Antibiotic allergy

Antibiotics are among the most frequently prescribed pharmaceuticals worldwide. Among these, amoxicillin achieved the top position (data from the Paul Ehrlich Society for Chemotherapy e.v.).

Like other drug allergies, antibiotic allergies are defined as reactions to drugs in which IgE- or T-cell-mediated immunological mechanisms are detectable or at least highly probable.

Immediate reactions (type I sensitizations): In principle, antibiotics can trigger all types of allergic reactions. The most common are immediate reactions with cutaneous (urticaria/angioedema) and/or respiratory symptoms (rhinitis, bronchial asthma) as well as anaphylactic reactions. Knowledge and management of antibiotic hypersensitivity are therefore of great clinical importance. Immediate reactions to betalactam antibiotics, sulphonamides and fluoroquinolones are the most common cutaneous hypersensitivity reactions.

Late reactions: Late reactions are characterized by various mechanisms involving T cells. Various mechanisms involving T-cells (type IV reactions), cytotoxic T-cells and NK-cells are considered. Clinical manifestations include maculo-papular drug exanthema, severe cutaneous drug reactions (SCAR) such as erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS).

According to the time of occurrence:

• cutaneous or respiratory immediate reactions (occurring within minutes or hours; by far the most common type of reaction)
• Delayed reactions (occurrence within > 24 hours)

Antibiotics are the frequent trigger of a drug hypersensitivity reaction in adults and children. Studies on the incidence of drug allergies in hospitalized patients, identified 30-50% of cases, antibiotics as the probable cause (Gamboa PM 2009), most commonly penicillins and 1st/2nd generation cefalosporins. Beta-lactams are responsible for 55-90% of all antibiotic reactions (Tong BY et al. 2011).

Betalactam antibiotics have no common allergenic determinants, although the chemical-pharmacological group name suggests that they do. Thus, allergic reactions to the beta-lactam ring are rare. In most cases the allergenic component is defined by the side chain. Thus, the exactly identical side chains of amoxicillin and cefaxdroxil lead to a high cross-reactivity. This also concerns Ampicillin, Cefalexin and Cefaclor.

Macrolides: The group of macrolide antibiotics includes e.g. erythromycin, clarithromycin, roxithromycin, azithromycin and telithromycin. Allergic reactions are rare.

Lincosamides: The only available member of this group is clindamycin. Allergic (late) reactions are not rare. Classic maculo-papular or pustular exanthema are observed. More rare are localized drug-related intertriginous and flexural exanthema, localized inflamed skin. Late readings of clindamycin intracutaneous/epicutaneous tests have only a low diagnostic sensitivity (Klimek L et al 2017). The diagnosis can only be confirmed by an oral provocation test.

Sulfonamide antibiotics: This group of drugs are derivatives of aminobenzenesulfonic acid (sulphanilic acid). 2 substances are available: sulfadiazine (with pyrimethamine against toxoplasmosis) and sulfmethoxazole (with trimethoprim = cotrimoxazole). In up to 4% of patients allergic ADRs (maculo-papular and bullous exanthema, hypersensitivity syndromes, more frequent in HIV patients.

Tetracyclines: All tetracyclines have a photosensitizing effect. Rare are maculo-papular exanthema against tetracycline, doxycycline, minocycline. Fixed drug reactions are most frequently observed.

Fluroquinolones (gyrase inhibitors): After norfloxacin, ciprofloxacin, ofloxacin and levofloxacin, anaphylaxis-like immediate reactions are described. The allergenic determinant of complex molecular structures is unknown. Fluroquinolones have histamine-liberating properties. A generalized flush (red man syndrome) may occur with rapid infusion speed. Whether an allergy applies to only one member or to the whole group can only be clarified by an oral provocation.

Immediate reactions: Careful anamnesis, skin tests, stationary placebo-controlled provocation procedures in emergency standby, laboratory tests: the determination of IgE antibodies are the only relevant laboratory tests for antibiotic allergies. Commercially available test formulations against penicilloyl G, penicilloyl V, ampicilloyl and amoxicilloyl are available, which achieve a sensitivity of up to 74% (Torres MJ et al. 2003). Only a few specific antibody assays are available for the diagnosis of cefalosporin-induced allergies, e.g. for cefaclor (Klimek L et al. 2017). Furthermore, intradermal tests are useful: concentration 1:10. Intradermal tests are not possible with tablets. They can only be pricked (pulverize tablet in a mortar and suspend with physiological saline solution). The basophil activation test or the lymphocyte transformation test are of little clinical relevance. In the case of respiratory reactions, nasal or bronchial provocation is also possible (Wedi B 2017). A careful risk assessment must be carried out for severe index reactions. Cross-reactions must be ruled out. Alternatively, evasive testing is recommended.

Late reactions: Careful medical history, skin biopsy, epicutaneous testing, inpatient placebo-controlled provocation procedures (gold standard), laboratory tests (usually only of minor relevance e.g. LTT). Alternatively, evasion tests are recommended.

Drug reactions to antibiotics are described inconsistently as hypersensitivity, hypersensitivity, idiosyncrasy, intolerance. Internationally, the term hypersensitivity is most commonly used. Drug hypersensitivity occurs particularly frequently together with infections, for example during concomitant infectious mononucleosis (exanthema of the 10th day), cytomegaly and lymphatic leukemia (Renn CN et al. 2002). In these constellations, a "real" antibiotic sensitization, e.g. to ampicillin, is only detectable in a small proportion of patients!

Up to 10% of the total population are thought to have a penicillin allergy. If these questionable allergies are tested, >80% of these assumptions prove to be unfounded (Solensky R et al. 2002).

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