Salazine®)

Sulfonamide non -antibiotics
Loop diuretics Sulfonamide non antibiotics
• Loop diuretics
– Furosemide (Lasix®)
– Tidorsemid e ( Unat®)
• Thaizide diuretics
– Hydrochlorothaizide (HCTZ)
– Indapamide (Natrilix®)
• Carbonic anhydrase inhibitors
– Acetazolamide (Diamox® )
– Dorzolamide (Cozopt®)
– Brinzolamide (Azo pt®, Aza gra® )
• Sulfonylureas
– Chlorpropamide (Diabenese®)
– Glibenclamide (Daonil®)
– Glipizide (Minidiab®)
– Gliclazide (Diamicron®)
– Glimeperide (Amaryl®)
• Cox -II inhibitors II inhibitors
– Celecoxib (Celebrex®)
– Parecoxib (Dynastat®)
• Others
– Topiramate (Topamax®)
– Zonisamide (Zonigrane®)

Sulfonamide antibiotics Sulfonamide nonantibiotics
Dorn JM,. Current allergy and asthma reports. 2018 Jul;18(7):1-0

Giles A, Sulfonamide allergies. Pharmacy. 2019 Sep;7(3):132.
Mechanisms of action of antimicrobial sulfonamides
microbial dihydropteroate synthetase
Competitive
inhibition

Antibacterial spectrum of sulfonamides
•Primary bacteriostatic against many gram-positive and gram-negative bacteria
In higher concentration it may be act as bactericidal.
•Sensitivity patterns among microbes changed time-to-time and place-to-place.
Sulfonamides are sensitive to Streptococcus pyogenes, Haemophilus influenza, Vibrio cholerae.
• Sulfonamides are primarily used to prevent urinary tract infections

Classification of
SulfonamideHypersensitivity Reactions
Immediated (IgE-mediated) reaction
Nonimmediate reaction

Manifestation of sulfonamide allergy
Immediated (IgE-mediated) reactions are rare
manifestations such as anaphylaxis, angioedema, and urticaria
N1 heterocyclic ring has been found to be recognized by IgE
◦ especially if a methyl group is in the position on the isoxazole ring
the sulfonamide-defining NH2-SO2 moiety has not been found to be bound by IgE

nonimmediate manifestations are most common
Cutaneous reactions :
Maculopapular exanthemas are the most common form of cutaneous reaction to sulfonamides
Risk of SJS/TEN is higher for sulfonamide antibiotics than for most other antibiotics
Extracutaneous reactions:
Drug-induced liver injury
◦ TMP-SMX : the most common single causative agents
◦ Occur within 2 to 12 days of initiation of therapy
◦ Pattern of injury being a mixed hepatocellular cholestasis
◦ Rare cases of hepatotoxicity and concomitant hemorrhagic pancreatitis
Khan DA, The Journal of Allergy and Clinical Immunology: In Practice. 2019 Sep 1;7(7):2116-23

Extracutaneous reactions
Gastrointestinal complaints (common), eosinophilic gastroenteritis ( rarely reported )
Hematologic abnormalities : neutropenia, leukopenia, thrombocytopenia and pancytopenia
Renal impairment : reported to be rare with TMP-SMX
◦ Most cases were asymptomatic
◦ Reversible on discontinuation of therapy but one did require dialysis
◦ unclear with little evidence for acute interstitial nephritis
Aseptic meningitis : started hours to several days after initiation of therapy
◦ headache and neck stiffness
◦ fever and 50%had nausea and vomiting
◦ Most patients became afebrile
◦ resolution of headache within 2 to 3 days of stopping therapy
◦ mechanism remainsunclear

Three potential mechanisms
(1) the parent molecule or reactive metabolites acting as haptens
(2) the molecule binding to a native protein stimulating a cellular or humoral immune response,
or
(3) a cellular protein causing direct cytotoxicity, or stimulation of T-cells to produce an immune
response

Non-type-1 hypersensitivity reactions are typically associated with metabolites of the
sulfonamide antimicrobial agents
◦ undergo acetylation, glucuronidation, and hydroxylation to various metabolites
N4-hydroxylated metabolite :
◦ A particular metabolite associated with allergic immunogenicity
◦ oxidized to a reactive nitroso compound
◦ reactive nitroso compound can bind directly to T cells to illicit maculopapular eruptions, including SJS
Reactive nitroso compound :
◦ reduced through a reaction utilizing glutathione, or acetylated using the NAT 2 enzyme
◦ Slow - acetylator phenotypes ( involves cytochrome P450 isoenzyme 2C9.6 ) or have deficiencies in
glutathione may be predisposed

Risk factor
- HIV positive patient
- Genetic predisposition
three HLA alleles (HLA-B*15:02, HLAC*06:02, and HLA-C*08:01) with sulfonamide-induced
SJS/TEN reactions

Objective
- To explore the cutaneous manifestations induced by
sulfonamide antibiotics in a large number of Thai patients,
including
◦ Human immunodeficiency virus (HIV)
◦ Non-HIV infected
- To determine the risk factors for development of sulfonamide
cutaneous reactions

Chantachaeng W. Asian Pacific journal of allergy and immunology. 2011 Sep 1;29(3):284

Cross reaction
Cross-Reactivity Within Sulfonamide Antibiotics
Cross-Reactivity Between Antibiotic and Non-antibiotic Sulfonamides
1.Khan DA, The Journal of Allergy and Clinical Immunology: In Practice. 2019 Sep 1;7(7):2116-23

Cross-Reactivity Within Sulfonamide
Antibiotics
• Structural similarities between antimicrobial agents
• Contain a five or six membered ring at the N1 position and an N4-arylamine group.
these positions are associated with the degree of immunologic response
>> high risk of cross-reactivity
• No large-scale clinical trials to determine true rates of cross reactivity among sulfonamide
antibiotics
• Some data in vitro and in vivo test

Cross-Reactivity Between Antibiotic and
Non-antibiotic Sulfonamides
- thiazide and loop diuretics, carbonic anhydrase inhibitors, nonsteroidal
anti-inflammatory drugs, sulfonylureas, antiretrovirals, and 5HT-3 receptor agonists
- None of the nonantimicrobial sulfonamides have an N-containing ring attached to the N1
- Based on review of the available evidence, sulfonamide antimicrobial agents do not appear
to have cross-reactivity with nonantimicrobial sulfonamide agents
- Develop reactions to a sulfonamide non-antimicrobial, there is no evidence to suggest that
sulfonamide antimicrobials and other sulfonamide non antimicrobials would cross-react

fosamprenavir
• contain sulfur, sulfites or bisulfate salts
• None of these medications are
sulfonamides, and there is no risk of
crosssensitivity with sulfonamide
antimicrobials

Khan DA, The Journal of Allergy and Clinical Immunology: In Practice. 2019 Sep 1;7(7):2116-23

- Sulfasalazine is not active in its ingested form but broken down by colon bacterial enzyme
azoreductase into 2 products: 5-aminosalicylic acid and sulfapyridine
- Sulfapyridine structurally related sulfamethoxazole
Zawodniak A, International archives of allergy and immunology. 2010;153(2):152-6.

Diagnosis
Validated diagnostic testing is not currently available for SMZ-TMP hypersensitivity
IgE-mediated : concentration of 1:100 dilution of 80 mg/mL, or 0.8 mg/mL
◦ positive result could suggest IgEmediated sensitization
◦ negative result would not rule out an IgE-mediated reaction to SMZ-TMP
Delayed skin testing including patch tests to sulfonamides is rarely positive
Drug challenges are a useful tool for patients with both immediate and delayed reactions
as a single full dose
as 1/10th of the dose followed by the full dose
may be considered on the basis of clinical history and skin test results
Broyles AD,The Journal of Allergy and Clinical Immunology: In Practice. 2020 Oct 1;8(9):S3-15

Management
Severe DHRs (SJS, TEN, DRESS, and others) to SMZ-TMP
◦ The drug should be avoided If no alternatives exist and the benefits of treatment with
SMZ-TMP outweigh the risk of death from a severe hypersensitivity reaction
◦ a previously reported temporary induction of tolerance protocol that was successfully
used for 2 patients may be considered
Desensitization to SMZ-TMP focuses on the HIV patient population
◦ various protocols for temporary induction of tolerance to SMZ-TMP have shown
similar success rates (initial success: 80%-90%; longterm: 60%-80%)
◦ no current consensus on the best protocol for SMZ-TMP temporary induction of
tolerance

Management
Pyle et al : reported that 90% of 72 patients with a history of SMZ-TMP
hypersensitivity who required the drug and underwent temporary induction of
tolerance had successful outcomes
appears to result in success rates comparable to those seen in patients with HIV
>> suggest that SMZ-TMP temporary induction of tolerance may be considered
in non-HIV patients with a history of related hypersensitivity
Temporary induction of tolerance to SMZ-TMP can be used safely and
effectively in patients with and without HIV who have SMZ-TMP
hypersensitivity.

Management
Few studies have examined the temporary induction of tolerance to
SMZ-TMP in non-HIV patient populations
◦ Mann et al: described 4 patients with a history of SMZ-TMP
hypersensitivity (leukopenia, hives, macular rash, morbilliform
rash) who underwent a successful temporary induction of
tolerance using either an 8-day protocol or a 22-day protocol

Patients with a history of mild to moderate SMZ-TMP hypersensitivity were randomized to
temporary induction of tolerance or full-dose challenge, they showed similar success rates in
tolerating the drug
Therefore, a full-dose challenge could be considered for patients with mild reactions to SMZ-TMP
as an alternative to an induction of tolerance procedure

A standardized temporary induction of tolerance protocol for SMZ-TMP
- not currently available, and a range of temporary induction of tolerance
protocols
- may be appropriate for use with HIV-positive patients
For HIV-positive patients with a history of a mild SMZ-TMP hypersensitivity
◦ a full-dose challenge can be considered
◦ may result in higher rates of ADRs than those associated with the temporary
induction of tolerance.
Management

Reported hypersensitivity reactions to NBLAs in children and the results of allergy evaluation
Include : NBLA allergy who had skin testing and/or an intravenous or oral challenge test (OCT)
ช่วง May 2011 and June 2018
Exclude : > 18 years old or did not complete the allergy evaluation
Positive OCT results being highest for trimethoprim-sulfamethoxazole (15 of 46; 32.6%) and
macrolides (8 of 77; 10.4%)
Grinlington L . Pediatrics. 2020 Jan 1;145(1).

Grinlington L . Pediatrics. 2020 Jan 1;145(1).

Sulfonamide allergy

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