Rocco Luigi Valluzzi

IgE-mediated hypersensitivity to cephalosporins: Cross-reactivity and tolerability of penicillins, monobactams, and carbapenems

BACKGROUND There have been few studies regarding the cross-reactivity and tolerability of penicillins, aztreonam, and carbapenems in large samples of subjects with cephalosporin allergy. OBJECTIVE We sought to evaluate the possibility of using penicillins, monobactams, and carbapenems in subjects with cephalosporin allergy who especially require them. METHODS We conducted a prospective study of 98 consecutive subjects who had 106 immediate reactions (mostly anaphylactic shock) to cephalosporins and had positive skin test results for these drugs. To assess the cross-reactivity with penicillins, monobactams, and carbapenems and the tolerability of such alternative β-lactams, all subjects underwent skin tests and serum-specific IgE assays with penicillin reagents, as well as skin tests with aztreonam, imipenem/cilastatin, and meropenem. Subjects with negative test results were challenged with meropenem, imipenem/cilastatin, aztreonam, and amoxicillin. RESULTS Positive allergologic test results to penicillins were displayed by 25 (25.5%) subjects, including 1 with positive results to all reagents tested and another with a positive result to aztreonam. Another subject had positive results to both ceftazidime and aztreonam. A reaction to cephalosporins with side-chain structures similar or identical to those of penicillins was a significant predictor of cross-reactivity because of an increased 3-fold risk of positive results on allergologic tests with penicillin determinants. Challenges with alternative β-lactams were tolerated, with the exception of 1 urticarial reaction to imipenem/cilastatin. CONCLUSIONS About 25% of subjects with cephalosporin allergy had positive results to penicillins, 3.1% to aztreonam, 2% to imipenem/cilastatin, and 1% to meropenem. In those who especially require alternative β-lactams, pretreatment skin tests are advisable because negative results indicate tolerability of the β-lactam concerned.

Diagnosing Hypersensitivity Reactions to Cephalosporins in Children

OBJECTIVES. The goals were to evaluate the usefulness of skin tests, patch tests, serum specific IgE assays, and challenges in diagnosing hypersensitivity reactions to cephalosporins and to clarify the pathogenic mechanism of such reactions. METHODS. Children with immediate manifestations (within 1 hour) underwent immediate-reading skin tests with penicillin reagents and any suspect cephalosporins, serum specific IgE assays, and challenges; some children underwent reevaluations. Children with nonimmediate manifestations (after >1 hour) were assessed with patch tests, delayed-reading skin tests, and challenges. RESULTS. We evaluated 148 children with hypersensitivity reactions to cephalosporins, mainly cefaclor and ceftriaxone; 105 had experienced nonimmediate manifestations (mostly urticarial eruptions and maculopapular rashes) and 43 immediate manifestations (anaphylactic shock, urticaria and/or angioedema, and erythema). None of the nonimmediate reactors demonstrated positive results in patch tests and/or delayed skin tests; only 1 subject displayed immediate positive responses to penicillin skin-test reagents. Among the 104 patients with negative results, 96 underwent challenges; 95 tolerated the challenges, and 1 reacted to the cefaclor pediatric suspension and tolerated the challenge with a cefaclor capsule. In the first allergologic evaluation, 33 of the 43 children with immediate reactions displayed skin-test positivity. Of the 10 patients with negative results, 7 underwent challenges, followed by therapeutic courses and reevaluations for 4. All challenges and therapeutic courses were tolerated; in the reevaluation, 1 girl demonstrated positive skin-test results for both the responsible cephalosporin and penicillin reagents. Overall, IgE-mediated hypersensitivity was diagnosed for 34 (79%) of 43 subjects. CONCLUSIONS. Extremely few nonimmediate manifestations associated with cephalosporin therapy are actually hypersensitivity reactions, whereas most immediate reactions to cephalosporins are IgE-mediated. Cephalosporin skin testing is a useful tool for evaluating such reactions.

A comparison of the performance of two penicillin reagent kits in the diagnosis of beta-lactam hypersensitivity

Background:  Skin testing with penicilloyl polylysine (PPL) and minor determinant mixture (MDM) represents the first‐line method for diagnosing β‐lactam hypersensitivity. However, in 2004, Allergopharma and Hollister‐Stier announced their decision to stop the production of penicillin reagents (Allergopen® and PrePen®, respectively) within 1 year. Therefore, we decided to compare PPL and MDM from Allergopharma (Allergopen) with those from Diater (DAP®).

Assessing potential determinants of positive provocation tests in subjects with NSAID hypersensitivity

Background Provocation tests (PTs) with the suspected compounds are considered the ‘gold standard’ for establishing or excluding a diagnosis of hypersensitivity to non‐steroidal anti‐inflammatory drugs (NSAIDs). However, only a few studies have evaluated the potential determinants of positive responses to PTs.

Hypersensitivity to aromatic anticonvulsants : In vivo and in vitro cross-reactivity studies

Aromatic antiepileptic drugs (phenytoin, carbamazepine, oxcarbazepine, and phenobarbital) are frequently associated with cutaneous eruptions. A cell-mediated pathogenic mechanism has been demonstrated in most of such reactions on the basis of positive responses to patch tests and/or lymphocyte transformation tests. Therefore, such tests are useful tools for evaluating anticonvulsant hypersensitivity reactions. Moreover, an in vitro lymphocyte toxicity assay, which exposes the patients lymphocytes to arene oxides, has detected lymphocyte susceptibility to toxic metabolites in a large percentage of patients with hypersensitivity reactions to aromatic anticonvulsants. Although several hypersensitivity reactions to sequential exposure to more than one aromatic anticonvulsant (i.e., clinical cross-reactivity) have been reported, there are few studies performed with patch tests and/or lymphocyte transformation tests assessing immunologic cross-reactivity, and their data are contradictory. In any case, considering studies performed in samples of at least 10 patients, the immunologic cross-reactivity rate among aromatic anticonvulsants appears to be low. On the other hand, the reported rate of the toxic cross-reactivity (i.e., assessed by lymphocyte toxicity assays) is high. Further in vivo and in vitro studies in large samples of subjects are needed to evaluate cross-reactivity among aromatic anticonvulsants.

Etoricoxib Tolerability in Patients with Hypersensitivity to Nonsteroidal Anti-Inflammatory Drugs

Background: Adverse reactions to nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly observed, particularly among patients with chronic urticaria or asthma. The identification of a safe and reliable alternative is a frequent problem in clinical practice. Our aim was to investigate the clinical tolerability of etoricoxib, a new selective cyclooxygenase-2 inhibitor, in a group of patients with well-established NSAID hypersensitivity. Methods: We assessed 31 adults (21 women and 10 men) who reported one or more adverse reactions to NSAIDs, manifested as cutaneous, respiratory or anaphylactic symptoms. Sixteen of them reported reactions to a single NSAID (single reactors) and 15 to more than one NSAID (multiple reactors); the most frequently involved drug was acetylsalicylic acid. First, each patient underwent allergologic tests (skin and/or oral challenge tests) with culprit NSAIDs and then tolerability tests with increasing doses of etoricoxib up to 120 mg. All challenges were performed under single-blind, placebo-controlled conditions. Results: NSAID hypersensitivity was diagnosed in all 31 patients: 3 displayed positive results to pyrazolone skin tests and the other 28 to challenges with culprit NSAIDs. None reacted to either placebos or etoricoxib. Conclusions: Etoricoxib seems to be a safe alternative for patients with well-demonstrated NSAID hypersensitivity.

Tolerability of aztreonam and carbapenems in patients with IgE-mediated hypersensitivity to penicillins

BACKGROUND Studies performed on samples larger than 100 subjects with a documented IgE-mediated hypersensitivity to penicillins have demonstrated a cross-reactivity rate of approximately 1% between penicillins and both imipenem and meropenem, whereas a single study found a cross-reactivity rate of 6.2% with aztreonam in 16 such subjects. OBJECTIVE To assess the cross-reactivity and tolerability of aztreonam and 3 carbapenems (imipenem-cilastatin, meropenem, and ertapenem) in patients with documented IgE-mediated hypersensitivity to penicillins. METHODS A total of 212 consecutive subjects with immediate reactions to penicillins and positive results on skin tests to at least 1 penicillin reagent underwent skin tests with aztreonam and carbapenems; subjects with negative results were challenged with escalating doses of aztreonam and carbapenems. RESULTS All subjects displayed negative skin test results to both aztreonam and carbapenems; 211 accepted challenges and tolerated them. Challenges were not followed by full therapeutic courses. CONCLUSIONS These data indicate the tolerability of both aztreonam and carbapenems in penicillin-allergic subjects. In those who especially require these alternative β-lactams, however, we recommend pretreatment skin tests, both because rare cases of cross-reactivity have been reported and because negative results indicate tolerability.

IgE-Mediated Hypersensitivity to Cephalosporins

Like penicillins, cephalosporins may cause IgE-mediated reactions such as urticaria, angioedema, and anaphylactic shock, which occur because of sensitization to determinants shared with penicillins or to unique cephalosporin haptens. In particular, side-chain structures may be responsible for selective sensitization or cross-reactivity. For this reason, individual free cephalosporins are usually employed in skin testing, in addition to the classic penicillin reagents. Cephalosporin skin tests are sensitive in diagnosing immediate hypersensitivity to these betalactams. As far as in vitro tests are concerned, IgE assays for cephalosporins, specifically sepharose-radioimmunoassays, are a potentially useful tool in evaluating immediate reactions and could be used as complementary tests. In selected cases displaying negative results in both skin tests and IgE assays, a graded challenge with the implicated cephalosporin can be performed. Cephalosporin IgE-mediated hypersensitivity may be a transient condition; therefore, allergologic exams should be repeated in patients with negative initial allergologic work-ups, including challenges. Performing allergologic tests with cephalosporins other than the culprit, as well as with penicillin reagents, allows the identification of cross-reactivity with penicillins, selective responses, or cross-reactivity among cephalosporins. In the latter group, cross-reactivity is more frequently related to R1 than to R2 side-chain recognition. In assessing the selectivity of the response, negative results in skin testing with cephalosporins other than the responsible one appear to be a reliable indicator of tolerability.

Natural evolution of skin-test sensitivity in patients with IgE-mediated hypersensitivity to cephalosporins

There are studies demonstrating that skin‐test sensitivity to penicillins can decrease over time and that allergic patients may lose sensitivity if the responsible compounds are avoided. With regard to subjects with IgE‐mediated hypersensitivity to cephalosporins, however, such studies are lacking. We evaluated prospectively in a 5‐year follow‐up 72 cephalosporin‐allergic patients. After the first evaluation, patients were classified into two groups according to their patterns of allergologic‐test positivity: to both penicillins and cephalosporins (group A), or only to cephalosporins (group B). Skin tests and serum‐specific IgE assays were repeated 1 year later and, in case of persistent positivity, 3 and 5 years after the first allergologic examination. Seven (43.7%) of the 16 subjects of group A and 38 (67.8%) of the 56 patients of group B became negative; one was lost to follow‐up. Patients of group B became negative sooner and more frequently than group A subjects.

The very limited usefulness of skin testing with penicilloyl‐polylysine and the minor determinant mixture in evaluating nonimmediate reactions to penicillins

To cite this article: Romano A, Gaeta F, Valluzzi RL, Caruso C, Rumi G, Bousquet PJ. The very limited usefulness of skin testing with penicilloyl‐polylysine and the minor determinant mixture in evaluating nonimmediate reactions to penicillins. Allergy 2010; 65: 1104–1107.