Study of Effectiveness and Safety of Azithromycin-based Extended-spectrum Prophylaxis to Prevent Post Cesarean Infection (C/SOAP)

Cesarean Section Optimal Antibiotic Prophylaxis Trial

The Cesarean Section Optimal Antibiotic Prophylaxis (C/SOAP) study is a large pragmatic multi-center randomized clinical trial designed to evaluate the comparative effectiveness and safety of azithromycin-based extended-spectrum antibiotic prophylaxis (azithromycin plus standard narrow-spectrum cephalosporin) relative to standard single-agent cephalosporin (preferably prior to surgical incision) to prevent post-cesarean infection.

Hypothesis: Compared to narrow-spectrum prophylaxis (i.e. cefazolin alone, or clindamycin if cephalosporin allergy) prior to surgical incision, the addition of extended-spectrum prophylaxis (azithromycin + cefazolin) reduces the incidence of post-cesarean infection.

Study Overview

• Status: Completed
• Conditions: Abscess; Surgical Site Infection; Wound Infection; Endometritis
• Intervention / Treatment: Drug: Placebo and standard of care; Drug: Azithromycin and standard of care

• Study Type: Interventional
• Enrollment (Actual): 2013
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
      • University of Alabama at Birmingham
  • Louisiana
    • New Orleans, Louisiana, United States, 70121
      • Ochsner Clinic Foundation
  • Mississippi
    • Jackson, Mississippi, United States, 39216
      • University of Mississippi Medical Center
  • New York
    • New York, New York, United States, 10032
      • Columbia University
  • North Carolina
    • Asheville, North Carolina, United States, 28801
      • Mission Hospital
    • Chapel Hill, North Carolina, United States, 27599-7516
      • University of North Carolina
  • Texas
    • Galveston, Texas, United States, 77555-0587
      • University of Texas Medical Branch
    • Houston, Texas, United States, 77225
      • University of Texas Health Science Center at Houston
  • Utah
    • Salt Lake City, Utah, United States, 84132
      • University of Utah

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (ADULT, OLDER_ADULT, CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

-

Pregnant Women aged 14 years and over at ≥ 24 weeks' viable gestation who will undergo unscheduled/non-elective cesareans with either:

1. Labor (spontaneous or induced): active labor (ongoing contractions and at least 4cm dilated or contractions for at least 4 hours with documented cervical change of ≥1cm dilatation or ≥50% effacement), or
2. Membrane rupture (standardized to duration of at least 4 hours prior to randomization).

Exclusion Criteria:

• Patient unwilling or unable to provide consent
• Multiple pregnancy
• Known azithromycin (or other macrolide) allergy
• Vaginal delivery
• Elective or scheduled cesarean prior to labor or membrane rupture.
• Azithromycin, erythromycin or other macrolide antibiotic use within 7 days of enrollment.
• Clinical chorioamnionitis or any other active bacterial infection (e.g. pyelonephritis, pneumonia, abscess) at time of randomization.
• Patient is unable or unlikely to follow-up after delivery (e.g. no prenatal care or a non-resident patient)
• Fetal demise or major congenital anomaly
• Significant liver disease defined as known cirrhosis or elevated transaminases of at least 3-fold upper limit of normal
• Significant renal disease defined as serum creatinine known to be >2.0 mg/dl or on dialysis.
• Active congestive heart failure (EF<45%) or pulmonary edema
• Active diarrhea at time of delivery
• Any patient with significant electrolyte abnormalities such as hypokalemia or hypocalcemia
• Any patient with structural heart disease or arrhythmias, or taking any medications known to prolong the QT interval
• Patient currently being treated with efavirenz, nelfinavir or fluconazole

Study Plan

How is the study designed?

Design Details

• Primary Purpose: PREVENTION
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
PLACEBO_COMPARATOR: Placebo and standard of care; 250 cc normal saline	Drug: Placebo and standard of care; 250 cc normal saline, plus standard of care (cephazolin or clindamycin); Other Names: normal saline
EXPERIMENTAL: Azithromycin and Standard of care; 500 mg Azithromycin in 250 cc normal saline	Drug: Azithromycin and standard of care; 500 mg in 250 cc normal saline 1 time dose plus standard of care (cephazolin or clindamycin); Other Names: Zithromax

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Participants With Endometritis and/or Wound Infection and/or Other Post-cesarean Infections (Occurring Within 6 Weeks of Delivery)	Endometritis was defined as the presence of at least two of the following signs with no other recognized cause: fever (temperature of at least 38°C [100.4°F]), abdominal pain, uterine tenderness, or purulent drainage from the uterus. Wound infection was defined as the presence of either superficial or deep incisional surgical-site infection characterized by cellulitis or erythema and induration around the incision or purulent discharge from the incision site with or without fever and included necrotizing fasciitis. Wound hematoma, seroma, or breakdown alone in the absence of the preceding signs did not constitute infection.	Up to 6 weeks after delivery

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Neonatal Morbidities (Listed Below)	morbidities include: death, Respiratory Distress Syndrome (RDS), Bronchopulmonary Dysplasia (BPD), Periventricular Leukomalacia (PVL) suspected or proven sepsis, Necrotizing Enterocolitis (NEC) Intraventricular Hemorrhage (IVH) and systemic inflammatory response syndrome	Up to 3 months after birth
Neonatal Intensive Care Unit (NICU) Admission	Neonates who are admitted to the NICU due to morbidities diagnosed from birth and up to three months of life. Morbidities as defined in the Neonatal morbidities outcome measure.	Up to 3 months after birth
Neonatal Readmission		Up to 3 months after birth
Maternal Fever		Up to 6 weeks after delivery
Maternal Postpartum Readmission or Unscheduled Visit	Maternal postpartum unscheduled visit or readmission to the hospital	Up to 6 weeks after delivery
Maternal Postpartum Antibiotic Use	Maternal postpartum use of antibiotics	Up to 6 weeks after delivery
Maternal Serious Adverse Events	All maternal serious adverse events	Up to 6 weeks after delivery
Neonatal Serious Adverse Events	Composite for all neonatal serious adverse events	Up to 3 months after birth
Infant Pyloric Stenosis	Any diagnosis of pyloric stenosis based on clinical presentation and radiological and/or surgical confirmation	up to 3 months after birth

Collaborators and Investigators

• Sponsor: Alan Tita
• Collaborators: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); The University of Texas Health Science Center, Houston; Columbia University; University of Texas; University of Utah; University of Mississippi Medical Center; Ochsner Health System; University of North Carolina; Mission Hospital
• Investigators: Principal Investigator: Alan TN Tita, MD, PhD, University of Alabama at Birmingham

Publications and helpful links

General Publications

• Tita ATN, Rouse DJ, Blackwell S, Saade GR, Spong CY, Andrews WW. Emerging concepts in antibiotic prophylaxis for cesarean delivery: a systematic review. Obstet Gynecol. 2009 Mar;113(3):675-682. doi: 10.1097/AOG.0b013e318197c3b6.
• Andrews WW, Hauth JC, Cliver SP, Savage K, Goldenberg RL. Randomized clinical trial of extended spectrum antibiotic prophylaxis with coverage for Ureaplasma urealyticum to reduce post-cesarean delivery endometritis. Obstet Gynecol. 2003 Jun;101(6):1183-9. doi: 10.1016/s0029-7844(03)00016-4.
• Tita AT, Hauth JC, Grimes A, Owen J, Stamm AM, Andrews WW. Decreasing incidence of postcesarean endometritis with extended-spectrum antibiotic prophylaxis. Obstet Gynecol. 2008 Jan;111(1):51-6. doi: 10.1097/01.AOG.0000295868.43851.39.
• Sanusi A, Ye Y, Boggess K, Saade G, Longo S, Clark E, Esplin S, Cleary K, Wapner R, Owens M, Blackwell S, Szychowski JM, Tita ATN, Subramaniam A. Timing of Adjunctive Azithromycin for Unscheduled Cesarean Delivery and Postdelivery Infection. Obstet Gynecol. 2022 Jun 1;139(6):1043-1049. doi: 10.1097/AOG.0000000000004788. Epub 2022 May 2.
• Boggess KA, Tita A, Jauk V, Saade G, Longo S, Clark EAS, Esplin S, Cleary K, Wapner R, Letson K, Owens M, Blackwell S, Beamon C, Szychowski JM, Andrews W; Cesarean Section Optimal Antibiotic Prophylaxis Trial Consortium. Risk Factors for Postcesarean Maternal Infection in a Trial of Extended-Spectrum Antibiotic Prophylaxis. Obstet Gynecol. 2017 Mar;129(3):481-485. doi: 10.1097/AOG.0000000000001899.
• Tita AT, Szychowski JM, Boggess K, Saade G, Longo S, Clark E, Esplin S, Cleary K, Wapner R, Letson K, Owens M, Abramovici A, Ambalavanan N, Cutter G, Andrews W; C/SOAP Trial Consortium. Adjunctive Azithromycin Prophylaxis for Cesarean Delivery. N Engl J Med. 2016 Sep 29;375(13):1231-41. doi: 10.1056/NEJMoa1602044.

Study record dates

Study Major Dates

• Study Start: May 1, 2011
• Primary Completion (ACTUAL): December 1, 2015
• Study Completion (ACTUAL): December 1, 2015

Study Registration Dates

• First Submitted: November 4, 2010
• First Submitted That Met QC Criteria: November 4, 2010
• First Posted (ESTIMATE): November 5, 2010

Study Record Updates

• Last Update Posted (ACTUAL): July 28, 2017
• Last Update Submitted That Met QC Criteria: June 29, 2017
• Last Verified: June 1, 2017

More Information

Terms related to this study

• Keywords: Pregnancy; Cesarean section; Antibiotic; Infections
• Additional Relevant MeSH Terms: Pathologic Processes; Postoperative Complications; Uterine Diseases; Disease Attributes; Adnexal Diseases; Pelvic Inflammatory Disease; Infections; Communicable Diseases; Surgical Wound Infection; Wound Infection; Endometritis; Anti-Infective Agents; Anti-Bacterial Agents; Azithromycin
• Other Study ID Numbers: F090323006; NIH 1R01HD064729-01A1 (OTHER_GRANT: NICHD)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO