Drugs as allergens: Detection and combining site specificities of IgE antibodies to sulfamethoxazole

doi:10.1016/0161-5890(88)90050-8

Molecular Immunology

Volume 25, Issue 12, December 1988, Pages 1347-1354

https://doi.org/10.1016/0161-5890(88)90050-8 Get rights and content

Abstract

An immunoassay was developed for the detection of sulfamethoxazole reactive IgE antibodies in the sera of patients who experienced life threatening anaphylactie reactions following the ingestion of co-trimoxazole (trimethoprim and sulfamethoxazole). Patients who had significant levels of sulfamethoxazole reactive IgE antibodies in their sera did not have IgE antibodies that reacted with trimethoprim-Sepharose. Inhibition experiments with a number of sulfonamides to determine the fine structural specificities of the sulfamethoxazole reactive IgE antibodies in three patients revealed that sulfamethoxazole and, depending on the serum, sulfamerazine and sulfamethizole, were the most potent inhibitors of IgE binding, whereas the parent sulfonamide, sulfanilamide, was a very poor inhibitor. From a detailed examination of structure-activity relationships, we concluded that the 5-methyl-3-isoxazolyl group on the sulfamethoxazole molecule was the allergenic determinant for all three patients with the 5-methyl group being particularly important for IgE antibody recognition. The assays for the detection of IgE antibodies to sulfamethoxazole and trimethoprim should prove useful for the diagnosis of immediate hypersensitivity to co-trimoxazole and perhaps for monitoring drug therapy in AIDS patients where a high incidence of adverse reactions to co-trimoxazole has been reported.

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Antibiotic prophylaxis in immunosuppressed patients – Missed opportunities from trimethoprim-sulfamethoxazole allergy label
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Trimethoprim-sulfamethoxazole (TMP-SMX) is a broad spectrum antibiotic in use for more than 50 years. It has an important indication as first line agent in the prophylaxis of opportunistic infections, particularly Pneumocystis jirovecii pneumonia (PJP), in immunosuppressed patients. For those who have a history of allergy or severe intolerance to TMP-SMX, pentamidine, dapsone or atovaquone may be substituted; however there is evidence that TMP-SMX offers superior coverage for PJP, toxoplasmosis, and nocardiosis. Compared to pentamidine, it has the added benefit of cost-effectiveness and self-administration as opposed to required hospital attendance for administration. Many patients who report a history of allergy or adverse reaction to TMP-SMX (or “sulfur allergy”) will be found not to be allergic; and even those who are allergic may be able to be desensitized. The evaluation and, where appropriate, removal of TMP-SMX allergy label enables the use of TMP-SMX for prophylaxis against opportunistic infections. This is a cost-effective intervention to optimize antimicrobial prescribing and reduce the risk of opportunistic infections in immunosuppressed patients.
Delayed Cutaneous Hypersensitivity Reactions to Antibiotics: Management with Desensitization
2017, Immunology and Allergy Clinics of North America
Sulfonamide Drug Allergy
2017, Drug Allergy Testing
Sulfonamide medication hypersensitivity is a common clinical entity. There can be multiple types of reactions to sulfonamide medications including skin exanthems, anaphylaxis, Stevens-Johnson syndrome, and DRESS. Although the mechanisms and specific components of the sulfonamide medications involved in these reactions are not clearly defined, progress has been made in delineating differences between sulfonamide antibiotics and sulfonamide nonantibiotics. Sulfonamide antibiotics are differentiated from nonantibiotics by both an arylamine group and nitrogen-containing ringed structure on specific parts of the drug. These structures are thought to play a central role in the pathogenesis of hypersensitivity reactions. Clinically, skin exanthems are the most common reaction. Hypersensitivity reactions occur at a higher rate in patients with HIV. A detailed history and physical examination remain the hallmarks of diagnosis because no objective diagnostic testing has proved definitive to date. Although individual case reports exist, the accumulation of data suggests limited or no cross-reactivity between sulfonamide antibiotics and nonantibiotics. Limited data exist on hypersensitivity specifically to each of the most commonly used classes of sulfonamide nonantibiotics as well as cross-reactivity within these classes of medications and with antibiotics. Management of hypersensitivity reactions and future use varies depending on the type of reaction and the future need. Desensitization to trimethoprim-sulfamethoxazole is well described and shown to be successful in both HIV and non-HIV populations.
Study of forced degradation behaviour of florfenicol by LC and LC-MS and development of a validated stability-indicating assay method
2012, Annales Pharmaceutiques Francaises
Citation Excerpt :
Several analytical methods have been reported for the quantification of florfenicol and its related compounds, for example gas chromatography, capillary electrophoresis, micellar electrokinetic chromatographic method and mass spectrometry [2–8]. Because residues of antibiotics in the food chain are of increasing concern due to their overall contribution to the increase of antibiotic resistance of pathogenic bacteria, as well as the potential allergenic reactions that they may illicit in certain individuals, it is absolutely necessary to do a severe quality control of veterinary commercials in terms of both qualitative and quantitative analysis [9]. Stability testing is an essential part of any drug development because the quality of a drug product changes with time under the influence of environmental factors such as temperature, humidity and light.
A stability-indicating high performance liquid chromatography (HPLC) method was developed for the analysis of florfenicol in presence of its two available identified degradation products (thiamphenicol and chlorfenicol). The drug was subjected to different International Conference On Harmonisation (ICH) prescribed stress conditions (hydrolysis, oxidation and photolysis). The products formed under different stress conditions were investigated by liquid chromatography (LC) and liquid chromatography-mass spectrometry (LC-MS). The LC method involved a Knauwer Eurospher C18 thermostated column at 25 °C; and ammonium acetate buffer 6.49 mM (pH adjusted to 4.5)–methanol (70:30 v/v) as mobile phase. The flow rate and detection wavelength were 1 ml/min and 225 nm respectively. The drug showed instability under acidic, alkaline and photolytic stress conditions mainly in solution state form; however, it remains stable in solid state form and under oxidative stress conditions. The developed method was validated for linearity, precision, accuracy and specificity. The degradation products were characterized by LC-MS. Through the mass/ionization (m/z) values and fragmentation patterns, two principal degradation products listed in bibliography have been shown: the florfenicol amine and thiamphenicol. Based on the results, a more complete degradation pathway of the drug could be proposed.
Une méthode de chromatographie liquide indicatrice de stabilité a été développée pour l’analyse de florfénicol en présence de ces deux produits de dégradation connus et disponibles (thiamphénicol et chlorfénicol). La substance a été soumise aux différentes conditions de dégradation forcée prescrites par la Conférence internationale d’harmonisation (ICH) (hydrolyse, oxydation et photolyse). Les produits formés dans les différentes conditions de dégradation forcée sont analysés par chromatographie liquide (CL) et chromatographie liquide-spectrométrie de masse (CL-SM). La CL implique une colonne C18 Knauwer Eurospher, thermostatée à 25 °C, et comme phase mobile, tampon acétate d’ammonium 6,49 mM (pH ajusté à 4,5)–méthanol (70:30 v/v). Le débit et la longueur d‘onde sont respectivement 1 mL/min et 225 nm. La substance médicamenteuse a été démontrée comme étant instable dans les conditions de dégradation forcée d’acide, basique et photolyse, notamment sous la forme d’une solution ; cependant, elle reste stable à l’état solide et dans les conditions de stress oxydatif. La méthode développée a été validée pour linéarité, fidélité, exactitude et spécificité. Les produits de dégradation ont été caractérisés par CL-SM. À partir du rapport masse–charge d’ionisation (m/z) et les modèles de fragmentation, deux principaux produits de dégradation inscrits en bibliographie ont été démontrés : le florfénicol amine et le thiamphénicol. En se basant sur ces résultats, un schéma de dégradation plus complet de la substance médicamenteuse peut être proposé.
Drug bioactivation and protein adduct formation in the pathogenesis of drug-induced toxicity
2011, Chemico-Biological Interactions
Citation Excerpt :
Nitroso-sulfonamides are directly toxic to immune cells [63,64], and unlike β-lactam antibiotics, they bind preferentially to cysteine residues on cellular protein [65]. Anti drug antibodies that interact with sulfonamide-modified protein have been detected [66]. Furthermore, skin and blood derived T-cells from hypersensitive patients have been shown to proliferate, secrete cytokines and kill target cells [67,68].
Adverse drug reactions (ADRs) remain a major complication of drug therapy and can be classified as ‘on-target’ or ‘off-target’ (idiosyncratic) reactions. On-target reactions can be predicted from the known primary or secondary pharmacology of the drug and often represent an exaggeration of the pharmacological effect of the drug. In contrast, off-target adverse reactions cannot be predicted from knowledge of the basic pharmacology of the drug. The exact mechanisms of idiosyncratic drug reactions are still unclear; however it is believed that they can be initiated by chemically reactive drug metabolites. It is well known that xenobiotics can undergo metabolic bioactivation reactions which have the potential to cause cellular stress and damage. Bioactivation of drugs is thought to have the potential of initiating covalent linkages between cellular protein and drugs which can be recognised by the adaptive immune system in the absence of detectable cellular stress.
This process cannot yet be predicted in pre-clinical models or discovered in clinical trials. Because of this hazard perception, the formation of chemically reactive metabolites in early drug discovery remains a serious impediment to the development of new medicines and can lead to withdrawal of an otherwise effective therapeutic agent. The fear of such reactions occurring at the post-licensing stage – when such problems first become evident – is a major contribution to drug attrition. The first step towards such methodology has been the development of chemically reactive metabolite screens. The chemical basis of drug bioactivation can usually be rationalised and synthetic strategies put in place to prevent such bioactivation. However, there is no simple correlation between drug bioactivation in vitro and adverse drug reactions in the clinic. Such a chemical approach is clearly limited by the facts that (a) not all drugs that can undergo bioactivation by human drug-metabolising enzymes are associated with hypersensitivity in the clinic and (b) drug bioactivation may not always be a mandatory step in drug hypersensitivity. To predict such reactions in early drug development, it will require an integrated understanding of the chemical, immunological and genetic basis of adverse drug reactions in patients, which in turn will depend on the development of novel in vitro experimental systems.
Drug allergy: An updated practice parameter
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Molecular Immunology

Abstract

References (19)

Anaphylaxis to muscle relaxant drugs: cross-reactivity and molecular basis of binding of IgE antibodies detected by radioimmunoassay

Molec. Immun.

Studies of human IgE to a sulfonamide determinant

J. Allergy Clin. Immun.

Management of drugs allergy in patients with acquired immunodeficiency syndrome

J. Allergy Clin. Immun.

Assays for, and cross-reactivities of, IgE antibodies to the muscle relaxants gallamine, decamethonium and succinylcholine (suxamethonium)

J. Immun. Meth.

Complications of co-trimoxazole in treatment of AIDS-associated Pneumocystis carinii pneumonia in homosexual men

Lancet

Penicillin allergy

J. Allergy Clin. Immun.

Treatment of infections in patients with the acquired immunodeficiency syndrome

Ann. Int. Med.

Rates of cutaneous reactions to drugs. A report from the Boston Collaborative Drug Surveillance Program

JAMA

Anaphylactic deaths: a clinicopathologic study of 43 cases

J. Forensic Sci.

Cited by (78)

Antibiotic prophylaxis in immunosuppressed patients – Missed opportunities from trimethoprim-sulfamethoxazole allergy label

Delayed Cutaneous Hypersensitivity Reactions to Antibiotics: Management with Desensitization

Sulfonamide Drug Allergy

Study of forced degradation behaviour of florfenicol by LC and LC-MS and development of a validated stability-indicating assay method

Drug bioactivation and protein adduct formation in the pathogenesis of drug-induced toxicity

Drug allergy: An updated practice parameter