Azithromycin Prophylaxis for Cesarean Delivery

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Tita AT, et al. "Adjunctive Azithromycin Prophylaxis for Cesarean Delivery". New England Journal of Medicine. 2016. 375(13):1231-1241.
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Clinical Question

In women undergoing non-elective cesarean section, does the addition of azithromycin to standard antibiotic prophylaxis of cefazolin reduce the rate of postoperative infection when compared to the standard antibiotic prophylaxis regimens alone?

Bottom Line

Utilizing the extended-spectrum prophylaxis with azithromycin regimen was proven to be more effective than placebo in reducing the risk of postoperative infections of women who undergo Cesarean sections.

Major Points

Pregnancy-associated infections remain one of the most common causes of maternal death around the world with it being the fourth most common cause in the United States. Infection is 5 to 10 times more likely with cesarean section as compared to vaginal delivery. Even with traditional cephalosporin-based prophylaxis, postoperative infection remains a major concern especially after a nonelective procedure. Studies have shown that the addition of azithromycin to standard prophylactic treatment may decrease the likelihood of an infection occurring.

The study was a double-blind, pragmatic, randomized clinical trial conducted at 14 hospitals across the US, testing whether the addition of azithromycin to standard traditional prophylactic treatment would decrease the number of post cesarean section infections. Postoperative infections occurred in 62 women (6.1%) when treated with azithromycin and traditional prophylaxis as compared to 119 women (12.0%) using only the traditional prophylactic treatment. There was no significant difference found between groups in secondary neonatal composite outcomes.

In future cases, azithromycin would be a good addition to traditional prophylactic treatment for women undergoing emergency cesarean sections when possible. Additional studies including more diverse subgroups such as women undergoing scheduled cesarean sections would improve the quality of evidence provided in this study.

Guidelines

  • American College of Obstetricians and Gynecologists (ACOG)
  • Reference - ACOG Committee Opinion 465 (Obstet Gynecol 2010 Sep;116(3):791)
  • American Society of Health-System Pharmacists/Infectious Diseases Society of America/Surgical Infection Society/Society for Healthcare Epidemiology of America (ASHP/IDSA/SIS/SHEA) recommendations for antimicrobial prophylaxis for cesarean section(1)

Design

  • Double-blind, pragmatic, randomized clinical trial conducted at 14 hospitals in the US.
  • Enrollment: April 2011 through November 2014
    • 17,790 patients were screened, 4,057 were screened and gave consent, 2,013 patients underwent randomization.
  • n= 2013
    • Traditional therapy plus azithromycin group: n=1019 (1018 received therapy)
    • Traditional therapy plus placebo treatment group: n=994 (992 received therapy)
  • Setting: 14 hospitals in United States
  • Follow-up: postpartum follow-up visits within 6 weeks; contacted via telephone after 3 months to report infant deaths and adverse effects.
  • Analysis: Intention-to-treat; using Chi-square test or Fisher’s exact test to analyze categorical variables and Student’s T-test for continuous variables.
  • Primary outcome: Cesarean section postoperative infections, defined as all postoperative infections.
  • Secondary outcomes: Adverse events related to drug therapies.

Population

Inclusion Criteria

  • Single child births
  • Gestation period of 24 weeks or longer
  • Undergoing cesarean delivery during labor or after membrane rupture

Exclusion Criteria

  • Inability to provide consent
  • Known allergy to azithromycin
  • Subsequent vaginal delivery
  • Azithromycin use within 7 days before randomization
  • Chorioamnionitis or other infection requiring postpartum antibiotic therapy
    • Unless the antibiotic therapy was for group B streptococcus
  • Fetal death or known major congenital anomaly
  • Substantial liver disease
    • Cirrhosis
    • Aminotransferase level at least three times the upper limit of the normal range
  • Serum creatinine level greater than 2.0 mg per deciliter
  • Need for dialysis
  • Diarrhea at the time of planned randomization
  • Cardiomyopathy
  • Pulmonary edema
  • Maternal structural heart disease
  • Arrhythmias
  • Use of medications that prolong the QT interval
  • Hypokalemia
  • Hypocalcemia
  • Hypomagnesemia

Baseline Characteristics

  • Average age:
    • Azithromycin group: 28.2土6.1 years
    • Placebo group: 28.4土6.5 years.
  • Race/ethnicity:
    • Azithromycin group:
      • 34.9% non-Hispanic white
    • Standard group:
      • 34.4% non-Hispanic white

The only significant difference between the azithromycin and placebo group was the number of women who smoked during pregnancy (p=0.047).

  • Azithromycin group: 97 women
  • Placebo group: 122 women

Interventions

Patients were randomly assigned to receive extended-spectrum prophylaxis (disease preventative therapy) with either adjunctive azithromycin (500 mg in 250 mL of saline) or an adjunctive identical-appearing saline placebo.

Patients with an allergy to cephalosporin or penicillin received clindamycin alone or clindamycin plus gentamicin, depending on the local alternative.

Antibiotic prophylaxis was given to the patients before surgical incision or as soon as possible after surgical incision.

Outcomes

Primary Outcomes

Postoperative infection occurred in 62 women (6.1%) who received azithromycin and in 119 (12.0%) who received placebo (relative risk, 0.51; 95% confidence interval [CI], 0.38 to 0.68; p<0.001, NNT 17). Significant differences were found between groups for outcomes including endometritis (3.8% vs. 6.1%, p=0.02, NNT 43), wound infection (2.4% vs. 6.6%, p<0.001, NNT 24), and serious maternal adverse events (1.5% vs. 2.9%, p=0.03, NNT 71).

Secondary Outcomes

There was no significant difference between groups in a secondary neonatal composite outcome that included neonatal death and serious neonatal complications (14.3% vs. 13.6%, p=0.63).

Adverse Events

A significant difference was found between patients treated with azithromycin and placebo for serious maternal adverse events (1.5% vs. 2.9%, p=0.03). No difference was found for serious neonatal adverse events.

Criticisms

  • Women undergoing scheduled cesarean sections, as well as those with intrapartum chorioamnionitis were excluded, omitting the generalizability of the study findings in these two groups.
  • The possibility of selection of resistant organisms as a potential concern regarding azithromycin based prophylaxis.
  • Women with a history of arrhythmia or cardiomyopathy were excluded based on a previous observational study reporting an association between multiple oral doses of azithromycin over a period of at least 5 days and the risk of cardiac death in a nonpregnant, older patient cohort with underlying coexisting conditions.
    • The inherent age difference between the groups, and the difference in dose/duration of azithromycin of each study raises question as to why women with a history of arrhythmia or cardiomyopathy were excluded.

Funding

This trial was funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development.