Piperacillin-Tazobactam Hypersensitivity: A Large, Multicenter Analysis

J Allergy Clin Immunol Pract. 2021 May;9(5):2001-2009. doi: 10.1016/j.jaip.2020.12.051. Epub 2021 Jan 11.


Background: Piperacillin/tazobactam is a broad-spectrum penicillin. Hypersensitivity reactions are less commonly reported than with other penicillins except in patients with cystic fibrosis.

Objective: Detailed clinical characterization of a patient cohort referred with suspected piperacillin-tazobactam hypersensitivity.

Methods: Retrospective analysis of the demographic characteristics, clinical presentation, investigation, and management of 87 patients presenting to 5 European allergy centers. Patients underwent skin prick and intradermal testing with piperacillin/tazobactam, major (penicilloyl-polylysine) and minor (sodium penilloate) determinants, amoxicillin, benzylpenicillin, flucloxacillin, co-amoxiclav, clavulanic acid, and meropenem with immediate and, where appropriate, delayed reading of tests. Skin test-negative patients underwent drug provocation to piperacillin/tazobactam and/or other penicillins. A multistep protocol was used, depending on risk assessment.

Results: Forty-eight of 87 (55%) patients were diagnosed with hypersensitivity to piperacillin/tazobactam with either positive skin or drug provocation test results, of whom 10 (21%) had a diagnosis of cystic fibrosis. Twenty-six (54%) patients presented with immediate and 22 (45%) with nonimmediate hypersensitivity. Patients with cystic fibrosis predominantly presented with nonimmediate hypersensitivity (70%). Reactions were severe in 52% of immediate reactors (Brown's anaphylaxis grade 3) and moderately severe (systemic involvement) in 75% of nonimmediate reactors. The number of patients with negative skin test results tolerating reintroduction was comparable in immediate (80%) and nonimmediate (88%) hypersensitivity. One-third of patients were cross-sensitized to other penicillins. The cross-sensitization pattern raised the possibility of tazobactam allergy in 3 patients. In 21 patients selectively sensitized to piperacillin/tazobactam (12 immediate, 9 nonimmediate), tolerance to other beta-lactams was demonstrated by drug provocation testing.

Conclusions: Piperacillin-tazobactam caused immediate and nonimmediate hypersensitivity with similar frequency. Most patients were selectively sensitized and tolerated other penicillins. Some patients may be allergic to the beta-lactamase inhibitor only.

Keywords: Anaphylaxis; Beta-lactam; Drug allergy; Drug provocation test; Immediate hypersensitivity; Nonimmediate hypersensitivity; Penicillins; Piperacillin; Skin prick test; Tazobactam.

Publication types

  • Multicenter Study

MeSH terms

  • Amoxicillin
  • Anti-Bacterial Agents / adverse effects
  • Drug Hypersensitivity* / diagnosis
  • Drug Hypersensitivity* / epidemiology
  • Humans
  • Hypersensitivity, Immediate* / diagnosis
  • Hypersensitivity, Immediate* / epidemiology
  • Penicillins / adverse effects
  • Retrospective Studies
  • Skin Tests


  • Anti-Bacterial Agents
  • Penicillins
  • Amoxicillin