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Cross-reactivity or coexisting antibodies in β -l actam allergy

Cross-reactivity or coexisting antibodies in β -l actam allergy. Antonino Romano aromano.allergy@gmail.com Complesso Integrato Columbus – Rome IRCCS Oasi Maria S.S. – Troina (EN). PENICILLINS. CEPHALOSPORINS. O. O. S. R -C-NH. R 1 -C-NH. N. N. O. COOH. O. C- R 2. MONOBACTAMS.

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Cross-reactivity or coexisting antibodies in β -l actam allergy

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  1. Cross-reactivity or coexisting antibodies in β-lactam allergy Antonino Romanoaromano.allergy@gmail.comComplesso Integrato Columbus – RomeIRCCS Oasi Maria S.S. – Troina (EN)

  2. PENICILLINS CEPHALOSPORINS O O S R-C-NH R1-C-NH N N O COOH O C-R2 MONOBACTAMS CARBAPENEMS O R1 R-C-NH S- R2 N N O O SO3H C=O OH Structure of the four classes of betalactam antibiotics in use today

  3. PENICILLINS CEPHALOSPORINS O O S R-C-NH R1-C-NH N N O COOH C-R2 O MONOBACTAMS CARBAPENEMS O R1 R-C-NH S-R2 N N O O SO3H C=O OH

  4. Diagnostic evaluation of a large group of patients with immediate allergy to penicillins: role of skin testing Positive skin tests to at least one determinant observed in 203 (70%) out of 290 subjects evaluated 38 (13.1%) out of 290 subjects were skin test negative and had positive benzylpenicilloyl and/or amoxicilloyl in vitro tests (CAP-FEIA) 49 (16.9%) out of 290 subjects were skin test and CAP-FEIA negative and reacted to the controlled administration MJ Torres et al, Allergy 2001

  5. Diagnostic evaluation of a large group of patients with immediate allergy to penicillins: role of skin testing 168 (57.9%) out of 290 subjects evaluated were nonselectiveresponders (i.e., with positive results to any test with benzylpenicillin reagents) 122 (42.1%) out of 290 subjects were selectiveresponders (i.e., negative to allergologic tests with benzylpenicillin reagents, good tolerance of benzylpenicillin, and positive to any test with amoxicillin and/or ampicillin) MJ Torres et al, Allergy 2001

  6. LONG ALGORITHM CLINICAL HISTORY AND BLOOD SAMPLE Prick PPL/MDM + + ID PPL/MDM ALLERGIC Non selective reactions + Test in vitro + DPT with BP 1 week + ALLERGIC Selective reactions Prick culprit drug + ID culprit drug + NON ALLERGIC DPT culprit drug M Blanca et al, Allergy 2009

  7. Selective immediate responders to amoxicillin and clavulanic acid tolerate penicillin derivative administration after confirming the diagnosis 58 (21.6%) of 268 subjects with histories of immediate reactions to AX or AX-CLV were confirmed as having immediate hypersensitivity 7 of these 58 subjects were positive to PG determinants 40 were classified as AX-selective responders with good tolerance to PG and PV (group A) 11 were classified as CLV-selective responders with good tolerance to PG, PV, and AX (group B) N Blanca-Lopez et al, Allergy 2015

  8. PENICILLINS CEPHALOSPORINS O O S R-C-NH R1-C-NH N N O COOH C-R2 O MONOBACTAMS CARBAPENEMS O R1 R-C-NH S-R2 N N O O SO3H C=O OH

  9. Safe use of selected cephalosporins in penicillin-allergic patients: a meta-analysis • A significant increase in allergic reactions to all first-generation cephalosporins plus cefamandole (OR = 4.8; CI = 3.7 to 6.2) was observed in penicillin-allergic patients • No increase was observed with second-generation cephalosporins (OR = 1.1; CI = 0.6 to 2.1) or third-generation cephalosporins (OR = 0.5; CI = 0.2 to 1.1) ME Pichichero and JR Casey, Otolaryngol Head Neck Surg 2007

  10. Benzylpenicillin Ampicillin Cefamandole Cephalothin

  11. Ampicillin Cephalexin

  12. Amoxicillin Cefadroxil

  13. Cross-reactivity and tolerability of cephalosporins in patients with IgE-mediated hypersensitivity to penicillins A Romano et al, Ann Intern Med 2004

  14. Allergologic work-up • Skin tests(prick and intradermal) • PPL, MDM, penicillin G • Ampicillin, amoxicillin, piperacillin • Cephalothin, cefamandole, ceftazidime, ceftriaxone, cefuroxime, cefotaxime • Specific IgE assays Penicilloyl G Penicilloyl V Ampicilloyl Amoxicilloyl • Challenges Cefuroxime axetil, ceftriaxone

  15. Clinical characteristics and patterns of reactivity of the 14 patients with skin-test positivity to cephalosporins A Romano et al, Ann Intern Med 2004

  16. Safe administration of cephalosporinsto penicillin-allergic subjects Because of possible coexisting sensitivities, it could be harmful to treat penicillin-allergic patients even with cephalosporins selected on the basis of side-chain differences Prophylactic skin tests with the cephalosporins concerned are advisable before their administration to penicillin-allergic patients

  17. PENICILLINS CEPHALOSPORINS O O S R-C-NH R1-C-NH N N O COOH C-R2 O MONOBACTAMS CARBAPENEMS O R1 R-C-NH S-R2 N N O O SO3H C=O OH

  18. Cross-reactivity and tolerability of aztreonam in subjects with IgE-mediated hypersensitivity to penicillins

  19. PENICILLINS CEPHALOSPORINS O O S R-C-NH R1-C-NH N N O COOH C-R2 O MONOBACTAMS CARBAPENEMS O R1 R-C-NH S-R2 N N O O SO3H C=O OH

  20. Cross-reactivity and tolerability of carbapenems in patients with IgE-mediated hypersensitivity to penicillins

  21. Imipenem cross-reactivity with penicillin in humans 9(47.4%)out of 19 patients with positive penicillin skin tests were also positive to imipenem/cilastatin and/or imipenem metabolites A Saxon et al, J Allergy Clin Immunol 1988

  22. H CEPHALOSPORINS S R1-N-CH-CH CH2 C-CH2.R2 CO - N C COO-

  23. Immediate allergic reactions to cephalosporins: Cross-reactivity and selective responses A Romano et al, J Allergy Clin Immunol 2000 Diagnosing immediate reactions to cephalosporins A Romano et al, Clin Exp Allergy 2005

  24. Immediate allergic reactions to cephalosporins: Evaluation of cross-reactivity with a panel of penicillins and cephalosporins C Antunez et al, J Allergy Clin Immunol 2006 Natural evolution of skin-test sensitivity in patients with IgE-mediated hypersensitivity to cephalosporins A Romano et al, Allergy 2014

  25. Patterns of reactivity in subjects with IgE-mediated hypersensitivity to cephalosporins Cross-reactivity with penicillins Selective reactivity to a culprit cephalosporin Cross-reactivity with other cephalosporins

  26. J Allergy Clin Immunol 2006

  27. Immediate allergic reactions to cephalosporins: Evaluation of cross-reactivity with a panel of penicillins and cephalosporins 24 patients with immediate allergic reactions to cephalosporins underwent skin tests and RAST with a panel of penicillins and cephalosporins, as well as RAST-inhibition studies with different monomeric conjugates of penicillins and cephalosporins 21 had positive skin tests to cephalosporins: 12 only to the responsible compound and 9 to more than one cephalosporin RAST and RAST-inhibition studies demonstrated that the side chain at the R1 position is crucial for recognition and cross-reactivity C Antunez et al, J Allergy Clin Immunol 2006

  28. Anaphylactic shock associated with cefuroxime axetil: structure-activity relationships F Hausdenteufel et al, Ann Pharmacother 2007

  29. J Allergy Clin Immunol 2015

  30. Allergologic work-up Skin tests(prick and intradermal) PPL, MDM, penicillin G Ampicillin, amoxicillin Cephalexin, cefaclor, cefazolin, cefadroxil, cefamandole, cefuroxime, ceftazidime, ceftriaxone, cefotaxime, ceftibuten, cefepime Specific IgE assays Penicilloyl G Penicilloyl V Ampicilloyl Amoxicilloyl Cefaclor Challenges Cefaclor, cefuroxime axetil, ceftriaxone, cefazolin, ceftibuten ARomano et al, J Allergy Clin Immunol 2015

  31. 102 subjects with an IgE-mediated hypersensitivity to cephalosporins were classified in 4 groups: group A, positive responses to 1 or more of ceftriaxone, cefuroxime, cefotaxime, cefepime, cefodizime, and ceftazidime group B, positive responses to aminocephalosporins group C, positive responses to cephalosporins other than those belonging to the aforementioned groups group D, positive responses to cephalosporins belonging to 2 different groups ARomano et al, J Allergy Clin Immunol 2015

  32. 73 subjects were classified as group A, 13 as group B, 7 as group C, and 9 as group D group A: 41 subjects had positive responses only to the responsible cephalosporins (32 to ceftriaxone 7 to ceftazidime, 1 to cefotaxime, and 1 to cefodizime), whereas 32 displayed different patterns of cross-reactivity group B: 11 had positive responses only to the responsible compound (9 to cefaclor and 2 to cephalexin), whereas 2 presented a pattern of cross-reactivity ARomano et al, J Allergy Clin Immunol 2015

  33. 73 subjects were classified as group A, 13 as group B, 7 as group C, and 9 as group D group C: 6 had positive responses only to the responsible compound (5 to cefazolin and 1 to cefamandole), and the remaining subject, who had reacted to cefoperazone, had positive responses to both cefoperazone and cefamandole group D: 9 subjects displayed different patterns of allergologic test positivity ARomano et al, J Allergy Clin Immunol 2015

  34. ARomano et al, J Allergy Clin Immunol 2015

  35. A Romano et al, J Allergy Clin Immunol 2015

  36. Group A subjects underwent challenges with cefaclor, cefazolin, and ceftibuten Group B participants underwent challenges with cefuroxime axetil, ceftriaxone, cefazolin, and ceftibuten Group C subjects underwent challenges with cefaclor, cefuroxime axetil, ceftriaxone, cefazolin, and ceftibuten, except those who had reacted to cefazolin, who were not challenged with it Group D subjects underwent challenges with some of the aforementioned cephalosporins selected on the basis of their patterns of positivity ARomano et al, J Allergy Clin Immunol 2015

  37. Challenges with alternative cephalosporins (ceftibuten in 101 subjects, cefazolin in 96, cefaclor in 82, and cefuroxime axetil and ceftriaxone in 22) were well tolerated IgE-mediated hypersensitivity to cephalosporins:Cross-reactivity and tolerability of alternative cephalosporins ARomano et al, J Allergy Clin Immunol 2015

  38. IgE-mediated hypersensitivity to cephalosporins:Cross-reactivity and tolerability of alternative cephalosporins Cephalosporin hypersensitivity is unlikely to be a class hypersensitivity We identified 2 groups (or subclasses) of cephalosporins: group A, which includes those with a methoxyimino group in their R1 side chains plus ceftazidime, and group B, which is composed of aminocephalosporins The limited number of subjects sensitive to cephalosporins other than those belonging to the aforementioned groups did not allow us to identify further groups ARomano et al, J Allergy Clin Immunol 2015

  39. IgE-mediated hypersensitivity to cephalosporins:Cross-reactivity and tolerability of alternative cephalosporins In subjects with an IgE-mediated hypersensitivity to cephalosporins, the risk of positive allergologic test responses with alternative cephalosporins is not related only to the structural similarities among their side-chain determinants Subjects with cephalosporin allergy might be treated with alternative cephalosporins, which have side-chain determinants different from those of the responsible compounds and elicit negative pretreatment skin test responses ARomano et al, J Allergy Clin Immunol 2015

  40. PENICILLINS CEPHALOSPORINS O O S R-C-NH R1-C-NH N N O COOH C-R2 O MONOBACTAMS CARBAPENEMS O R1 R-C-NH S-R2 N N O O SO3H C=O OH

  41. J Allergy Clin Immunol 2006

  42. Immediate allergic reactions to cephalosporins: Evaluation of cross-reactivity with a panel of penicillins and cephalosporins • 24 patients with immediate allergic reactions to cephalosporins underwent skin tests and RAST with a panel of penicillins and cephalosporins, as well as RAST-inhibition studies with different monomeric conjugates of penicillins and cephalosporins • 2 (8.3%) displayed positive responses to penicillin determinants, while 22 were skin-test negative to penicillin determinants and tolerated benzylpenicillin challenges C Antunez et al, J Allergy Clin Immunol 2006

  43. Ceftazidime Aztreonam

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