Piperacillin-Tazobactam Hypersensitivity: A Large, Multicenter Analysis

Casimir-Brown, Rosamund Sara; Kennard, Lucinda; Kayode, O. Stephanie; Siew, Leonard; Makris, Michaël; Tsilochristou, Olympia; Chytiroglou, Evangelia; Nakonechna, Alla; Rutkowski, Krzysztof; Mirakian, Rita; Wagner, Annette

doi:10.1016/j.jaip.2020.12.051

Cited by 18 publications

(8 citation statements)

References 42 publications

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“…Among all (87) patients (48)55% patients showed hypersensitivity to piperacillin-tazobactam, of whom (26)54% patients presented with immediate and (22)45% non-immediate hypersensitivity. Patients with cystic fibrosis are more prone to develop hypersensitivity reactions [13] . Another study discussed a 31 year old patient with cystic fibrosis who developed FDE (Fixed Drug Eruption) to piperacillintazobactam.…”

Section: Resultsmentioning

confidence: 99%

Prevalence of Piperacillin-Tazobactam induced Hypersensitivity Reaction in Workers of Stallion’s Pharmaceutical Factory at Lahore

Sulehri¹,

Yaqub

Imam

et al. 2022

JUMDC

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BACKGROUND & OBJECTIVE: Piperacillin is an antibiotic that belongs to the ureidopenicillin family. Piperacillin-tazobactam provides cover against gram-positive, gram-negative bacteria and some bacteria of anaerobic nature. It is an extended-spectrum antibiotic and is used along with tazobactam which is an inhibitor of beta-lactamase. The main objective of our research was to identify the hypersensitivity reactions of piperacillin-tazobactam in pharmaceuticals factory and office workers. METHODOLOGY: A Cross-sectional study was conducted at Stallion Pharmaceuticals (Pvt) Ltd located at Sundar Industrial Estate Lahore, Pakistan, from March to April 2018, after approval from the institutional research committee. All the workers, including factory workers and office workers at Stallion Pharmaceuticals (Pvt) Ltd were included in this study. Data was collected from each respondent by immediate-type skin testing. Data analysis was done by SPSS version 25, the demographic data was evaluated by descriptive statistics, Fisher Exact test was used for comparison and p≤0.05 was taken as significant. RESULTS: The results of the study presented that hypersensitivity reaction was present in (7.5%) of males and (3.8%) of females. It was also observed that (8.8%) of factory workers had hypersensitivity reactions when they are gone through skin tests, and only (2.5%) of office workers were skin test positive. From the above results (11.2%) of all the respondents developed hypersensitivity reactions and (88.8%) showed no reaction when they were gone through skin tests, which contain 0.1 ml of piperacillin and tazobactam. Fisher exact test was applied, and results showed no significant difference between hypersensitivity reactions among factory and office workers as the p-value was 01. CONCLUSION: Hypersensitivity reaction to piperacillin-tazobactam was minimal in the factory & office workers, and this was not significant.

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Section: Resultsmentioning

confidence: 99%

Prevalence of Piperacillin-Tazobactam induced Hypersensitivity Reaction in Workers of Stallion’s Pharmaceutical Factory at Lahore

Sulehri¹,

Yaqub

Imam

et al. 2022

JUMDC

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“…The one exception is a recent study that evaluated immediate and nonimmediate piperacillin-tazobactam hypersensitivity from a large multicenter cohort. 23 The skin-testing cross-sensitization pattern indicated that 3 of 87 patients may have developed selective reactions to tazobactam, and cross-reactivity was detected with clavulanic acid. In the current study, three clavulanic acid hypersensitive patients and one tazobactam hypersensitive patient were identified through diagnostic testing and PBMC were used to generate T-cell clones.…”

Section: Discussionmentioning

confidence: 99%

“…Evaluation of the potential for crossreactivity of β-lactamase inhibitors is purely based on the chemical structure and known chemical reactivity, which sometimes can be misleading. The one exception is a recent study that evaluated immediate and nonimmediate piperacillin-tazobactam hypersensitivity from a large multicenter cohort . The skin-testing cross-sensitization pattern indicated that 3 of 87 patients may have developed selective reactions to tazobactam, and cross-reactivity was detected with clavulanic acid.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, tazobactam-responsive T-cell clones were generated from one patient with cystic fibrosis that developed a delayed-type maculopapular eruption following exposure to piperacillin-tazobactam. It would be interesting to speculate that the two study drugs produce these polarized types of reaction; however, a recent study exploring skin and provocation testing in piperacillin-tazobactam hypersensitive patients identified three patients selectively sensitized against tazobactam (displaying cross-reactivity against clavulanic acid) that developed immediate or delayed-type reactions . The study was conducted according to the Declaration of Helsinki principles and was approved by the local Ethics Committees of Málaga, Spain, and Leeds, UK.…”

Section: Methodsmentioning

confidence: 99%

“…It would be interesting to speculate that the two study drugs produce these polarized types of reaction; however, a recent study exploring skin and provocation testing in piperacillin-tazobactam hypersensitive patients identified three patients selectively sensitized against tazobactam (displaying cross-reactivity against clavulanic acid) that developed immediate or delayed-type reactions. 23 The study was conducted according to the Declaration of Helsinki principles and was approved by the local Ethics Committees of Málaga, Spain, and Leeds, UK. All subjects were informed orally about the study, and they signed the corresponding informed consent form.…”

Section: Methodsmentioning

confidence: 99%

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Shared Clavulanate and Tazobactam Antigenic Determinants Activate T-Cells from Hypersensitive Patients

Ariza

Jaruthamsophon

Meng

et al. 2022

Chem. Res. Toxicol.

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β-Lactamase inhibitors such as clavulanic acid and tazobactam were developed to overcome β-lactam antibiotic resistance. Hypersensitivity reactions to these drugs have not been studied in detail, and the antigenic determinants that activate T-cells have not been defined. The objectives of this study were to (i) characterize clavulanate-and tazobactam-responsive Tcells from hypersensitive patients, (ii) explore clavulanate and tazobactam Tcell crossreactivity, and (iii) define the antigenic determinants that contribute to T-cell reactivity. Antigen specificity, pathways of T-cell activation, and crossreactivity with clavulanate-and tazobactam-specific T-cell clones were assessed by proliferation and cytokine release assays. Antigenic determinants were analyzed by mass spectrometry-based proteomics methods. Clavulanateand tazobactam-responsive CD4 + T-cell clones were stimulated to proliferate and secrete IFN-γ in an MHC class II-restricted and dose-dependent manner. T-cell activation with clavulanate-and tazobactam was dependent on antigen presenting cells because their fixation prevented the T-cell response. Strong crossreactivity was observed between clavulanate-and tazobactam-T-cells; however, neither drug activated β-lactam antibiotic-responsive T-cells. Mass spectrometric analysis revealed that both compounds form multiple antigenic determinants with lysine residues on proteins, including an overlapping aldehyde and hydrated aldehyde adduct with mass additions of 70 and 88 Da, respectively. Collectively, these data show that although clavulanate and tazobactam are structurally distinct, the antigenic determinants formed by both drugs overlap, which explains the observed Tcell cross-reactivity.

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What’s been Hapten-ing over the last 88 years?

et al. 2023

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Definition of the relationship between drug protein adduct formation (haptenation) and development of immunological adverse drug reactions (drug hypersensitivity) has been an area of active research for over 80 years. The hapten hypothesis which states that “immunogenicity of low molecular weight organic chemicals is dependent on modification of self-proteins,” evolved from Landsteiner and Jacob’s discovery of a correlation between the reactivity of dinitro-halogenated benzenes and their sensitization potential. The hypothesis rapidly evolved to encompass drugs that often require metabolic activation to generate electrophilic, protein-reactive intermediates. As tissue culture methods advanced, the importance of drug hapten-specific T-cells in the disease pathogenesis was defined. This led to a plethora of studies describing the uptake and processing of drug(metabolite) protein adducts by antigen presenting cells, and the subsequent surface display of hapten-modified peptides in the context of MHC molecules. Although the pathway of hapten-specific T-cell activation is now well established, several questions need to be addressed: first, what is the nature of the hapten-modified peptides displayed by MHC? Second, how many of these peptides stimulate T-cells?; third, what are the critical protein modifications involved in T-cell activation; and finally, what is the role of hapten-specific T-cells in the iatrogenic disease? These questions will become increasingly important as more and more targeted covalent binding inhibitor drugs are approved for human use. In this review, we provide a brief synopsis of hapten research and then describe the approaches used by Pharma and academia to study hapten covalent binding and the role of drug protein adducts in the activation of human T-cells.

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Piperacillin-Tazobactam Hypersensitivity: A Large, Multicenter Analysis

Cited by 18 publications

References 42 publications

Prevalence of Piperacillin-Tazobactam induced Hypersensitivity Reaction in Workers of Stallion’s Pharmaceutical Factory at Lahore

Prevalence of Piperacillin-Tazobactam induced Hypersensitivity Reaction in Workers of Stallion’s Pharmaceutical Factory at Lahore

Shared Clavulanate and Tazobactam Antigenic Determinants Activate T-Cells from Hypersensitive Patients

What’s been Hapten-ing over the last 88 years?

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