Antibiotics for Premature Rupture of Membranes

Recruiting at 2 trial locations

Overseen By Felicia LeMoine, MD

Age: 18+

Sex: Female

Trial Phase: Phase 4

Sponsor: University Hospitals Cleveland Medical Center

Must be taking: Antibiotics

Must not be taking: Antibiotics, Macrolides, Penicillins

Disqualifiers: Fetal anomaly, Vaginal bleeding, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 1

Duration: 1 week

88 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial examines how well antibiotics can delay labor for women whose water breaks too early, specifically between weeks 18 and 22 of pregnancy. Participants will either receive two antibiotics—azithromycin (Zithromax or Zmax) and amoxicillin (Amoxil, Moxatag, or Trimox)—or follow standard care practices without antibiotics. The goal is to determine if these medications can delay childbirth by at least 28 days after membrane rupture. Suitable candidates have experienced their water breaking without labor starting, are between 18 and 22 weeks pregnant, and are carrying one baby. As a Phase 4 trial, this study involves treatments already FDA-approved and proven effective, aiming to understand how these antibiotics can benefit more patients.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot be on antibiotics at the time of membrane rupture diagnosis.

What is the safety track record for amoxicillin and azithromycin?

Research has shown that both amoxicillin and azithromycin are generally safe for pregnant women with preterm prelabor rupture of membranes (PPROM). Amoxicillin, a well-known antibiotic, has been studied for its effects during pregnancy. One study developed a model to understand amoxicillin's action in pregnant women with PPROM, demonstrating that its use is well understood and managed.

Azithromycin is also considered safe and effective. Research indicates that it maintains high levels in the amniotic fluid, which is crucial for fighting infections. Additionally, using azithromycin instead of erythromycin has been linked to lower infection rates in mothers.

Both antibiotics are well-tolerated, with no major safety concerns reported in studies. This suggests that participants taking these medications for this condition can expect a relatively safe experience. ^{1 2 3 4 5}

Why are researchers enthusiastic about this study treatment?

Researchers are excited about using amoxicillin and azithromycin for premature rupture of membranes (PPROM) because this combination targets a broader range of bacteria compared to standard treatments. While traditional management might focus on single antibiotics, this dual approach helps prevent infections by covering both common and atypical bacteria. Additionally, the short course of azithromycin, with its initial high dose followed by a few days of maintenance, aims to quickly reduce bacterial load, potentially improving outcomes for both mothers and babies.

What evidence suggests that these antibiotics might be an effective treatment for premature rupture of membranes?

In this trial, participants in the antibiotics arm will receive a combination of amoxicillin and azithromycin. Studies have shown that antibiotics like amoxicillin can help prevent infections in women with preterm premature rupture of membranes (PPROM). Research indicates that penicillin-type antibiotics significantly lower the risk of maternal infections, such as chorioamnionitis, an infection of the fetal membranes. When combined with other antibiotics, azithromycin can help extend pregnancy, as studies suggest. Women who took both azithromycin and amoxicillin experienced a longer interval between their water breaking and delivery. This combination is believed to be effective because it maintains high antibiotic levels in the amniotic fluid, potentially preventing harmful bacterial infections. These findings support using these antibiotics to manage PPROM. ^{2 5 6 7 8}

Who Is on the Research Team?

David Hackney, MD

Principal Investigator

University Hospitals Cleveland Medical Center

Justin Lappen, MD

Principal Investigator

The Cleveland Clinic

Brian Mercer, MD

Principal Investigator

MetroHealth Hospitals

Are You a Good Fit for This Trial?

This trial is for English-speaking pregnant women with a single baby, between 18 and nearly 23 weeks along, who've had their water break early without labor starting. They must be able to consent and not want to end the pregnancy. Excluded are those with major fetal issues, recent related procedures or infections, certain medication use, heavy bleeding or fever at rupture time.

Inclusion Criteria

Patient able to provide informed consent

Gestational age between 18 weeks and 0 days and 22 weeks and 6 days at the time of membrane rupture

English-speaking

Exclusion Criteria

Cervical dilation of ≥ 4 cm

I am allergic to macrolide or penicillin antibiotics.

Active preterm labor at the time of membrane rupture diagnosis (i.e., consistent contraction pattern associated with cervical change) and/or within first 24 hours of diagnosis

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

Treatment

Participants receive a seven-day course of oral azithromycin and amoxicillin

1 week

1 visit (in-person) for initial dosing, followed by home administration

Follow-up

Participants are monitored for delivery within 28 days and severe maternal morbidity up to 6 weeks post-delivery

6 weeks

Neonatal Follow-up

Neonates are monitored for severe morbidity until hospital discharge

Up to 6 months

What Are the Treatments Tested in This Trial?

Interventions

• Amoxicillin
• Azithromycin

Trial Overview The study tests if taking oral antibiotics (Azithromycin and Amoxicillin) after an early water break can delay birth beyond 28 days. It's a randomized trial where some get the drugs while others don't, aiming to see which group stays pregnant longer.

How Is the Trial Designed?

Group I: Antibiotics Experimental Treatment 2 Interventions

Patients randomized into the treatment (i.e., antibiotics) arm of the study will be treated with a seven-day course of oral azithromycin and amoxicillin. Azithromycin will be dosed as single 500 mg dose (2-250mg oral tablets) administered immediately following randomization, yet prior to discharge to home, followed with 1-250mg oral tablet daily for 4 additional days (for a total of 5 days). Amoxicillin will be dosed as a single-500mg oral tablet three times daily for 7 days with first dose also being given prior to discharge home.

Group II: No antibiotics Active Control 1 Intervention

Patients randomized into the control (i.e., no antibiotics arm) will be managed according to standard of care practices for previable PPROM desiring of expectant management.

Amoxicillin is already approved in European Union, United States, Canada for the following indications:

Approved in European Union as Amoxicillin for:

• Bacterial infections
• Respiratory tract infections
• Urinary tract infections
• Skin and soft tissue infections
• Ear, nose and throat infections

Approved in United States as Amoxicillin for:

• Infections of the ear, nose, throat, genitourinary tract, skin and skin structure, and lower respiratory tract

Approved in Canada as Amoxicillin for:

• Bacterial infections
• Respiratory tract infections
• Urinary tract infections
• Skin and soft tissue infections

Who Is Running the Clinical Trial?

University Hospitals Cleveland Medical Center

Lead Sponsor

Trials

348

Recruited

394,000+

The Cleveland Clinic

Collaborator

Trials

1,072

Recruited

1,377,000+

MetroHealth Medical Center

Collaborator

Trials

125

Recruited

22,600+

Published Research Related to This Trial

In a study of 287 patients with preterm premature rupture of membranes, extended administration of azithromycin (7 days) significantly increased the latency period before delivery by more than 3 days compared to limited administration (less than 2 days).

The use of extended azithromycin did not lead to any differences in rates of chorioamnionitis or adverse neonatal outcomes, indicating it is a safe option for prolonging gestational latency in these cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Outcomes after extended azithromycin administration in preterm premature rupture of membranes. DiSciullo, AJ., Hand, M., Iqbal, SN., et al.[2023]

Antibiotic treatment in cases of preterm premature rupture of membranes (PPROM) has been shown to reduce the risk of maternal infections and chorioamnionitis, which can improve outcomes for both mothers and their babies.

The guidelines developed by the Society of Obstetricians and Gynaecologists of Canada recommend the use of antibiotics in PPROM to enhance patient management and reduce neonatal morbidity and mortality, based on a thorough review of systematic reviews and clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

No. 233-Antibiotic Therapy in Preterm Premature Rupture of the Membranes. Yudin, MH., van Schalkwyk, J., Van Eyk, N.[2022]

Antibiotics, specifically a 7-day course of ampicillin and erythromycin (or azithromycin), are recommended for women with preterm prelabor rupture of membranes (PPROM) to prevent infections and are effective up to 34 weeks of gestation.

Meta-analyses indicate that using antibiotics in this context leads to lower rates of maternal and fetal infections and helps prolong the duration of pregnancy, making it a crucial intervention for managing PPROM.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antibiotics for Prophylaxis in the Setting of Preterm Prelabor Rupture of Membranes. Dotters-Katz, S.[2021]

In a study of 207 women with preterm premature rupture of membranes, azithromycin resulted in a significantly longer latency period (14.09 days) compared to roxithromycin (7.87 days), suggesting it may be more effective in prolonging pregnancy.

Despite the longer latency with azithromycin, rates of chorioamnionitis, cesarean deliveries, Apgar scores, and birth weights were similar between the two groups, indicating that azithromycin is a safe and convenient first-line treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Macrolide antibiotics roxithromycin vs. azithromycin for preterm premature rupture of membranes: a retrospective comparison. Schreiber, H., Shitrit, P., Man-El, G., et al.[2020]

Antibiotics are recommended for women with preterm premature rupture of membranes (PPROM) at or before 32 weeks' gestation to prolong pregnancy and reduce risks of maternal and neonatal complications, based on a systematic review of evidence from various studies.

For PPROM occurring after 32 weeks' gestation, antibiotics should still be administered if fetal lung maturity is uncertain or if delivery is not imminent, with specific regimens suggested to optimize safety and efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antibiotic therapy in preterm premature rupture of the membranes. Yudin, MH., van Schalkwyk, J., Eyk, NV.[2022]

In a study of 85 women with premature rupture of membranes at 34 weeks, those treated with antibiotics experienced significantly lower rates of chorioamnionitis and endometritis compared to the control group, indicating a clear maternal-fetal health benefit.

The antibiotic treatment not only prolonged the time from rupture to delivery but also resulted in better infant outcomes, including significant weight gain and higher Apgar scores, while the control group had increased rates of complications like sepsis and respiratory distress.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antibiotic therapy in preterm premature rupture of membranes: a randomized, prospective, double-blind trial. Johnston, MM., Sanchez-Ramos, L., Vaughn, AJ., et al.[2019]

In a study of 124 women with preterm premature rupture of membranes, the antibiotic regimen of cefuroxime combined with roxithromycin resulted in significantly lower maternal infectious morbidity and neonatal adverse outcomes compared to the ampicillin and roxithromycin regimen.

Cefuroxime was associated with a longer latency period in primiparas (first-time mothers), suggesting it may be a more effective prophylactic option in this population, with a notable odds ratio of 3.69 for latency periods greater than 4 days compared to the ampicillin group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Compared perinatal outcomes of two prophylactic antibiotic regimens for preterm premature rupture of membranes: a randomized controlled trial. Sgayer, I., Francis, YN., Miron, D., et al.[2023]

In a study of women with preterm premature rupture of membranes (pPROM) between 22 and 27 weeks of gestation, the antibiotic regimen of ampicillin-sulbactam and azithromycin significantly reduced the incidence of moderate or severe bronchopulmonary dysplasia (BPD) in infants compared to a different antibiotic regimen.

The use of the SBT/ABPC and AZM regimen also resulted in fewer total days on mechanical ventilation for the infants, suggesting improved perinatal outcomes with this treatment approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New antibiotic regimen for preterm premature rupture of membrane reduces the incidence of bronchopulmonary dysplasia. Tanaka, S., Tsumura, K., Nakura, Y., et al.[2019]

In a study of 64 patients, direct infusion of antibiotics into the amniotic cavity effectively maintained high concentrations of the drugs for about 24 hours, suggesting a reliable method for preventing infections in cases of premature rupture of membranes.

A single daily dose of 100 mg of antibiotics is likely sufficient for prophylaxis, while higher doses (up to 500 mg) can be used if an intrauterine infection is suspected, without significantly affecting maternal or fetal blood levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transcervical amnioinfusion of antibiotics: a basic study for managing premature rupture of membranes. Ogita, S., Imanaka, M., Matsumoto, M., et al.[2019]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/37094635/

Efficacy of prophylactic antibiotics for preterm premature ... Only penicillins (odds ratio, 0.46; 95% confidence interval, 0.27-0.77) had significantly superior effectiveness for maternal chorioamnionitis. Clindamycin plus ...

2. ajogmfm.org ajogmfm.org/article/S2589-9333(23)00120-9/fulltext

Efficacy of prophylactic antibiotics for preterm premature ... Ampicillin has been the first-line prophylactic antibiotic for pregnant women with preterm premature rupture of membranes for a long time.

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC3964356/

Antibiotic Therapy for Premature Rupture of Membranes ... Meta-analysis of the 7 studies showed a higher rate of pregnancy prolongation by more than 7 days (46.0 vs. 25.9 % [RR 1.8; 95 % CI: 1.52–2.13]) in the group ...

4. obgyn.onlinelibrary.wiley.com obgyn.onlinelibrary.wiley.com/doi/full/10.1002/uog.21884

Effect on perinatal outcome of prophylactic antibiotics in ... In women with preterm prelabor rupture of membranes (PPROM), most antibiotics are superior to placebo/no treatment for prevention of ...

5. sciencedirect.com sciencedirect.com/science/article/pii/S0002937825000316

No difference in outcomes with early vs late antibiotic ... There was no substantial difference in the efficacy and safety of antibiotics administered within 6 to 12 hours after rupture of membranes compared with that ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9546066/

Antibiotic prophylaxis in preterm premature rupture of ... In preterm premature rupture of membranes at 24–31 weeks, antibiotic prophylaxis based on third‐generation cephalosporin may be associated with improved ...

7. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0002937807006321

Amoxicillin pharmacokinetics in pregnant women with ... In this study, a pharmacokinetic model was developed to describe the pharmacokinetics of amoxicillin in pregnant women with PPROM. The pharmacokinetics in our ...

8. ajog.org ajog.org/article/S0002-9378(25)00031-6/fulltext

No difference in outcomes with early vs late antibiotic ... There was no substantial difference in the efficacy and safety of antibiotics administered within 6 to 12 hours after rupture of membranes compared with that ...