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

Trial Summary

What is the purpose of this trial?

The goal of this study is to help identify the best antibiotic treatment for pregnant people when their water breaks prematurely (a condition abbreviated as PPROM). Current practice is to attempt to maintain the pregnancy until at least 34 weeks gestational age, when the risks of prematurity to the baby are lessened. Research shows that antibiotics help the pregnancy last longer, but there have been limited studies about which combination works best. Currently, both azithromycin and erythromycin are accepted antibiotic treatments, in addition to ampicillin and amoxicillin. Participants diagnosed with PPROM will be randomized to receive ampicillin and amoxicillin plus either azithromycin or erythromycin, in addition to the care they would normally receive. Studying these two drugs will help decide the best care for future patients with PPROM.

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.

What data supports the effectiveness of the drug azithromycin for premature rupture of membranes?

Azithromycin is often used instead of erythromycin for managing premature rupture of membranes due to its ease of use, lower cost, and fewer side effects. Studies suggest that azithromycin is a suitable alternative to erythromycin, especially given erythromycin shortages. ^{1 2 3 4 5}

Is azithromycin safe for humans?

Azithromycin is generally considered safe, but it can cause some side effects like stomach issues and reversible hearing loss. Rarely, it may lead to serious problems like liver damage or heart issues, especially in people with existing heart conditions. ^{1 2 6 7 8}

How does azithromycin differ from erythromycin for treating preterm premature rupture of membranes?

Azithromycin is preferred over erythromycin for treating preterm premature rupture of membranes due to its easier administration, lower cost, and better side effect profile, especially given the national shortages of erythromycin. ^{1 2 3 5 9}

Research Team

Antonio Saad, MD, MBA

Principal Investigator

Inova Health Care Services

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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 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]

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 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 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]

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]

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 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]

References

1. United States pubmed.ncbi.nlm.nih.gov

Azithromycin vs erythromycin for the management of preterm premature rupture of membranes. [2020]

2. England pubmed.ncbi.nlm.nih.gov

Different azithromycin protocols for management of preterm prelabour rupture of membranes: a randomized clinical trial. [2022]

3. United States pubmed.ncbi.nlm.nih.gov

A retrospective comparison of antibiotic regimens for preterm premature rupture of membranes. [2021]

4. United States pubmed.ncbi.nlm.nih.gov

Erythromycin vs azithromycin for treatment of preterm prelabor rupture of membranes: a systematic review and meta-analysis. [2022]

5. United States pubmed.ncbi.nlm.nih.gov

Outcomes after extended azithromycin administration in preterm premature rupture of membranes. [2023]

6. United States pubmed.ncbi.nlm.nih.gov

Azithromycin and the risk of cardiovascular death. [2022]

7. England pubmed.ncbi.nlm.nih.gov

Use and safety of azithromycin in neonates: a systematic review. [2022]

8. India pubmed.ncbi.nlm.nih.gov

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

9. Germany pubmed.ncbi.nlm.nih.gov

Macrolide antibiotics roxithromycin vs. azithromycin for preterm premature rupture of membranes: a retrospective comparison. [2020]