Studies on the Mechanism of the Formation of the Penicillin Antigen

Levine, Bernard B.; Óváry, Zoltán

doi:10.1084/jem.114.6.875

Cited by 330 publications

(101 citation statements)

References 19 publications

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“…Penicillins are too small to be full antigens but develop immunogenicity by acting as haptens covalently binding tissue or serum proteins. Once administered, penicillin undergoes spontaneous degradation because of a chemically unstable b-lactam ring, forming reactive intermediate products which can bind to lysine residue aminogroups on soluble or cell-bound proteins [13,78,79]. This results in the formation of benzyl penicilloyl, the major antigenic determinant of penicillin against which the majority of allergic patients react [80,81].…”

Section: Molecular Structurementioning

confidence: 99%

Management of allergy to penicillins and other beta‐lactams

Mirakian

Leech

Krishna

et al. 2015

Clin Experimental Allergy

225

229

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SummaryThe Standards of Care Committee of the British Society for Allergy and Clinical Immunology (BSACI) and an expert panel have prepared this guidance for the management of immediate and non-immediate allergic reactions to penicillins and other beta-lactams. The guideline is intended for UK specialists in both adult and paediatric allergy and for other clinicians practising allergy in secondary and tertiary care. The recommendations are evidence based, but where evidence is lacking, the panel reached consensus. During the development of the guideline, all BSACI members were consulted using a Web-based process and all comments carefully considered. Included in the guideline are epidemiology of allergic reactions to beta-lactams, molecular structure, formulations available in the UK and a description of known beta-lactam antigenic determinants. Sections on the value and limitations of clinical history, skin testing and laboratory investigations for both penicillins and cephalosporins are included. Cross-reactivity between penicillins and cephalosporins is discussed in detail. Recommendations on oral provocation and desensitization procedures have been made. Guidance for beta-lactam allergy in children is given in a separate section. An algorithm to help the clinician in the diagnosis of patients with a history of penicillin allergy has also been included.Keywords allergy, anaphylaxis, beta-lactam, BSACI, carbapenem, cephalosporin, children, cross-reactivity, desensitization, drug provocation test, epidemiology, hypersensitivity, monobactam, oral challenges, paediatrics, penicillin, serum-specific IgE, skin tests, Standards of Care Committee • This guideline addresses immediate and non-immediate allergic reactions to beta-lactams.• Up to 20% of drug-related anaphylaxis deaths in • Individuals with a positive skin test to an aminopenicillin but negative skin tests to penicillin determinants are likely to be sensitized to the aminopenicillin side chain. (B) In this situation, a cautious challenge to benzyl or phenoxymethyl penicillin can be considered to ascertain whether the patient has a selective penicillin allergy. (D) • If a cephalosporin is required in a patient with a clinical history of penicillin allergy and positive skin tests -the patient should undergo skin testing using a cephalosporin with a different side chain and, if negative, provocation testing should be undertaken to exclude allergy to the specific cephalosporin. (D)• If penicillin is required in a patient with a clinical history of cephalosporin allergy, skin testing should be undertaken with penicillins and, if negative, provocation testing to exclude allergy to penicillin. (B) If skin tests are positive, then penicillin avoidance or desensitization can be considered. (B)• If a cephalosporin is required by a patient with a previous reaction, skin testing to penicillins and the required cephalosporin should be carried out to establish whether sensitization is to the beta-lactam core or side chain. (B) This should be followed by either provo...

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Section: Molecular Structurementioning

confidence: 99%

Management of allergy to penicillins and other beta‐lactams

Mirakian

Leech

Krishna

et al. 2015

Clin Experimental Allergy

225

229

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“…In the present study we have attempted to apply rigorous criteria, based on hapten inhibition ELISA assays, to the unambiguous identification of IgM, IgG and IgE antibodies directed against BPO (the major antigenic determinant formed by benzylpenicillin; Levine & Ovary, 1961). It is evident that the different antisera differed widely in their susceptibility to hapten inhibition by BPO-caproate.…”

Section: Discussionmentioning

confidence: 99%

“…Such adverse reactions A wide variation in the prevalence of antimay be manifested in almost any of the clinical penicillin antibodies has been reported. For forms of hypersensitivity (de Weck, 1983); anti-example, Levine et al (1966) detected IgM antibodies of IgG, IgM and IgE classes are suspected benzylpenicilloyl (BPO, the major antigenic of mediating penicillin-induced haemolytic determinant formed from benzylpenicillin; Levine & Ovary, 1961) antibodies in 97% (16% IgG + ve) of a group of patients who had received no penicillin in the preceding 2 years, and in 100% of a group of patients (39% IgG + ve) who had received recent penicillin therapy. More recently, the prevalence of IgG anti-BPO antibodies in patients following high dose penicillin therapy has been variously reported to be 33% (de Haan & Kalsbeek, 1983), 38% (Adkinson & Wheeler, 1983) and 46% (Lee et al, 1986).…”

Section: Introductionmentioning

confidence: 99%

A survey of the prevalence of penicillin‐specific IgG, IgM and IgE antibodies detected by ELISA and defined by hapten inhibition, in patients with suspected penicillin allergy and in healthy volunteers.

Christie

Coleman

Newby

et al. 1988

Brit J Clinical Pharma

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1. IgG, IgM and IgE anti‐benzylpenicilloyl (BPO) antibody activities were determined by enzyme‐linked immunosorbent assay (ELISA) in sera from 100 patients who claimed to be allergic to penicillin, and from 50 healthy volunteers. Continuous frequency distributions for all three classes of anti‐BPO antibody, defined as differential binding (delta OD) to BPO‐human serum albumin (HSA) and HSA, were obtained for both groups. 2. For IgM and IgE classes the anti‐BPO activities were slightly but statistically significantly higher in the patient group compared with the volunteer group. 3. Hapten inhibition ELISAs were performed to confirm specificity for the BPO determinant. On the basis of antibody activities (delta OD values) greater than or equal to 0.3 and 50% inhibition of binding in the presence of 100 micrograms ml‐1 BPO‐caproate, BPO‐specific IgG antibody was identified in 4/100 of the patients' sera and in 1/50 of the volunteers' sera; BPO‐specific IgM was identified in 7/100 patients' sera and 1/50 volunteers' sera; and BPO‐specific IgE in 5/100 patients' sera and 1/50 volunteers' sera. 4. Not all sera with differential antibody binding to BPO‐HSA/HSA were inhibited by the BPO hapten. Hence, hapten inhibition assays are essential for the unambiguous demonstration of drug specific antibodies.

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“…Rabbits were used for experimentation 7-10 days after the last pair of injections (33-36 days after the initial immunization). This immunization regimen was modified from Levine and Ovary (5).…”

Section: Methodsmentioning

confidence: 99%

Studies on the Mechanism of Penicillin-Induced Fever

Chusid

Atkins

1972

The Journal of Experimental Medicine

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Fever is one of the most common manifestations of allergy to penicillin (i). In unsensitized individuals, the febrile response typically appears on the 7th-10th day of drug administration, but occurs more rapidly in previously sensitized individuals (2). Despite the frequency and clinical importance of this phenomenon, the factors which produce penicillin (PCN)i-induced fever do not appear to have been investigated.In a search for possible allergens in the normal metabolism of benzylpenicillin G in the host, Levine (3-5) has demonstrated that an initial breakdown product, benzylpenicillenic acid, may be metabolized to the benzylpenicilloyl (BPO) hapten which produces cutaneous penicillin hypersensitivity in rabbits. Further, rabbits sensitized to benzylpenicillin develop serum antibodies specific to BPO as demonstrated by precipitin techniques (5, 6), passive cutaneous anaphylaxis (5, 7, 8), and hemagglutination inhibition (9).Certain immediate reactions of hypersensitivity in man, such as anaphylaxis, have been shown to be caused primarily by minor penicillin determinants such as benzylpenicilloate, benzylpenicillamine, and penicilloate (7, 10, 11); reactions such as rashes, arthritis, and fever which appear later (12) are thought to be due to the BPO hapten. The nature of the antibody responsible for the allergic reaction that produces fever has not been identified, although the delay in onset of this reaction in sensitized individuals suggests an antibody of the IgG class.The purpose of the experiments described here was to determine whether the penicilloyl hapten, in the form of a penicillin-rabbit serum protein conjugate, would produce fevers in rabbits sensitized to penicillin and, if so, to determine what immunologic factors might be responsible for the release of the endogenous pyrogen (EP) that presumably mediates this as well as other forms of hypersensitivity fever (13).

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Studies on the Mechanism of the Formation of the Penicillin Antigen

Cited by 330 publications

References 19 publications

Management of allergy to penicillins and other beta‐lactams

Management of allergy to penicillins and other beta‐lactams

A survey of the prevalence of penicillin‐specific IgG, IgM and IgE antibodies detected by ELISA and defined by hapten inhibition, in patients with suspected penicillin allergy and in healthy volunteers.

Studies on the Mechanism of Penicillin-Induced Fever

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