By Alexandra Morell, MD
In a retrospective review of 3,087 patients undergoing hysterectomy or laparotomy for gynecologic surgery at a single institution who received cefazolin alone or a combination cefazolin and metronidazole for surgical prophylaxis, the combination resulted in a significantly lower surgical site infection rate (4.5% vs. 2.3%; P = 0.0115).
Knisely A, Iniesta MD, Marten CA, et al. Metronidazole and cefazolin vs cefazolin alone for surgical site infection prophylaxis in gynecologic surgery at a comprehensive cancer center. Am J Obstet Gynecol 2024;231:326.e1-326.e13.
Surgical site infections (SSIs) are a major source of surgical morbidity and have significant associated healthcare costs.1 SSIs complicate approximately 2% of hysterectomies, but rates likely are underestimated because of patients presenting to alternative healthcare facilities after initial discharge from surgery.
SSIs can be divided into three main categories: superficial incisional (skin and subcutaneous tissue infection), deep incision (infection involving deeper soft tissues, such as muscle or fascia), and organ/space (infection involving an area other than the incisional layers). Most gynecologic SSIs are superficial incisional infections. Known risk factors for SSIs include obesity, tobacco use, increased surgical time, perioperative glycemic control, steroid use surrounding surgery, poor nutrition, multiple prior surgeries, and perioperative blood transfusion.
Although there are many measures taken to decrease SSIs, preoperative preventive antibiotics are a main strategy. The American College of Obstetricians and Gynecologists (ACOG) currently recommends 2 g of intravenous (IV) cefazolin (or 3 g for patients weighing > 120 kg) for antibiotic prophylaxis prior to hysterectomy (of any surgical approach) and recommends consideration of the same antibiotic regimen for patients undergoing laparotomy without entry into the bowel or vagina.2 Of note, antibiotics are recommended to be re-dosed for longer surgeries (for cefazolin, four hours from initial dose), and for excessive blood loss (quantified as greater than 1,500 mL).
This was a retrospective cohort study at a single cancer center from May 2017 through June 2023 to assess the effect of adding metronidazole to cefazolin for surgical site prophylaxis at the time of gynecologic surgery. Patients were included if they underwent gynecologic surgery (which included open and minimally invasive hysterectomies and laparotomies without hysterectomies) without a planned bowel surgical procedure during the study time frame. Patients were excluded if they had a known penicillin allergy, did not receive any preoperative antibiotics, or had a joint surgery with other surgical teams.
During the study period, in April 2022, a quality improvement initiative was started to change preoperative antibiotics for gynecologic surgeries from cefazolin alone to cefazolin plus metronidazole. Cefazolin was given as a 2-g dose, with an increase to 3 g for patient weight greater than 120 kg. Metronidazole was given as a 500-mg dose prior to surgery. The final cohort was split into two groups: a preintervention group (those who had surgery prior to April 19, 2022) and a postintervention group (those who had surgery after April 20, 2022).
Patient charts were reviewed for demographic, clinical, surgical, and SSI variables. The primary outcome of the study was the 30-day SSI rate. SSIs were categorized based on the Centers for Disease Control and Prevention definitions as superficial, deep, or organ space infections. The secondary outcome of the study was wound-related complications, such as dehiscence, trocar site hernia, or wound seroma.
For statistical analyses, chi-square/Fisher exact tests were used for categorical variables, and t-tests were used for continuous variables. Crude SSI rates were calculated for the entire final cohort, the preintervention and postintervention groups, and multiple subgroups looking at surgery type. SSI rates were compared using chi-square/Fisher exact tests.
A multivariable logistic regression was conducted to assess factors associated with SSI. In addition, two sensitivity analyses were performed. One specifically compared cefazolin alone with combination cefazolin and metronidazole as opposed to the groups divided by time intervention. A second looked at only patients undergoing a hysterectomy.
A total of 3,343 patients were included, with 2,572 patients in the preintervention group and 771 patients in the post-intervention group. The final sensitivity analysis included 3,087 patients (2,470 patients received cefazolin alone and 617 patients received combination cefazolin and metronidazole). A majority of patients were white (n = 2,317; 69%), undergoing surgery for malignant indications (n = 2,044; 61%), were non-smokers (n = 3,147; 94%), and underwent a minimally invasive surgery ( n = 2,197; 66%).
The pre- and post-intervention groups differed regarding current smoking status (6.2% vs. 4.0%, respectively; P = 0.0212), laparotomy as part of surgical approach (35.8% vs. 29.1%, respectively; P = 0.0005), surgical time (mean 177.0 minutes vs. 163.1 minutes, respectively; P < 0.0001), estimated blood loss (186.8 mL vs. 144.6 mL, respectively; P = 0.0004), and use of appropriate antibiotics (90.7% vs. 95.6%, respectively; P < 0.0001).
Comparing the pre-intervention and post-intervention groups, the SSI rate was 4.7% vs. 2.6% (P = 0.0103). For the sensitivity analysis looking at cefazolin alone or combination cefazolin plus metronidazole, the SSI rate was 4.5% vs. 2.3% (P = 0.0115), respectively. On multivariable analysis, factors associated with an increased risk of SSI included being a current smoker (odds ratio [OR], 2.15; 95% confidence interval [CI], 1.50-3.07; P < 0.001), higher body mass index (OR, 1.03; 95% CI, 1.02-1.05; P < 0.0001), and higher hemoglobin A1c level (OR, 1.27; 95% CI, 1.09-1.48; P = 0.0034).
In contrast, factors associated with a decreased risk of SSI included minimally invasive surgical approach (OR, 0.46; 95% CI, 0.34-0.61; P < 0.0001), Hispanic ethnicity (OR, 0.70; 95% CI, 0.50-0.97; P = 0.0324), older age (OR, 0.98; 95% CI, 0.98-0.99; P = 0.0014), and receiving the correct antibiotics (OR, 0.59; 95% CI, 0.38-0.92; P = 0.0193). For the secondary outcome of wound-related complications, a decreased risk was seen in the post-intervention group (OR, 0.79; 95% CI, 0.74-0.84; P < 0.0001).
Commentary
This study demonstrated that the addition of metronidazole to cefazolin statistically reduced SSIs from 4.5% to 2.3% at a single institution. Currently, the standard of care for surgical site prophylaxis at the time of hysterectomy or laparotomy is cefazolin, per ACOG guidelines.2 This study does highlight that other antibiotic regimens potentially may be superior.
Although this study did have a significant proportion of patients with gynecologic malignancies, approximately 34% of patients had benign indications for surgery, so the findings may be generalizable to a broader gynecologic patient population. However, given the retrospective nature of the current study and its data limited to a single site, additional studies replicating the addition of metronidazole to standard of care antibiotics are necessary.
It is well known that bacterial vaginosis is a risk factor for SSI at the time of hysterectomy.2 While treating for a symptomatic bacterial vaginosis prior to surgery makes sense, many patients are asymptomatic. Routine preoperative testing for bacterial vaginosis has been posited as a method for reducing SSIs and can be considered per ACOG, but there are no strict guidelines recommending its use.
Bacterial vaginosis often is treated with 500 mg of oral metronidazole for seven days, but there are other possible options as well, such as metronidazole gel, clindamycin cream, or oral secnidazole.3 One potential strategy for decreasing SSIs could be adding metronidazole to antibiotic prophylaxis in geographic locations where the incidence of bacterial vaginosis is high, especially in the context of the findings of this study.
It is important to remember that there are several strategies other than antibiotic prophylaxis that can be used to reduce SSIs. These include not removing hair at the surgical site if possible, using chlorhexidine gluconate-alcohol-based agents to prepare the skin for surgery, maintaining normal body temperatures throughout surgery, and ensuring strict glycemic control perioperatively (with levels between 110 mg/dL to 150 mg/dL preferred).4
In general, consideration of modifiable risk factors prior to surgery, such as patient body mass index, preoperative hemoglobin A1c, and smoking status, and delaying elective surgeries to optimize patient status regarding these factors before surgery, also is a method for decreasing SSIs. Lastly, SSI bundles, which typically include both prophylactic antibiotic use and many of the strategies listed earlier, also have demonstrated success in SSI prevention.4
REFERENCES
- Steiner HL, Strand EA. Surgical-site infection in gynecologic surgery: Pathophysiology and prevention. Am J Obstet Gynecol 2017;217:121-128.
- [No authors listed]. ACOG Practice Bulletin No. 195 summary: Prevention of infection after gynecologic procedures. Obstet Gynecol 2018;131:1177-1179.
- [No authors listed]. Vaginitis in nonpregnant patients: ACOG Practice Bulletin, Number 215. Obstet Gynecol 2020;135:e1-e17.
- Seidelman JL, Mantyh CR, Anderson DJ. Surgical site infection prevention: A review. JAMA 2023;329:244-252.
Alexandra Morell, MD, is Adjunct Instructor, Department of Obstetrics and Gynecology, University of Rochester Medical Center, Rochester, NY.
