Multiple allergy to cephalosporins confirmed by patch test: From the first to the fifth generation

Cephalosporins are antibiotics frequently used both in hospitalized patients and outpatients due to their efficacy in several infectious diseases.1 Early generation cephalosporins are mainly used for surgical site infection prophylaxis with good activity against gram-positive bacteria and a very limited activity against gram-negative, while late generation products have better pharmacokinetic and pharmacodynamic profiles with an increasing activity against gram-negative bacteria in severe and resistant infections. Like penicillins, cephalosporins can cause both immediate and delayed-type adverse drug reactions (ADRs). In the latter, patch testing is a valuable tool to demonstrate the role of the culprit drug and to assess possible cross-reactivity among cephalosporins themselves and among cephalosporins and penicillins.2 Herein, we report a rare case of multiple allergy to several cephalosporins without penicillin sensitivity in a patient with delayed hypersensitivity to ceftazidime. A 62-year-old man affected by chronic kidney insufficiency and epilepsy, was referred to us for a generalized maculopapular exanthema following the first administration of ceftazidime pentahydrate (2 g ev) for recurrent lobar pneumonia. Itchy skin lesions started on the upper limbs rapidly involving chest and legs and completely resolved in 2 days after betamethasone sodium phosphate administration (4 mg ev/die). Patient's history revealed a similar but less extensive maculopapular eruption involving chest and lower limbs 3 days after starting ceftazidime penthaydrate (2 g ev/three times a day) and teicoplanin (200 mg/twice a day) also for lobar pneumonia. Two months after the complete resolution of skin lesions and after receiving the patient's informed consent, skin tests with beta-lactam series including penicillins (amoxicillin alone and with clavulanic acid, benzylpenicillin-G), cephalosporins (one for each generation from the first to the fifth), and meropenem with the addition of ceftazidime and teicoplanin, were carried out.3 We used the powder of the commercial drugs from intravenous preparations (ceftazidime, teicoplanin, amoxicillin/clavulanic acid, cefazolin, cefuroxime, ceftriaxone, cefepime, ceftaroline, meropenem), intramuscular preparation (benzylpenicillin-G), and from tablets (amoxicillin), appropriately diluted in our hospital pharmacy (Table 1). Patch tests were applied on the upper back and occluded for 2 days using Haye's Test Chambers (Haye's Service, Alphen aan den Rijn, The Netherlands) on Soffix tape (Artsana, Grandate, Italy). Immediate reading was performed 20 min after applying patch tests and delayed readings were performed on day (D)2, D4 and D7.3 In case of negative patch test, prick tests and intradermal tests were carried out with immediate and delayed (D1) readings3 (Table 1). Patch tests were positive at D2 for ceftazidime (Figure 1A) and all five cephalosporins tested (Figure 1B). These positive reactions were confirmed in D4 and D7. Patch, prick and intradermal tests to penicillins, meropenem and teicoplanin were negative. Drug challenge tests with amoxicillin (1 g) orally and teicoplanin (200 mg) intramuscularly, administering a dose of one thousandth on D0, one hundredth on D1, one tenth on D2, and full dose after 1 week, resulted negative. Cephalosporins are responsible for ADRs ranging from exanthema to anaphylaxis or severe cutaneous adverse reactions, reported by 1.3% to 1.7% of patients, more frequently in hospitalized patients.1 The culprit ones were cephalexin4 and the new fifth generation cephalosporin (i.e., ceftaroline)5 in US population, and the third (i.e., ceftriaxone) and the second (i.e., cefuroxime) generation cephalosporins in South Korean in hospitalized patients.6 Regarding non-immediate maculopapular or morbilliform eruptions and delayed-onset urticaria-angioedema, ceftazidime was the third culprit cephalosporin (9.0%) after ceftriaxone (22.1%) and cephalexin (11.1%).7 In these ADRs, the diagnostic role of patch test, together with delayed reading intradermal test, is well known.8 The recognition of antigenic determinants comes primarily from IgE-mediated reactions taking into account the whole beta-lactam and protein carrier molecule, since cephalosporins are small molecules not able to independently induce an allergic reaction. Cephalosporins share a core four-member beta-lactam ring with bactericidal activity and an adjacent 6-member sulfur-containing dihydrothiazine ring for resistance to beta-lactamases,5 differing in R1 and R2 side chains in position 3 (affecting drug metabolism) and 7 (altering resistance to beta-lactamases), respectively (Figure 1C). Cross-reactivity among cephalosporins is more closely related to side-chain R1 homology and possibly to the small beta-lactam fragment linked to the carrier protein during cephalosporin conjugation, rather than the central beta-lactam ring.9, 10 In our patient patch tests allowed us to demonstrate the culprit role of ceftazidime (Figure 1D) and cross-reactivity to five cephalosporins to which he had not been previously exposed. He resulted negative to skin tests and drug provocation test with amoxicillin, belonging to amino-penicillins, characterized by the same alfa-amino group R1 side-chain as amino-cephalosporins such as cephalexin and cefaclor. Unfortunately, the patient refused to undergo further tests with the latter cephalosporins. We documented cross-reactivity to five cephalosporins, of which four (ceftriaxone, cefepime, cefuroxime, ceftaroline) share similar R1 side-chain with the culprit ceftazidime,1, 11 that might suggest a similar interpretative model of cross-reactions to that proposed for immediate reactions. Nevertheless, the fifth cross-reacting cephalosporin (cefazolin) differs from the other for its tetrazole R1 side-chain,1 making difficult to explain this cross-reactivity with ceftazidime. In conclusion, our report emphasizes the role of patch test in nonimmediate ADRs induced by cephalosporins not only to confirm the role of the culprit drug but also to study the cross-reactivity among them, probably not only related to their different side-chain structures. Therefore, patch test should always be performed in non-immediate cephalosporin ADRs before proceeding with challenge test in order to find an alternative cephalosporin. Rossella Marietti: Conceptualization; methodology; data curation; writing – review and editing; writing – original draft. Leonardo Bianchi: Conceptualization; methodology; data curation; writing – original draft. Katharina Hansel: Conceptualization; investigation; data curation; writing – review and editing. Gabriele Casciola: Writing – original draft; data curation. Filippo Biondi: Conceptualization; methodology; data curation. Marta Tramontana: Conceptualization; methodology; data curation. Luca Stingeni: Conceptualization; methodology; data curation; writing – original draft; investigation; supervision; writing – review and editing. The article has not been previously published and is not currently submitted elsewhere. Open Access Funding provided by Universita degli Studi di Perugia within the CRUI-CARE Agreement. None. All authors have no interests to report. Written informed consent was provided by patient to the data publication.