Erythromycin vs Azithromycin for Premature Rupture of Membranes

(PRACET Trial)

Recruiting at 1 trial location

Overseen By Ellen M Murrin, DO

Age: 18 - 65

Sex: Female

Trial Phase: Phase 3

Sponsor: Inova Fairfax Hospital

Must be taking: Antibiotics

Disqualifiers: Non-reassuring fetal heart, others

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

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

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

Compensation: Varies

Number of Visits: Unknown

Duration: 7 days

140 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial seeks the best antibiotic treatment for pregnant individuals experiencing preterm premature rupture of membranes (PPROM). Researchers aim to determine whether azithromycin (Zithromax or Zmax) or erythromycin, when combined with other standard antibiotics, can help maintain pregnancy stability longer. Participants will receive either azithromycin or erythromycin along with standard care. Pregnant individuals between 22 and 32 weeks with confirmed early water breaking may qualify, provided there is no medical need for immediate delivery and no allergies to the medications being tested. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants a chance to contribute to significant medical advancements.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that both azithromycin and erythromycin are generally safe for pregnant individuals with preterm premature rupture of membranes (PPROM).

Azithromycin is often chosen because it may reduce the risk of clinical chorioamnionitis, an infection affecting the tissues around the baby. Studies have found that azithromycin can help delay delivery after the water breaks, benefiting the baby's development.

Erythromycin is also effective and can help prolong pregnancy, leading to better outcomes for the baby. However, some people experience stomach upset with erythromycin, which can sometimes lead to discontinuation.

Both medications are generally well-tolerated, but each has potential side effects. The choice between them often depends on how well a person can manage these effects. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for premature rupture of membranes because they offer potential improvements over standard options like ampicillin or penicillin. Azithromycin, for instance, is appealing due to its simpler dosing regimen—just one dose of 1 gram or a tapered course over five days, which could improve patient compliance. Erythromycin, on the other hand, is being tested for its dual administration method, starting with intravenous doses before switching to oral, which may provide more robust initial coverage. These unique features could lead to more effective and convenient management of infections associated with premature rupture of membranes.

What evidence suggests that this trial's treatments could be effective for PPROM?

This trial will compare the effectiveness of azithromycin and erythromycin in managing preterm premature rupture of membranes (PPROM). Research has shown that both azithromycin, administered to participants in one arm of this trial, and erythromycin, given to participants in another arm, can help extend pregnancy when the water breaks too early. Specifically, studies found that women who took azithromycin experienced a longer interval between their water breaking and giving birth compared to some other treatments. Azithromycin also reduces the risk of infections such as chorioamnionitis, an infection of the fetal membranes, and postpartum endometritis, an infection of the uterus lining after birth.

Erythromycin is also effective in prolonging pregnancy and is generally well-tolerated. It has been used for a long time and is known to reduce the risk of infections during pregnancy. Both antibiotics are considered effective, with some studies suggesting they yield similar results, making them common choices for managing PPROM. ^{1 2 6 7 8}

Who Is on the Research Team?

Antonio Saad, MD, MBA

Principal Investigator

Inova Health Care Services

Are You a Good Fit for This Trial?

This trial is for pregnant individuals whose water has broken prematurely (PPROM) before reaching 34 weeks of gestation. They should not have any known allergies to the antibiotics being tested and must be in a condition where prolonging pregnancy is considered safe.

Inclusion Criteria

Cervical dilation 3 cm or less and 4 or fewer contractions within 60-minutes at the time of admission

Membrane rupture within the past 36 hours

Rupture of membranes confirmed by biochemical testing

Exclusion Criteria

Multiple gestations

Allergy to penicillin, erythromycin, or azithromycin

I was admitted with concerns like abnormal fetal heart rate, bleeding, or infection.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

Treatment

Participants receive either azithromycin or erythromycin in addition to standard care to prolong pregnancy until 34 weeks gestational age

7 days

Daily monitoring during hospital stay

Follow-up

Participants are monitored for safety and effectiveness after treatment until delivery

Up to 105 days

What Are the Treatments Tested in This Trial?

Interventions

• Azithromycin
• Erythromycin

Trial Overview The study aims to determine which antibiotic, azithromycin or erythromycin, when combined with ampicillin and amoxicillin, is more effective at extending pregnancy after early water breakage. Participants will receive one of these antibiotics randomly along with standard care.

How Is the Trial Designed?

Group I: Azithromycin Active Control 1 Intervention

Azithromycin 1 gm PO once or 500 mg PO followed by 250 mg PO daily for a total of 5 days

Group II: Erythromycin Active Control 1 Intervention

Erythromycin 250 mg IV every 6 hours for 48 hours, followed by 250 mg PO or 333 mg PO every 8 hours for 5 days

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

Approved in European Union as Azithromycin for:

• Respiratory tract infections
• Skin and soft tissue infections
• Sexually transmitted diseases
• Toxoplasmosis
• Malaria
• Preterm prelabor rupture of membranes

Approved in United States as Azithromycin for:

• Respiratory tract infections
• Skin and soft tissue infections
• Sexually transmitted diseases
• Toxoplasmosis
• Malaria
• Preterm prelabor rupture of membranes

Approved in Canada as Azithromycin for:

• Respiratory tract infections
• Skin and soft tissue infections
• Sexually transmitted diseases
• Toxoplasmosis
• Malaria
• Preterm prelabor rupture of membranes

Who Is Running the Clinical Trial?

Inova Fairfax Hospital

Lead Sponsor

Trials

12

Recruited

7,700+

Inova Health Care Services

Lead Sponsor

Trials

80

Recruited

22,700+

Eastern Virginia Medical School

Collaborator

Trials

77

Recruited

16,500+

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]

In a systematic review of 5 studies involving 1289 women, azithromycin and erythromycin showed similar effects on the duration of latency in preterm prelabor rupture of membranes, with mean latency periods of 6.6 days and 6.7 days respectively.

However, azithromycin was associated with a significantly lower rate of clinical chorioamnionitis (14%) compared to erythromycin (25%), indicating that azithromycin may be a safer option for these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Erythromycin vs azithromycin for treatment of preterm prelabor rupture of membranes: a systematic review and meta-analysis. Seaman, RD., Kopkin, RH., Turrentine, MA.[2022]

In a clinical trial involving pregnant women with preterm prelabor rupture of membranes, a single high dose of Azithromycin (1000 mg) resulted in a significantly longer latency period before delivery compared to a lower dose regimen (500 mg followed by 250 mg daily).

While the higher dose of Azithromycin improved maternal and neonatal outcomes, it was associated with lower rates of postpartum endometritis and respiratory distress syndrome compared to the lower dose regimen.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Different azithromycin protocols for management of preterm prelabour rupture of membranes: a randomized clinical trial. Abdelfattah, LE., Aboshama, RA., Abdelbadie, AS., et al.[2022]

In a study of 453 women with preterm premature rupture of membranes, different dosing regimens of azithromycin did not show a significant difference in the time from rupture to delivery compared to erythromycin, suggesting that azithromycin can be a suitable alternative when erythromycin is unavailable.

However, the 5-day azithromycin regimen was associated with a higher incidence of respiratory distress syndrome in newborns compared to both the 1-day azithromycin and erythromycin groups, indicating a potential safety concern with longer azithromycin treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Azithromycin vs erythromycin for the management of preterm premature rupture of membranes. Navathe, R., Schoen, CN., Heidari, P., et al.[2020]

Azithromycin is generally considered a safe medication, with serious side effects like angioedema and cholestatic jaundice occurring in less than 1% of patients.

However, this report highlights a rare but severe case of dilated cardiomyopathy and significant liver toxicity leading to hepatic encephalopathy in a patient taking Azithromycin, suggesting that even commonly used medications can have unexpected serious effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Azithromycin induced hepatocellular toxicity and hepatic encephalopathy in asymptomatic dilated cardiomyopathy. Das, BK.[2021]

In a study of over 1.3 million patients, azithromycin was found to significantly increase the risk of cardiovascular death during a 5-day treatment period, with a hazard ratio of 2.88 compared to those not taking antibiotics.

Patients with a high baseline risk of cardiovascular disease experienced the greatest increase in risk, with an estimated 245 additional cardiovascular deaths per 1 million courses of azithromycin, highlighting the need for caution in prescribing this antibiotic to at-risk populations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Azithromycin and the risk of cardiovascular death. Ray, WA., Murray, KT., Hall, K., et al.[2022]

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]

In a study of 168 women with preterm premature rupture of membranes, the use of azithromycin instead of erythromycin did not change the length of latency before delivery, with both groups showing similar durations (approximately 9.6 days for erythromycin and 9.4 days for azithromycin).

No significant differences were found in secondary outcomes such as rates of chorioamnionitis, cesarean delivery, or neonatal complications, indicating that azithromycin can be a safe alternative to erythromycin without compromising maternal or fetal health.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A retrospective comparison of antibiotic regimens for preterm premature rupture of membranes. Pierson, RC., Gordon, SS., Haas, DM.[2021]

Azithromycin significantly reduces the risk of bronchopulmonary dysplasia (BPD) in extremely premature neonates, with a relative risk of 0.83 based on a review of 11 studies involving 473 neonates.

While azithromycin is associated with various adverse events, including respiratory and gastrointestinal issues, there was no significant increase in liver enzyme levels compared to placebo, indicating a relatively safe profile for this medication in neonates.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Use and safety of azithromycin in neonates: a systematic review. Smith, C., Egunsola, O., Choonara, I., et al.[2022]

Citations

1. sciencedirect.com sciencedirect.com/science/article/abs/pii/S2589933324001496

Azithromycin dosing and preterm premature rupture of ... Approximately 500 mg daily dosing of azithromycin maintains higher amniotic fluid concentrations and more consistently greater than common minimum inhibitory ...

2. dig.pharmacy.uic.edu dig.pharmacy.uic.edu/faqs/2024-2/january-2024-faqs/what-evidence-supports-the-use-of-azithromycin-for-ruptured-membranes-in-preterm-prelabor/

What evidence supports the use of azithromycin for ruptured ... Women who received azithromycin and amoxicillin had a longer median latency from time of membrane rupture to delivery compared to those who ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT01556334

Erythromycin Versus Azithromycin in Preterm Premature ... The goal of this study is to see if there is a difference between the antibiotic (azithromycin) compared to the antibiotic (erythromycin) in prolonging ...

4. bmcpregnancychildbirth.biomedcentral.com bmcpregnancychildbirth.biomedcentral.com/articles/10.1186/s12884-022-05189-7

RETRACTED ARTICLE: Different azithromycin protocols for ... Azithromycin in the treatment of preterm prelabor rupture of membranes demonstrates a lower risk of chorioamnionitis and postpartum endometritis ...

5. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/25162251/

A retrospective comparison of antibiotic regimens for preterm ... Results: Of 168 women who met inclusion criteria, 75 received ampicillin and erythromycin and 93 received ampicillin and azithromycin. There was no difference ...

6. ajogmfm.org ajogmfm.org/article/S2589-9333(24)00149-6/abstract

Azithromycin dosing and preterm premature rupture of ... We aimed to compare the pharmacokinetics of 1-time vs daily dosing of azithromycin in the setting of preterm prelabor rupture of membranes.

7. clinicaltrials.gov clinicaltrials.gov/study/NCT07183462

NCT07183462 | Azithromycin and Ampicillin for Late PPROM It is associated with significant maternal, fetal, and neonatal risks, including infections, respiratory complications, and adverse ...

8. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7368187/

Azithromycin in the Treatment of Preterm Prelabor Rupture ... Our study suggests that latency antibiotic regimens substituting azithromycin for erythromycin have lower rates and decreased risk of clinical chorioamnionitis.