Discussion

In the present study, we found that patients with reported penicillin allergy who underwent oncologic surgery had a non-significantly higher risk for surgical site infections, complications per patient, and overall complications. A significantly higher CCI was found in patients with penicillin allergy compared to patients without reported penicillin allergy. We found no difference between groups in terms of length of hospital stay and higher treatment costs.

Our results extend the literature describing the association of reported penicillin allergy with postoperative complications. Most of them focused on the effect of penicillin allergy in patients undergoing orthopedic surgery. ^{Reference Roebke, Malik and Khan5,Reference Blumenthal, Ryan and Li9-Reference Wu, Iloanya and Sanchez15} Some others examined this in patients undergoing colorectal and abdominal surgery, ^{Reference Blumenthal, Ryan and Li9,Reference Khan, Wolford and Ogola16,Reference Schlosser, Maloney and Horton17} cardiac interventions, ^{Reference Blumenthal, Ryan and Li9} oral surgery, ^{Reference Roistacher, Heller and Ferraro18} or gynecologic surgery. ^{Reference Blumenthal, Ryan and Li9} However, to the best of our knowledge, there is no study that has investigated the impact of a reported penicillin allergy in patients who have undergone cancer surgery.

Most of the studies that investigated the impact of reported penicillin allergy on postoperative outcomes defined the occurrence of surgical site infections as the primary end point and were able to demonstrate a higher incidence in patients with penicillin allergy. ^{Reference Roebke, Malik and Khan5,Reference Blumenthal, Ryan and Li9,Reference Roistacher, Heller and Ferraro18} In a 2017 study by Blumenthal and colleagues, the authors retrospectively examined the impact of reported penicillin allergy on the incidence of surgical site infections in 8,385 patients undergoing hip arthroplasty, knee arthroplasty, hysterectomy, colon surgery, and coronary artery bypass grafting and found reported penicillin allergy in 11% of patients. Moreover, in their descriptive statistics, they could show a higher but not significantly risk for infectious complications in patients with reported penicillin allergy compared those without penicillin allergy, with 3.5% versus 2.6%, respectively (p = 0.1). In their multivariable marginal structural model, the effect of reporting penicillin allergy on the development of SSI was fully mediated by receipt of non-beta-lactam antibiotics. The same conclusion was reached by Wilhelm and colleagues, who identified the use of non-beta-lactam antibiotics as perioperative prophylaxis as the sole independent predictor of surgical site infection in their multivariable regression analysis. ^{Reference Wilhelm, Bonsall and Miller19} The use of beta-lactam antibiotics in 94% of our patients with reported penicillin allergy may thus explain why we did not detect a significant difference in the incidence of infectious complications, as shown in other studies.

However, despite recommendations in most guidelines to use beta-lactam antibiotics as perioperative prophylaxis, the literature suggests that non-beta-lactam antibiotics such as vancomycin, clindamycin, gentamycin, or fluoroquinolones are commonly used in patients with reported penicillin allergy. ^{Reference Blumenthal, Peter and Trubiano3,Reference Blumenthal, Ryan and Li9} This is due to the fear of possible cross-reactivity between penicillin and other beta-lactams. However, cephalosporins and other beta-lactams are known to be widely safe to use in patients with established penicillin allergy because the likelihood of immunologic cross-reactivity is very low. ^{Reference Blumenthal, Peter and Trubiano3,Reference Macy20} Thus, a 2021 systematic review and meta-analysis demonstrated a dual antibiotic allergy to penicillin and cefazolin of 0.6% in patients with reported penicillin allergy and 3% in patients with verified penicillin allergy. ^{Reference Sousa-Pinto, Blumenthal and Courtney21} However, the literature recommends preoperative testing of reported penicillin allergy to ensure, if indicated, beta-lactam antibiotic prophylaxis to prevent even the small possibility of a cross-reaction and postoperative infection complications. ^{Reference Reilly, Backer and Basta22} In case of rapid assessment of penicillin allergy in cancer patients requiring urgent surgery, the PEN-FAST score is an established rule that accurately identifies patients at low risk of allergy. ^{Reference Trubiano, Vogrin and Chua23} We believe that allergy de-labeling is particularly important in cancer patients, as they tend to be older and have more comorbidities, exposing them to an even higher risk of complications.

The CCI is known to be a more sensitive alternative to measure overall morbidity instead of counting the number of complications. It is calculated as the sum of all Clavien-Dindo complications weighted by their severity ^{Reference Slankamenac, Graf and Barkun8} . Moreover, this continuous complication score has the advantage of reflecting the overall burden of the postoperative course that affects patients’ health and quality of life ^{Reference Slankamenac, Nederlof and Pessaux24} . In the present study, the influence of reported penicillin allergy on CCI was investigated for the first time, and we recorded a significantly higher CCI in these patients. Fifty percent of the complications recorded in the penicillin allergy group were surgical site infections and more complications were recorded per patient, which explains the higher CCI. Thus, it appears that if an infectious complication occurs, it has a severe downstream effect and add more postoperative complications. This could be explained by the need to manage infection complications with alternative antibiotics, which in turn may promote further adverse postoperative outcomes by additional complications.

Previous studies investigating the impact of reported penicillin allergy on hospitalization duration and treatment costs have reported conflicting results. ^{Reference Roebke, Malik and Khan5,Reference Pérez-Encinas, Lorenzo-Martínez and Losa-García6,Reference Khan, Wolford and Ogola16,Reference Bhathal, Joseph and Nailor25,Reference Sacco, Bates and Brigham26} Our patient groups showed no difference in hospitalization duration and treatment costs, but this should be considered with caution as our cohort consists of patients with different surgical procedures, which in turn are associated with different hospitalization durations and costs and thus may be strong confounders for these end points.

The present study has several limitations. First, the retrospective study design did not include potential confounders for the occurrence of postoperative complications, such as simple or multiple comorbidities. Furthermore, we lack specific data on wound classifications, which could influence surgical site infections and related outcomes. Moreover, it should be noted that patients with different cancer types at different disease stages were included, and that, in addition to the heterogeneity of the surgeries performed, may have an impact on complications, hospitalization duration, and treatment costs. Second, the small single-center cohort allowed only a purely descriptive analysis, so that we recorded an insufficient number of end points, and thus, no analyses with adjustment for possible confounders were possible.

In patients scheduled for elective cancer surgery, reported penicillin allergy is common. Failure to question the unproven antibiotic allergies may impair perioperative outcomes. For this reason, patient and provider education on which reactions constitute a true allergy would also assist in allergy de-labeling. In addition, skin testing and oral antibiotic challenges can be performed to identify the safe antibiotics and to de-label appropriate patients.