Pre-Operative Management of the Penicillin Allergic Patient: A Narrative Review

Introduction

Beta-lactam antibiotics are a commonly prescribed drug class that comprises 65% of the total antibiotic market, amounting to nearly $15 billion US dollars annually.¹ The beta-lactam ring is composed of 3 carbons and 1 nitrogen group, making it highly reactive. This biochemical structure is found in 5 commonly used antimicrobial agents: penicillins, cephalosporins, carbapenems, monobactams, and beta-lactamase inhibitors.²

A penicillin allergy is one of the most frequently reported antibiotic allergies.³ This can present a challenge for physicians when beta-lactams are the first line of treatment. For example, cefazolin, a first-generation cephalosporin, is considered the first line in perioperative surgical prophylaxis and is often not administered to patients with a reported penicillin allergy.^4,5 When identifying a penicillin-allergic patient in the perioperative setting, it is necessary to consider the risks and benefits of administering versus avoiding a cephalosporin. Avoidance may lead to the use of an alternative antibiotic that is less efficacious or associated with avoidable side effects and increased pathogen resistance.⁶ This review summarizes the epidemiology and clinical consequences of a reported penicillin allergy, as well as the value of allergy testing and current recommendations.

Methods

This review includes articles published from 2010 to 2024 analyzing outcomes of patients with reported penicillin allergies and who underwent various orthopaedic procedures. Using PRISMA, 11 relevant studies were identified.

Epidemiology of the Penicillin Allergy

Approximately 30 million people have a documented penicillin allergy in the United States.⁷ Although many patients report an allergy to penicillin, true IgE-mediated or T-lymphocyte hypersensitivity, manifesting as bronchospasm, angioedema, urticaria, or hypotension, is uncommon (approximately 0.5% to 2.0%).^4,8 A retrospective cohort study evaluating allergy documentation found that many patients with a reported penicillin allergy had “unknown” documented as their reaction, as well as hives/rashes, GI upset, and itching. Anaphylaxis was noted to be present in about 5% of patients.⁹ Obtaining accurate reaction histories from patients with a reported penicillin allergy can improve patient outcomes and management of infectious diseases. Patients with isolated, nonallergic symptoms such as non-specific cutaneous rashes, GI upset, pruritus without rash, or remote unknown histories should be considered low-risk and safe to receive cefazolin.^4,10

Misconceptions exist regarding cross-reactivity between penicillin and cephalosporins. Early studies performed in the 1960s and 1970s by Petz and Dash found the immunologic cross-reactivity rate between these two antimicrobials to be 8-18%.^6,11–13 This high cross-reactivity is now believed to be due to contamination of the study drugs during the manufacturing process. Before the 1980s, pharmaceutical companies used the same genus of fungus, Acremonium (formally called Cephalosporium), to create both penicillin and cephalosporins.^6,8 These studies led to a common belief that 10% of patients with a reported penicillin allergy will also experience an allergy to cephalosporins. Many laboratory and cohort studies have investigated the mechanism of cross-reactivity and have found that the R1 side chain of the beta-lactam ring is responsible, not the beta-lactam ring itself (which was initially proposed to be the source of cross-reactivity).¹⁴ Campagna et al. found that the cross-reactivity rate between penicillins and cephalosporins in individuals who report a penicillin allergy is approximately 1% and, in those with a confirmed penicillin allergy, 2.55%.⁶

Increased Risk of Infection for the Penicillin Allergic Patient

The consequences of being labeled as having a penicillin allergy are independently associated with the risk of post-operative infection in elective spine surgery as well as arthroplasty.

Arthroplasty

A retrospective, comparative study by Wu et al. was designed to determine if patients with a self-reported penicillin allergy were more likely to have a prosthetic joint infection (PJI) after total hip arthroplasty (THA), total knee arthroplasty (TKA), or total shoulder arthroplasty than patients without such a reported allergy. They found that patients with a self-reported penicillin allergy were at increased odds of having a PJI within 1 year following TKA and total shoulder arthroplasty (OR 3.9 [95% CI 2.7 to 5.4]; p < 0.01 and OR 1.3 [95% CI 1.1 to 1.4]; p < 0.01 respectively). They did not find an increased odds of PJI within 1 year following THA (OR 1.1 [95% CI 0.9 to 1.3]; p = 0.36).¹⁵

Similarly, Bahoravitch et al. identified patients who underwent total shoulder arthroplasty with a reported allergy to penicillin and found that patients with a penicillin allergy had an increased likelihood of all-cause revision within 30 days (OR: 1.766); revision indicated by PJI was significant within 30 days (OR: 4.811), 90 days (OR: 2.91), 1 year (OR: 2.105), and 2 years (OR: 2.72) when compared to patients without a reported allergy history.¹⁶ They also found that patients had a higher risk of anemia (OR: 1.151), blood transfusion (OR: 1.301), readmission (OR: 1.573), renal failure (OR: 1.28), and SSI (OR: 1.463) within 90 days of TSA.

Elective Spine Surgery

Recently, few studies have investigated the postoperative outcomes after spine surgery in the setting of patient-reported penicillin allergies. Raso et al, identified all patients <85 years who underwent elective posterior lumbar fusion (PLF) or anterior cervical discectomy and fusion (ACDF) with the diagnosis of a penicillin allergy in a retrospective database review. They found that within the PLF cohort group, patients with a penicillin allergy had a significantly increased risk of sepsis (2.6% vs. 2.0%; p = 0.020), urinary tract infection (10.8% vs. 8.4%; p < 0.001), emergency room visits (27.3% vs. 20.2%; p < 0.001) and readmissions (9.6% vs. 6.4%; p < 0.001) within 90 days index of surgery. Similarly, within the ACDF cohort, analysis showed that a penicillin allergy was associated with an increased risk of sepsis (1.8% vs. 1.1%; p < 0.001), emergency room visits (27.2% vs. 20.7%; p < 0.001), and readmissions (6.8% vs. 5.6%; p = 0.003) within 90 days index of surgery.¹⁷

Another study by Roebke et al. identified patients with a reported penicillin allergy who underwent elective posterior lumbar fusions. They found that patients with a reported penicillin allergy group had significantly higher odds of experiencing surgical site infections (SSIs) (3.8% vs 3.1%, OR 1.20 [95% CI 1.07–1.36]; p = 0.002), urinary tract infections (12.3% vs 10.0%, OR 1.16 [95% CI 1.08–1.24]; p < 0.001), sepsis (1.5% vs 1.2%, OR 1.24 [95% CI 1.02–1.50]; p = 0.026), acute kidney injuries (3.8% vs 3.2%, OR 1.19 [95% CI 1.05–1.34]; p = 0.006), readmissions (9.8% vs 8.5%, OR 1.15 [95% CI 1.07–1.25]; p < 0.001), increased inpatient charges (+$4340; p < 0.001), and increased reimbursements (+$1221; p < 0.001).¹⁸

All authors come to similar conclusions that the increased risk of infection found in patients with a reported penicillin allergy is likely due to the use of alternative antibiotics that are less efficacious and suboptimal at covering suspected microorganisms such as gram-negative organisms, S. aureus, S. epidermidis, MRSA, and VRE.

Cefazolin Alternatives

Cefazolin is considered the first line for perioperative surgical prophylaxis given its spectrum of activity against gram-positive and gram-negative aerobic bacteria, as well as activity against anaerobic bacteria such as C. acnes (clinically significant in shoulder arthroplasty patients).⁵ Patients with a reported penicillin allergy often receive alternative antibiotics such as vancomycin or clindamycin. Many studies have investigated the efficacy of these alternative antibiotics. Yian et al. investigated whether infection rates differed between perioperative vancomycin and clindamycin for patients with a reported penicillin allergy versus patients without a penicillin allergy who received cefazolin before undergoing shoulder arthroplasty. They found that patients treated with vancomycin alone did not have a difference in infection rate when compared to patients treated with cefazolin (hazard ratio = 1.17, 95% confidence interval 0.42 to 3.30, p = 0.8), but a higher risk of infection was identified for those treated with clindamycin alone (hazard ratio = 3.45, 95% confidence interval 1.84 to 6.47, P < 0.001).¹⁹

Kheir et al investigated post-operative differences between patients undergoing primary total joint arthroplasty (TJA) who received prophylactic cefazolin versus vancomycin monotherapy. They also looked at vancomycin dosing to determine if patients received adequate or inadequate dosing. They found that among primary TJAs, patients receiving vancomycin had a higher rate of PJI compared with patients receiving cefazolin prophylaxis (adjusted odds ratio, 1.587 [1.004–2.508]; p = 0.048). They also found that the majority of patients given vancomycin prophylaxis received a fixed 1-gram dose of vancomycin and were considered underdosed according to weight-based dosage recommendations. In the patients who were adequately dosed with vancomycin, they found that Methicillin-resistant Staphylococcus aureus (MRSA) did not occur.²⁰

Grant et al. explored the use of cefazolin in patients with a history of penicillin anaphylaxis in the perioperative setting, including a wide array of surgical procedures in varying specialties such as general surgery, orthopedics, urology, and gynecology. They found that there was no statistically significant difference in adverse events (p = .32) with cefazolin compared to other antibiotics. They concluded that based on their investigation, the administration of cefazolin in penicillin-anaphylactic patients for surgical prophylaxis is safe and within the acceptable threshold of minimal risk.²¹

The Value of Allergy Testing

With primary THA volume projected to grow between 71.2% and 145% and TKA between 85% and 147% by the year 2030, reducing expensive postoperative complications has been at the forefront of investigative literature.²² In the United States, standard penicillin allergy testing uses penicilloyl-poly-lysine as the major antigenic determinant as well as dilutions of penicillin G, corresponding to a 95% negative predictive value (NPV). This can then be followed with an observed test dose challenge of amoxicillin, increasing the negative predictive value to nearly 100%.²³ Wyles et al. assessed the efficacy and positive impact of preoperative antibiotic allergy testing to increase cefazolin usage in patients undergoing primary TKA or THA at a single academic institution. They found that among those tested, 96.8% were cleared by the allergist to use cephalosporins in the perioperative period. The study went on to determine that infection-free survivorship was significantly higher among arthroplasties receiving cefazolin compared with non-cefazolin antibiotics (p < 0.001). Similar to previous reports, they found that the overall risk of PJI was 32% lower in patients treated with cefazolin ( p < 0.001) than in antibiotic alternatives.²⁴

Few studies have investigated the economic value of pre-operative allergy testing. Pagani et al. investigated the health and financial burden of total joint arthroplasty complicated by prosthetic joint infection. They estimated the cost of a standard penicillin allergy evaluation to be $225.71. Whereas the cost for treating PJI after THA was estimated to be $34,445. The cost for treating PJI after TKA was estimated to be $27,870. They concluded that at a cost of $225.71, the attributable risk reduction (ARR) for preoperative penicillin allergy testing to be cost-effective was 0.810% for TKA and 0.655% for THA. This corresponds to a number needed to treat (NNT) of 123 and 153 for TKA and THA in suspected-allergy patients, respectively.²³ Similarly, Lee et el. concluded that the implementation of preoperative penicillin allergy testing leads to a potential savings of nearly $37 million to payors in the first year, increasing to about $411.6 million over 10 years and $1.18 billion over a 20-year span.¹⁰

Recommended Treatment Strategies

Many investigators have implemented antibiotic stewardship interventions to optimize cefazolin use in penicillin-allergic patients. Few studies have proposed risk stratification for patients with a reported penicillin allergy.^25–27

Sarfani et al. categorized patients as “low-risk” with the following side effects:

• GI symptoms, headache, muscle aches, or psychiatric disturbances

• Limited hypersensitivity reactions (self-limited cutaneous rash, urticaria >5 yr ago, or itching)

• Nonspecific (unknown reaction, or remote childhood reaction)

“Moderate-risk” patients were categorized by the following:

• Disseminated hypersensitivity or anaphylaxis (swelling of the face or throat, angioedema, difficulty breathing, or urticaria <5 yr ago)

“High-risk” patients were categorized by those who had the following:

• Stevens-Johnson syndrome or toxic epidermal necrolysis (diffuse ulceration, blistering, or pustulosis)

• Multiorgan hypersensitivity response (history of kidney or liver injury)

Low-risk patients were recommended to receive cefazolin despite a history of penicillin allergy. The authors found that 60% of patients fell into the category based on initial history. Moderate-risk patients were recommended to proceed with allergy testing for elective procedures. High-risk patients, found to be <0.5% of patients, should receive vancomycin or clindamycin.²⁵

Penicillin allergy skin testing has previously been discussed to have a significant economic benefit. Khan et al. found that 90% of patients with a negative penicillin skin test can safely receive cephalosporins (as well as other β-lactams). Patients with positive penicillin skin test have a slightly increased risk of reaction to cephalosporins, and therefore they should be administered through a graded challenge or an induction of tolerance procedure.⁸

Conclusion

Patient-reported penicillin allergies are prevalent, however true IgE-mediated or T-lymphocyte hypersensitivity is uncommon. A penicillin allergy has been associated with increased risk of orthopaedic postoperative infection which is attributed to the use of less efficacious antibiotics such as clindamycin and vancomycin.^17,18 Preoperative penicillin allergy testing has been demonstrated to be a cost-effective measure in the prevention of prosthetic joint infection and is recommended for all penicillin-allergic patients in the peri-operative setting.²¹