Cross-Reactivity and Tolerability of Ertapenem in Patients with Ige

Home , Bacampicillin, Cefprozil

ORIGINAL ARTICLE Cross-reactivity and Tolerability of Ertapenem in Patients With IgE-Mediated Hypersensitivity to β-Lactams Buonomo A*, Pascolini L*, Rizzi A, Aruanno A, Pecora V, Ricci AG, Mezzacappa S, Di Rienzo A, Centrone M, Nucera E, Schiavino D

Department of Allergy, Università Cattolica del Sacro Cuore, Rome, Italy *These authors contributed equally to the manuscript

J Investig Allergol Clin Immunol 2016; Vol. 26(2): 100-105 doi: 10.18176/jiaci.0019

Abstract Background and Objective: Administration of carbapenems to β-lactam-allergic patients has always been considered potentially harmful because of a 47.4% rate of cross-reactivity to imipenem reported in a single study. Nevertheless, recent studies have shown that the rate of cross-reactivity of imipenem and meropenem with penicillins is lower than 1%. The aim of this study was to evaluate the possibility of using ertapenem in patients with an established IgE-mediated β-lactam allergy. Patients and Methods: We studied all participants who came to our allergy unit and had a clinical history of immediate hypersensitivity reactions to β-lactams. The inclusion criteria were a positive skin test result to at least 1 β-lactam molecule and/or positive specific IgE (when available). All participants underwent immediate-type skin tests with several β-lactam molecules including ertapenem. Challenges with intravenous ertapenem were performed on 2 different days in patients with negative skin test results. Results: We examined 49 patients with a clinical history of immediate reactions to β-lactams. All the patients had positive skin tests and/or positive specific IgE to at least 1 β-lactam reagent and negative carbapenem skin tests. Thirty-six patients agreed to undergo the challenges and 35 tolerated the full dose of ertapenem. Conclusions: The practice of avoiding carbapenems in patients with β-lactam allergy should be abandoned considering the very low rate of cross-reactivity. β-Lactam-allergic patients who need ertapenem therapy should undergo skin tests and, if negative, a graded challenge to assess tolerability. Key words: β-lactams. IgE-mediated hypersensitivity. Ertapenem. Cross-reactivity.

Resumen Introducción y Objetivo: Siempre se ha considerado peligrosa la administración de carbapenems a pacientes alérgicos a betalactámicos por la presencia de reactividad cruzada en el 47,4% de los casos descrita en un estudio previo. Sin embargo, estudios recientes han mostrado que la reactividad cruzada de imipenem y meropenem con penicilinas es inferior al 1%. El objetivo de este estudio es valorar el uso de ertapenem en pacientes diagnosticado de alergia IgE mediada a betalactámicos. Pacientes y Métodos: Se incluyeron todos los pacientes que acudieron a nuestra unidad de Alergia con historia clínica de alergia inmediata a betalactámicos. Los criterios de inclusión fueron prueba cutánea positiva con al menos un betalactámico y/o IgE específica positiva (cuando estuviese disponible). Se realizaron pruebas cutáneas con betalactámicos, incluyendo ertapenem, con lectura inmediata en todos los pacientes. Se realizaron pruebas de provocación endovenosas con ertapenem en los pacientes con pruebas cutáneas negativas frente al mismo en dos días diferentes. Resultados: Se incluyeron 49 pacientes con historia clínica de alergia inmediata a betalactámicos. Todos los pacientes tenían pruebas cutáneas positivas y/o IgE específica positiva al menos a uno de los betalactámicos así como prueba cutánea negativa con carbapenémicos. Treinta y seis pacientes aceptaron la realización de pruebas de provocación con ertapenem que fueron tolerados por treinta y cinco de dichos pacientes. Conclusión: El hecho de recomendar evitar carbapenems en pacientes con alergia a betalactámicos debería ser abandonado, dada la baja reactividad cruzada que presentan. En los pacientes con alergia a betalactámicos que necesiten ertapenem se deberían realizar pruebas cutáneas con el fármaco y en caso de ser negativas, realizar un test de exposición progresiva para confirmar su tolerancia. Palabras clave: Betalactámicos. Hipersensibilidad mediada por IgE. Ertapenem. Reactividad cruzada.

Introduction case of negative results, the intradermal method. For the skin prick tests with drugs not available in parenteral form (ie, Ertapenem is a 1-beta-methyl-carbapenem that is stable to penicillin V, bacampicillin, cefaclor, and cephalexin) tablets dehydropeptidase and binds preferentially to penicillin-binding were smashed in a mortar and the powder was dissolved in proteins 2 and 3. It has a very broad spectrum of antibacterial saline. Histamine (10 mg/mL) and saline were employed as activity, including activity against gram-positive and gram- positive and negative controls, respectively. Skin tests and negative aerobic and anaerobic pathogens. However, in readings were performed as previously described [9,10]. contrast to imipenem and meropenem, ertapenem has limited in vitro activity against Pseudomonas and Acinetobacter In Vitro Tests species [1]. Administration of carbapenems to β-lactam-allergic Assays (UniCAP System, Phadia) were performed for patients has always been considered potentially harmful specific IgE to penicilloyl G, penicilloyl V, ampicilloyl, because of a single report of a 47.4% cross-reactivity rate amoxicilloyl, and cefaclor according to the manufacturer’s to imipenem [2]. Nevertheless, recent studies have shown instructions. A value of 0.35 kU/L or less was considered that the rate of cross-reactivity of imipenem and meropenem positive. Blood samples were taken at the first evaluation and with penicillins is lower than 1% in both adults [3,4] and sera were stored at -20°C until tested. children [5,6]. Furthermore, a recent study showed a lack of cross-reactivity and tolerability of both aztreonam and Ertapenem Test Dosing carbapenems (imipenem, meropenem, and ertapenem) in a Challenges with intravenous ertapenem were performed on group of penicillin-allergic patients [7]. Finally, tolerability 2 separate days in patients with negative skin test results. On of ertapenem in a group of 42 individuals who reported a the first day we administered an initial dose of one-hundredth clinical history of penicillin allergy was recently demonstrated, of the therapeutic dose (10 mg) followed 1 hour later by a dose although it should be noted that no allergy testing was of one-tenth of the therapeutic dose (100 mg) in patients with a performed in this case [8]. negative result. If the result was again negative, on the second The aim of this prospective study was to evaluate the day we administered a full therapeutic dose (1000 mg). During possibility of using ertapenem in patients with established the challenge, all the patients were strictly monitored, with IgE-mediated penicillin and/or cephalosporin allergy. measurement of peak expiratory flow rate, blood pressure, and heart rate at the start of the challenge and 1 hour afterwards. Ready-to-use emergency materials (epinephrine, external Methods defibrillator, oxygen, etc) were available and all the personnel Between March 2011 and April 2014, we studied all were skilled in treating anaphylaxis. patients with a clinical history of immediate hypersensitivity reactions to β-lactams seen at the allergy unit of the Università Cattolica del Sacro Cuore in Rome, Italy. The inclusion criteria Results were a positive skin test result to at least 1 β-lactam molecule We examined 49 patients (11 men and 39 women; median and/or positive specific IgE when available. The exclusion age of 48.1 years [range, 21-76 years]) with a clinical history of criteria were pregnancy, treatment with β-blockers, and the immediate reactions to β-lactams. Our work-up was performed presence of cardiovascular, renal, or respiratory disease. A at intervals ranging from 1 to 48 months (median, 10.8 months) clinical history of anaphylaxis was not an exclusion criterion. after the most recent reaction. None of the patients had any Written informed consent was obtained from all the exclusion criteria. participants (or from their parents in the case of patients The 49 patients experienced 60 immediate reactions, and younger than 18 years of age). The study was approved by amoxicillin (plus clavulanic acid) was the most common the local ethics committee (EUDRACT 2009-017828-54) and drug involved. Urticaria and anaphylaxis, as defined by the registered at www.clinicaltrials.gov (NCT 01159379). clinical criteria proposed by Sampson et al [11], were the most commonly reported symptoms (Table). Skin Tests Seven patients had a family history of IgE-mediated Immediate-type skin tests (prick and intradermal tests) allergic disease and 5 had a personal history of allergic were performed with penicilloyl polylysine (PPL), minor disease: IgE-mediated Hymenoptera venom allergy in 2 determinant mixture (MDM), and penicillin G at final cases, respiratory allergy in 2 cases, and shrimp allergy concentrations of 1.07 × 10-2 mmol/L, 1.5 mmol/L, and in 1 case. 10 000 IU/mL, respectively. Both PPL and MDM were All the individuals had positive skin tests and/or positive produced by Diater Laboratorios in Madrid, Spain. The specific IgE to at least 1 β-lactam reagent and negative skin maximum drug concentrations were 20 mg/mL for ampicillin, test results to carbapenem (imipenem-cilastatin, meropenem, amoxicillin, and piperacillin; 2 mg/mL for aztreonam; 1 mg/mL ertapenem) (Table). for imipenem-cilastatin, meropenem, and ertapenem; and Thirty-six patients agreed to undergo the challenges and 2 mg/mL for cefazolin, cefuroxime, ceftriaxone, and cefepime. 35 tolerated the full dose of ertapenem; patient #5 refused to Skin tests were carried out with the preparation for undergo the second part of the challenge and tolerated only parenteral use first using the prick method and second, in the 110 mg of ertapenem.

© 2016 Esmon Publicidad J Investig Allergol Clin Immunol 2016; Vol. 26(2): 100-105 doi: 10.18176/jiaci.0019 102 Buonomo A, et al. ------ND - ND ND - - + ------ND ND - ND ------ND ------CCL CCL - - - ND ND ND ND ND ND - - + - ND ND ND ND - ND ND ND ND - + ND + ND ND - - ND ND ND - - ND - - - ND ND ND ND ND ND ND - ND ND CFZ ND ND - b b - - ND - - - ND - + + - - + ------ND - - ND - - - ND ND - - - - - ND ND ------CLX - -

b ------+ - - - - + - + - - + - - - - ND ------CPM - ND ND ND - ND - - - - - + ND ND - ND + - ND ND - + ND - - - ND - - ND ND ND - ND ND ND ND ND - ND ND - - ND - - - ND ND CFU ------Me ------I -

- - T T T T T T T T - T T T T - T T T T T - T T T T T - - T - T T T T T T - - T T - T T* T T - - T E

b - - - - - + - - - - + - - - - + - + - + + ------+ - - CTX - - - - - + + + + + + - + + ------+ - - - + ------+ - - - - + - + Tests Skin PI - + + - + + + + + + - + + + + - + - + ------+ + + + + + - + + + + + - - + + + - + + - + + + AX + + + - + + + + + + - + + + + - + ------+ + - - + - - - + + + + - - + + + - + + + + + + AM

+ - + - + + - + - + - - + + - - + ------+ + - - + ------+ ------+ BP ------+ ------+ ------+ ------MDM

------+ - - - - + ------+ ------+ - - + - + - PPL

ND ND ND ND 0.05 ND ND ND 0.06 0.47 ND ND ND ND 0.11 0.07 ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND 0.18 ND 2.68 0.26 ND ND CCL

0.15 1.15 4.39 0.65 0.10 0.02 N.D. 0.95 1.24 1.78 0.07 2.06 0.07 0.04 0.06 0.03 0.10 0.00 0.12 0.04 0.00 0.16 3.00 0.01 0.34 0.07 0.04 0.03 0.06 7.89 0.02 2.68 0.04 0.00 0.91 0.06 0.01 0.53 0.16 0.12 0.03 0.01 7.24 0.20 0.01 0.42 4.36 2.33 0.30 Axy 3.75 2.69 7.70 0.38 0.16 0.05 N.D. 2.66 0.21 7.71 0.34 0.57 4.54 0.12 0.13 0.11 0.14 0.02 0.15 0.05 0.02 0.18 2.20 0.03 1.16 0.15 0.08 0.04 0.15 4.07 0.04 3.05 0.09 0.04 0.05 0.05 0.03 0.77 0.84 0.04 0.05 0.02 22.1 0.24 0.09 4.62 0.34 2.12 0.91 Amy

7.93 0.14 8.69 0.73 0.12 0.02 N.D. 28.2 0.08 5.35 0.49 0.72 6.88 0.04 0.04 0.10 0.07 0.00 0.33 0.01 0.01 0.15 2.91 0.01 2.58 0.37 0.05 0.02 0.18 5.67 0.10 4.63 0.04 0.01 0.03 0.03 0.01 1.63 0.65 0.01 0.03 0.01 19.9 0.08 0.01 5.22 0.35 2.40 1.04 Specific IgE, kU/L PV 4.37 0.71 8.35 0.19 0.09 0.01 N.D. 33.7 0.03 3.04 0.05 0.38 11.3 0.02 0.01 0.04 0.05 0.00 0.36 0.00 0.00 0.09 0.58 0.01 3.87 0.15 0.02 0.01 0.01 2.69 0.02 4.44 0.01 0.03 0.00 0.01 0.01 0.32 0.12 0.01 0.01 0.01 15.9 0.07 0.01 6.18 0.09 2.36 1.15 PG

U AS AS B U/AS AS U/A U UA UA U/U AS AS AS U AS B/U UA AS UA U AS UA UA A AS U/UA U/AS AS AS U UA UA/UA U U UA A AS U U AS AS AS UA AS/AS AS U AS A Reaction Involved AXC AXC AXC AXC AXC/ AXC AX AXC/ AXC CTX/ AX AXC/ AXC AX/ AX CPZ AM/ CTX AM CLX PI CTX AXC/ AXC CTX CTX CTX AX CFZ AM AX AX CFZ AX/ AX/ AM AXC AXC AXC AXC AXC AXC/ AX AX AXC AX AXC AXC AXC AXC AX AM AXC AXC AXC/ CCL AX AXC AXC AXC Drug

42 50 67 52 65 54 53 76 37 70 21 47 48 53 39 48 48 70 47 31 45 35 54 48 63 38 70 31 31 64 40 42 58 50 23 47 53 32 33 44 48 36 44 26 67 55 58 43 60 Age, y F F F F F F F M F M M F M F F F F F F F F F M M F F F M F F F F F F M M F F F F F F F F M F F M F Sex

26 25 24 23 22 46 21 45 44 19 20 43 18 42 17 41 16 39 40 38 15 37 12 13 14 36 35 11 34 10 33 4 8 9 32 31 3 7 30 2 6 48 29 28 1 5 49 47 27 Patient

Characteristics of Patients and Skin Test Results Test and Skin of Patients Characteristics Table.

J Investig Allergol Clin Immunol 2016; Vol. 26(2): 100-105 © 2016 Esmon Publicidad doi: 10.18176/jiaci.0019 Ertapenem and β-Lactam Cross-reactivity 103 ------ND - ND ND - - + ------ND ND - ND ------ND ------CCL CCL CCL - - - ND ND ND ND ND ND - - + - ND ND ND ND - ND ND ND ND - + ND + ND ND - - ND ND ND - - ND - - - ND ND ND ND ND ND ND - ND ND CFZ CFZ ND ND - b b - - ND - - - ND - + + - - + ------ND - - ND - - - ND ND - - - - - ND ND ------CLX CLX - -

b ------+ - - - - + - + - - + - - - - ND ------CPM CPM - ND ND ND - ND - - - - - + ND ND - ND + - ND ND - + ND - - - ND - - ND ND ND - ND ND ND ND ND - ND ND - - ND - - - ND ND CFU CFU ------Me Me ------I I - a a

- - T T T T T T T T - T T T T - T T T T T - T T T T T - - T - T T T T T T - - T T - T T* T T - - E T E

b - - - - - + - - - - + - - - - + - + - + + ------+ - - CTX CTX - - - - - + + + + + + - + + ------+ - - - + ------+ - - - - + - + Tests Skin PI Tests Skin PI - + + - + + + + + + - + + + + - + - + ------+ + + + + + - + + + + + - - + + + - + + - + + + AX AX + + + - + + + + + + - + + + + - + ------+ + - - + - - - + + + + - - + + + - + + + + + + AM AM

+ - + - + + - + - + - - + + - - + ------+ + - - + ------+ ------+ BP BP ------+ ------+ ------+ ------MDM MDM

------+ - - - - + ------+ ------+ - - + - + - PPL PPL

ND ND ND ND 0.05 ND ND ND 0.06 0.47 ND ND ND ND 0.11 0.07 ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND 0.18 ND 2.68 0.26 ND ND CCL CCL

0.15 1.15 4.39 0.65 0.10 0.02 N.D. 0.95 1.24 1.78 0.07 2.06 0.07 0.04 0.06 0.03 0.10 0.00 0.12 0.04 0.00 0.16 3.00 0.01 0.34 0.07 0.04 0.03 0.06 7.89 0.02 2.68 0.04 0.00 0.91 0.06 0.01 0.53 0.16 0.12 0.03 0.01 7.24 0.20 0.01 0.42 4.36 2.33 0.30 Axy Axy 3.75 2.69 7.70 0.38 0.16 0.05 N.D. 2.66 0.21 7.71 0.34 0.57 4.54 0.12 0.13 0.11 0.14 0.02 0.15 0.05 0.02 0.18 2.20 0.03 1.16 0.15 0.08 0.04 0.15 4.07 0.04 3.05 0.09 0.04 0.05 0.05 0.03 0.77 0.84 0.04 0.05 0.02 22.1 0.24 0.09 4.62 0.34 2.12 0.91 Amy Amy

7.93 0.14 8.69 0.73 0.12 0.02 N.D. 28.2 0.08 5.35 0.49 0.72 6.88 0.04 0.04 0.10 0.07 0.00 0.33 0.01 0.01 0.15 2.91 0.01 2.58 0.37 0.05 0.02 0.18 5.67 0.10 4.63 0.04 0.01 0.03 0.03 0.01 1.63 0.65 0.01 0.03 0.01 19.9 0.08 0.01 5.22 0.35 2.40 1.04 Specific IgE, kU/L PV Specific IgE, kU/L PV 4.37 0.71 8.35 0.19 0.09 0.01 N.D. 33.7 0.03 3.04 0.05 0.38 11.3 0.02 0.01 0.04 0.05 0.00 0.36 0.00 0.00 0.09 0.58 0.01 3.87 0.15 0.02 0.01 0.01 2.69 0.02 4.44 0.01 0.03 0.00 0.01 0.01 0.32 0.12 0.01 0.01 0.01 15.9 0.07 0.01 6.18 0.09 2.36 1.15 PG PG

U AS AS B U/AS AS U/A U UA UA U/U AS AS AS U AS B/U UA AS UA U AS UA UA A AS U/UA U/AS AS AS U UA UA/UA U U UA A AS U U AS AS AS UA AS/AS AS U AS A Involved Reaction Reaction Involved AXC AXC AXC AXC AXC/ AXC AX AXC/ AXC CTX/ AX AXC/ AXC AX/ AX CPZ AM/ CTX AM CLX PI CTX AXC/ AXC CTX CTX CTX AX CFZ AM AX AX CFZ AX/ AX/ AM AXC AXC AXC AXC AXC AXC/ AX AX AXC AX AXC AXC AXC AXC AX AM AXC AXC AXC/ CCL AX AXC AXC AXC

Drug Drug

42 50 67 52 65 54 53 76 37 70 21 47 48 53 39 48 48 70 47 31 45 35 54 48 63 38 70 31 31 64 40 42 58 50 23 47 53 32 33 44 48 36 44 26 67 55 58 43 60 y Age, Age, y F F F F F F F M F M M F M F F F F F F F F F M M F F F M F F F F F F M M F F F F F F F F M F F M F Sex Sex

These patients had a positive challenge despite skin tests. These T indicates patients who underwent an ertapenem challenge; the patient who tolerated 110 mg of intravenous ertapenem and refused to undergo a second challenge on day 2 is indicated with an 110 mg of intravenous the patient who tolerated T indicates patients who underwent an ertapenem challenge; 26 25 24 23 22 46 21 45 44 19 20 43 18 42 17 41 16 39 40 38 15 37 12 13 14 36 35 11 34 10 33 4 8 9 32 31 3 7 30 2 6 48 29 28 1 5 49 47

Patient 27 Patient

Abbreviations: A, angioedema; AM, ampicillin; Amy, ampicilloyl; AS, anaphylaxis; AX, amoxicillin; Axy, amoxicilloyl; B, bronchospasm; BP, benzylpenicillin; CCL, cefaclor; CFU, cefuroxime; CFZ, cefazolin; cefazolin; CFZ, cefuroxime; CFU, cefaclor; CCL, benzylpenicillin; BP, bronchospasm; B, amoxicilloyl; Axy, amoxicillin; AX, anaphylaxis; AS, ampicilloyl; Amy, ampicillin; AM, angioedema; A, Abbreviations: G; Penicilloyl PG, piperacillin; PI, minor determinant mixture; MDM, meropenem; Me, male; M, female; F, ertapenem; E, imipenem; I, ceftriaxone; CTX, cefprozil; CPZ, cefepime; CPM, cephalexin; CLX, urticaria and angioedema. UA, urticaria; U, V; penicilloyl PV, penicilloyl-polylysine; PPL, a b Characteristics of Patients and Skin Test Results Test and Skin of Patients Characteristics Table. asterisk.

In the absence of in vitro studies to define the antigenic an aminothiazole side chain. Patients #42 to #49 had positive determinants, we divided the patients into 4 groups (Table): skin tests to both penicillin and cephalosporin determinants, a) Group 1: patients #1 to #8. These had selective but did not show cross-reactions with carbapenems. aminopenicillin allergy and some degree of cross- In conclusion, our data indicate a lack of cross-reactivity reactivity with aminocephalosporins (patient #1 reacted between ertapenem and β-lactams, irrespective of the cross- to cefaclor and patient #4 reacted to a challenge with reactivity pattern. Intradermal testing represents a simple cephalexin); yet reliable diagnostic tool with a high negative predictive b) Group 2: patients #9 to #35. These reacted to selective value. The practice of avoiding carbapenems (and ertapenem) penicillin determinants but showed no cross-reactivity in patients with β-lactam allergy should be abandoned, with cephalosporins; considering the very low rate of cross-reactivity. A graded c) Group 3: patients #36 to #41. These reacted only to challenge, which is a time-consuming procedure, may also be selective cephalosporin determinants; omitted, since several studies have shown the good negative d) Group 4: patients #42 to #49. These reacted to both predictive value of skin tests with carbapenems in a large group penicillins and cephalosporins. of penicillin-allergic patients [3-7]. The main limitation of our study is that challenges were not followed by a full therapeutic course. Some authors have proposed prolonged challenges for Discussion assessing β-lactam tolerability [17], but this may be helpful for delayed rather than immediate reactions. Our patients Our study confirms the lack of cross-reactivity between all had a confirmed diagnosis of IgE-mediated allergy to a penicillins and cephalosporins and ertapenem in a group of β-lactam moiety and we think a 1-day challenge is sufficient patients with demonstrated IgE-mediated hypersensitivity for assessing tolerability. However, since we do not know the to β-lactams. Previous studies have found a cross-reactivity sensitizing power of ertapenem in β-lactam-allergic patients rate of 7% to 9% among patients who claimed to be allergic after a therapeutic course, ertapenem retesting is recommended to penicillins [11-13]. Cunha et al [8], in turn, found no to exclude sensitization before any new treatment. cross-reactivity between ertapenem and penicillins, either in patients with anaphylactic reactions (urticaria, angioedema) Funding or in those with nonanaphylactic reactions (rash, pruritus, unknown). However, the patients in that study did not undergo The authors received an unrestrictive grant from Merck allergy testing. The main limitation of the above studies was Sharp & Dohme. that patients did not undergo any allergy evaluation, as it has been clearly demonstrated that as many as 80% to 90% of all Conflicts of Interest patients who claim to be allergic to penicillin are not [14]. For The authors declare that they have no conflicts of interest. these reasons, our study is similar to more recent studies of imipenem and meropenem [3,4,7], although we also included Previous Presentation patients with cephalosporin allergy. Saxon et al [2] observed cross-reactivity to imipenem Part of the data were presented as an oral presentation and in 19 of 40 patients with penicillin allergy. The difference abstract at the 2014 XXXIII European Academy of Allergy and between this rate of 47.5% and rates reported by more recent Clinical Immunnology Congress. studies may be explained by the fact that all the patients in the study by Saxon et al reacted to benzylpenicillin; this drug is no longer used in southern Europe, explaining why most References recently reported allergic reactions are due to aminopenicillins and cephalosporins. 1. Shah PM, Isaacs RD. Ertapenem, the first of a new group of The lack of cross-reactivity between penicillins and carbapenems. J Antimicrob Chemother. 2003;52:538-42. ertapenem, imipenem, and meropenem could be explained 2. Saxon A, Adelman DC, Patel A, Hajdu R, Calandra GB. by the fact that IgE antibodies recognize specific penicillin Imipenem cross-reactivity with penicillins in humans. J Allergy determinants, such as the thiazolidine ring and side chains, Clin Immunol. 1988;82:213-7. rather than the β-lactam ring which is shared by penicillins, 3. Romano A, Viola M, Guéant-Rodriguez RM, Gaeta F, cephalosporins, and carbapenems (patients #1 to #35). Pettinato R, Guéant JL. Imipenem in patients with immediate As regards the antigenicity of cephalosporins, both the R1 hypersensitivity to penicillins. N Engl J Med. 2006;354:2835-7. and the R2 side chains may be involved in the configuration of 4. Romano A, Viola M, Guéant-Rodriguez RM, Gaeta F, Valluzzi different epitopes. Once the β-lactam ring has been opened by R, Guéant JL. Tolerability of meropenem in patients with IgE- the amino group of the carrier, the R2 side chain disappears, mediated hypersensitivity to penicillins. Ann Intern Med. 2007 resulting in heterogeneous fragmentation of the cephalosporin. 146:266-9. The resulting epitope is therefore formed by the remaining 5. Atanasković-Marković M, Gaeta F, Medjo B, Viola M, β-lactam and the R1 side chain [15]. Nestorović B, Romano A. Tolerability of meropenem in Patients #36 to #41 had a selective response to children with IgE-mediated hypersensitivity to penicillins. cephalosporins. In these cases, the main antigenic epitope Allergy. 2008;63:237-40. appears to be the R1 side chain of these molecules; cefazolin, for 6. Atanasković-Marković M, Gaeta F, Gavrović-Jankulović M, example, has a single R1 side chain [16], while ceftriaxone has Čirković Veličković T, Valluzzi RM, Romano A. Tolerability of

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