Cristiano Caruso

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.

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.

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.

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.

Absence of cross-reactivity to carbapenems in patients with delayed hypersensitivity to penicillins

Studies performed on subjects with IgE‐mediated hypersensitivity to penicillins have demonstrated a 1% rate of cross‐reactivity between penicillins and both imipenem and meropenem, while a single study found a 5.5% rate of cross‐reactivity with imipenem/cilastatin in subjects with T‐cell‐mediated hypersensitivity to β‐lactams, mostly penicillins. We studied 204 consecutive subjects with a well‐demonstrated T‐cell‐mediated hypersensitivity to assess the cross‐reactivity with carbapenems and the tolerability of such alternative β‐lactams. All 204 subjects underwent skin tests with imipenem/cilastatin and meropenem; 130 of them were skin‐tested also with ertapenem. Subjects with negative test results were challenged with these carbapenems. All subjects displayed negative skin tests to carbapenems and tolerated challenges. These data demonstrate the absence of clinically significant T‐cell‐mediated cross‐reactivity between penicillins and carbapenems. Negative delayed‐reading skin testing with carbapenems in individuals with documented T‐cell‐mediated hypersensitivity to penicillins correlates well with subsequent clinical tolerance of therapeutic doses of carbapenems.

Celecoxib Tolerability in Patients with Hypersensitivity (Mainly Cutaneous Reactions) to Nonsteroidal Anti-Inflammatory Drugs

Background: Adverse reactions to nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly observed in clinical practice, particularly among patients with chronic urticaria or asthma. The identification of a safe and reliable alternative is a frequent problem for both general practitioners and allergists. Methods: We assessed 120 patients (83 women and 37 men) who had experienced adverse reactions to one or more NSAIDs; 64 (53.3%) of them had reacted to only one NSAID (single reactors) and 56 (46.7%) to multiple NSAIDs (multiple reactors). Among our subjects, 76.7% reported cutaneous reactions, 8.3% respiratory symptoms, 10.8% both cutaneous and respiratory symptoms, and 4.2% anaphylaxis. All patients were subjected to a single-blind, placebo-controlled oral challenge with two different doses of celecoxib (50 + 150 mg 1 h later = cumulative dose of 200 mg). Results: None of the patients reacted to the placebo and only one (0.8%) suffered a reaction (urticaria) after the second dose of celecoxib. Conclusions: Celecoxib showed a 98.9% rate of tolerability in the 92 patients with exclusively cutaneous reactions and was well tolerated by all 28 subjects with NSAID-related respiratory or anaphylactic symptoms.

Omalizumab efficacy in a girl with atopic eczema.

Atopic eczema (AE) is a chronic, relapsing form of skin inflammation characterized by a disturbance of the epidermalbarrier function, which culminates in dry skin, as well as by an IgEmediated sensitization to food and environmental allergens (1). Elevated levels of serum IgE to environmental allergens are generally found in about 80% of patients with AE (2). Atopic eczema often precedes the occurrence of food allergy, allergic rhinitis, and asthma. In the last few years, a number of studies have shown the efficacy of omalizumab in the treatment of AE either in monotherapy (3) or in combination with other therapies (e.g., topical steroids, tacrolimus, antihistamines, antileukotrienes, oral corticosteroids, and UV treatment) (4–7). In the aforementioned studies (4–7), some patients suffered only from AE (3, 5), while the great majority also suffered from asthma (4, 6, 7). Omalizumab, (Xolair; Novartis, Nürnberg, Germany) a recombinant humanized IgG1 monoclonal antibody is derived from the murine antibody MAE11. It specifically binds to the high-affinity FceRI domain of free circulating IgE, and thus prevents binding of free serum IgE to mast cells and other effector cells. We present the case of a 15-year-old girl with severe AE, according to the criteria of Hanifin and Rajka (8), as well as with rhinoconjunctivitis and asthma due to sensitization to parietaria judaica, birch, and hazel [a FEV1 and a peak expiratory flow (PEF) lower than 70% of the predicted value]. At the time of the first evaluation, she was under treatment with budesonide/formoterol (100/6 lg twice daily), montelukast (10 mg daily), and desloratadine (5 mg daily). Our patient had a 6-year-long history of severe generalized AE, treated with a standard therapy (topical corticosteroids, topical pimecrolimus, systemic corticosteroids, UV treatment, and oral antihistamines), without long-lasting and satisfactory relief from symptoms. The patient had also been treated with cyclosporine A, with a good clinical response. However, this therapy was withdrawn because of an increase in blood creatinine levels (from 0.8 to 1.9 g/l). Taking into account the literature data (4–6), and her total IgE, we decided to treat our patient with 300 mg of omalizumab subcutaneously for a month. The therapeutic protocol was approved by the institutional review board. To evaluate the clinical efficacy of omalizumab therapy, we monitored the eczema area and severity index (EASI) (9), as well as the Scoring Atopic Dermatitis (SCORAD) (4), at each visit; moreover, a detailed photo documentation was taken. In addition, we monitored total and allergen-specific IgE serum levels, as well as inflammatory cells and cytokine expression in the peripheral blood before and after therapy (Table 1). The patient tolerated the eight omalizumab doses we administered. In the first evaluation, the SCORAD was 55. After 2 months of therapy, the patient displayed a very good clinical response (SCORAD reduction of more than 50%), and after 5 months she showed a significant total SCORAD decrease of about 80% (Table 1). The EASI evaluation demonstrated reasonably good overall reliability (EASI score at baseline was 44, after 5 months of therapy it was eight). Five months after the start-up of the therapy, total and allergen-specific IgE serum levels showed no reduction, while the CD4/ CD8 antibodies ratio was lower (Table 1). The patient also experienced good relief of rhinoconjunctivitis and asthma symptoms (a FEV1 and a PEF of about 90%). We should emphasize that our patient experienced much improvement (1) in monotherapy, (2) with low-dose anti-IgE therapy, and (3) from the very beginning of the treatment. It is interesting to note that the patients with AE described in the study by Forman et al. (3), who successfully responded to omalizumab, had actually been treated during the first Success of omalizumab as monotherapy in a young girl with severe atopic eczema.