Discussion

Several antibiotic regimens and surgical types were evaluated in this study. Despite heterogeneity in patient characteristics, intraoperative and postoperative antibiotic protocols, and definitions of SSIs owing to limited clinical data, our findings indicate that patients with a reported β-lactam allergy face a significantly higher risk of developing SSIs than those without such an allergy. Notably, our meta-analysis demonstrates that reported β-lactam allergy is associated with an approximately 50% higher incidence of SSIs. Furthermore, the analysis comparing prophylactic antibiotic classes revealed that patients who received β-lactam antibiotics had a significantly lower risk of SSIs than that of patients who received non-β-lactam alternatives, underscoring the clinical importance of antibiotic selection in perioperative management.

Subgroup analysis revealed that the association between reported β-lactam allergy and SSI risk remained statistically significant regardless of the allergy verification method. Although studies based solely on patient-reported histories showed slightly higher point estimates, the elevated risk of SSI was observed consistently across all subgroups. These findings emphasize the clinical importance of β-lactam allergy assessment in surgical patients and reinforce the need for standardized evaluation to guide antimicrobial decision-making. Most patients labeled as penicillin- or β-lactam-allergic are not truly allergic. For example, Park et al. found that 85–90% of patients with self-reported penicillin allergy had negative results on penicillin skin testing, highlighting the high prevalence of inaccurate allergy labels. ^{Reference Park, Markus, Matesic and Li39} Similarly, Blanca et al. reported that β-lactam hypersensitivity often diminishes over time, with allergic reactions resolving in approximately 50% of patients after 5 years and 80% after 10 years. ^{Reference Blanca, Torres and García40} These findings underscore the importance of accurate allergy assessment and support the re-evaluation of reported β-lactam allergies. The Penicillin Allergy Decision Rule (PEN-FAST) tool has emerged as a validated clinical decision aid that identifies patients at low risk of true penicillin allergy, enabling the safe use of β-lactam in surgical settings. ^{Reference Trubiano, Vogrin and Chua41} Accordingly, a recent pharmacist-driven penicillin allergy de-labeling intervention among patients who undergone cardiothoracic and spine surgery significantly increased preoperative cefazolin use from 71.0% to 88.9%, without increasing hypersensitivity-related complications. ^{Reference Crum, Gagnon, Thumann, Sidebottom, Vacquier and Gens42} Such structured assessments in high-risk surgical populations may help optimize antimicrobial prophylaxis and reduce unnecessary vancomycin use. Accurately distinguishing patients without a true allergy allows for the effective and safe administration of β-lactam antibiotics during surgery, potentially lowering the risk of SSIs.

Our meta-analysis found no significant differences in hypersensitivity reaction rates between patients receiving β-lactam antibiotics and those given alternative agents, with only mild, non-severe reactions reported in the two studies that assessed this outcome. In particular, Beltran et al. ^{Reference Beltran, Kako, Chovanec, Ramesh, Bissonnette and Tobias16} recorded urticaria in one patient (0.7%) receiving cephalosporins and mild cutaneous symptoms in eight patients (2.0%) receiving clindamycin. Meanwhile Fosnot et al. ^{Reference Fosnot, Currier, Pendell and Jeffres24} observed non-severe reactions, such as hypotension, flushing, angioedema, and dyspnea across all antibiotic groups. Although concerns remain regarding penicillin–cephalosporin cross-reactivity, current evidence suggests that the risk is low and primarily related to side-chain similarities rather than the β-lactam ring itself. Cefazolin, which exhibits a unique side-chain structure, ^{Reference Blumenthal, Peter, Trubiano and Phillips43} poses minimal cross-reactivity risk—even in patients with a reported penicillin allergy—making it a reasonable prophylactic option for those without a confirmed history of severe hypersensitivity reactions.

While we did not observe significant differences in secondary outcomes, such as LOS, this finding should be interpreted with caution. SSIs frequently develop after discharge, and LOS may not fully capture the extent of postoperative complications. Additionally, readmissions or outpatient management of SSIs may have been inconsistently reported across the included studies, potentially underestimating the true clinical burden. Therefore, our analysis does not reflect postdischarge events or the associated economic implications, which remain relevant to patient care and outcomes.

This study has some limitations. First, all included studies were observational and differed in their definition of β-lactam allergy, SSIs, and antibiotic protocols. While several studies used matching or adjustment to address confounding, residual bias is likely. Potential confounders include patient demographic characteristics, comorbidities, surgical complexity, antibiotic choice, and other contextual factors, such as healthcare exposure and socioeconomic status, which were inconsistently accounted for. In addition, many studies were evaluated to have a serious risk of bias; however, our subgroup analysis excluding these studies confirmed the robustness of the association between β-lactam allergy and SSI risk. Nonetheless, the presence of study-level bias may influence the observed estimates. Future prospective studies with standardized definitions and allergy verification are warranted to reduce confounding and improve causal inference. Second, the reliance on retrospective data and inconsistent documentation of intraoperative and postoperative antibiotic protocols may introduce information bias. In particular, methicillin-resistant Staphylococcus aureus (MRSA) colonization status—an important modifier of infection risk and determinant of prophylactic antibiotic selection—was not reported in most studies, precluding our ability to adjust for this variable in the analysis. Third, only a few studies reported secondary outcomes such as mortality or Clostridioides difficile infection, limiting our ability to draw definitive conclusions on broader clinical consequences. Despite these limitations, this study has several strengths. To the best of our knowledge, it represents the most comprehensive quantitative synthesis to date of the impact of β-lactam allergy on SSI risk, incorporating over 460,000 patients across diverse surgical populations. Rigorous inclusion criteria, sensitivity analyses, and subgroup assessments provide robustness to our findings.

In conclusion, reported β-lactam allergy is associated with a significantly higher risk of SSIs, likely mediated by the substitution of β-lactam agents with less effective alternatives. These results emphasize the clinical importance of verifying β-lactam allergy histories, ideally through structured assessments, including skin testing and direct oral challenge when appropriate. Efforts to de-label inappropriate β-lactam allergies should be prioritized as part of antibiotic stewardship. Future prospective studies and interventional trials are warranted to further elucidate optimal strategies for perioperative antibiotic prophylaxis in this high-risk population.