Endometritis, Wound Infection, Abscess, Surgical Site Infection
Conditions
Keywords
Pregnancy, Cesarean section, Antibiotic, Infections
Brief summary
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.
Interventions
DRUGAzithromycin and standard of care
500 mg in 250 cc normal saline 1 time dose plus standard of care (cephazolin or clindamycin)
250 cc normal saline, plus standard of care (cephazolin or clindamycin)
Sponsors
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
University of Texas
University of North Carolina
Mission Hospital
Ochsner Health System
The University of Texas Health Science Center, Houston
Columbia University
University of Utah
University of Mississippi Medical Center
Alan Tita
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
14 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Participants With Endometritis and/or Wound Infection and/or Other Post-cesarean Infections (Occurring Within 6 Weeks of Delivery) | Up to 6 weeks after 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. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Neonatal Intensive Care Unit (NICU) Admission | Up to 3 months after birth | 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. |
| Neonatal Readmission | Up to 3 months after birth | — |
| Maternal Fever | Up to 6 weeks after delivery | — |
| Maternal Postpartum Readmission or Unscheduled Visit | Up to 6 weeks after delivery | Maternal postpartum unscheduled visit or readmission to the hospital |
| Neonatal Morbidities (Listed Below) | Up to 3 months after birth | 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 |
| Maternal Serious Adverse Events | Up to 6 weeks after delivery | All maternal serious adverse events |
| Neonatal Serious Adverse Events | Up to 3 months after birth | Composite for all neonatal serious adverse events |
| Infant Pyloric Stenosis | up to 3 months after birth | Any diagnosis of pyloric stenosis based on clinical presentation and radiological and/or surgical confirmation |
| Maternal Postpartum Antibiotic Use | Up to 6 weeks after delivery | Maternal postpartum use of antibiotics |
Countries
United States
Participant flow
Recruitment details
Patients were randomly assigned to receive either azithromycin (at a dose of 500mg in 250 ml of saline, one time dose) or an identical-appearing saline placebo and the standard of care (cephazolin or clindamycin)
Pre-assignment details
The addition of azithromycin and the standard of care (cephazolin or clindamycin) for antibiotic prophylaxis before cesarean delivery may further reduce the rate of postoperative infection. We evaluated the benefits and safety of azithromycin prophylaxis and the standard of care in women undergoing nonelective cesarean section.
Participants by arm
| Arm | Count |
|---|---|
| Placebo With Standard Prophylaxis Placebo: 250 cc normal saline Standard Prophylaxis: standard cephalosporin prophylaxis | 994 |
| Azithromycin (Zithromax) With Standard Prophylaxis Azithromycin: 500 mg in 250 cc normal saline 1 time dose Standard Prophylaxis: standard cephalosporin prophylaxis | 1,019 |
| Total | 2,013 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Protocol Violation | 1 | 1 |
| Overall Study | Staff error, medication not administered | 1 | 0 |
Baseline characteristics
| Characteristic | Total | Placebo With Standard Prophylaxis | Azithromycin (Zithromax) With Standard Prophylaxis |
|---|---|---|---|
| Age, Continuous | 28.3 years STANDARD_DEVIATION 6.3 | 28.4 years STANDARD_DEVIATION 6.5 | 28.2 years STANDARD_DEVIATION 6.1 |
| Region of Enrollment United States | 2013 participants | 994 participants | 1019 participants |
| Sex: Female, Male Female | 2013 Participants | 994 Participants | 1019 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
| Smoking Prevalence | 219 Participants | 122 Participants | 97 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 992 | 0 / 1,018 |
| other Total, other adverse events | 14 / 992 | 9 / 1,018 |
| serious Total, serious adverse events | 29 / 992 | 15 / 1,018 |
Outcome results
Primary
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.
Time frame: Up to 6 weeks after delivery
Population: The specific characteristics related to the cesarean delivery, including indications for cesarean delivery, receipt of standard prophylaxis, timing of receipt of study medication, and type of surgical skin preparation, were similar in the two groups.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Participants With Endometritis and/or Wound Infection and/or Other Post-cesarean Infections (Occurring Within 6 Weeks of Delivery) | 119 Participants |
| Azithromycin | Participants With Endometritis and/or Wound Infection and/or Other Post-cesarean Infections (Occurring Within 6 Weeks of Delivery) | 62 Participants |
Other Pre-specified
Infant Pyloric Stenosis
Any diagnosis of pyloric stenosis based on clinical presentation and radiological and/or surgical confirmation
Time frame: up to 3 months after birth
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Infant Pyloric Stenosis | 1 Participants |
| Azithromycin | Infant Pyloric Stenosis | 2 Participants |
Other Pre-specified
Maternal Fever
Time frame: Up to 6 weeks after delivery
Population: Postpartum Fever
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Maternal Fever | 81 Participants |
| Azithromycin | Maternal Fever | 51 Participants |
Other Pre-specified
Maternal Postpartum Antibiotic Use
Maternal postpartum use of antibiotics
Time frame: Up to 6 weeks after delivery
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Maternal Postpartum Antibiotic Use | 166 Participants |
| Azithromycin | Maternal Postpartum Antibiotic Use | 126 Participants |
Other Pre-specified
Maternal Postpartum Readmission or Unscheduled Visit
Maternal postpartum unscheduled visit or readmission to the hospital
Time frame: Up to 6 weeks after delivery
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Maternal Postpartum Readmission or Unscheduled Visit | 123 Participants |
| Azithromycin | Maternal Postpartum Readmission or Unscheduled Visit | 83 Participants |
Other Pre-specified
Maternal Serious Adverse Events
All maternal serious adverse events
Time frame: Up to 6 weeks after delivery
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Maternal Serious Adverse Events | 29 Participants |
| Azithromycin | Maternal Serious Adverse Events | 15 Participants |
Other Pre-specified
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.
Time frame: Up to 3 months after birth
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Neonatal Intensive Care Unit (NICU) Admission | 169 Participants |
| Azithromycin | Neonatal Intensive Care Unit (NICU) Admission | 171 Participants |
Other Pre-specified
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
Time frame: Up to 3 months after birth
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Neonatal Morbidities (Listed Below) | 135 Participants |
| Azithromycin | Neonatal Morbidities (Listed Below) | 146 Participants |
Other Pre-specified
Neonatal Readmission
Time frame: Up to 3 months after birth
Population: Hospitalization after discharge
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Neonatal Readmission | 43 Participants |
| Azithromycin | Neonatal Readmission | 39 Participants |
Other Pre-specified
Neonatal Serious Adverse Events
Composite for all neonatal serious adverse events
Time frame: Up to 3 months after birth
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Neonatal Serious Adverse Events | 5 Participants |
| Azithromycin | Neonatal Serious Adverse Events | 7 Participants |