Penicillin Allergy: The Formation of the Penicilloyl Determinant

Batchelor, F. R.; Dewdney, Janet M.; Gazzard, D.

doi:10.1038/206362a0

Cited by 151 publications

(74 citation statements)

References 7 publications

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“…␤-Lactam antibiotics are known to be targeted by specific Lys residues on protein (Levine and Ovary, 1961;Batchelor et al, 1965;Meng et al, 2011). Nucleophilic attack leads to ring opening, binding of the penicilloyl group, and ultimately formation of a stable adduct.…”

Section: Discussionmentioning

confidence: 99%

“…It is well established that ␤-lactam antibiotics form covalent bonds with lysine residues on protein (Levine and Ovary, 1961;Batchelor et al, 1965;Jenkins et al, 2009;Meng et al, 2011), and drug-protein binding is thought to be an obligatory step in the instigation of an immune response (Brander et al, 1995;Padovan et al, 1997). Consequently, we have recently developed and used mass spectrometry methods to characterize the amino acid residues on albumin modified with piperacillin in patients (Whitaker et al, 2011a).…”

Section: Introductionmentioning

confidence: 99%

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Characterization of the Antigen Specificity of T-Cell Clones from Piperacillin-Hypersensitive Patients with Cystic Fibrosis

El-Ghaiesh¹,

Monshi²,

Whitaker³

et al. 2012

J Pharmacol Exp Ther

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␤-Lactam antibiotics provide the cornerstone of treatment and reduce the rate of decline in lung function in patients with cystic fibrosis, but their use is limited by a high frequency of delayedtype allergic reactions. The objective of this study was to use cloned T-cells expressing a single T-cell receptor from five piperacillin-hypersensitive patients to characterize both the cellular pathophysiology of the reaction and antigen specificity to define the mechanism of activation of T-cells by piperacillin. More than 400 piperacillin-responsive CD4ϩ, CD4ϩCD8ϩ, or CD8ϩ T-cell clones were generated from lymphocyte transformation test and ELIspot-positive patients. The T-cell response (proliferation, T helper 2 cytokine secretion, and cytotoxicity) to piperacillin was concentration-dependent and highly specific. Enzyme-linked immunosorbent assay, gel electrophoresis, and mass spectrometry revealed that piperacillin bound exclusively to albumin in T-cell culture. Irreversible piperacillin binding at Lys 190, 195, 199, 432, and 541 on albumin and the stimulation of T-cells depended on incubation time. A synthetic piperacillin albumin conjugate stimulated T-cell receptors via a major histocompatibility complex-and processing-dependent pathway. Flucloxacillin competes for the same Lys residues on albumin as piperacillin, but the resulting conjugate does not stimulate T-cells, indicating that binding of the ␤-lactam hapten in peptide conjugates confers structural specificity on the activation of the T-cell receptors expressed on drug-specific clones. Collectively, these data describe the cellular processes that underlie the structural specificity of piperacillin antigen binding in hypersensitive patients with cystic fibrosis.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Characterization of the Antigen Specificity of T-Cell Clones from Piperacillin-Hypersensitive Patients with Cystic Fibrosis

El-Ghaiesh¹,

Monshi²,

Whitaker³

et al. 2012

J Pharmacol Exp Ther

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“…For Ag formation, the b-lactam ring is targeted by nucleophilic lysine residues, leading to ring opening and binding of the penicilloyl group (17)(18)(19). We have developed novel mass spectrometric techniques to define unequivocally the chemistry of drug-protein conjugation in patients under physiological conditions (20)(21)(22)(23).…”

mentioning

confidence: 99%

Mass Spectrometric Characterization of Circulating and Functional Antigens Derived from Piperacillin in Patients with Cystic Fibrosis

Whitaker

Meng

Lavergne

et al. 2011

The Journal of Immunology

100

142

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A mechanistic understanding of the relationship between the chemistry of drug antigen formation and immune function is lacking. Thus, mass spectrometric methods were employed to detect and fully characterize circulating antigens derived from piperacillin in patients undergoing therapy and the nature of the drug derived-epitopes on protein which can function as an antigen to stimulate T-cells. Albumin modification with piperacillin in vitro resulted in the formation of two distinct haptens, one formed directly from piperacillin and a second in which the dioxopiperazine ring had undergone hydrolysis. Modification was time- and concentration-dependent, with selective modification of Lys541 observed at low concentrations, whereas at higher concentrations up to 13/59 lysine residues were modified, four of which (Lys190, 195, 432 and 541) were detected in patients’ plasma. Piperacillin-specific T-lymphocyte responses (proliferation, cytokines and granzyme-B release) were detected ex vivo with cells from hypersensitive patients, and analysis of incubation medium showed that modification of the same lysine residues in albumin occurred in situ. The antigenicity of piperacillin-modified albumin was confirmed by stimulation of T-cells with characterized synthetic conjugates. Analysis of minimally-modified T-cell stimulatory albumin conjugates revealed peptide sequences incorporating Lys190, 432 and 541 as principal functional epitopes for T-cells. This study has characterized the multiple haptenic structures on albumin in patients, and showed that they constitute functional antigenic determinants for T-cells.

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“…2). For benzylpenicillin (BP), a number of products have been described such as the benzylpenicilloyl (BPO), formed after its spontaneous conjugation to proteins and represents 95 % of the antibody recognition [4]. The remaining percentage is formed by structures produced after metabolism (benzylpenicillenate, benzylpenicilloic acid, benzylpenicillanyl, benzylpenamaldate, benzylpenaldate, D-benzylpenicillamine, and benzylpenicilloyl), which have not been fully characterized immunochemically [5].…”

Section: Bl Antigenic Determinantsmentioning

confidence: 99%

Cross-Reactivity in Betalactam Allergy: Alternative Treatments

Montañez

Ariza

Mayorga

et al. 2015

Curr Treat Options Allergy

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Opinion statementIt was originally thought that, as all betalactams share a four-member ring, they would cross-react, and so the classical recommendation was for allergic patients to avoid all betalactams. However, later studies found that some individuals selectively responded to one betalactam only and tolerated others. This was shown to be more frequent than initially thought, and this finding has led to a change from the initial recommendations of complete avoidance. Selective responses to amoxicillin are mainly due to recognition of the side chain structure, making benzylpenicillin a safe alternative. These amoxicillin-selective responders comprise up to 55 and 90 % of patients with immediate allergic reactions to amoxicillin and amoxicillin-clavulanic, respectively. Additionally, more than 85 % of penicillin-allergic patients can tolerate cephalosporins with different R 1 side chains, decreasing to 65 % if the side chain is identical. It is known that third and fourth generation cephalosporins are well tolerated by penicillin-allergic patients, probably because their chemical structures differ more from penicillins that those from the first generation. In patients with IgE-mediated allergic reactions to cephalosporins, penicillins can be an alternative treatment in up to 75 % of cases. Moreover, 40 % of patients primarily sensitized to a given cephalosporin also react to others, which might be because some cephaloporins have the same (ceftriaxone and cefotaxime) or very similar (ceftriaxone and cefuroxime) side chain structures. Finally, carbapenems and monobactams are good alternative for patients with penicillin and/or cephalosporin allergy because cross-reactivity occurs in G1 % of these cases. For all betalactams, tolerance is higher in T-cell-mediated reactions than IgE-mediated. These results show that alternative treatments for infectious disease are available to patients with allergic reactions to betalactams, from within the same group of antibiotics. Nevertheless, this general rules need to be analyzed patient by patient, and skin tests and graded challenge with the betalactam that is going to be administered are recommended. Keypoints• Patients with IgE-or T-cell-mediated allergy to betalactams can have selective reactions, specific to one betalactam with good tolerance to others, or be crossreactive, recognizing several different chemically related betalactams.• The percentage of selective reactions to the different betalactam compounds is higher than previously reported and patients should be studied in order to increase the treatment options available.

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Penicillin Allergy: The Formation of the Penicilloyl Determinant

Cited by 151 publications

References 7 publications

Characterization of the Antigen Specificity of T-Cell Clones from Piperacillin-Hypersensitive Patients with Cystic Fibrosis

Characterization of the Antigen Specificity of T-Cell Clones from Piperacillin-Hypersensitive Patients with Cystic Fibrosis

Mass Spectrometric Characterization of Circulating and Functional Antigens Derived from Piperacillin in Patients with Cystic Fibrosis

Cross-Reactivity in Betalactam Allergy: Alternative Treatments

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