Antimicrobial Stewardship in Patients with Penicillin Allergy Undergoing Hysterectomy for Benign Indications

Introduction

Allergies to antibiotic medications are common and represent a challenge to the treatment of infectious diseases. Penicillin allergy is the most commonly reported drug allergy in the United States and is reported by 5%–10% of the population.^1,2 Patients' personal reports of penicillin allergy have low diagnostic accuracy and only 10%–20% of patients reporting allergy have positive penicillin skin testing.^3,4 This discrepancy in reporting is often due to viral symptoms present at the time penicillin was prescribed, often during childhood illness, or poor recollection of a reaction that occurred many years prior. Over-reporting and propagation of unverified allergies can affect patient outcomes and lead to unnecessary costs and health care utilization.^5–8

Hysterectomy is one of the most commonly performed surgical procedures for reproductive-age women, second only to cesarean section. ⁹ To prevent surgical-site infections at the time of hysterectomy, cefazolin is recommended as the first-line prophylactic antibiotic therapy.^10,11 It is a first-generation cephalosporin, and belongs to the class of β-lactam antibiotics—a penicillin derivative. For patients with type 1 immediate hypersensitivity (immunoglobulin [IgE]–mediated) reactions—anaphylaxis, bronchospasm, or hives—the American College of Obstetricians and Gynecologists (ACOG) recommends alternative antibiotic prophylaxis. Alternatives include a combination of clindamycin or metronidazole with gentamycin or aztreonam. For patients with non–IgE-mediated penicillin allergy, cephalosporin prophylaxis is preferred.

Despite published recommendations, patients with non–IgE-mediated penicillin allergies or nonspecific reactions may receive antibiotic prophylaxis intended for patients with anaphylactic reactions prior to surgery. ¹² The primary objective of this study was to evaluate the incidence of appropriate use of prophylactic antibiotic therapy prior to hysterectomy in patients with self-reported penicillin allergy. Secondary objectives were to determine predictors of receiving appropriate prophylactic antibiotic therapy and the incidence of preoperative penicillin allergy testing.

Materials and Methods

This was a retrospective cohort study of all patients with self-reported penicillin allergy undergoing hysterectomy for benign indications, from January 1 to December 31 of 2018, at a tertiary academic center. The study was approved by the center's institutional review board.

The electronic patient database was queried. The cohort of patients was identified using current procedural terminology (CPT) codes for hysterectomy, with a penicillin allergy listed in the medical charts. Cases of women with suspected malignancy or concomitant bowel surgery were excluded. Patients who were already receiving antibiotics for another indication at the time of surgery were also excluded.

Patients' demographics, clinical characteristics, medical comorbidities, operative details and performance status as measured by the American Society of Anesthesiologists (ASA) classification score ¹³ were collected. Allergic reactions to penicillin and other medications were recorded. A medical comorbidity was defined to include any of the following: diabetes mellitus; hypertension; heart disease (coronary-artery disease, myocardial infarction, arrhythmia, valvular disease, and heart failure); renal disease; chronic steroid use; chemotherapy within 2 weeks; and dementia.

Queries to the database included: Methicillin-resistant Staphylococcus aureus (MRSA) carrier status; total number of medication allergies; and patient-reported reaction to penicillin. Preoperative penicillin allergy testing was defined as documentation of skin testing, oral-challenge testing, or formal evaluation by an allergy and immunology specialist prior to surgery.

Operative details were collected, including indication for hysterectomy, surgeon subspecialty training, and mode of surgery (vaginal, laparoscopic, robotic-assisted, and abdominal), and mesh implantation. Postoperative events were collected, such as surgical-site infection (SSI; superficial or deep infection) in the 6 weeks after surgery, Clostridium difficile infection, and length of stay. SSIs were classified per Centers for Disease Control and Prevention (CDC) guidelines ¹⁴ as infections of the surgical incision (defined as infection of the skin or subcutaneous tissue) or target organ space (defined as infection of the vaginal cuff).

For the study's primary outcome, the antibiotic(s) used prior to surgery were recorded from the intraoperative anesthesia records. At the current authors' institution, preoperative antibiotics are ordered by the surgeon prior to a procedure and are discussed during the preoperative huddle when both the surgical and anesthesia care teams agree with the final antibiotic(s) choice. Patients were categorized based on definitions made a priori: (1) appropriate antibiotics (AA) and (2) inappropriate antibiotics (IA).

Appropriate prophylactic antibiotic usage was determined based on if the documented allergy was IgE-mediated (anaphylaxis/bronchospasm or hives) or non–IgE-mediated (rash, gastrointestinal upset, dizziness, headache, other, and unspecified/unlisted allergy). The AA group was subcategorized for IgE-mediated penicillin allergy as treatment with (1) metronidazole or clindamycin with either gentamycin or aztreonam or (2) ciprofloxacin and metronidazole prior to June of 2018.

While ciprofloxacin +and metronidazole is not currently considered to be an appropriate preoperative antibiotic regimen for patients with IgE-mediated penicillin allergies, this was the recommendation prior to the ACOG's updated guidelines in June 2018. The non–IgE-mediated penicillin allergy group, had an AA group of patients who received cefazolin. Any antibiotic treatment other than the regimen listed above per the allergy type were placed in the IA group. (Table 1).

Approximately normally distributed continuous measures were summarized, using means and standard deviations and compared between 2-sample t-tests. Continuous measures that showed departure from normality and ordinal measures were summarized, using medians and quartiles or frequencies and percentages, and compared using Wilcoxon rank-sum tests. Categorical factors were summarized using frequencies and percentages and were compared using Pearson's χ ² tests or Fisher's exact tests. One exploratory logistic regression was fit predicting the appropriate antibiotics use. Candidate variables including race (Caucasian versus Non-Caucasian), MRSA carrier, presence of (any) medical comorbidities, ASA (1 or 2 versus 3 or 4), and total number of antibiotics allergies (≥ 3 versus <3). Backward selection with staying p-values <0.10 was applied.

All analyses were performed using SAS (version 9.4, SAS Institute, Cary, NC, USA) and a p < 0.05 was considered to be statistically significant.

Results

There were 230 patients whose cases met the inclusion criteria for the study. Appropriate antibiotics were administered to 42.6% (n = 98) of the patients, and 57.4% (n = 132) of patients received inappropriate antibiotics. Preoperative penicillin testing was performed in 3.9% of patients (n = 9). Table 2 shows patients' demographics and clinical data. There were no significant differences in age, race, body mass index, MRSA carrier status, ASA class, or preoperative renal function between the groups. In the AA group, there was a significantly higher percentage of patients with heart disease (n = 11, 11.3%), compared to the IA group (n = 5, 3.8%); p = 0.03. There was no significant difference in the incidence of medical comorbidities between the AA and IA groups.

For patients in the AA group, the median number of antibiotic allergies was 2 (interquartile range [IQR]: 1–3) compared to 1 (IQR: 1–2) patient in the IA group (p = 0.01). More patients in the AA group had ≥3 documented antibiotic allergies, compared to the IA group (27.8% versus 14.3%, p = 0.01).

With respect to perioperative characteristics, there were no significant differences between the 2 groups. The most-common indication for surgery was abnormal uterine bleeding/fibroids (n = 119, 51.7%), with no significant difference between the 2 groups (p = 0.87). The most-common modality of surgery was laparoscopic hysterectomy (n = 101, 43.9%), with no significant differences in mode of surgery between the 2 groups (p = 0.08). Additional variables, such as mesh implantation, surgeon type (generalist versus subspecialist), and length of stay, did not differ between the 2 groups.

With respect to the reactions to penicillin, 99 (43.0%) women had IgE-mediated hypersensitivity reactions and 131 (57.0%) has non–IgE-mediated reactions (Table 3). In the AA group, 69.4% (n = 68) had IgE-mediated hypersensitivity reaction to penicillin, compared to 23.5% (n = 31) in the IA group (p < 0.001). Conversely, 30.6% (n = 30) of patients in the AA group had non–IgE-mediated reactions to penicillin, while 76.5% (n = 101) in the IA group had non–IgE-mediated reactions (p < 0.001). Thus, patients with IgE-mediated allergies received appropriate antibiotics more frequently, while patients with non–IgE-mediated allergies received inappropriate antibiotics more frequently.

Documented clinical reactions were compared between the AA and IA groups. In the AA group, there was a significantly higher proportion of patients with IgE-mediated allergy, such as anaphylaxis (n = 23, 23.5%) and hives (n = 45, 45.9%), compared to the IA group (p < 0.001). Patients who received appropriate antibiotics had a lower incidence of reported rash (16.3% versus 32.6%), other (5.1% versus 14.4%) or unspecified allergy (6.1% versus 26.5%), compared to the IA group (p = 0.01, p = 0.03, and p < 0.001, respectively).

Of the entire cohort, no patient had an allergic reaction as a result of preoperative antibiotic prophylaxis. Among the patients with non–IgE-mediated penicillin allergies who received cefazolin, not one had an allergic response to cefazolin. Four (1.7%) patients developed SSIs. There was a higher incidence of SSI in the IA group, compared to the AA group (3% versus 1%), although this was not statistically significant (p = 0.40). All patients who developed SSIs received non-cephalosporin antibiotic prophylaxis at the time of surgery. The SSIs included 1 deep infection and 3 superficial infections as defined by the CDC. ¹⁴

An exploratory logistic regression was fit predicting appropriate prophylactic antibiotic use (Table 4). While holding other variables constant, patients with ≥3 documented antibiotic allergies had 2.5-times higher odds of receiving appropriate antibiotics, compared to those with <3 allergies (odds ratio [OR]: 2.50; confidence interval [CI]: 1.15, 5.42; p = 0.02). The presence of any comorbidity also resulted in doubled odds of receiving appropriate antibiotics (OR: 1.97; CI 1.06, 3.67; p = 0.03). Patients with IgE-mediated allergies, such as anaphylaxis and hives, had higher odds of receiving appropriate antibiotics (OR: 8.94: [CI: 3.53, 22.63] and OR: 6.24 [CI: 3.17, 12.29], respectively). Patients who were MRSA carriers had lower odds of receiving appropriate antibiotics (OR: 0.16 [CI 0.03. 0.91]).

Discussion

In this retrospective cohort study of patients with reported penicillin allergy undergoing hysterectomy for benign indications, more than half of the women received inappropriate antibiotic prophylaxis for SSIs. Patients with a high number of listed antibiotic allergies, patients with cardiac disease, and patients with IgE-mediated hypersensitivity reactions had higher odds of receiving appropriate prophylaxis.

While the current study is the first to demonstrate that patients with documented penicillin allergy undergoing hysterectomy commonly receive nonstandard antimicrobial therapy, these findings have been seen in other populations. Studies in Group B Streptococcus (GBS) colonized pregnant women with penicillin allergies demonstrated that more than half of women with non–IgE-mediated, vague, or unlisted allergies received inappropriate antibiotics for intrapartum GBS prophylaxis.^15–17 Similar trends have been demonstrated in general surgery and otolaryngology where patients with penicillin allergies were less likely to receive appropriate antibiotic prophylaxis and ultimately had higher rates of SSIs.^12,18,19 Together, these results indicate that this is a highly prevalent issue across surgical subspecialties.

In the current study, women with IgE-mediated reactions had higher odds of receiving appropriate antibiotic prophylaxis. Conversely, inappropriate antibiotic prophylaxis most commonly occurred when a patient had a non–IgE-mediated allergy, such as a childhood reaction, rash, or gastrointestinal upset. These findings suggest that providers are keenly aware of the risks of anaphylaxis but less aware of the risks of using of second-line antibiotics in patients with non–IgE-mediated reactions to penicillin. Furthermore, women with ≥3 antibiotic allergies had higher odds of receiving appropriate antibiotic prophylaxis. It is possible that longer allergy lists prompt providers to make careful considerations on the choice of antibiotics.

It was interesting to find that patients with positive MRSA carrier status were more likely to receive inappropriate antibiotic prophylaxis. This may be a consequence of attempts to cover MRSA with non-cephalosporin antibiotics. Although this is an important consideration if MRSA status is known prior to surgery, these patients are still candidates for cephalosporin prophylaxis with the addition of vancomycin if surgery via a skin incision is planned.^10,11

Use of inappropriate antibiotics is not without consequence. The impact of inappropriate antibiotic administration on patient outcomes has been demonstrated in both surgical and nonsurgical settings. Patients with listed penicillin allergy have increased rates of infection with antimicrobial-resistant bacteria, C. difficile infection, treatment failure and increased health care utilization costs and length of hospital stay.^5–8 In gynecology, women who received ß-lactam alternatives at the time of hysterectomy had higher incidence of postoperative infection. ²⁰ Data from a large retrospective study showed that addition of metronidazole to cefazolin reduced the risk adjusted rate of SSI further after hysterectomy. ²¹

These studies highlight the importance of careful preoperative antibiotic selection further for optimization of postoperative outcomes. Although the current study did not show a significant difference in rate of SSI between the 2 groups, this study was not powered for this outcome. Continued research on this subject would be valuable and is warranted for gynecologic specialties.

The current study highlights a need for better medical documentation and health care provider education. When verifying medication allergies, providers should document allergic response by IgE-mediated and non–IgE-mediated reactions carefully. ²² Providers should also use this time to educate patients on the importance of an accurate medication allergy list and its impact on future care.^12,23,24 With regard to the high rates of patients with non–IgE-mediated allergies receiving inappropriate antibiotic prophylaxis, the current authors suspect that this may reflect providers' concern for crossreactivity between cephalosporins and penicillins. Guidelines for antibiotic administration are supported by many studies demonstrating the safety of cephalosporin use in patients with self-reported penicillin allergy.^25–27

It has been suggested that crossreactivity between penicillin and cephalosporins in early studies may be attributed to penicillin contamination,^28,29 and the majority of patients with anaphylactic reactions to cephalosporins do not have documented penicillin allergies.^27,30 Overall, only 1% of patients with listed penicillin allergy and 2.55% of patients with confirmed penicillin allergy have had adverse reactions to cephalosporins. ³¹ Given that hysterectomy is the second most-common surgical procedure performed in women, optimizing care surrounding this procedure is highly impactful.

Most of the current authors' surgical cases involved fellows, residents, and trainees, who should all be empowered to partake in preoperative decision-making to ensure that patients receive the correct and recommended antibiotics. Strides toward best practices can be achieved through adherence to national guidelines for antibiotic prophylaxis ¹¹ and stringent review of medication allergies preoperatively. Continued medical education and intermittent auditing may ensure that antibiotic administration is appropriate.

Another area of potential improvement is the use of preoperative penicillin allergy testing. In 2019, the American Academy of Allergy, Asthma and Immunology, the Infectious Diseases Society of America, and the Society for Healthcare Epidemiology of America recommended penicillin-allergy evaluation during routine care. ³²

In the current study, very few patients underwent preoperative penicillin-allergy evaluation, representing an area of improvement in perioperative management as the current authors' institute does not currently have a protocol for preoperative allergy evaluation. In a large meta-analysis, >94% of patients were able to tolerate penicillin-derived medications upon oral challenge. ³³ Preoperative penicillin testing can achieve the ultimate goal of administering narrower-spectrum antibiotics to reduce the incidence of SSIs and C. difficile infections.

Strategies for investigation of penicillin allergy before surgery are both effective and cost-effective. The 2 most-common methods of penicillin testing include skin testing and a supervised oral amoxicillin challenge. While skin testing is the conventional method of evaluating drug allergies, it is time prohibitive for patients and costly to the health care system. ³⁴ The alternative to conventional skin testing is a supervised oral amoxicillin challenge. With this outpatient strategy, patients take 10%, 50%, then 100% of a 500-mg amoxicillin dose in 20 minute-increments, and are observed for 1 additional hour for allergic reactions. This strategy is less expensive and less time consuming than penicillin-skin testing, requiring only a single outpatient visit.^35,36

Strengths of this study included an analysis of the practice patterns at an academic tertiary-care center with numerous providers, both within generalist and subspecialist divisions. Because the hospital system utilizes a single electronic medical record system, it was possible to capture any referrals, prior testing, and complications related to penicillin allergies.

Limitations of this study included weaknesses inherent to its retrospective design. Some patients may have presented elsewhere for penicillin testing. Some demographic data were not available for all subjects, including 3 patients without documented race or MRSA status and 1 patient without documented ASA class. These numbers represented a very small portion of the sample size and were unlikely to influence the statistical analyses. In addition, this was a single-center study; however, given that this was a large academic training center, the poor adherence to ACOG guidelines is likely reflective of systemwide issues, rather than individual practice patterns, and thus the current study's findings may not be generalizable.

Finally, the ACOG recommendations for appropriate alternative antibiotics were updated during the midway point of the study's time frame. However, it was possible to mitigate this with the use of strict definitions for the appropriate antibiotic group, therefore the overall aims of the study were not affected by this update.

Conclusions

The findings of the current study demonstrate the need for improved preoperative practices in patients with penicillin allergies undergoing hysterectomy. In this cohort, more than half of the patients received inappropriate antibiotics at the time of hysterectomy and very few received preoperative penicillin-allergy evaluation. Given the number of hysterectomies performed annually in the United States, updates to practice patterns can be highly impactful.