Cross-reactivity and tolerability of Ertapenem in patients with IgE-mediated hypersensitivy to Beta-lactams

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 (AU)

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 (AU)

Cross-reactivity and tolerability of imipenem in patients with delayed-type, cell-mediated hypersensitivity to beta-lactams.

BACKGROUND: Administration of imipenem-cilastatin to patients with IgE-mediated hypersensitivity to beta-lactams has always been considered potentially harmful. Recent studies have demonstrated the tolerability of carbapenems (imipenem-cilastatin and meropenem) in patients with IgE-mediated hypersensitivity to beta-lactams; there are no studies on this topic regarding patients with cell-mediated allergy to beta-lactams. The aim of this study is to assess cross-reactivity and tolerability of imipenem in patients with cell-mediated allergy to beta-lactams. METHODS: From our database we selected 73 patients with cell-mediated allergy to beta-lactams, diagnosed by means of immediate-type skin tests, delayed reading intradermal tests, patch tests and detection of specific IgE. Patients with negative patch tests with imipenem-cilastatin underwent an intramuscular test dosing. RESULTS: Our patients had a total of 94 nonimmediate reactions to penicillins. All patients had positive patch tests and/or delayed reading intradermal tests for at least one of the penicillin reagent tested and negative immediate-type skin tests and specific IgE. Four patients out of 73 had a positive patch tests to at least one penicillin reagent and imipenem-cilastatin showing cross-reactivity. Sixty-four patients underwent the imipenem-cilastatin intramuscular test dosing and none of them had a clinical reaction. CONCLUSIONS: Our rate of cross-reactivity between imipenem-cilastatin and other beta-lactams was 5.5%. This result is different from previous findings and this may be explained by the fact that we investigated patients with cell-mediated allergy to beta-lactams. Patients with cell-mediated allergy to beta-lactams should undergo patch tests and a tolerance challenge test before treatment with imipenem-cilastatin.

Immune response in patients with intra-abdominal infections treated with carbapenems.

The immune responses against isolated microorganisms in patients with intraabdominal infections treated with meropenem or imipenem/cilastatin were investigated. Fifty-nine patients received meropenem 500 mg t.i.d. intravenously for 3-21 days (mean 5.4 days) and 50 patients imipenem/cilastatin 500 mg/500 mg t.i.d. intravenously for 3-17 days (mean 5.1 days). Three serum samples were taken from each patient, the first sample at admission, the second sample between three and seven days after start of antibiotic treatment, and the third sample between 14 and 28 days later. Ninety-eight per cent of the patients in the meropenem group and 95% of the patients in the imipenem/cilastatin group were cured. There was no difference in the clinical outcome between the two treatment groups. Escherichia coli, Bacteroides fragilis group, anaerobic cocci, Staphylococcus epidermidis, and Klebsiella spp. predominated among the isolated microorganisms. Thirty-nine patients in the meropenem group had significant immune responses against one or more of the isolated microorganisms while 31 patients in the imipenem/group had significant responses. E. coli and B. fragilis gave rise in antibody titres in most patients indicating that these species are the most important pathogens in intraabdominal infections.

Comparison of cross-reactivities of imipenem and other beta-lactam antibiotics by delayed-type hypersensitivity reaction in guinea pigs.

The cross-reactivity of imipenem (IPM) in a delayed-type hypersensitivity (DTH) reaction was investigated by intradermal skin reaction, macrophage migration inhibition tests (MIT) and lymphocyte stimulation tests (LST) in guinea pigs. The animals were immunized with IPM, ampicillin (ABPC) or cephalexin (CEX) using Freund's complete adjuvant. Three sensitized-drugs exhibited the same immunogenicity in the skin reaction. The cross-reactivities in skin reaction among IPM, sulbactam, aztreonam, ABPC and 6-aminopenicillanic acid as penam, and CEX, ceftizoxime, 7-aminocephalosporanic acid as cephem were examined. IPM did not show cross-reactions with any of the tested drugs in three sensitized groups, indicating that the drugs possessed no cross-reactivity with tested beta-lactams in DTH. In MIT, 4 or 5 of 6 animals reacted to be sensitized drugs in each group. The cross-reactivity of IPM- and ABPC-sensitized groups in MIT was similar to that of a skin reaction, however, the CEX-sensitized animals showed broad cross-reactions. Using a kind of test drug, one or two animals in the ABPC-sensitized group showed migration enhancement, but IPM- or CEX-sensitized animals did not exhibit migration enhancement. In LST, most of the animals tested exhibited lymphocyte prolifration by sensitized drugs but a cross-reaction was scarcely observed. The above results suggest that among beta-lactams, IPM has a very low cross-reactivity. LST is considered to be more a useful assay than MIT for in vitro identification of causative drugs in animal models.

Immune response in patients with intraabdominal infections treated with imipenem. Swedish Study Group.

In the present investigation the humoral immune response against isolated microorganisms in patients treated with imipenem was studied. Sixty-six patients (34 men and 32 women, 18-86 years of age) with suspicion of intraabdominal infections entered the study. Five patients were excluded for various reasons and the remaining 61 patients were treated with imipenem/cilastatin 0.5-1.0 g t.i.d. for 5-29 days (median nine days). Three serum samples were taken from each patient, the first sample at admission, the second between three and seven days after the first dose of imipenem/cilastatin and the third between 14 and 31 days after the first dose. One third of the patients had a malignant disease and the verified intraabdominal infections were judged to be severe in 23 and moderately severe in 33 of the patients. Fifty-six patients (92%) were cured and five patients (8%) were considered improved after the treatment. The immune response against isolated microorganisms was measured in the three serum samples by indirect immunofluorescence tests and enzyme-linked immunosorbent assays. Among the aerobic microorganisms isolated Escherichia coli (46 strains) Staphylococcus epidermidis (22 strains), Streptococcus milleri (15 strains) and Enterococcus faecalis (11 strains) dominated and among the anaerobic bacteria Bacteroides fragilis (39 strains). Thirty-two patients had significant immune responses against one or more of the isolated microorganisms. E. coli and B. fragilis gave rises in antibody titers in 13 and 20 cases respectively, while significant titers against S. epidermidis were noticed in only three cases, against S. milleri in two cases and against E. faecalis in three cases.(ABSTRACT TRUNCATED AT 250 WORDS)