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To conduct an unblinded pragmatic randomized controlled trial (pRCT) "Improvement of PPROM Management with Prophylactic Antimicrobial Therapy (iPROMPT)" of a seven-day course of ceftriaxone, clarithromycin, and metronidazole versus the current standard of care of a seven-day course of ampicillin/amoxicillin and azithromycin or erythromycin to prolong pregnancy and decrease adverse perinatal outcomes among hospitalized pregnant individuals undergoing expectant management of PPROM <34 weeks.
Preterm prelabor rupture of membranes (PPROM) is the most common identifiable risk factor associated with preterm birth and affects 1 in 3 pregnant individuals in the United States with spontaneous preterm birth. Individuals diagnosed with PPROM who meet criteria for expectant management are currently admitted to the hospital for observation until delivery, which is generally recommended at 34 weeks' gestation unless indicated sooner. Initially upon admission, a course of prophylactic antibiotics is administered as this has been shown to prolong pregnancy and improve neonatal outcomes. The standard antibiotic regimen, primarily based on data published in 1997, includes ampicillin followed by amoxicillin with erythromycin or azithromycin for a total of 7 days. Ongoing studies are needed to determine the optimal prophylactic antibiotic regimen given changes in bacterial sensitivities over time, lack of adequate coverage for common organisms including genital mycoplasma, inadequate placental transfer of currently used antibiotic agents, ineffective antibiotic response at reducing the fetal inflammatory response, and new promising antibiotic agents that address these limitations. A promising expanded-spectrum alternative regimen with proof-of-concept is ceftriaxone, clarithromycin, and metronidazole. Observational studies have shown successful eradication of intraamniotic inflammation/infection using this new regimen. This regimen offers multiple potential advantages, including: higher bioavailability, higher transplacental transfer, and effectiveness against genital mycoplasma (clarithromycin), greater anaerobic coverage (metronidazole), and a longer half-life and expanded coverage against gram-negative bacteria (ceftriaxone) compared with the current standard regimen.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Intervention group | Experimental | Participants randomized to the intervention group will receive the following regimen:
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| Standard of care | Other | Participants randomized to the standard care group will receive the following regimen:
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Ceftriaxone 1000 MG | Drug | Ceftriaxone 1 g IV q 24 hours x 7 days (in addition to clarithromycin and metronidazole) |
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| Measure | Description | Time Frame |
|---|---|---|
| Latency | Latency will be measured in hours, and also reported as days for clinical interpretability. | From randomization to delivery |
| Measure | Description | Time Frame |
|---|---|---|
| Neonatal outcome composite checklist | Includes neonatal sepsis, respiratory distress syndrome, any mechanical ventilation, bronchopulmonary dysplasia, intraventricular hemorrhage, periventricular leukomalacia, necrotizing enterocolitis, stillbirth, or neonatal death | From birth to up to 6 weeks postpartum |
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Inclusion criteria
Exclusion criteria
This study is restricted to pregnant individuals.
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Marissa Berry, MD | Contact | 614-293-4780 | Marissa.Berry@osumc.edu |
| Name | Affiliation | Role |
|---|---|---|
| Marissa Berry, MD | Ohio State University | Principal Investigator |
| Kartik K Venkatesh, MD, PhD | Ohio State University | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| The Ohio State University Wexner Medical Center OB/GYN Maternal and Fetal Medicine | Recruiting | Columbus | Ohio | 43210 | United States |
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| Clarithromycin 500mg | Drug | Clarithromycin 500 mg PO BID x 7 days (in addition to ceftriaxone and metronidazole) |
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| Metronidazole 500 mg | Drug | Metronidazole 500 mg PO q 12 hours x 7 days (in addition to clarithromycin and ceftriaxone) |
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| Ampicillin 2 GM Injection | Drug | Ampicillin 2 g IV q 6 hours x 48 hours (prior to amoxicillin and in addition to either azithromycin or erythromycin) |
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| Amoxicillin 250 MG | Drug | Amoxicillin 250 mg q 8 hours for an additional 5 days (following ampicillin and in addition to either azithromycin or erythromycin) |
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| Azithromycin | Drug | Azithromycin 1 g PO x 1 dose (in addition to ampicillin and amoxicillin) |
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| Erythromycin | Drug | Erythromycin 250 mg IV q 6 hours x 48 hours followed by erythromycin 333 mg PO TID for an additional 5 days (in addition to ampicillin and amoxicillin) |
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| Endometritis |
Diagnosed If the patient develops two of the following 1) oral body temperature ≥101°F at any time, or a temperature of ≥100.4 °F 24 hours after delivery, 2) maternal tachycardia that parallels the temperature, 3) uterine tenderness, 4) purulent vaginal discharge, or 5) associated findings with advanced endometritis (dynamic ileus, pelvic peritonitis, pelvic abscess, bowel obstruction, necrosis of the lower uterine segment) |
| From birth to up to 6 weeks postpartum |
| Surgical site infection | Presence of either superficial or deep incisional SSI described as cellulitis/erythema and induration around the incision or purulent discharge from the incision site, with or without fever, such as necrotizing fasciitis (diagnosed based on necrotizing wound infection). Intraabdominal abscess may or may not be present. Wound hematoma, seroma, or incisional breakdown alone in the absence of the above signs does not constitute infection. | From birth to up to 6 weeks postpartum |
| Individual clinical infections | From birth to up to 6 weeks postpartum |
| Puerperal fever | temperature ≥ 100.4 °F at least twice 30 minutes apart, or once with the use of antipyretic, or ≥ 101 °F once. This will be analyzed for intrapartum and postpartum fever. | From birth to up to 6 weeks postpartum |
| Histopathologic chorioamnionitis/funisitis on histologic placental evaluation | From randomization to delivery |
| Antibiotic receipt postpartum | From birth to up to 6 weeks postpartum |
| Adverse events | Allergic reactions (anaphylaxis, angioedema, urticaria), Stevens Johnsons syndrome, gastrointestinal side effects (nausea, vomiting, constipation, diarrhea, ileus) | From randomization to delivery |
| University of Texas Medical Branch | Recruiting | Galveston | Texas | 775555 | United States |
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| ID | Term |
|---|---|
| C563032 | Preterm Premature Rupture of the Membranes |
| D047928 | Premature Birth |
| D002821 | Chorioamnionitis |
| ID | Term |
|---|---|
| D007752 | Obstetric Labor, Premature |
| D007744 | Obstetric Labor Complications |
| D011248 | Pregnancy Complications |
| D005261 | Female Urogenital Diseases and Pregnancy Complications |
| D000091642 | Urogenital Diseases |
| D005315 | Fetal Diseases |
| D005322 | Fetal Membranes, Premature Rupture |
| D010922 | Placenta Diseases |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
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| ID | Term |
|---|---|
| D002443 | Ceftriaxone |
| D017291 | Clarithromycin |
| D008795 | Metronidazole |
| D000658 | Amoxicillin |
| D017963 | Azithromycin |
| D004917 | Erythromycin |
| ID | Term |
|---|---|
| D002439 | Cefotaxime |
| D002505 | Cephacetrile |
| D002511 | Cephalosporins |
| D047090 | beta-Lactams |
| D007769 | Lactams |
| D000577 | Amides |
| D009930 | Organic Chemicals |
| D013843 | Thiazines |
| D013457 | Sulfur Compounds |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D006571 | Heterocyclic Compounds |
| D018942 | Macrolides |
| D061065 | Polyketides |
| D007783 | Lactones |
| D009593 | Nitroimidazoles |
| D009574 | Nitro Compounds |
| D007093 | Imidazoles |
| D001393 | Azoles |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D000667 | Ampicillin |
| D010400 | Penicillin G |
| D010406 | Penicillins |
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