Allergy to penicillin and betalactam antibiotics

Abstract

Betalactams are the most frequent cause of hypersensitivity reactions to drugs mediated by a specific immune mechanism. Immediate reactions occur within 1 to 6 hours after betalactam administration, and are generally IgE-mediated. They clinically translate into urticaria, angioedema and anaphylaxis. Non-immediate or delayed reactions occur after 1 hour of administration. These are the most common reactions and are usually mediated by T cells. The most frequent type is the maculopapular or morbilliform exanthematous eruption. Most individuals who report allergies to penicillin and betalactams can tolerate this group of antibiotics. To make diagnosis, a detailed medical history is essential to verify whether it was an immediate or non-immediate reaction. Thereafter, in vivo and/or in vitro tests for investigation may be performed. The challenging test is considered the gold standard method for diagnosis of betalactam hypersensitivity. The first approach when suspecting a reaction to betalactam is to discontinue exposure to the drug, and the only specific treatment is desensitization, which has very precise indications. The misdiagnosis of penicillin allergy affects the health system, since the "penicillin allergy" label is associated with increased bacterial resistance, higher rate of therapeutic failure, prolonged hospitalizations, readmissions, and increased costs. Thus, it is essential to develop strategies to assist the prescription of antibiotics in patients identified with a label of "betalactam allergy" at hospitals, and to enhance education of patients and their caregivers, as well as of non-specialist physicians.

Figure 1. Molecular structure of betalactam antibiotics. (A) Penicillins, (B) Cephalosporins, (C) Carbapenems, (D) Monobactams and (E) Clavulanic acid. Penicillin and the other betalactams share the beta lactam ring (marked in red), but differ from the adjacent ring (absent only in monobactams, shown in image D) and from the lateral chains of group R, R1 (blue), and R2 (green). Betalactams of the penicillin class have only one group R1 (1A). The lateral chain R1 is shared between some penicillins and cephalosporins. Clavulanic acid (E) is a betalactamase inhibitor, formulated with amoxicillin, and has been associated with immunoglobulin E-mediated reactions

Figure 2. Antigenic determinants of penicillins. Major antigenic determinants (A) Penicilloyl and minor, (B) Penicillin, (C) Penicillinoate and (D) Penilloate

Figure 3. Suggested algorithm for investigation of reactions to betalactams

Figura 1. Estrutura molecular dos antibióticos beta-lactâmicos. (A) Penicilinas, (B) Cefalosporinas, (C) Carbapenens, (D) Monobactans e (E) Ácido clavulânico. A penicilina e os demais beta-lactâmicos compartilham o anel beta-lactâmico (assinalado em vermelho), mas diferem em relação ao anel adjacente (ausente apenas nos monobactans, evidenciado na imagem D) e às cadeias laterais do grupo R, R1 (azul) e R2 (verde). Os beta-lactâmicos da classe penicilina possuem apenas um grupo R1 (1A). A cadeia lateral R1 é compartilhada entre algumas penicilinas e cefalosporinas. O ácido clavulânico (E) é um beta-lactâmico que também é um inibidor da beta-lactamase, é formulado com amoxicilina e foi associado a reações mediadas pela imunoglobulina E

Figura 2. Determinantes antigênicos das penicilinas. Determinantes antigênicos principal (A) Peniciloil e secundários, (B) Penicilina, (C) Peniciolato e (D) Peniloato

Figura 3. Algoritmo sugerido para investigação de reações aos beta-lactâmicos