Adverse drug reactions (ADRs) result in major health problems in the United States in both the inpatient and outpatient setting. ADRs are broadly categorized into predictable (type A and unpredictable (type B) reactions. Predictable reactions are usually dose dependent, are related to the known pharmacologic actions of the drug, and occur in otherwise healthy individuals, They are estimated to comprise approximately 80% of all ADRs. Unpredictable are generally dose independent, are unrelated to the pharmacologic actions of the drug, and occur only in susceptible individuals. Unpredictable reactions are subdivided into drug intolerance, drug idiosyncrasy, drug allergy, and pseudoallergic reactions. Both type A and B reactions may be influenced by genetic predisposition of the patient

Drug allergy: an updated practice parameter.

Anaphylaxis

That mast cells and allergic mechanisms play at least some role in bronchial asthma has been suggested for at least 75 years [92]. The incidence of these mechanisms in a cross section of all asthmatics [31, 77], and the importance of allergic mechanisms as compared with neural mechanisms is controversial, however, and has been discussed and debated for at least as long [16, 113].

/pdf/mast-cells-and-basophils-2suvtsp6l8.pdf

Mast cells and basophils.

Allergic reactions to the beta-lactam antibiotics (penicillins, cephalosporins, carbapenems, and monobactams) are a major factor limiting their use. Immediate hypersensitivity reactions to penicillins depend on the presence of preformed allergic (IgE) antibodies to several penicillin determinants. These materials can be used in in-vivo skin testing to exclude those patients at risk for immediate or accelerated allergic reactions. The cephalosporins have not had their relevant determinants defined as related to allergic reactions. The results of in-vivo challenges of patients with IgE to penicillin suggest the incidence of reactivity of cephalosporins in patients allergic to penicillin is less than generally appreciated. The monocyclic beta-lactam antibiotic, aztreonam (a monobactam), failed to show cross-reactivity with penicillin antibodies, because immune reactivity toward the monobactam was directed against side chain rather than nuclear determinants. On the other hand, the new bicyclic carbapenem beta-lactam drugs, represented by imipenem, showed extensive in-vivo cross-reactivity with penicillins.

Immediate hypersensitivity reactions to beta-lactam antibiotics.

Introduction The discovery of penicillin by Fleming led to tremendous benefits in clinical medicine. Penicillin quickly became one of the most commonly prescribed drugs in the world. Despite a wide therapeutic index, it soon became clear that the penicillins could produce a vast array of immunological responses that could cause severe and fatal allergic reactions in some patients. The first reported case of anaphylaxis due to penicillin was in 1946 [I], and the first reported death was in 1949 [2]. Subsequently, a broad spectrum of allergic reactions to penicillin have been recognized. Available data do not permit exact conclusions as to the true frequency of allergic reactions to penicillin but they are reported to occur from 0-7 to S% of treatment courses in different studies [3], Allergenicity of penicillins is the major clinical problem that precludes the use of this class of antibiotics in a significant portion of the general population who are believed to be sensitive. In this article we will discuss allergic reactions to ^-lactam antibiotics, with special emphasis on IgE-dependent reactions in man.

Immediate hypersensitivity reactions to penicillin and related antibiotics

When patients allergic to penicillin develop life-endangering infections that require treatment with beta-lactam antibiotics, they face a fatal infection or the possibility of a fatal allergic reaction. We have approached this situation by using an oral desensitization procedure before full-dose antibiotic therapy. Thirty consecutive patients with histories of allergic reactions to penicillin, positive immediate wheal and flare skin-test reactions to penicillin determinants, and life-threatening infections were studied. Bacterial endocarditis requiring penicillin G therapy led to desensitization of 19 patients, Pseudomonas sepsis of pneumonia requiring treatment led to desensitization of nine subjects, and staphylococcal infections requiring therapy with a penicillinase-resistant penicillin led to desensitization of two patients. Penicillin G or carbenicillin were administered orally, beginning with 100 U or 60 microgram, respectively. At 15-min intervals, progressively doubled doses were given during continuous monitoring for the appearance of allergic reactions. Within 5 hr, full therapeutic doses were administered intravenously. Skin-test reactions disappeared or diminished in all 23 subjects who were retested after desensitization. Full courses of antibiotic therapy and cure of the infections were accomplished in 30 of 30 patients. No deaths, anaphylaxis, or severe acute allergic reactions occurred. Pruritic cutaneous eruptions appeared in nine patients (30%) 6 to 48 hr after the onset of therapy. One patient developed reversible nephritis 3 wk into therapy with penicillin G. The results of this study suggest that oral desensitization is an effective, relatively safe approach to administering beta-lactam antibiotics to penicillin-allergic patients with life-threatening infections.

https://www.jacionline.org/article/S0091-6749(82)80004-3/pdf

Desensitization of patients allergic to penicillin using orally administered β-lactam antibiotics

When rat peritoneal mast cells were exposed to the ionophore A23187, a principle was released that possessed the biologic properties of slow reacting substance (SRS) from various sources. The response was dose, time, and temperature dependent with no activity being demonstrated in unstimulated cells. Supporting evidence that the mast cell product was similar or identical to SRS obtained from other sources include: 1) appropriate differential bioassay profile, 2) resistance to lipolysis and proteolysis, 3) acid lability and base stability, 4) inactivation by limpet arylsulfatase, and 5) inhibition by low concentrations FPL 55712. These data demonstrate that the isolated rat peritoneal mast cell contains the biosynthetic capacity to produce a bioreactive substance with the properties of SRS.

Slow Reacting Substance (SRS) from Ionophore A23187-Stimulated Peritoneal Mast Cells of the Normal Rat: I. Conditions of Generation and Initial Characterization

The generation of slow reacting substance (SRS) from ionophore A23187-stimulated rat peritoneal mast cells was enhanced by arachidonic acid (AA). This SRS generation was inhibited by 5,8,11,14-eicosatetraynoic acid (ETYA), an acetylenic analogue of AA and an inhibitor of both fatty acid cyclooxygenase and lipoxygenase. Indomethacin, a fatty acid cyclooxgenase inhibitor, had an enhancing effect upon SRS generation. This suggests SRS generation occurred through an ETYA sensitive step--perhaps a lipoxygenase. Radiolabel from [14C]-AA was incorporated into SRS with comigration of radioactivity and bioreactivity in silicic acid and thin layer chromatographies. Upon silicic acid chromatography, the active principle was eluted in the methanol fraction. Two-dimensional thin layer chromatography revealed chromatographic separation from other known spasmogenic substances and phospholipids. Mast cell SRS was found to display physiochemical properties similar to those of rat basophilic leukemia cell SRS, namely: that mast cell SRS generation was 1) enhanced by arachidonic acid; 2) inhibited by ETYA but not by indomethacin; 3) incorporation of [14C]-AA into the active principle; and 4) similar behavior during purification in silicic acid and thin layer chromatographies.

Slow Reacting Substance (SRS) from Ionophore A23187-Stimulated Peritoneal Mast Cells of the Normal Rat: II. Evidence for a Precursor Role of Arachidonic Acid and Further Purification

SRS was generated from human leukemic basophils upon stimulation with ionophore A23187. Radiolabel from [14C]-AA was incorporated into SRS with continued comigration of radioactivity and bioactivity through several chromatographic systems including DEAE-cellulose, silicic acid, and RP-HPLC. Human basophilic leukemia SRS displayed physiochemical properties similar to those of rat basophilic leukemia cell SRS.

Slow Reacting Substance (SRS) from Ionophore A23187-Stimulated Human Leukemic Basophils: I. Evidence for a Precursor Role of Arachidonic Acid and Initial Purification

H J Wedner

Papers

Desensitization of patients allergic to penicillin using orally administered β-lactam antibiotics

Slow Reacting Substance (SRS) from Ionophore A23187-Stimulated Peritoneal Mast Cells of the Normal Rat: I. Conditions of Generation and Initial Characterization

Slow Reacting Substance (SRS) from Ionophore A23187-Stimulated Peritoneal Mast Cells of the Normal Rat: II. Evidence for a Precursor Role of Arachidonic Acid and Further Purification

Slow Reacting Substance (SRS) from Ionophore A23187-Stimulated Human Leukemic Basophils: I. Evidence for a Precursor Role of Arachidonic Acid and Initial Purification

7. Polar metabolites of arachidonic acid in rat mast cells