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Piperacillin-tazobactam hypersensitivity: lessons learned from a large, multicenter analysis

Published Online: May 2021

Piperacillin-tazobactam (PPZ-TZB) was approved for use in 1981 and various immediate and non-immediate hypersensitivity reactions (IHR, NIHR) have been reported since 1984, including cases of occupational sensitization. It has also previously been reported as the most frequent cause of hypersensitivity reactions in patients with cystic fibrosis (CF).

In this article in The Journal of Allergy and Clinical Immunology: In Practice, R Casimir-Brown et al report the largest study of Piperacillin-Tazobactam (PPZ-TZB) hypersensitivity to date. Five European allergy centers contributed data on 87 patients referred with suspected hypersensitivity to PPZ-TZB between 2012 and 2019. Retrospective analysis was conducted of patients’ clinical characteristics and drug allergy workup including age, gender, index reaction, skin test results (skin prick tests and immediate/ delayed intradermal tests) and drug provocation testing (DPT) results. Skin tests (ST) were performed with a panel of other beta lactam antibiotics, including penicillins and penicillin major and minor determinants. The diagnosis of IHR/NIHR was based on the timing of the index reaction, with severity of IHR graded according to Brown’s classification of systemic reactions. In NIHR, a diagnosis of drug reaction with systemic symptoms (DRESS) was made using the RegiSCAR criteria.

Forty-eight of 87 (55%) patients were diagnosed with hypersensitivity to PPZ-TZB with positive ST or DPT results, 10 of whom (21%) had a diagnosis of CF. Reactions were graded severe (Brown’s anaphylaxis grade 3) in 52% of IHR and moderate-to-severe (cutaneous reactions with systemic involvement) in 75% of NIHR. PPZ-TZB was found to cause IHR and NIHR with similar frequency (54% IHR, 45% NIHR), except in patients with CF (70% NIHR). Four patients with IHR were nurses whose index reactions were via occupational exposure.

This study demonstrates the value of comprehensive allergy testing and its impact on antibiotic stewardship. Most patients (both IHR and NIHR) with PPZ-TZB allergy were selectively sensitized and tolerated other penicillins. In 21 patients selectively sensitized to PPZ-TZB (12 IHR, 9 NIHR) tolerance to other penicillins/beta-lactams was demonstrated by DPT. Thus, those with allergy to PPZ-TZB are likely not to be allergic to other beta-lactam antibiotics when confirmed by skin testing. Cross-sensitization to other beta-lactam antibiotics was seen in one-third of patients. In 3 patients, the cross-sensitization pattern raised the possibility of TZB allergy, with potential cross-reactivity between TZB and clavulanic acid. ST were safe for both IHR and NIHR, strengthening the recommendation for ST before DPT. DPT was found to be safe and reintroduction of PPZ-TZB following negative ST was tolerated by 80% in IHR and 88% in NIHR.

Results from Casimir-Brown et al therefore confirm what is becoming increasingly known: in a significant proportion of patients with confirmed beta-lactam allergy the immune response is directed against the unique side chain of individual beta-lactams, whereas some patients (for PPZ-TZB, a minority) demonstrate cross-reactivity. These results give further insight into improving the precision of diagnosing allergy to specific penicillin antibiotics, in order to avoid the detrimental effects on health care costs and patient outcomes of a “false” label of penicillin or beta-lactam allergy.

The Journal of Allergy and Clinical Immunology: In Practice is an official journal of the AAAAI, focusing on practical information for the practicing clinician.

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