Beta-lactam antibiotics are the most common drug allergens due to their chemical structure
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Evidence confirms that beta-lactam antibiotics are frequently reported as common drug allergens and discusses their chemical haptenation mechanisms, but individual sources provide partial support rather than jointly establishing both atoms with full scope.
Mitigating the risk of drug hypersensitivity reactions is an important facet of a given pharmaceutical, with poor performance in this area of safety often leading to warnings, restrictions and withdrawals. In the last 50 years, efforts to diagnose, manage, and circumvent these obscure, iatrogenic diseases have resulted in the development of assays at all stages of a drugs lifespan. Indeed, this begins with intelligent lead compound selection/design to minimize the existence of deleterious chemical reactivity through exclusion of ominous structural moieties. Preclinical studies then investigate how compounds interact with biological systems, with emphasis placed on modeling immunological/toxicological liabilities. During clinical use, competent and accurate diagnoses are sought to effectively manage patients with such ailments, and pharmacovigilance datasets can be used for stratification of patient populations in order to optimise safety profiles. Herein, an overview of some of the <i>in-vitro</i> approaches to predict intrinsic immunogenicity of drugs and diagnose culprit drugs in allergic patients after exposure is detailed, with current perspectives and opportunities provided.
In the last 50 years, efforts to diagnose, manage, and circumvent these obscure, iatrogenic diseases have resulted in the development of assays at all stages of a drugs lifespan. Indeed, this begins with intelligent lead compound selection/design to minimize the existence of deleterious chemical reactivity through exclusion of ominous structural moieties. Preclinical studies then investigate how compounds interact with biological systems, with emphasis placed on modeling immunological/toxicological liabilities.
Rather, they are determined through experience with the compounds themselves, for example; while many drugs are assigned a threshold SI of >2, Beta lactams tend to be assigned a threshold of >3, and some radio contrast media responses must reach SIs >4 to be deemed positive ( 57 ). With this comes several issues which the field has failed to address universally, the first of which being inconsistent threshold SI values utilized throughout literature for compounds. For example; SIs of >2 ( 59 ), >3 ( 60 ) and >4 ( 57 ) have been adjudicated as positive responses for radio contrast media.
A second, seemingly less rectifiable issue, is that if SI threshold values may only be set retrospectively, the LTT (although useful as a diagnostic tool for hypersensitive individuals), is inherently flawed for use in determining/diagnosing potential immunogenicity of a prospective therapeutic compound in early clinical development. Concomitant therapy is common in the aftermath of drug hypersensitivity reactions, not least due to medication taken to alleviate the reaction itself.
With regards to hypersensitivity, these examples serve to demonstrate that avoidance of structural alerts is not essential, that total body burden of chemically reactive metabolites (and therefore ensuing antigenic density) can be an important determinant, and that subtle re-design can save a lead compound. For now, due to the emphasis on chemical reactivity with structural alerts, this type of approach currently only has utility for drugs which exert antigenicity via hapten/covalent binding related mechanisms.
However, as patterns of drug hypersensitivity via the various mechanisms continue to emerge, perhaps we will eventually see inclusion of chemical codifications which confer immunogenicity, through each or all of the described antigenicity mechanisms [ Figure 1 , ( 8 )], and/or particularly high affinity interactions for (common) constituents of the immunological synapse. One can envision that a nascent database of such “Immunocophores” could be procured from compounds that have failed at various stages of development due to idiosyncratic, immune-mediated toxicity and used to mitigate risk.
Despite protein adduction of a compound not converting to a compounds liabilities in terms of capacity to elicit hypersensitivity reactions in a straightforward fashion. Drug-protein adducts have been successfully identified with antibiotics such as piperacillin ( 163 ), flucloxacillin and amoxicillin ( 164 , 165 ) as well as reverse transcriptase inhibitors such as nevirapine ( 166 ). This approach has also been utilised to identify a range of peptides susceptible to covalent modification by the drug/hapten in question ( 121 ).
Antigen Presenting Cell Maturation/Activation Assays While the antigenicity of a compound is important in terms of density/affinity/variety of antigens produced, another important component of drugs liabilities for hypersensitivity reactions may well be its capacity to generate signal 2. Indeed, classic studies have elegantly demonstrated a distinction and synergy between a chemical sensitizer and an irritant ( 191 – 193 ), thus, a compound’s intrinsic capacity to elicit both signal 1 and 2 contributes to its overall sensitization
In-Silico Approaches The recent emergence of nascent in-silico modelling systems in toxicological prediction of compounds hopefully portends a new era in the field of prediction of idiosyncratic adverse drug reactions. Systems currently available include aforementioned structural alert/chemical characteristic based softwares ( 109 , 226 – 228 ), and models that attempt to integrate in-vitro findings to a toxicity assessment output ( 229 , 230 ).
Perspective of Preclinical Assays Great strides have been made in the last 50 years to utilise empirical evidence relating chemical structure to direct and immuno-toxicological profiles, and to use this alongside preclinical screening assays in weight of evidence decision making processes. Despite this, the process is far from perfect, and several high profile therapeutics have failed at late stages of development in recent years. The current approach in industrial drug development heavily relies on chemical properties, particularly reactivity.
Humans are exposed to numerous electrophilic chemicals either as medicines, in the workplace, in nature, or through use of many common cosmetic and household products. Covalent modification of human proteins by such chemicals, or protein haptenation, is a common occurrence in cells and may result in generation of antigenic species, leading to development of hypersensitivity reactions. Ranging in severity of symptoms from local cutaneous reactions and rhinitis to potentially life-threatening anaphylaxis and severe hypersensitivity reactions such as Stephen-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), all these reactions have the same Molecular Initiating Event (MIE), i.e. haptenation. However, not all individuals who are exposed to electrophilic chemicals develop symptoms of hypersensitivity. In the present review, we examine common chemistry behind the haptenation reactions leading to formation of neoantigens. We explore simple reactions involving single molecule additions to a nucleophilic side chain of proteins and complex reactions involving multiple electrophilic centers on a single molecule or involving more than one electrophilic molecule as well as the generation of reactive molecules from the interaction with cellular detoxification mechanisms. Besides generation of antigenic species and enabling activation of the immune system, we explore additional events which result directly from the presence of electrophilic chemicals in cells, including activation of key defense mechanisms and immediate consequences of those reactions, and explore their potential effects. We discuss the factors that work in concert with haptenation leading to the development of hypersensitivity reactions and those that may act to prevent it from developing. We also review the potential harnessing of the specificity of haptenation in the design of potent covalent therapeutic inhibitors.
These are idiosyncratic with a prevalence ranging from 1 in 10,000–100,000 and thus often fail to be detected until postmarketing. 2 In contrast, skin sensitization is very prevalent, with 20% of the general population being diagnosed as allergic to at least one chemical allergen. 3 , 4 For chemical respiratory sensitization, prevalence is
5 − 7 Adverse effects resulting from the exposure to electrophilic drugs, metabolites, or chemicals encountered via oral, inhalation, or skin exposure all share the common Molecular Initiating Event (MIE), i.e. haptenation. 2 − 7 Despite sharing the MIE, hypersensitivity reactions can progress via divergent responses and ultimately result in Type I or Type IV hypersensitivity reactions. Beyond the MIE, these two divergent responses proceed via different molecular pathways, with considerably different clinical manifestations.
While Type IV skin hypersensitivity reactions are typically characterized by skin redness, itchy rash, and edema at the site of skin exposure to the chemical allergen, 4 type I reactions are characterized by a markedly faster appearance of symptoms which often depend on the type of exposure the chemical allergen is encountered by.
For example, formaldehyde initially reacts with amine nucleophiles to form Schiff base adducts, but further reaction steps result in complex structures involving adjacent nucleophiles on the same or different proteins 35 − 37 ( Figure 3 A). In general, haptenation by drugs is more complex, as multiple reactive intermediates could be involved. For example, clavulanic acid forms multiple adducts through direct nucleophilic addition to the β-lactam ring, its degradation products formed under hydrolysis, and cross-linking through multiple reactive intermediates ( Figure 3 B). 38 , 39 In addition, the stability of the initial adducts could also potentially lead to more complex adducts.
J.; Hennink, W. E.; Crommelin, D. J.; Jiskoot, W. Identification of formaldehyde-induced modifications in proteins: reactions with insulin. Bioconjug Chem 2006, 17 (3), 815–822. DOI: 10.1021/bc050340f. Copyright [2006] American Chemical Society). (B) Clavulanic acid forms multiple adducts through direct nucleophilic addition to the beta-lactam ring, its degradation products formed under hydrolysis, and cross-linking through multiple reactive intermediates (reproduced from Meng, X.; Earnshaw, C. J.; Tailor, A.; Jenkins, R. E.; Waddington, J. C.; Whitaker, P.; French, N. S.; Naisbitt, D. J.; Park, B. K.
90 Topical nonsteroidal anti-inflammatory drugs (NSAIDs) and organic UV light absorbers in sunscreens are clinically the most relevant photoactivated small molecule allergens, but the list is extended to numerous antibiotics, antifungal agents, agrochemicals, food additives, plant extracts, and fragrances. 91 − 99 Phase II metabolism enzymatically conjugates reactive metabolites or haptens to endogenous hydrophilic groups, aiming to generate readily excretable molecules.
While this mechanism remains to be demonstrated, it is generally accepted that oral exposure most often leads to tolerance. 213 Specifically for skin sensitization, An et al. have recently reviewed development of tolerance to skin sensitization by common naturally occurring allergens and those encountered in occupational settings (nickel, urushiols, sesquiterpene lactones). 214 Does Human Leukocyte Antigen (HLA) Binding Play a Role in Who Becomes Allergic?
215 − 217 It is interesting to note that some common haplotypes are associated with structurally unrelated drugs, for example, the association of HLA-B*57:01 with abacavir hypersensitivity 218 and flucloxacillin- and pazopanib-induced liver injury. 219 , 220 While all three share the same genetic predisposition, it is not fully understood why flucloxacillin and pazopanib result in drug induced liver injury (DILI) when abacavir manifests as a skin reaction. It is possible that these drugs may interact with HLA-B*57:01 differently due to the structural difference, leading to the presentation of novel drug associated antigens.
Abstract Background Non‐immediate reactions to beta‐lactam antibiotics ( BL ) occur more than one hour after drug administration, and the most common manifestations are maculopapular exanthemas and delayed‐appearing urticaria and/or angioedema. Infections can lead to skin eruptions and mimic drug hypersensitivity reactions ( DHR ), if a drug is taken at the same time. The most of children are labeled as ‘drug allergic’ after considering only the clinical history. Objective To diagnose/detect a hypersensitivity or an infection which mimic DHR in children with non‐immediate reactions to BL Methods A prospective survey was conducted in a group of 1026 children with histories of non‐immediate reactions to BL by performing patch tests, skin tests, and in case of negative results, drug provocation tests ( DPT s). In 300 children, a study was performed to detect infections by viruses or Mycoplasma pneumoniae. Results Urticaria and maculopapular exanthemas were the most reported non‐immediate reactions. Only 76 (7.4%) of 1026 children had confirmed non‐immediate hypersensitivity reactions to BL . Fifty‐seven children had positive delayed‐reading intradermal tests (18 of these with a positive patch test). Nineteen children had positive DPT . Sixty‐six of 300 children had positive tests for viruses or Mycoplasma pneumoniae and 2 of them had a positive allergy work‐up. Conclusions A diagnostic work‐up should be performed in all children with non‐immediate reactions to BL , to remove a f
Summary Background and aim Pediatric patients increasingly report allergies, including allergies to food and medications. We sought to determine the incidence and, nature of parent‐reported allergies in children presenting for surgery and its significance for anesthetists. Methods We prospectively collected data on admissions through our surgical admission unit over a 2‐month period at a pediatric tertiary care teaching hospital. Data collected included patient demographics, history of atopy, with more comprehensive information collected if an allergy was reported. A clinical immunologist and an anesthetist reviewed the documentation of all patients reporting an allergy. Results We reviewed 1001 pediatric patients, 158 (15.8%) patients with parent‐reported allergies; to medications/drugs (n = 73), food (n = 66), environmental allergens (dust/grasses, n = 35), tapes/dressings (n = 27), latex (n = 4), and venom (eg, bee, wasp, n = 9). Forty‐one patients reported antibiotic allergies, with Beta‐lactam antibiotics being the most common, with the majority presenting with rash alone (57%). Ten patients reported allergies to nonsteroidal anti‐inflammatory drugs and eight to opioids. Twenty‐four patients reported egg and/or peanut allergy. Only 3/1001 (0.3%) patients were deemed to have evidence of likely IgE‐mediated drug allergy. Of the reported allergies, only 60 (38.2%) had been investigated prior, most likely to be followed up were food (53%) and environmental allergies (44.4%).
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