![]() Prior studies have previously demonstrated cross-reactivity between R1-side chains of aminopenicillins (amoxicillin, ampicillin, amoxicillin-clavulanate) and aminocephalosporins (cefalexin, cefaclor, cefadroxil, cefprozil, cefatrizine, cefonicid, cefmandole) in delayed (T-cell-mediated) hypersensitivity, and the absence of cross-reactivity with non-cross reactive cephalosporins, carbapenems and monobactams. The vast majority of these patients subsequently tolerated oral cephalosporins. We provide evidence for apparent cross-reactivity within penicillin class drugs by demonstrating penicillin IDT cross-reactivity in patients reporting a penicillin-associated severe T-cell mediated hypersensitivity. Five of 12 (41.6%) patients were positive to the primary implicated drug on IFN-γ ELISpot testing ( Supplementary Figure E1). One remaining patient has yet to undergo oral provocation. Eleven of 12 (92%) patients tolerated an oral 1 st or 2 nd generation cephalosporin provocation after IDT ( Table 1). A similar delayed pattern was not observed in healthy controls or in 255 patients with immediate IgE mediated hypersensitivity reactions to penicillins ( Supplementary Table E1). ![]() In patients with piperacillin-tazobactam as the primary implicated drug or immunocompromised, piperacillin-tazobactam IDT was performed and positive in all tested (8/8). saline, PPL (neat), MDM (neat), cefazolin and ceftriaxone ( Figure 1). ![]() All patients were positive to tested IDT concentrations of ampicillin, penicillin G and flucloxacillin and negative to 0.9% N. No systemic adverse events to skin testing were reported. Positive reactions to IDT occurred as early as 6 hours post inoculation and all patients were positive by 24 hours with persistence of skin redness and induration for greater than 72 hours. The median time between rash onset and intradermal testing and PBMC sampling was 395.5 days (IQR 195-1308). The median age was 52.5 years (IQR 36-48), 50% (6/12) female, and 5 (41.6%) immunocompromised (solid organ transplant recipient, cancer, autoimmune/connective tissue disorder requiring immunomodulating therapy). The primary implicated penicillins were piperacillin-tazobactam (6, 50%) amoxicillin (4, 33%) and flucloxacillin (2, 17%). The patient phenotypes and characteristics of the 12 patients positive to > 2 intradermal test reagents are demonstrated in Table 1. #Poor CD3 response reflecting recent cladribine (660) and cytarabine (859) chemotherapy Liver transplant recipient for alcoholic liver disease Pre-existing skin disease or medical comorbidities Patient 1 IDT was performed with amoxicillin in addition to the standard panel ( Panel G) to correlated with patch testing performed to amoxicillin ( Panel H).Ībbreviations PPL, DAP-major (benzylpenicilloyl poly-L-lysine final concentration 1.07 X10 −2 mol/L), MDM, minor-determinate (sodium benzylpenicillin, benzylpenicilloic acid, sodium benzylpenicilloate), Penicillin G†, Penicillin G 1000 IU/mL PenicillinG ‡, Penicillin G 10000 IU/mL. Panel H illustrates a Grade 3 positive patch test result from same patient with IDT demonstrated in Panel G (PT performed 6 months following positive IDT). Please note that a bruise is noted in Patient E where the Normal Saline was inoculated. Further patients with identical pattern of intradermal test cross-reactivity demonstrated in ( E, F, G ). Intradermal testing 24 hours post inoculation showing widespread penicillin cross-reactivity (pustule formation noted on penicillin 1000IU/ml IDT) (D). Pustular exanthem of a patient with flucloxacillin-associated AGEP (A-B) with corresponding histopathology demonstrating pustule formation (upper arrow) and upper dermal edema (lower arrow) (low power x10 magnification upper image) and spongiosis and neutrophil migrating through epidermis (high power x100 magnification lower image) (C). Pictorial representation of patients reporting penicillin-associated severe T-cell mediated hypersensitivity from tested cohort. Currently, a significant driver of Ig-E-mediated cross-reactivity between penicillins/cephalosporins is thought to be the R1 side chain, with contemporary cephalosporin cross-reactivity with penicillin allergy occurring at a rate of 2 reagents from the routine IDT panel ( Figure 1, Table 1). ![]()
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