Should metronidazole be used pre-operation in hysterectomy?

Comment by InpharmD Researcher

Available societal guidelines recommend single-dose cefazolin as the standard prophylactic agent for hysterectomy, with metronidazole reserved as part of alternative regimens only when cephalosporins cannot be used. Evidence on adding metronidazole to standard prophylaxis is mixed, with some randomized trials of vaginal metronidazole showing no reduction in postoperative symptoms or infections, while some other studies report lower surgical site infection rates when metronidazole is added to the stand-of-care antibiotic. Comparative data do not clearly favor one regimen, and guideline panels have not issued a recommendation supporting routine use of metronidazole in this setting.

Background

Multisociety guidelines for antimicrobial prophylaxis in surgery published in 2013 provide comprehensive recommendations on prophylactic agents to use based on type of procedure. For women undergoing vaginal or abdominal hysterectomy, whether through an open or laparoscopic approach, the recommended prophylactic antibiotic regimen is a single dose of cefazolin. Alternative options include cefoxitin, cefotetan, or ampicillin-sulbactam. For patients with a beta-lactam allergy, the alternatives are combinations such as clindamycin or vancomycin with an aminoglycoside, aztreonam, or a fluoroquinolone, and metronidazole with an aminoglycoside or a fluoroquinolone. The strength of evidence supporting this prophylactic approach is rated as A, indicating strong evidence for effectiveness. [1]

The 2018 American College of Obstetricians and Gynecologists (ACOG) Practice Bulletin presents comprehensive guidelines for the prevention of infection following gynecologic procedures. Patients undergoing various types of hysterectomy, whether vaginal, abdominal, laparoscopic, or robotic, including supracervical hysterectomy, are advised to receive single-dose antimicrobial prophylaxis to minimize postoperative infections. Currently, cefazolin is recommended as the primary prophylactic antibiotic for hysterectomies, backed by evidence from over 30 prospective randomized clinical trials and four meta-analyses. These studies demonstrate that prophylactic antibiotics effectively reduce postoperative infectious morbidity and shorten hospital stays in women undergoing these procedures. A Cochrane review identified significant reductions in postoperative infections, including abdominal wound infections, urinary tract infections, pelvic infections, and postoperative fevers, for abdominal and vaginal hysterectomies when compared to placebo. However, the review did not establish the superiority of any specific antibiotic regimen. While the panel did not provide a specific recommendation for metronidazole in this setting, it noted that a combination of metronidazole or clindamycin with gentamicin or aztreonam is generally recommended for patients with contraindications to cephalosporins. [2]

A 2017 Cochrane review assessed the effectiveness and safety of antibiotic prophylaxis in hysterectomy, incorporating 37 randomized controlled trials (RCTs) with 6,079 women, revealing varied evidence quality from very low to moderate. The review found that antibiotic prophylaxis notably reduced the risk of postoperative infections, urinary tract infections, pelvic infections, and postoperative fevers across both vaginal and abdominal hysterectomies. Head-to-head comparisons between different antibiotics, as well as single versus combined antibiotic regimens, were limited and showed no significant differences, except for fewer infections with cephalosporins compared to antiprotozoals (e.g. metronidazole, anitroimidazole) in vaginal hysterectomy. Most comparisons lacked robust evidence on adverse effects due to methodological limitations and imprecision. It was highlighted that there is insufficient evidence to determine whether prophylactic antibiotic use affects rates of adverse effects, or to identify the safest and most effective individual antibiotic, dose regimen, or route of administration. The review included studies that were 14 years old at the time of the search, suggesting that their findings may not align with current perioperative and postoperative care practices, nor do they reflect current locoregional antimicrobial resistance patterns. [3]

References:

[1] Bratzler DW, Dellinger EP, Olsen KM, et al. Clinical practice guidelines for antimicrobial prophylaxis in surgery. Am J Health Syst Pharm. 2013;70(3):195-283. doi:10.2146/ajhp120568
[2] ACOG Practice Bulletin No. 195: Prevention of Infection After Gynecologic Procedures. Obstet Gynecol. 2018;131(6):e172-e189. doi:10.1097/AOG.0000000000002670
[3] Ayeleke RO, Mourad S, Marjoribanks J, Calis KA, Jordan V. Antibiotic prophylaxis for elective hysterectomy. Cochrane Database Syst Rev. 2017;6(6):CD004637. Published 2017 Jun 18. doi:10.1002/14651858.CD004637.pub2

Literature Review

A search of the published medical literature revealed 8 studies investigating the researchable question:

Should metronidazole be used pre-operation in hysterectomy?

Level of evidence

B - One high-quality study or multiple studies with limitations  Read more→



Please see Tables 1-8 for your response.


 

PROJECT PREVENT: a randomized controlled trial of preoperative vaginal metronidazole to decrease patient issues and infections after hysterectomy

Design

Randomized controlled trial

N= 133

Objective

To evaluate if vaginal metronidazole for 5 days before hysterectomy decreases postoperative infections and patient issues

Study Groups

Vaginal metronidazole (n= 68)

Control (n= 65)

Inclusion Criteria

Candidates 18 years or older scheduled for subtotal or total hysterectomy, including laparoscopic, robotic, open, and vaginal approaches

Exclusion Criteria Hysterectomy scheduled within 5 days from the date of consent
Methods

Patients were randomized 1:1 to receive metronidazole 0.75% gel intravaginally once nightly for five nights before hysterectomy in addition to standard perioperative intravenous prophylactic antibiotics, or to receive standard care alone. Follow-up continued for 8 weeks postoperatively.

Duration

July 2020 to September 2022

Outcome Measures

Primary: Composite of patient-reported issues and/or documented postoperative infection up to 8 weeks

Secondary: Individual rates of patient-reported issues and documented postoperative infections

Baseline Characteristics   Vaginal metronidazole (n= 68)

Control (n= 65)

Age, years 55.5 ± 12.2

52.4 ± 12.9

BMI, kg/m2 31.8 ± 6.2

31.9 ± 9.4

Indication for surgery

Abnormal bleeding/fibroids/adenomyosis/pelvic pain/endometriosis

Prolapse

Cancer/suspected cancer

Cervical dysplasia

 

26 (38.2%)

6 (8.8%)

33 (48.5%)

3 (4.4%)

 

25 (38.5%)

3 (4.6%)

35 (53.8%)

2 (3.1%)

Medical history

Diabetes

Smoking

Chronic steroid use

 

13 (19.1%)

2 (2.9%)

1 (1.5%)

 

11 (16.9%)

7 (2.9%)

0

Abbreviations: BMI, body mass index.

Results   Vaginal metronidazole (n= 68) Control (n= 65)

p-value

Patient-reported symptom or documented postoperative infection 29/68 (42.6%) 24/65 (36.9%)

0.50

Patient-reported symptoms

Dysuria

Vaginal discharge

Subjective fever

Wound redness/erythema/drainage documented in postoperative visit

Issue that generates additional postoperative visit for evaluation

28 (41.2%)

8 (11.8%)

8 (11.8%)

3 (4.4%)

7 (10.3%)

12 (17.6%)

23 (33.8%)

7 (10.8%)

5 (7.7%)

4 (6.2%)

7 (10.8%)

6 (9.2%)

0.49

0.86

0.43

0.65

0.93

0.16

Documented postoperative infections

Urinary tract infection

Vaginal discharge that warrants treatment
with antibiotics including vaginal cuff
cellulitis or vaginitis

Pelvic cuff abscess confirmed by imaging
that results in antibiotic use

15 (22.0%)

6 (8.8%)

9 (13.2%)

 

1 (1.5%)

10 (15.4%)

5 (7.7%)

5 (7.7%)

 

1 (1.5%)

0.33

0.81

0.30

 

0.97

Adverse Events

Drug adverse events included vaginal discharge (2.9%), vulvovaginal irritation (1.5%), and gastrointestinal distress (1.5%) in the intervention group.

Study Author Conclusions

There is insufficient evidence to suggest a significant benefit of preoperative vaginal metronidazole to prevent surgical site infections and postoperative patient issues in patients undergoing hysterectomy.

Critique

The study's strengths include its randomized controlled design and diverse participant population. However, limitations include potential symptom reporting bias and the inability to blind participants and providers. Additionally, the study was conducted during the COVID-19 pandemic, which may have influenced surgical indications and outcomes.

 

References:

Pradhan T, Zhang H, Kadesh A, et al. PROJECT PREVENT: a randomized controlled trial of preoperative vaginal metronidazole to decrease patient issues and infections after hysterectomy. BMJ Surg Interv Health Technol. 2024;6(1):e000241. Published 2024 Apr 4. doi:10.1136/bmjsit-2023-000241

 

Project Prevent: Utility of Pre-operative Metronidazole Gel in Reduction of Patient Symptoms and Infections After Elective Hysterectomy

Design

Prospective randomized trial

N= 117

Objective

To evaluate if vaginal metronidazole use for five days prior to elective hysterectomy decreased post-operative symptoms and infection rate

Study Groups

Metronidazole (n= 58)

No treatment (n= 59)

Inclusion Criteria

Patients undergoing elective hysterectomy for benign and oncological indications across Ob/Gyn divisions at a single academic medical center

Exclusion Criteria

Not specified.

Methods

Patients were randomized to receive vaginal metronidazole 0.75% (MetroGel or Vandazole) for five days prior to elective hysterectomy or no treatment. Patient clinical and safety outcomes were documented up to 8 weeks after surgery.

Duration

Post-operative follow-up period: up to 8 weeks

Outcome Measures

Patient reported symptoms up to 8 weeks after surgery, documented post-operative infection

Baseline Characteristics

 

Metronidazole (n= 58)

No treatment (n= 59)

p-Value

Age, years

55.5 ± 12.0 53.0 ± 13.3 0.29

Body mass index, kg/m2

31.3 ± 5.8 32.6 ± 8.9 0.35 

Race

White

Black

Hispanic

Asian/Pacific Islander

Other

 

25 (43.1%)

9 (15.5%)

20 (34.5%)

2 (3.4%)

2 (3.4%)

 

26 (44.1%)

11 (18.6%)

17 (28.8%)

1 (1.7%)

4 (6.8%)

 

0.91

0.66

0.50

0.56

0.40 

Indication for surgery

AUB/fibroids/adenomyosis/pelvic pain/endometriosis

Prolapse

Cancer/suspected cancer

Cervical dysplasia

 

20 (34.5%)

6 (10.3%)

20 (50%)

3 (5.2%)

 

22 (37.3%)

3 (5.1%)

32 (54.2%)

2 (3.4%)

 

0.75

0.29

0.65

0.63

Route of hysterectomy

Robot-assisted total laparoscopic

Total laparoscopic

Total vaginal

Laparoscopic-assisted vaginal

Robot-assisted supracervical

Laparoscopic supracervical

Abdominal

 

19 (32.8%)

14 (24.1%)

6 (10.3%)

1 (1.7%)

2 (3.4%)

1 (1.7%)

15 (25.9%)

 

22 (37.3%)

7 (11.9%)

3 (5.1%)

3 (5.1%)

1 (1.7%)

1 (1.7%)

22 (37.3%)

 

0.61

0.09

0.29

0.31

0.56

-

0.18

There was no significant difference in age, body mass index, race/ethnicity, indication for surgery, or surgical route between the two groups.

Most subjects had no medical history, while 21 (17.9%) had diabetes, 8 (6.8%) smoked, and 1 (0.9%) had chronic steroid use.

In the metronidazole group, 72.4% of subjects received all 5 doses of medication.

Results

Endpoint

Metronidazole (n= 58)

No treatment (n= 59)

p-value

Patient-reported symptoms by 8 weeks after surgery

24 (41.3%)  20 (33.9%) 0.26

Post-operative infection

11 (19%) 9 (15.2%) 0.38

There were no differences between the two groups in the rate of patient-reported symptoms or documented infections.

Adverse Events

No significant toxicities were reported due to the study drug.

No adverse effects were reported in the control group.

The metronidazole group reported vaginal discharge (n= 2), vulvovaginal irritation (n= 1), and GI distress (n= 1).

Study Author Conclusions

The use of prophylactic vaginal metronidazole did not appear to decrease surgical site symptoms or documented infections up to 8 weeks after surgery in a diverse group of patients undergoing elective hysterectomy for various indications.

InpharmD Researcher Critique

The study design, focusing on the use of pre-operative metronidazole gel to reduce symptoms and infections following elective hysterectomy, is potentially strong due to its targeted intervention, which directly addresses a common post-surgical complication.

However, the placebo effect and patients' awareness of the treatment can influence subjective symptom reporting, potentially skewing results.



References:

Pradhan T, Zhang H, Kadesh A, et al. Project prevent: utility of pre-operative metronidazole gel in reduction of patient symptoms and infections after elective hysterectomy. American Journal of Obstetrics and Gynecology. 2023;228(3):S829-S830. doi:10.1016/j.ajog.2022.12.063

 

Prophylaxis Effect of Metronidazole Vaginal Gel in Decreasing the Risk of Surgical Site Infections after Elective Hysterectomy

Design

Randomized prospective, double-blind controlled clinical trial

N= 108

Objective

To investigate and evaluate the beneficial effects of metronidazole vaginal gel on the rate of surgical site infections in women undergoing elective abdominal hysterectomy

Study Groups

Control group (n= 52)

Metronidazole group (n= 52)

Inclusion Criteria

18 years or older, candidates for elective abdominal hysterectomy

Exclusion Criteria

Hysterectomy followed by cesarean section, hysterectomy following normal delivery or postpartum period, emergent hysterectomy, broad-spectrum antibiotics before surgery, vaginitis or cervicitis

Methods

Patients were randomized into two groups: one received a lubricant vaginal gel, and the other received a 0.75% metronidazole vaginal gel the night before surgery. All patients received cefazolin 2 g 30 min before surgery or clindamycin if allergic. Vaginal lavage with betadine-impregnated gas was performed after anesthesia induction. Patients were followed up to 6 weeks post-surgery for infection symptoms.

Duration

Duration: not specified

Follow-up: 6 weeks

Outcome Measures

Primary: Rate of surgical site infections

Other: infection rates in relation to blood loss, diabetes, body mass index (BMI), and hospitalization duration

Baseline Characteristics   Control group (n= 52)

Metronidazole group (n= 52)

Age, years 49.6 ± 8.7

51.2 ± 9.2

Hospitalization duration, days 6.9 ± 3.3

5.3 ± 2.4

Menopause status 9 (8.65%)

7 (6.75%)

Past surgical history 34 (32.7%)

48 (46.1%)

Past medical history

36 (34.6) 42 (40.4%)

Cause of hysterectomy

Oncology

Resistant of AUB

 

12 (11.54%)

38 (36.54%)

 

14 (13.46%)

40 (38.46%)

Oncologic surgery

22 (21.1%) 26 (24.9%)

Type of abdominal wall incision

Vertical

Transverse

 

14 (13.46%)

36 (34.61%)

 

16 (15.4%)

38 (36.54%)

Abbreviations: AUB, abnormal uterine bleeding.

Results

Infection rates were lower in the metronidazole group (5.8%) compared with the control group (11.6%) (p= 0.03).

Results from an exploratory association analysis showed that patients with estimated blood loss >500 mL had higher infection rates than those with <500 mL (13.46% vs 1.9%; p= 0.001). Infection was more frequent in patients with diabetes (13.5% vs 5.8%; p= 0.001) and in those with BMI >30 kg/m² (13.5% vs 11.5%; p= 0.001). Longer hospitalization duration was associated with higher infection rates (p= 0.009). No significant differences in infection rates were observed by suture type, oncologic surgery, hypertension, anemia, immunosuppression, or age.

Adverse Events

Not specifically reported

Study Author Conclusions

Administration of a single dosage of metronidazole vaginal gel before abdominal hysterectomy may reduce surgical site infection and have clinical values.

Critique

The study was limited by its single-center design, restricted sample size, and use of only one dose of metronidazole vaginal gel.

 

References:

Sabet F, Ravan S, Shahraki AD. Prophylaxis Effect of Metronidazole Vaginal Gel in Decreasing the Risk of Surgical Site Infections after Elective Hysterectomy. J Res Pharm Pract. 2023;12(1):9-14. Published 2023 Nov 27. doi:10.4103/jrpp.jrpp_66_21

Reducing surgical site infections after hysterectomy: metronidazole plus cefazolin compared with cephalosporin alone
Design

Retrospective cohort study

N= 18,255

Objective To evaluate whether the combination of cefazolin plus metronidazole before hysterectomy was more effective in the prevention of surgical site infection than existing recommendations of cefazolin or second-generation cephalosporin
Study Groups

Cefazolin (n= 14,971)

Second-generation cephalosporin (n= 2,365)

Cefazolin plus metronidazole (n= 919)

Inclusion Criteria Patients >18 years old who underwent abdominal, vaginal, laparoscopic, or robotic hysterectomy for benign or malignant indications and received cefazolin, second-generation cephalosporin, or cefazolin plus metronidazole
Exclusion Criteria Cases with no recorded antibiotic information, use of beta-lactam alternative antibiotics, and receipt of antibiotics not recommended by the American College of Obstetricians and Gynecologists or Surgical Care Improvement Project
Methods Patients received one of the prophylactic antibiotic regimens: cefazolin, second-generation cephalosporin, or cefazolin plus metronidazole. Multivariate logistic regression modeling and propensity score matching were used to evaluate the independent effect of an antibiotic regimen. 
Duration July 2012 to February 2015
Outcome Measures Surgical site infection rate
Baseline Characteristics   Cefazolin (n= 14,971) Second-generation (n= 2,365) Cefazolin + metronidazole (n= 919)
Age ≥ 65 y 1481 (9.9%) 338 (14.3%) 157 (17.1%)
Non-white race 3680 (24.6%) 446 (18.9%) 264 (28.7%)
Body mass index ≥ 30 kg/m2 7170 (47.9%) 1068 (45.2%) 461 (50.2%)
American Society of Anesthesiologists Class ≥ 3 3034 (20.3%) 479 (20.3%) 314 (34.2%)
Diabetes mellitus 1200 (8.0%) 217 (9.2%) 112 (12.2%)
Tobacco use in past year 3475 (32.3%) 480 (20.3%) 209 (22.7%)
Hypertension 4365 (29.2%) 745 (31.5%) 361 (39.3%)
Preoperative indication cancer 872 (5.8%) 230 (9.7%) 170 (18.5%)
Results   Cefazolin (n= 14,971) Second-generation (n= 2,365) Cefazolin + metronidazole (n= 919) p-value
Surgical site infection rate 267 (1.8%)  49 (2.1%)  13 (1.4%)  <0.05
Adverse Events Not specified
Study Author Conclusions In this large cohort, the use of prophylactic cefazolin plus metronidazole resulted in lower surgical site infection rates after hysterectomy compared with cefazolin or second-generation cephalosporin. 
Critique The study's strengths include a large multi-institutional cohort and a well-validated database. However, the retrospective, nonrandomized design limits the ability to control for unknown confounders. The generalizability may be limited as the database includes hospitals only within Michigan. A randomized controlled trial would provide more definitive results but would require a large cohort, making it time-intensive and costly. 
References:

Till SR, Morgan DM, Bazzi AA, et al. Reducing surgical site infections after hysterectomy: metronidazole plus cefazolin compared with cephalosporin alone. Am J Obstet Gynecol. 2017;217(2):187.e1-187.e11. doi:10.1016/j.ajog.2017.03.019

Preoperative Vaginal Metronidazole Decreases the Risk of Pelvic Infections After Radical Robotic Hysterectomy
Design

Retrospective chart review

N= 94

Objective To determine if a solitary dose of vaginal metronidazole the night before surgery decreases the risk of pelvic infection after radical robotic hysterectomy
Study Groups

Nonusers (n= 48)

Users (n= 46)

Inclusion Criteria Patients undergoing robotic radical hysterectomy for gynecologic malignancy from April 2010 through April 2016
Exclusion Criteria Not specified.
Methods

Study investigators performed a retrospective chart review of patients undergoing radical robotic hysterectomies. Data on patient demographics, medical and clinical history, procedures, and metronidazole use were collected from electronic medical records.

Patients were categorized into those who self-administered a single dose of vaginal metronidazole (users) and those who did not
(nonusers). Statistical analyses were performed to evaluate the impact of metronidazole on infection rates.

Duration April 2010 through April 2016
Outcome Measures

Primary: Pelvic infection rate

Secondary: Genitourinary infection rate

Baseline Characteristics  

Nonusers (n= 48)

Users (n= 46)

p-Value
Age, years 44 ± 1.6 50 ± 1.5 0.01*
BMI, kg/m2 29 ± 1.1 27.7 ± 1.0d 0.30
History of CKC or LEEP 26 21 0.27
Uterine weight, g 146 ± 9.5a 145 ± 10.6e 0.94
Preoperative hemoglobin 13.1 ± 0.2b 12.5 ± 0.2 0.02*
Estimated blood loss, mL 99 ± 13c 66 ± 8 0.11
History of smoking 18 8 0.03*
History of stroke or TIA 1 1 0.74
Diagnosis of Type 2 DM 6 5 0.53
Length of stay, days 0.15 ± 0.05b 0.13 ± 0.07 0.81
Steroid use 13 7 0.124
Operative time, min 182 ± 9b 170 ± 10 0.38
Perioperative transfusion 0b 2 0.25

*p< 0.05 is statistically significant.

a. n= 41, b. n= 46, c. n= 47, d. n= 45, e. n= 39

Abbreviations: CKC= cold knife cone. DM= diabetes mellitus. LEEP= loop electrosurgical excision procedure. TIA= transient ischemic attack.

Results   Nonusers (n= 48) Users (n= 46) p-value
Pelvic infection rate 0.02*
Genitourinary infection 8a 1b 0.02*

*p< 0.05 is statistically significant.

a. n= 40, b. n= 45

Adverse Events Not specified.
Study Author Conclusions A single dose of preoperative vaginal metronidazole reduces the risk of pelvic and genitourinary infection after robotic radical hysterectomy.
Critique The study provides valuable insights into the potential benefits of preoperative vaginal metronidazole in reducing infection rates. However, it is limited by its retrospective design and the assumption that patients who picked up the prescription were compliant with administration. Additionally, the study did not assess patients for bacterial vaginosis before surgery, which could have been a useful stratification factor.
References:

Avila M, Funston JR, Axtell AA, Lentz SE. Preoperative Vaginal Metronidazole Decreases the Risk of Pelvic Infections After Radical Robotic Hysterectomy. Int J Gynecol Cancer. 2017;27(8):1783-1787. doi:10.1097/IGC.0000000000001083

Metronidazole and cefazolin versus cefazolin alone for surgical site infection prophylaxis in gynecologic surgery at a comprehensive cancer center
Design

Retrospective, single-center, cohort study

N= 3343

Objective To evaluate the impact of a quality improvement project adding metronidazole to cefazolin for antibiotic prophylaxis on surgical site infection (SSI) rate for women undergoing gynecologic surgery at a comprehensive cancer center
Study Groups

Pre-intervention group (n= 2572)

Post-intervention group (n= 771)

Inclusion Criteria Patients who underwent surgery in the Gynecologic Oncology department from 5/2017 to 6/2023
Exclusion Criteria Patients with penicillin allergies, undergoing concomitant bowel resection(s), joint cases, or who did not receive pre-operative antibiotics
Methods Retrospective chart review comparing SSI rates before and after the addition of metronidazole to cefazolin for prophylaxis. Pre-operative antibiotic order set included cefazolin 2g (or 3g for weight ≥ 120kg) and metronidazole 500mg. Re-dosing practices followed consensus guidelines. 
Duration May 2017 to June 2023
Outcome Measures 30-day SSI rate
Baseline Characteristics   Pre-intervention (n= 2572) Post-intervention (n= 771)
Current smokers 6.2% 4.0%
Laparotomy 35.8% 29.1%
Surgical time, minutes 177.0 163.1
Estimated blood loss, mL 186.8 144.6
Results   Pre-intervention (n= 2572) Post-intervention (n= 771) p-value
Overall SSI rate 4.7% 2.6% 0.0103
SSI rate for hysterectomy 4.9% 2.8% 0.0361
Adverse Events Not stated
Study Author Conclusions The addition of metronidazole to cefazolin before gynecologic surgery decreased the SSI rate by half, even after accounting for other known predictors of SSI and differences in practice patterns over time. Providers should consider this combination regimen in women undergoing gynecologic surgery, especially for cases involving hysterectomy. 
Critique The study's strengths include a large sample size and detailed data collection. However, the retrospective design and potential unmeasured temporal factors may limit the findings. The study did not include information on metronidazole side effects, and the primary outcome was based on timing of surgery rather than actual antibiotic use, though sensitivity analyses were performed to address this limitation.
References:

Knisely A, Iniesta MD, Marten CA, Chisholm G, Schmeler KM, Taylor JS. 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(3):326.e1-326.e13. doi:10.1016/j.ajog.2024.03.043

Antibiotic prophylaxis for hysterectomy, a prospective cohort study: cefuroxime, metronidazole, or both?
Design

Observational non-randomised prospective cohort study

N= 5,279

Objective To evaluate cefuroxime and metronidazole antibiotic prophylaxis
Study Groups

Cefuroxime alone (n= 2,019)

Metronidazole alone (n= 518)

Cefuroxime + Metronidazole (n= 2,252)

Inclusion Criteria Women undergoing hysterectomy for benign indications
Exclusion Criteria Not specified.
Methods

Data on abdominal hysterectomies (AHs), laparoscopic hysterectomies (LHs), and vaginal hysterectomies (VHs) were prospectively collected from 53 hospitals and analysed using logistic regression adjusted for confounding factors. A study form for each patient was completed at discharge by their gynaecological surgeon, and infections following discharge were documented on a separate form at outpatient clinics connected to the respective hospitals.

Common dosages were intravenous (IV) cefuroxime 1.5 g and metronidazole 0.5 g at induction.

Duration January 1, 2006 to December 31, 2006
Outcome Measures

Primary: Postoperative infections

Secondary: Febrile events, wound infections, pelvic infections, urinary tract infections

Baseline Characteristics   Cefuroxime alone (n= 2,019) Metronidazole alone (n= 518) Cefuroxime + Metronidazole (n= 2,252)
Abdominal hysterectomy 405 178 532
Laparoscopic hysterectomy 645 90 806
Vaginal hysterectomy 969 250 914
Results   Cefuroxime alone (n= 2,019) Metronidazole alone (n= 518) Cefuroxime + Metronidazole (n= 2,252)
Total infections 1.38 (0.74–2.57) 3.63 (1.99–6.65) Reference
Febrile events 0.61 (0.19–1.96) 2.86 (1.09–7.49) Reference
Wound infections 2.68 (0.71–10.16) 6.88 (2.12–22.30) Reference
Pelvic infection 3.18 (0.53–18.95) 2.67 (0.35–20.29) Reference
Urinary tract infection 1.13 (0.42–3.02) 2.20 (0.79–6.16) Reference

Cefuroxime had a risk-reducing effect on total infections (adjusted OR 0.29, 95% CI 0.22–0.39), but the independent effect of metronidazole and the interaction effect of cefuroxime and metronidazole were nonsignificant.

Abbreviations: CI= confidence interval. OR= odds ratio. 

Adverse Events Not specified.
Study Author Conclusions Cefuroxime appeared to be effective in prophylaxis against infections. Metronidazole appeared to be ineffective, with no additional risk-reductive effect when combined with cefuroxime.
Critique The study's lack of randomisation may introduce bias, and the choice of antibiotics was based on local hospital policy or surgeon preference, which could affect the results. However, the large sample size and prospective data collection are strengths. The study did not specify adverse events, which is a limitation.
References:

Brummer TH, Heikkinen AM, Jalkanen J, et al. Antibiotic prophylaxis for hysterectomy, a prospective cohort study: cefuroxime, metronidazole, or both?. BJOG. 2013;120(10):1269-1276. doi:10.1111/1471-0528.12178

Addition of metronidazole to standard-of-care perioperative prophylaxis at the time of hysterectomy for gynecologic malignancies
Design

Retrospective cohort study

N= 1055

Objective To evaluate whether the combination of cefazolin or a second-generation cephalosporin plus metronidazole is associated with a reduced risk of surgical site infection in women undergoing hysterectomy for gynecologic cancer compared to using cefazolin or a second-generation cephalosporin alone
Study Groups

Standard-of-care (SOC) antibiotics (n= 533)

SOC + metronidazole (n= 522)

Inclusion Criteria Women who underwent abdominal, robotic-assisted, or laparoscopic hysterectomy for presumed malignancy and received either a first- or second-generation cephalosporin with or without metronidazole, or gentamicin with clindamycin
Exclusion Criteria Women who underwent hysterectomy for reasons other than cancer, patients with missing or unknown antibiotic regimens, anesthesia records, or operative records
Methods Retrospective cohort study of patients undergoing hysterectomy for gynecologic malignancy at 4 centers. Patients received either cefazolin or a second-generation cephalosporin with or without metronidazole, or gentamicin with clindamycin. Data were collected using REDCap
Duration January 2020 to June 2022
Outcome Measures Surgical site infection
Baseline Characteristics   SOC (n= 533) SOC + metronidazole (n= 522)
Age <65 years 261 (48.9%) 269 (51.5%)
Age ≥65 years 272 (51.1%) 253 (48.5%)
Diabetes present 120 (22.5%) 109 (20.9%)
Diabetes absent 413 (77.5%) 413 (79.1%)
Current smoker 32 (6%) 27 (5.2%)
Former smoker 108 (20.3%) 91 (17.4%)
Never smoked 393 (73.7%) 404 (77.4%)
Results   SOC (n= 533) SOC + metronidazole (n= 522) p-value
Surgical site infection 23 (4.3%) 11 (2.1%) 0.04
Adverse Events Surgical site infection was independently associated with diabetes and smoking. No significant difference in infection rates with the addition of metronidazole after adjusting for covariates. 
Study Author Conclusions While there was evidence supporting an independent association between antibiotic regimen and surgical site infection rate, after adjusting for open incision, smoking status, and diabetes, there was no statistical difference in infection rates with the addition of metronidazole. Future studies with larger sample sizes are warranted. 
Critique The study was well-designed with a large sample size and balanced groups. However, its retrospective nature and the low incidence of infection may limit the ability to detect significant differences. The study was also limited to an urban and suburban academic setting, which may affect generalizability. The change in vaginal preparation protocol during the study period may have confounded results. 
References:

Gorman M, Kredentser A, Katehis IA, et al. Addition of metronidazole to standard-of-care perioperative prophylaxis at the time of hysterectomy for gynecologic malignancies. Int J Gynecol Cancer. 2025;35(10):102036. doi:10.1016/j.ijgc.2025.102036