Single-Shot Perioperative Antibiotic Prophylaxis in Patients With a History of Penicillin Allergy

An Algorithm for the Safe Administration of Cefuroxime

Background: Patients with a history of penicillin allergy are often given a less suitable non–ß-lactam antibiotic as single-shot perioperative prophylaxis, for fear of an allergic reaction. This endangers these patients’ health, particularly exposing them to a higher risk of wound infection.

Methods: With the aid of a quality management tool and three iterative “Plan–Do–Study–Act (PDSA)” cycles, we developed and evaluated an algorithm for the safe administration of single-shot cefuroxime as perioperative antibiotic prophylaxis in patients with a history of penicillin allergy.

Results: 6045 anesthesia records were evaluated in three PDSA cycles. 340 patients (5.6%) reported a penicillin allergy in their medical history, and 166 of these patients (2.7% of the total) received perioperative antibiotic prophylaxis: 156 (2.5%) patients were given cefuroxime, and 7 (0.1%) were given another antibiotic, mainly for surgery-specific reasons. In two cases, clindamycin was given despite the algorithm; these two led to quality improvement measures, so that in the third PDSA cycle, over an observation period of 6 months, no patient was denied cefuroxime because they had a penicillin allergy. No allergic reactions to cefuroxime were observed.

Conclusion: As part of a quality management measure, we developed an algorithm that allowed cefuroxime to be given as single-shot perioperative antibiotic prophylaxis to almost all patients with a history of penicillin allergy. Only patients with severe T-cell–mediated reactions should not be given ß-lactam antibiotics.

Cite this as: Rüggeberg A, Lommel K, Tiedt N, Nickel E: Single-shot perioperative antibiotic prophylaxis in patients with a history of penicillin allergy: An algorithm for the safe administration of cefuroxime. Dtsch Arztebl Int 2025; 122: 517–22. DOI: 10.3238/arztebl.m2025.0107

Perioperative antibiotic prophylaxis is a short-time, in general single-shot administration of an antibiotic before a surgical procedure to prevent postoperative wound infections(1). The antibiotic is given with the aim to either kill pathogens contaminating the surgical site or reduce their numbers and prevent their multiplication. According to the German S3-level clinical practice guideline “Perioperative and Peri-interventional Antibiotic Prophylaxis“ published by the Association of the Scientific Medical Societies (AWMF) in 2024, cefazolin and cefuroxime are the main antibiotics used for this purpose, besides aminopenicillins (1). They are highly effective against skin pathogens that can cause wound infections, while having only minimal effects on the normal microbial flora.

The global mean of patients with a history of penicillin allergy is just under 10% of the population; in Europe, the mean is at 5.7% (2). However, an allergy to penicillin is confirmed only in about 5% of patients with a history of penicillin allergy (3). Nevertheless, for fear of an allergic reaction, these patients are often given a single-shot, perioperative antibiotic prophylaxis with a less suitable non-β-lactam antibiotic, such as clindamycin or vancomycin (4, 5, 6). This approach puts patients operated on at risk: They are more likely to develop postoperative wound infections, urinary tract infections and sepsis (5, 7, 8). As a result, the length of hospital stay is prolonged among these patients, readmissions to hospital are more common and the costs to the health care system increase (7, 9). Therefore, Choosing Wisely Canada recommends: “Do not prescribe alternative second-line antimicrobials to patients reporting nonsevere reactions to penicillin when beta-lactams are the recommended first-line therapy” (10).

Many cephalosporins show cross-reactivity with penicillins. Contrary to previous beliefs, this cross-reactivity is not mediated through the β-lactam ring, but arises from similarities in the R1 side chains (11, 12, 13). Cefazolin and cefuroxime, which are mainly used for single-shot perioperative antibiotic prophylaxis (1), have R1 side chains that bear no similarity with penicillins, making cross-reactivity unlikely (13). For example, 39% of 252 patients with allergic, primarily anaphylactic reactions to penicillins tested positive to cephalosporins in allergy testing. However, all of these tested patients tolerated cefuroxime well in provocation testing (14). An IgE-mediated sensitization to penicillin und cefuroxime/cefazolin is most likely coincidental (13). A meta-analysis, including 6001 patients with and 13 149 patients without a history of penicillin allergy, found comparable rates of sensitization to cefazolin in the two groups (0.7% and 0.6%, respectively) (15). Based on this finding, the 2023 Dutch guideline already recommends the administration of cefazolin/cefuroxime in patients with IgE-mediated allergic reaction to penicillins, irrespective of the severity of the allergic reaction (16).

Even though we evaluated only cefuroxime in this study, all theoretical considerations regarding the allergenic risk of cefuroxime also apply to cefazolin.

The aim of this study

In this study, we describe a quality management (QM) project to develop and evaluate an algorithm that allows almost all patients where a single-shot perioperative antibiotic prophylaxis with cefuroxime is indicated to receive one. The only exceptions are patients allergic to cefuroxime and patients who developed a very rare, severe T-cell–mediated delayed hypersensitivity reaction after receiving a β-lactam antibiotic. These exceptional cases must be reliably identified and another antibiotic must then be used.

Methods

Status quo

The Helios Hospital Emil von Behring, an academic teaching hospital of Charité Berlin, has more than 500 beds and provides 10 000 anesthesia services per year. The surgical departments include:

• General surgery
• Vascular surgery
• Hand surgery
• Pediatric orthopedics
• Plastic surgery
• Orthopedics/trauma surgery
• Thoracic surgery.

In accordance with our hospital hygiene standard procedures, cefuroxime is the standard antibiotic agent used for one-shot perioperative antibiotic prophylaxis in most surgical procedures. The current guideline recommends cefuroxime especially in thoracic surgery and colorectal surgery (1). Only in endoprosthetics, cefazolin is recommended as the first-line drug of choice and cefuroxime as an alternative (17). Cefazolin is not kept in stock in our operating rooms to prevent accidental administration.

Problem

In patients with a history of penicillin allergy, it is common practice to not use one of the first-line antibiotics cefuroxime or cefazolin, but administer a non-β-lactam antibiotic instead, typically clindamycin.

Solution of the problem

As part of a continuous, clinically intended quality improvement measure, an algorithm was to be developed and evaluated, using iterative Plan-Do-Study-Act (PDSA) cycles, to administer cefuroxime for single-shot perioperative antibiotic prophylaxis to most patients. All electronically available anesthesia records were analyzed for evaluation with regard to the following information:

• History of penicillin allergy
• Antibiotic administered
• Presence of an allergic reaction.

The PDSA cycle serves as a pragmatic scientific method for problem solving and continuous improvement in complex systems (eMethods) (18).

Data analysis

MS Excel (Excel Office 2019; Microsoft) was used for data analysis. Since our study was part of a quality management measure, no pre-registration as a clinical trial and separate informed consent were required. Patients were informed about the allergy risk during the standard pre-anesthesia discussions.

Results

Figure 1 provides a flow chart of the iterative PDSA cycles performed to develop and evaluate the algorithm; Table 1 shows the results of the individual cycles. Details on the respective cycles can be found in the eMethods section.

Figure 1

Structure of the three Plan-Do-Study-Act cycles

Table 1

Number of anesthesia records, frequency of history of penicillin allergy as well as single-shot perioperative antibiotic prophylaxis used in the various PDSA cycles

Based on a literature search on cefuroxime in patients with penicillin allergy, we developed an algorithm that allowed to administer cefuroxime for single-shot perioperative antibiotic prophylaxis to the majority of patients with a history of penicillin allergy. In patients at risk of a severe IgE-mediated reaction to penicillins, a test dose of 150 mg cefuroxime was administered to the patient in the anesthesia induction room, while monitoring heart rate, blood pressure and oxygen saturation. If this was well tolerated, the total cefuroxime dose was given. Only patients with evidence of severe T-cell–mediated reactions should not be given ß-lactam antibiotics.

Both in the first PDSA cycle (573 anesthesia records, 22 cases with documented penicillin allergy) and in the second PDSA cycle (1287 anesthesia records; 80 cases with documented penicillin allergy), a violation of the algorithm occurred, triggering QM measures (Figure 1). No further violation of the algorithm occurred in the following six months (4185 anesthesia records; 238 cases with documented penicillin allergy).

In the analysis of a total of 6045 anesthesia records, 340 (5.6%) patients with a history of penicillin allergy were identified. Of these, 166 (2.7%) had received perioperative antibiotic prophylaxis. Of those, 156 (2.5%) patients received cefuroxime, 7 (0.1%) primarily received another antibiotic agent for surgical reasons and in two cases clindamycin was administered in deviation from the recommendations of the algorithm.

Table 2 lists the characteristics of the 238 patients with a history of penicillin allergy from the third PDSA cycle. In accordance with the algorithm, it was possible to administered cefuroxime to all patients with a history of penicillin allergy in whom a single-shot perioperative antibiotic prophylaxis with cefuroxime was indicated. In three cases with a history of severe dyspnea or significant drop in blood pressure/anaphylaxis, a test dose of 10% of the cefuroxime dose was administered as a short infusion over five minutes, followed by monitoring for 30 minutes. Since no allergic reactions occurred, all three patients then received the remaining cefuroxime dose ten minutes prior to the induction of anesthesia. Given the lack of a pathophysiological justification for the test dose in the algorithm and the fact that the Dutch guideline on antibiotic allergy published in 2023 does no longer recommend a test dose with cefuroxime (16), the algorithm was adapted accordingly (Figure 2).

Figure 2

Final algorithm for the single-shot administration of cefuroxime in patients with a history of penicillin allergy

Table 2

Characteristics of 238 patients with a history of penicillin allergy in the third cycle

Discussion

At 5.6%, the incidence of a history of penicillin allergy found in our study is consistent with the incidence rates for Europe reported in the literature (2). In almost half of the patients in this study, a single-shot perioperative antibiotic prophylaxis was indicated. During the study period, cefuroxime could be administered safely to all patients with a history of penicillin allergy and an indication for single-shot perioperative antibiotic prophylaxis with cefuroxime, if the algorithm was applied correctly. The two cases, in which clindamycin was given to patients with a history of penicillin allergy in deviation from the recommendations of the algorithm highlight the need to evaluate measures systematically and to identify problem areas in a timely and sustainable manner. Three patients received a test dose in the third PDSA cycle that was unremarkable in all cases. In twelve further patients, the algorithm would have allowed a test dose to be administered, but that did not happen. These twelve patients also tolerated cefuroxime well.

Cross-reactivity between penicillins and cefuroxime

At the heart of the algorithm is the notion that frequently a hypersensitivity to penicillins is not sufficiently established and that there is no evidence of Ig E-mediated cross-reactivity between penicillins and cefuroxime (12). In the past, patients with penicillin allergy often experienced allergic reactions to cephalosporins too. This led to the assumption that the ring structure common to all β-lactam antibiotics was the most important allergenic structure (19). However, this alleged cross-reactivity was the result of contamination of cephalosporins with benzylpenicillin during the manufacturing process (13).

The cross-reactivity between penicillins and cephalosporins is mainly based on similarities in the R1 side chains (11, 12). Yet, penicillin and cefuroxime differ in their R1 side chains; this also applies to cefazolin. For this reason, cross-reactivity between penicillins and cefuroxime seems very unlikely. An IgE-mediated sensitization to penicillin und cefuroxime/cefazolin is most likely coincidental (13). A meta-analysis, including 6001 patients with and 13 149 patients without a history of penicillin allergy, found comparable rates of sensitization to cefazolin in the two groups (0.7% and 0.6%, respectively) (15). Accordingly, a cross-allergy cannot be substantiated either pathophysiologically (different R1 side chains) or clinically (the incidence of cefazolin allergy is in patients with and without a history of penicillin allergy at the same level).

The German S3-level clinical practice guideline “Perioperative and Periinterventional Antibiotic Prophylaxis in Surgery“ shows in Table 18 that it is possible to administer cefazolin and cefuroxime based on the medical history; however, it remains cautious in its recommendation for patients with a history of systemic allergic reaction (1), citing an increased rate of allergic reactions in patients with confirmed penicillin allergy. However, other authors think that this elevated rate is more likely to be caused by multiple drug hypersensitivity syndrome (15, 20). In agreement with this view, the Dutch guideline classifies the use of cefazolin and cefuroxime in patients with a history of penicillin allergy as safe, regardless of the severity of the allergic reaction (16). In our study, all patients with a history of severe systemic reaction to penicillin tolerated the administration of cefuroxime well.

A common recommendation for the management of patients with a history of penicillin allergy is to perform a PEN-FAST test (21). Solely based on the patient’s medical history, the PEN-FAST score provides a predictive probability for the presence of a penicillin allergy and thus makes a substantial contribution to the delabeling of penicillin allergy. In all patients with a history of penicillin allergy, it is strongly recommended to use the PEN-FAST score. This test is useful in situations where it was decided to give penicillin derivatives or an antibiotic cross-reacting with penicillins, such as cefaclor, to patients with a history of amoxicillin intolerance (16, 22). However, it is not necessary to obtain a PEN-FAST score for making the decision to administer a single dose of antibiotic agents that do not cross-react with penicillins, such as cefuroxime and cefazolin.

Most of the literature states that a test dose of cefuroxime or cefazolin should be administered in patients with a history of severe IgE-mediated allergic reactions to penicillin (23). We do not see any real indication for a test dose. In case of an IgE-mediated reaction to penicillin, affected patients will tolerate the cefuroxime test dose very well. Our study confirmed this observation. Nevertheless, we included the test dose in the first algorithm (see eMethods), because it is recommended in the literature (23). In addition, this approach addresses the fears and concerns of both patients and staff, thereby increasing acceptance of the algorithm. In our hospital, however, the test dose was only administered in 20% of the eligible cases.

While our study was being conducted, the Dutch guideline on the approach to suspected antibiotic allergy was published (16). This guideline recommends the administration of cephalosporins without similar side chains, such as cefazolin and cefuroxime, without test dose, even in patients with penicillin allergy and a history of severe IgE-mediated reaction, such as anaphylaxis. We therefore adapted our algorithm at the end of the third PDSA cycle accordingly (Figure 2) and removed the option of a test dose without replacement.

Differentiating between an IgE-mediated immediate reaction within minutes or a few hours accompanied by acute skin manifestations—which usually resolve within 24 hours without scar formation—and T-cell–mediated reactions is of clinical importance. Severe T-cell–mediated reactions develop within days or weeks, frequently showing mucous membrane and/or organ involvement and usually requiring inpatient treatment (24, 25). Patients who experienced severe T-cell–mediated hypersensitivity reactions after penicillin administration should not receive cephalosporins (1, 16). Here again, a β-lactam ring-based cross-reaction between penicillins and cephalosporins was assumed in the past; however, the reaction is likely to also be determined by the side chains (13). Nevertheless, when assessing the risk, it is useful and recommended to avoid administering β-lactam antibiotics for perioperative antibiotic prophylaxis because of these very rare reactions, including severe, in some cases life-threatening conditions, such as Stevens-Johnson syndrome and toxic epidermal necrolysis, and because of the delayed nature of the reactions (in outpatients, symptoms often only appear after discharge) (1, 16).

The label “penicillin allergy” by itself increases morbidity and mortality

Not only are patients with a history of penicillin allergy put at risk by the administration of less suitable non-β-lactam antibiotics prior to surgery, as described in the introduction (26), a penicillin allergy label in the medical record was by itself associated with prolonged lengths of hospital stay and poorer outcomes (27, 28). The quality of life of these patients is often negatively impacted by fear of an anaphylactic reaction (29).

However, if patients receive first-line perioperative antibiotic prophylaxis despite their history of penicillin allergy, the rate of treatment failure does not appear to be increased (30). Preoperative allergy testing of all surgical patients with a history of penicillin allergy, which is frequently recommended (13, 31, 32), would involve up to 5% of all surgical patients. This would by far exceed the capacities of the facilities available for drug allergy testing. In addition, these laboratory capacities would no longer be available for patients with an urgent need for allergy testing, putting these patients at risk of harm. The use of the algorithm allows for the administration of cefuroxime as first-line perioperative antibiotic prophylaxis without prior allergy testing.

Risk stratification

By classifying patients with a history of penicillin allergy in the flow chart (Figure 2), it is possible to stratify risk into one of the following two groups: contraindication to β-lactam antibiotics versus no contraindication to the administration of cefuroxime to patients with known penicillin allergy.

If there is no contraindication to the use of cefuroxime, this should be clearly noted on the anesthesia records. Adding a justification helps to make this note more understandable; for example: “Urticaria, Quincke‘s edema and dyspnea after taking amoxicillin 15 years ago“. Postoperatively issuing a medical certificate, stating that the one-shot administration of cefuroxime was well tolerated, may be considered in these patients (23). Besides this important information for future antibiotic treatments, this would also reduce the fear of antibiotic-related anaphylaxis experienced by patients scheduled for surgery, thereby increasing their quality of life. It should be recommended that these patients have their known penicillin allergy investigated further.

Limitations

The algorithm is exclusively designed to answer the question of whether cefuroxime can be used for single-shot perioperative antibiotic prophylaxis in patients with a history of penicillin allergy. From a pathophysiological perspective, this algorithm can also be applied to cefazolin. Cefuroxime and cefazolin are the most important medications for perioperative antibiotic prophylaxis (1); for antibiotic therapy, other β-lactam antibiotics are often better suited. The algorithm, however, is neither applicable to patients with a history of an allergy to another antibiotic nor to the administration of other cephalosporins. Consequently, while this algorithm is not designed to delabel penicillin allergy, it does serve as an important interface in the sense of antibiotic stewardship by preventing postoperative wound infections.

Conclusion for clinical practice

By applying the algorithm, the unjustified administration of non-β-lactam antibiotics for single-shot perioperative antibiotic prophylaxis, which is solely based on the “medical record” diagnosis “penicillin allergy“, can be avoided. In almost all patients with a history of penicillin allergy, it was possible to safely administer cefuroxime as single-shot perioperative antibiotic prophylaxis during anesthesia induction with close monitoring of the patient. From a pathophysiological perspective, the same applies to cefazolin, but we did not address this question in our study. However, it is critical to reliably identify the few patients who are put at risk by the administration of β-lactam antibiotics and to treat them with an alternative medication.

eFigure 1

Structure of the three iterative PDSA cycles of this study

eFigure 2

Algorithm in the first PDSA cycle for the administration of cefuroxime in patients with a history of penicillin allergy

Conflict of interest
The authors declare no conflict of interest.

Manuscript received on 21 December 2024; revised version accepted on 12 June 2025

Translated from the original German by Ralf Thoene, M.D.

Correspondence
Dr. med. Anne Rüggeberg

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