Cross-reactive Drugs Research Articles

Diagnosis and Treatment of Perioperative Allergic Complications: A Practical Review.

Reported drug allergies are commonly encountered by surgeons and can lead to uncertainty in selecting an appropriate agent due to concerns of associated risks with related and cross-reactive drugs. This uncertainty can ultimately lead to increased infection rates. A literature review was conducted in PubMed using a combination of the terms "allergy," "allergic reaction," "anaphylaxis," and "surgery," "surgical," or "operating room" for articles published within the last 10 years. Publications identified with these search terms were then filtered for review articles, sorted by "best match," and a maximum of 100 articles were manually reviewed for each combination of search terms. Search results yielded 46,484 articles, 676 of which were ultimately included for manual review, based on selection criteria. Specifically, articles selected for inclusion focused on surgical allergic reactions that were either related to mechanism of action, causative agent for the allergic reaction, timing of allergic reaction, or recommendations for appropriate management. Allergic reactions can be a common occurrence in the operative room. Knowledge of likely causative agents, timing of a reaction to various agents, and appropriate management in the immediate and delayed setting can improve outcomes and safety for plastic surgery patients.

The assessment of severe cutaneous adverse drug reactions.

SUMMARYSevere cutaneous adverse drug reactions include Stevens-Johnson syndrome, toxic epidermal necrolysis and acute generalised exanthematous pustulosis. These eruptions are a type of delayed hypersensitivity reaction and can be life-threatening.The assessment of a severe cutaneous drug reaction requires a detailed clinical history and examination to identify the culprit drug and evaluate the allergy. Allopurinol, antibiotics and anticonvulsants are often implicated.Patch testing and delayed intradermal testing can assist in determining if the reaction was allergic, however there is limited evidence about the sensitivity and specificity of skin testing in severe cutaneous adverse drug reactions. If the testing is non-conclusive or negative, it is recommended to avoid the suspected culprit drug and any structurally similar drug in future.Any decision to reintroduce a drug should be made after considering the harm–benefit ratio. Caution is also needed if considering a possibly cross-reactive drug in a patient with a history of severe cutaneous adverse drug reactions.

Patterns of response and drugs involved in hypersensitivity reactions to beta-lactams in children.

Beta-lactams generate different allergenic determinants that induce selective or cross-reactive drug hypersensitivity reactions (DHRs). We aimed to identify the drugs involved, the selectivity of the response, the mechanism, and the value of the different diagnostic tests for establishing a diagnosis in children evaluated for DHRs to beta-lactams. Prospective study evaluating children aged under 16years reporting DHRs to beta-lactams. Reactions were classified as immediate and non-immediate reactions. The workup included sIgE, skin testing, and drug provocation tests (DPTs) for immediate reactions and patch testing and DPTs for non-immediate ones. Of the 510 children included, 133 were evaluated for immediate reactions and confirmed in 8.3%. Skin test/in vitro IgE contributed to diagnosing half of the cases. Selective reactions occurred with amoxicillin (63%), followed by common penicillin determinants (27%) and cephalosporins (0.9%). Among non-immediate reactions (11.4% of the 377 children evaluated), most required DPTs, 52.7% of which were positive at 6-7days of drug challenge. Selective reactions were identified with amoxicillin (80%), penicillin G (7.5%), cephalosporins (7.5%), and clavulanic acid (5%). Urticaria and maculopapular exanthema were the most frequent entities. There were few confirmed cases of either type of reaction. Skin testing proved less valuable in non-immediate reactions, over half of which would also have been lost in a short DPT protocol. Selective responders to amoxicillin were more likely to have non-immediate reactions, while clavulanic acid selectivity was exclusive to the non-immediate typology. Over half the cases with DPTs required 6-7days of treatment for DHR confirmation.

Delabeling Delayed Drug Hypersensitivity: How Far Can You Safely Go?

Delayed immune-mediated adverse drug reactions (IM-ADRs) are defined as reactions occurring more than 6 hours after dosing. They include heterogeneous clinical phenotypes that are typically T-cell-mediated reactions with distinct mechanisms across a wide spectrum of severity from benign exanthems through to life-threatening cutaneous or organ-specific diseases. For mild reactions such as benign exanthem, considerations for delabeling are similar to immediate reactions and may include a graded or single-dose drug challenge with or without preceding skin or patch testing. Evaluation of challenging cases such as the patient who is on multiple drugs at the time a severe delayed IM-ADR occurs should prioritize clinical ascertainment of the most likely phenotype and implicated drug(s). Although not widely available and validated, procedures such as patch testing, delayed intradermal skin testing, and laboratory-based functional drug assays or genetic (human leukocyte antigen) testing may provide valuable information to further help risk stratify patients and identify the likely implicated and/or cross-reactive drug(s). The decision to use a drug challenge as a diagnostic or delabeling tool in a patient with a severe delayed IM-ADR should weigh the risk-benefit ratio, balancing the severity and priority for the treatment of the underlying, and the availability of alternative efficacious and safe treatments.

Fixed Drug Eruption: Case Report

Drug allergy is characterized by hypersensitivity reactions to pharmacological agents, having an immune mechanism of development. In these reactions antibody and/or activated T cells are directed against medications or their metabolites. This problem is rather urgent for practical healthcare, as over 7% of people suffer from drug allergy. A 54-year old male presented at the emergency room Hospital Zainoel Abidin with redness and swelling of the bodies of a burning sensation, itching pain. In the detailed anamnesis taken from the patient, it was learned that 1 days previously he had consulted a nurse with the fever and 60 min after examination had been prescribed with acid mefenamic. Hypersensitivity immune reactions to medications, according to the present concepts, are divided into immediate reactions (within 1–6 h after starting the preparation manifesting with various forms—from mild to life-threatening symptoms of anaphylaxia), or delayed reactions (several hours to several days after the offending medication is started, manifesting clinically with exanthemas in the majority of cases). Drug allergy should be prevented.Steps to prevent allergic drug reactions include (1) a careful history to determine host risk factors, (2) avoidance of cross-reactive drugs, (3) use of predictive tests when available, (4) proper and prudent prescribing of drugs (especiallyantibiotics) that are frequently associated with adverse reactions,(5) use of oral drugs when possible, and (6) documentation of drug allergy in the patient’s medical record.

Medikamentenunverträglichkeit bei Histaminintoleranz und Mastozytose: «facts and fictions»

Drug hypersensitivity in patients with presumed histamine intolerance and mast cell activation disease Abstract. There is no evidence to suggest that sensitization against drugs occurs more frequently among patients with presumed histamine intolerance compared to patients with normal tolerance to histamine. However, preclinical data suggest interactions between some drugs and histamine catabolism. Nevertheless, the clinical relevance of these findings remains unclear as histamine in humans can be catabolized by different pathways. There are no drugs for which induction or worsening of histamine intolerance has been established clinically. In patients with mastocytosis an increased rate of sensitization and specific allergies to drugs is unlikely. However, pathophysiologic understanding suggests that mast cell activation disease might enhance drug reactions, which are induced by mast cell degranulation. Additionally a possible lower threshold for unspecific mast cell degranulation in patients with mastocytosis could lead to pseudoallergic drug reactions. However an increase in the number of drug substances triggering such reactions is not expected. Nevertheless, there are lists of drug substances which are assumed to cause anaphylactic / anaphylactoid reactions especially in patients with mastocytosis. Conversely, these lists are rarely based on clinical evidence. A recently published prospective trial did not find any relevant increase of acetyl salicylic acid hypersensitivity in patients with mastocytosis. Patients with mastocytosis and a history of drug hypersensitivity should be thoroughly assessed by an allergological workup and advised to avoid triggering and / or cross reactive drug substances. We recommend that these patients avoid drugs which may interfere with the treatment of anaphylaxis like beta blockers, certain antidepressants or Catechol-O-methyltransferase inhibitors because of the increased risk for enhanced hypersensitivity reactions.

Antibiotic Allergy, When to Test, Challenge or Desensitise

Antibiotics are widely used for treatment of bacterial infections and for prophylaxis during instrumental procedures and in certain conditions such as immunodeficiency and splenectomy. Hypersensitivity (allergic) reactions are unpredictable and can occur in some patients even if they have taken the antibiotic in the past with no reaction. Drug allergy accounts for 11.3% of all adverse drug reactions. Drug allergy drugs can be generally classified (according to the World Allergy Organization) based on timing of symptoms into immediate (Immunoglobulin E (IgE) mediated) occurring within 1 hour and delayed (non IgE mediated) allergic reactions occurring after 1 hour. Many patients are mislabeled with drug allergy especially when the diagnosis is made based on history alone. In such cases, a referral to an allergist is important to confirm or exclude allergy through a detailed clinical history, in vitro and/or in vivo testing, as over diagnosis of drug allergy leads to the unnecessary use of broader spectrum and expensive antibiotics contributing to the emergence of multidrug resistant pathogens. Also, in cases of confirmed drug allergy it is important to establish potential cross reactivity with other drugs. Equally, patients with confirmed drug allergy, who have an absolute requirement for the drug or cross reactive drug (as in penicillin allergic females with syphilis) can undergo a process of desensitization in order to complete their treatment through induction of temporary tolerance of the drug.

Structures of Human DPP7 Reveal the Molecular Basis of Specific Inhibition and the Architectural Diversity of Proline-Specific Peptidases

Proline-specific dipeptidyl peptidases (DPPs) are emerging targets for drug development. DPP4 inhibitors are approved in many countries, and other dipeptidyl peptidases are often referred to as DPP4 activity- and/or structure-homologues (DASH). Members of the DASH family have overlapping substrate specificities, and, even though they share low sequence identity, therapeutic or clinical cross-reactivity is a concern. Here, we report the structure of human DPP7 and its complex with a selective inhibitor Dab-Pip (L-2,4-diaminobutyryl-piperidinamide) and compare it with that of DPP4. Both enzymes share a common catalytic domain (α/β-hydrolase). The catalytic pocket is located in the interior of DPP7, deep inside the cleft between the two domains. Substrates might access the active site via a narrow tunnel. The DPP7 catalytic triad is completely conserved and comprises Ser162, Asp418 and His443 (corresponding to Ser630, Asp708 and His740 in DPP4), while other residues lining the catalytic pockets differ considerably. The “specificity domains” are structurally also completely different exhibiting a β-propeller fold in DPP4 compared to a rare, completely helical fold in DPP7. Comparing the structures of DPP7 and DPP4 allows the design of specific inhibitors and thus the development of less cross-reactive drugs. Furthermore, the reported DPP7 structures shed some light onto the evolutionary relationship of prolyl-specific peptidases through the analysis of the architectural organization of their domains.

Anticonvulsant hypersensitivity syndrome: cross-reactivity with tricyclic antidepressant agents

Aromatic anticonvulsant agents such as carbamazepine and phenytoin can induce anticonvulsant hypersensitivity syndrome (AHS) at a frequency of 1 in 10,000 to 1 in 1,000 treated patients. The hypersensitivity syndrome is a potentially life-threatening adverse drug reaction with multiorgan involvement, and incidental reexposure must be strictly avoided. Patients and treating physicians must be informed and educated about the causal drug and its potential immunologic or toxicologic cross-reactivity with other compounds. It has been well established that for future antiepileptic drug therapy, carboxamides (carbamazepine and oxcarbazepine), phenytoin, and barbiturates (phenobarbital and primidone) have to be avoided owing to their high degree of cross-reactivity. Other anticonvulsant agents, such as valproic acid, benzodiazepines, and gabapentin, may be prescribed. To present the clinical data for and to describe the potential cross-reactivity between aromatic anticonvulsant and tricyclic antidepressant agents in patients with carbamazepine- and phenytoin-induced AHS. The knowledge of cross-reactivity among aromatic anticonvulsant agents mainly emerged from clinical experience and observations because diagnostic challenge tests are not advisable. Thirty-six patients with the diagnosis of AHS were instructed to contact our unit if the symptoms relapsed. Despite better knowledge of AHS, one third of the patients had avoidable recurrences after exposure to cross-reactive drugs. Besides the known cross-reactivity among aromatic anticonvulsant agents, we observed a recurrence of the hypersensitivity syndrome in 5 patients after the administration of tricyclic antidepressant agents. The important potential cross-reactivity between aromatic anticonvulsant and tricyclic antidepressant drugs should be brought to the attention of treating physicians.

Sulfonamide Allergies and Outcomes Related to Use of Potentially Cross-Reactive Drugs in Hospitalized Patients

To characterize patient-reported sulfonamide allergies, assess the influence of these allergies on drug prescribing practices, and determine the frequency and nature of adverse reactions in patients with sulfonamide allergies who receive potentially cross-reactive drugs. Prospective observational study. Tertiary care hospital. Ninety-four hospitalized adult patients with reported sulfonamide allergies. Patients were followed during their hospital stay to document prescribing of and adverse reactions to sulfonamide antibiotics and sulfonamide nonantibiotics. Allergy characteristics and prescribing of sulfonamide-containing drugs were analyzed with descriptive statistics. Trimethoprim-sulfamethoxazole (TMP-SMX) allergy was reported by 42 patients (45%), whereas 42 patients (45%) did not recall the drug to which they were allergic. Fifty-nine patients (63%) reported the allergy's physical manifestation as rash, 13 (14%) anaphylaxis, and 2 (2)% Stevens-Johnson's syndrome. Median time since last reported allergic reaction to a sulfonamide-containing agent was 20 years. Forty patients (43%) had been taking a sulfonamide nonantibiotic as an outpatient for an average of 6.2 years; 24 (60%) of those patients took furosemide. Sixteen (40%) of the patients receiving sulfonamide nonantibiotics reported an allergy to TMP-SMX. Nine patients (10%) with no past sulfonamide nonantibiotic use received a sulfonamide nonantibiotic as an inpatient, with furosemide most commonly prescribed. No adverse events were reported before admission or observed during the inpatient stay (range 2-23 days). Inpatient and outpatient use of potentially cross-reactive drugs was observed in 52% of patients, although numerous patients were unable to give an accurate allergy history. No adverse effects were reported or documented with outpatient or inpatient sulfonamide nonantibiotic use, even among patients with histories of life-threatening reactions to sulfonamides.

Drug Hypersensitivity to Previously Tolerated Phenytoin by Carbamazepine-induced DRESS Syndrome

Drug rash with eosinophilia and systemic symptoms (DRESS) syndrome associated with anticonvulsant drugs is a rare but potentially life-threatening disease that occurs in response to arene oxide producing anticonvulsant such as phenytoin and carbamazepine. There have been many reports of cross reactivity among the anticonvulsants upon first exposure to the offending drugs. However, there has been few data describing the development of DRESS syndrome after switching medication from previously well-tolerated phenytoin to carbamazepine, and the induction of hypersensitivity to phenytoin by DRESS to carbamazepine. We experienced a case of a 40-yr-old man who had uncontrolled seizure that led to the change of medication from the long-term used phenytoin to carbamazepine. He developed DRESS syndrome after changing the drugs. We stopped carbamazepine and restored phenytoin for seizure control, but his clinical manifestations progressively worsened and he recovered only when both drugs were discontinued. Patch tests with several anticonvulsants showed positive reactions to both carbamazepine and phenytoin. Our case suggests that hypersensitivity to a previously tolerated anticonvulsant can be induced by DRESS to another anticonvulsant, and that the patch test may be a useful method for detecting cross-reactive drugs in anticonvulsant-associated DRESS syndrome.

Toxic epidermal necrolysis: Effector cells are drug-specific cytotoxic T cells

Toxic epidermal necrolysis (TEN) is a very rare but extremely severe drug reaction characterized by widespread apoptosis of epidermis with extensive blisters. We previously found drug-specific cytotoxic CD8 T lymphocytes in the blisters of a single patient. To confirm the role of drug specific cytotoxic lymphocytes in a larger series, to test the cytotoxicity on keratinocytes, and to look for cross-reactivity between chemically related drugs. The phenotype of lymphocytes present in the blister fluids of 6 patients with TEN was analyzed by flow cytometry. Cytotoxic functions were tested by chromium release assay on a variety of target cells (autologous or MHC class I-matched EBV-transformed lymphocytes, autologous keratinocytes) after nonspecific (CD3 monoclonal antibody) or specific (suspected and potentially cross-reactive drugs) activation. Blister lymphocytes were CD8 + HLA-DR + CLA + CD56 + . In all 6 cases, they were cytotoxic after nonspecific activation. A drug-specific cytotoxicity was observed in 4 cases (3 related to cotrimoxazole and 1 to carbamazepine) toward lymphocytes. Blister cells also killed IFN-gamma-activated autologous keratinocytes in the presence of drug in the 2 patients tested. Blister cells showed a strong immunoreactivity for granzyme B, and cytotoxicity was abolished by EGTA, but not by anti-Fas/CD95, suggesting perforin/granzyme-mediated killing. By using several sulfonamides for testing the specificity of the drug T-cell receptor interaction, we observed cross-reactivity only between 4 structurally closely related medications. These results strongly suggest that drug-specific, MHC class I-restricted, perforin/granzyme-mediated cytotoxicity probably has a primary role in TEN.

Patients with sulfonamide antimicrobial “allergy”: Are they able to tolerate sulfonamide-containing non-antimicrobial agents?

Rationale The clinical significance of potential cross-reactivity between sulfonamide antimicrobials and other sulfonamide-containing medications is uncertain. Pharmacy records were surveyed to determine whether patients with a history of sulfonamide antimicrobial adverse reactions were prescribed other sulfonamide-containing non-antimicrobials and, if so, whether these patients experienced adverse reactions to those agents. Methods All inpatients and outpatients at Parkland Memorial Hospital with reported sulfonamide “allergy” were retrospectively cross-referenced with an extensive list of potentially cross-reactive drugs dispensed by the pharmacy over the past 8 years. Pharmacy records of adverse reactions to these non-antimicrobial sulfonamides were also surveyed. Results This search generated 247 drug dispensations in 215 patients, of whom 25 (11.6%) received medications from more than 1 class. Despite reporting a sulfonamide antimicrobial adverse reaction, each patient received 1 to 3 of the following sulfonamides: a sulfonylurea, thiazide, loop diuretic, carbonic anhydrase inhibitor, triptan, celecoxib, amprenavir, or dapsone (a sulfone). Four adverse reactions were listed (1.6% of drug dispensations), one each to glyburide, sumatriptan, furosemide, and celecoxib; none were serious or life-threatening. While a system establishing absence of cross-reactions in patients was not available, 80% of drugs were refilled at least once, suggesting they were tolerated. Conclusions In general, patients who report a sulfonamide “allergy” can safely receive a wide variety of potentially cross-reactive non-antimicrobial sulfonamides, as suggested by repeated dispensations in most, lack of serious reported adverse reactions, and low incidence of reported adverse reactions. Future prospective studies should be undertaken to confirm the trends observed here.

Development of a monoclonal antibody-based cELISA for the analysis of sulfadimethoxine. 1. Development and characterization of monoclonal antibodies and molecular modeling studies of antibody recognition.

Sulfonamide antibiotics are used to treat a variety of bacterial and protozoan infections in cattle, swine, and poultry. Current residue methods for the analysis of sulfonamides in animal-based food products include bioassays, chromatographic methods (HPLC, GLC), and immunoassays. Most immunoassays have employed highly specific polyclonal antibodies. In this paper, we describe the isolation of monoclonal antibodies against sulfadimethoxine (SDM) that vary in their sensitivities and cross-reactivities against a large number of sulfonamides. The most sensitive monoclonal antibody, designated SDM-18, exhibits an IC(50) value for SDM of 1.53 ppb. Another monoclonal antibody, designated SDM-44, exhibits IC(50) values for six sulfonamides well below the established threshold level of 100 ppb for animal tissues. Molecular modeling studies of the cross-reactive drugs suggest that, depending on the monoclonal antibody, both steric and electronic features govern antibody binding. Due to the diversity of these monoclonal antibodies, it should be possible to design both compound- and class-specific monoclonal antibody-based immunoassays.

The role of melatonin in pathogenesis of aspirin-sensitive asthma.

Platelets are involved in the pathogenesis of bronchial asthma, including aspirin-sensitive asthma (ASA). The pineal hormone melatonin (MT) has been described as inhibiting several physiological processes in platelets. The MT metabolite - N-acetyl-5-methoxy-kynurenamine - has a chemical structure similar to that of acetylsalicylic acid. Because ASA patients usually suffer from an active disease, despite the avoidance of aspirin and cross-reactive drugs, it has been suggested that the MT synthesis may be lower and sensitivity of platelet reception to MT may be higher in aspirin-sensitive asthmatic subjects than in aspirin-tolerant ones. The objective of this study was to investigate this hypothesis. We studied the urinary excretion of 6-sulphatoxymelatonin, the major metabolite of melatonin, and the effect of different MT doses on ADP-induced platelet aggregation in vitro in 17 ASA patients, 17 patients with aspirin-tolerant asthma (ATA) and 16 healthy subjects. The results of the study have revealed a lower level of daytime aMT6s excretion in ASA patients (12.7 +/- 2.7 ng mL-1) than in ATA patients (32.7 +/- 9.9 ng mL-1, P < 0.05) and control subjects (19.9 +/- 5.8 ng mL-1, P < 0.05). The preincubation of platelet-rich plasma with the MT in a dose of 0.01 pg mL-1 plasma results in an increase in the intensity and the rate of the first platelet aggregation phase only in the ASA patients compared with the ATA patients and control subjects. We conclude that the reduction in MT production in ASA patients defines the character of ADP-induced platelet aggregation and the change in its first phase after the further addition of MT in vitro. The latter is associated with the opening of some receptor-operated channels for Ca2+ or/and its mobilization from the intracellular stores. The higher sensitivity of platelet reception and a distorted reaction not only to MT but also to its metabolite may be prerequisites for aspirin intolerance in ASA patients.

Development of a Cross-Reactive Monoclonal Antibody to Sulfonamide Antibiotics: Evidence for Structural Conformation-Selective Hapten Recognition

A unique anti-sulfonamide antibody-secreting hybridoma that cross-reacts with several sulfonamides was isolated. This was possible by using a N-sulfanilyl-4-aminobenzoic acid hapten-protein conjugate as the immunogen. Most of the antibodies that were detected in immunized mice did not recognize the free drug. However, by screening a large number of antibody-secreting hybridomas, cell lines were isolated that produced antibodies which recognized the free drug. The sensitivities of one such monoclonal antibody (MAb), referred to as Sulfa-1, for sulfanitran, sulfapyridine and sulfathiazole (expressed as IC50 values), were 1.41, 22.8, and 322 ng ml−1, respectively. Molecular modeling studies showed that the calculated minimum energy conformation of the hapten used as immunogen was different than those of the cross-reactive drugs. It was postulated that the MAb was derived from a cell line responsive to a form of the immunogen in which the structural conformation of the hapten was different than the molecular modeling calculated minimum energy conformation of the hapten. This was supported by further molecular modeling studies, including the use of potential energy-conformational maps, and competitive ELISA experiments conducted at two different temperatures. The immunogen appeared to be in a structural conformation achieved at an energy of + 0.193 kcal mol−1 with an energy barrier of 3.13 kcal above the minimum energy conformation; an energy easily found within the body temperature of the immunized mouse. Design of haptens for the purpose of generating cross-reactive antibodies should not just consider the two-dimensional structure, but also the three-dimensional conformation as well as the various structural combinations that can be easily attained within the body temperature of the immunized animal.

Substrate-labeled fluorescent immunoassay for measuring dibekacin concentrations in serum and plasma.

We have developed a homogeneous substrate-labeled fluorescent immunoassay for the measurement of dibekacin concentrations in serum and plasma. The fluorogenic enzyme substrate beta-galactosyl-umbelliferone was covalently attached to tobramycin, an aminoglycoside structurally similar to dibekacin, to prepare a fluorogenic drug reagent (FDR). The FDR is nonfluorescent under assay conditions, but fluoresces upon hydrolysis by beta-galactosidase. However, binding of the FDR by antiserum to the cross-reactive drug kanamycin prevents enzyme hydrolysis. The fixed level of FDR competes with dibekacin within the sample for the limiting number of antibody-binding sites in the reaction mixture. Unbound FDR is hydrolyzed by beta-galactosidase to release a fluorescent product that is proportional to the dibekacin concentration in the sample. The assay exhibits good precision, standard curve reproducibility, recovery, sensitivity, and correlation with a comparative method. Additionally, the substrate-labeled fluorescent immunoassay is rapid and easy to perform.