Hypersensitivity of b- lactam antibiotics : Pharmaceutical chemistry point of view

b– Lactam is a group of antibiotic that includes penicillins ( such as ampicillin and amoxicillin) and cephalosporins such as cephalexin, cefuroxime, cefotaxime, and ceftriaxone). These antibiotics composed from semi-complex chemical structure contains an essential four member ring which is called b- lactam.
 In terms of therapeutic action, they are broad spectrum antibiotics that used , for example, to treat upper and lower respiratory tract infections, UTI and skin and soft tissue infections,
 However, in terms of adverse effect, these antibiotics have an allergic reaction or it is named as ‘classic penicillin hypersensitivity’. The allergic reaction is ranging from anaphylaxis, urticaria, Stevens–Johnson syndrome, and acute exanthematic pustulosis to b- lactam. There are two categories of allergic reaction to b-lactam. The first is occurring immediately (primarily concerned with IgE-mediated responses) and the second one is associated with a delayed reaction (mediated by T cells). The adverse reactions most often associated with the b-lactams have become known as classic penicillin hypersensitivity and fall within the immediate (primarily concerned with IgE-mediated responses) category.
Mechanism of hypersensitivity
The b-lactam ring structure can be cleaved in vivo, resulting in serum binding and covalent adduct formation with cell-membrane proteins. These products are referred to as hapten (A hapten is a small molecule that illicits an immune response when joined to a protein molecule) carrier conjugates, which are processed by antigen-presenting cells to eventually be presented to T cells. The T cells react with B cells and thus produce immunoglobulin E (IgE). This b-lactam interaction, as with most other hypersensitivity reactions, provokes an immunological cascade, with the subsequent release of inflammatory mediators. The first steps in hapten formation by the b-lactams are illustrated in the scheme below. As you can see, this process is initiated by the formation of penicillenic and penicilloic acids. These inactive penicillin derivatives then react with a range of amino acid side chains from proteins, such as lysine and cysteine, to form adducts. This process occurs in vitro as well as in vivo and is facilitated by low pH and also the presence of cations, especially copper, zinc, and iron. The penicillenic acid reacts irreversibly with lysine amino groups to form penicillinoyl-amine haptenic groups (known as the ‘major determinant’ because this form is most commonly observed; it is usually formed with human serum albumen lysine groups) (Levine and Ovary, 1961). Penicillenic acid can also react with other amino acid side chains to form other haptens (e.g. penicillenic acid-cysteine mixed disulfide), which are known as ‘minor determinants’ because they are formed less frequently than the major determinant (Svensson et al., 2001).
The major determinant and minor determinants can be applied to the skin to establish whether a patient is going to be hypersensitive to a penicillin. If a wheal-type skin reaction with erythema is produced (a positive test), there is a good chance the patient will be hypersensitive to penicillin (and, because of the structural similarity between agents, there is also a chance that the patient will also be hypersensitive to other b-lactams, such as cephalosporins, penems, and monobactams). Around 10% of patients who are allergic to penicillins are also allergic to cephalosporins. It has been suggested that the lower rates of hypersensitivity to cephalosporins in comparison to the penicillins are best explained by the reactivity of the two systems. Indeed, the high degree of torsion experienced in the penicillin nucleus (the thiazolidine and b-lactam ring) results in greater reactivity when compared to the less-strained heterocycles found in the cephalosporin nucleus. Cross-reactivity between cephalosporins and penicillins has, however, been observed, particularly between those that share identical/similar side chains. Among patients with a selective response to amoxicillin, 38% were shown to develop cross-reactivity with cefadroxil, a cephalosporin with a side chain identical to that of amoxicillin (Miranda et al., 1996).
References: (selected)
  • Miranda, A., Blanca, M., Vega, J. M., Moreno, F., Carmona, M. J., García, J. J., … & Juarez, C. (1996). Cross-reactivity between a penicillin and a cephalosporin with the same side chain. Journal of allergy and clinical immunology98(3), 671-677.
  • Svensson, C. K., Cowen, E. W., & Gaspari, A. A. (2001). Cutaneous drug reactions. Pharmacological reviews53(3), 357-379.
By: Mohammed Fanokh Al-Owaidi/ MSc Drug chemistry from Newcastle University-UK/ Assistant lecturer in College of Pharmacy/ Kerbala University.