Study Background and Disease Burden
Amoxicillin, a commonly prescribed beta-lactam antibiotic, is associated with allergic reactions in a notable subset of patients. Penicillin allergies, reported by approximately 10% of the general population, complicate antibiotic therapy and can limit treatment options. Piperacillin-tazobactam, a combination of an extended-spectrum penicillin and a beta-lactamase inhibitor, is frequently used for a broad range of infections, including serious hospital-acquired infections. However, concerns regarding cross-reactivity in patients with documented amoxicillin allergy have led to uncertainty about its safety in this population. Clinicians require evidence to guide safe prescribing practices and to avoid unnecessary avoidance of this effective agent, which could otherwise contribute to suboptimal treatment and antimicrobial resistance.
Study Design
This retrospective study evaluated the tolerance of piperacillin-tazobactam in 28 patients who had immediate allergic reactions to amoxicillin. The mean patient age was 39.5 years, with an equal gender distribution (50% women). Participants were identified between January 2023 and December 2024. Amoxicillin allergy was confirmed based on at least one of the following criteria: specific immunoglobulin E (IgE) levels greater than 0.35 kU/L, positive skin tests, or a positive drug provocation test (DPT). Subsequent to confirmation, all patients underwent allergy testing for piperacillin-tazobactam through skin testing, DPT, or both, to assess cross-reactivity and tolerance.
Key Findings
The principal findings revealed that 23 out of 28 patients (82.1%) tolerated piperacillin-tazobactam upon drug provocation testing, indicating no immediate allergic response. Moreover, 67.9% of patients also tolerated other beta-lactams, such as cefuroxime and ceftriaxone, which suggests a broader tolerance profile among these patients.
Conversely, 5 patients (17.8%) demonstrated allergy to piperacillin-tazobactam: two with positive skin tests and three confirmed through DPT. Among the DPT-positive group, all experienced acute urticaria after the initial 500-mg dose. One patient’s reaction was severe enough to require adrenaline administration for persistent hives, underscoring the potential risk.
Crucially, the study found no significant correlation between the phenotype of the initial amoxicillin allergic reaction (anaphylaxis versus urticaria) and piperacillin-tazobactam tolerance, indicating that initial severity does not predict cross-reactivity risk.
Expert Commentary
The authors emphasize that although a substantial majority of patients with amoxicillin allergy tolerated piperacillin-tazobactam, a meaningful minority exhibited cross-reactivity. This finding has direct clinical implications, particularly when piperacillin-tazobactam is considered necessary in patients with a documented amoxicillin allergy.
Experts recommend that in such scenarios, skin testing should precede a carefully monitored oral challenge or intravenous administration, ideally conducted by allergists experienced in drug hypersensitivity management. This approach balances the need for effective antimicrobial therapy with patient safety.
The study’s limitations include its retrospective design and variable testing for specific IgE, which may introduce bias or underestimation of allergy prevalence. Additionally, delayed hypersensitivity reactions were not assessed, and the small sample size limits generalizability. Long-term tolerance with repeated piperacillin-tazobactam exposure remains unknown, which highlights an area for further research.
Conclusion
This study contributes important insight into the safety of piperacillin-tazobactam in patients with documented immediate hypersensitivity to amoxicillin. While over 80% of such patients may safely tolerate piperacillin-tazobactam, nearly one-fifth may experience cross-reactive allergic reactions. Clinical practice should integrate diagnostic allergy testing including skin testing and DPT under specialist supervision before piperacillin-tazobactam use in this group.
These findings help clinicians to avoid unnecessarily withholding a valuable therapeutic option and encourage personalized antibiotic stewardship. Further prospective studies with larger cohorts and longer follow-up are warranted to solidify these observations and optimize management algorithms.
References
Moncada-Salinero A, González-Labrador M, Tejedor-Alonso MA, Rosado-Ingelmo A. Tolerance of Piperacillin-Tazobactam in Patients with Amoxicillin Allergy. J Allergy Clin Immunol Pract. 2025 Aug 22:S2213-2198(25)00816-5. doi: 10.1016/j.jaip.2025.08.015. Epub ahead of print. PMID: 40850631.
