Antibiotics for Premature Rupture of Membranes

Overseen By Marissa Berry, MD

Age: 18+

Sex: Female

Trial Phase: Phase 4

Sponsor: Ohio State University

Must not be taking: Prophylactic antibiotics

Disqualifiers: Infection, Allergy, Immunosuppression, 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: Unknown

Duration: 1 week

56 Participants Needed

Trial Summary

What is the purpose of this trial?

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.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, if you are on antibiotics, you may need to stop if you've had more than one dose, as this is part of the exclusion criteria.

What data supports the effectiveness of the drug combination Ceftriaxone and Metronidazole for treating premature rupture of membranes?

Research shows that a combination of Ceftriaxone and Metronidazole is effective in treating perforated appendicitis, suggesting it could be beneficial for other infections due to its broad-spectrum antibacterial activity. ^{1 2 3 4 5}

Is the use of antibiotics for premature rupture of membranes generally safe for humans?

Research shows that antibiotics like ampicillin, erythromycin, and cefazolin are commonly used for premature rupture of membranes and are generally considered safe, as they help prevent infections without significant increases in fetal or maternal blood levels. ^{6 7 8 9 10}

How does the drug combination of Ceftriaxone, Clarithromycin, and Metronidazole for premature rupture of membranes differ from other treatments?

This drug combination is unique because it combines three antibiotics, each with different mechanisms of action, to potentially address a broad range of bacterial infections that could occur with premature rupture of membranes, whereas other treatments might not use this specific combination or target such a wide spectrum of bacteria. ^{4 11 12 13 14}

Research Team

Marissa Berry, MD

Principal Investigator

Ohio State University

Kartik K Venkatesh, MD, PhD

Principal Investigator

Ohio State University

Eligibility Criteria

This trial is for hospitalized pregnant individuals with PPROM (preterm premature rupture of membranes) who are less than 34 weeks into their pregnancy. The goal is to see if a new combination of antibiotics can help prolong pregnancy and improve outcomes.

Inclusion Criteria

Gestational age between 23 0/7 and 32 6/7 weeks

I am hospitalized for the management of water breaking early in pregnancy.

Exclusion Criteria

Maternal immunosuppression

Allergy or contraindication to an antibiotic in either arm

I am currently being treated for an infection with antibiotics.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

Treatment

Participants receive a seven-day course of either the standard antibiotic regimen or the experimental regimen to manage PPROM

1 week

Follow-up

Participants are monitored for safety and effectiveness after treatment, including monitoring for endometritis, surgical site infection, and neonatal outcomes

6 weeks postpartum

Treatment Details

Interventions

• Ceftriaxone
• Clarithromycin
• Metronidazole

Trial Overview The study compares two antibiotic regimens for managing PPROM: one group receives ceftriaxone, clarithromycin, and metronidazole for seven days; the other follows standard care with ampicillin/amoxicillin plus azithromycin or erythromycin.

Participant Groups

Group I: Standard of care Experimental Treatment 4 Interventions

Participants randomized to the standard care group will receive the following regimen: * Ampicillin 2 g IV q 6 hours x 48 hours followed by amoxicillin 250 mg q 8 hours for an additional 5 days * Azithromycin 1 g PO x 1 dose OR erythromycin 250 mg IV q 6 hours x 48 hours followed by erythromycin 333 mg PO TID for an additional 5 days

Group II: Intervention group Experimental Treatment 3 Interventions

Participants randomized to the intervention group will receive the following regimen: * Ceftriaxone 1 g IV q 24 hours x 7 days * Clarithromycin 500 mg PO BID x 7 days * Metronidazole 500 mg PO q 12 hours x 7 days

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

Approved in European Union as Rocephin for:

• Sepsis
• Bacterial infections
• Meningitis
• Gonorrhea
• Pelvic inflammatory disease

Approved in United States as Rocephin for:

• Sepsis
• Bacterial infections
• Meningitis
• Gonorrhea
• Pelvic inflammatory disease
• Lower respiratory tract infections
• Skin and skin structure infections
• Urinary tract infections

Approved in Canada as Rocephin for:

• Sepsis
• Bacterial infections
• Meningitis
• Gonorrhea
• Pelvic inflammatory disease
• Lower respiratory tract infections
• Skin and skin structure infections
• Urinary tract infections

Who Is Running the Clinical Trial?

Ohio State University

Lead Sponsor

Trials

891

Recruited

2,659,000+

Findings from Research

A new 2-drug regimen of ceftriaxone and Flagyl for treating children with perforated appendicitis allows for once-a-day dosing, leading to lower maximum temperatures post-surgery compared to the traditional 3-drug regimen.

This simpler regimen not only reduces the length of hospital stays (6.8 days vs. 7.8 days) but also significantly lowers medication costs, saving patients over $1,186 for a 5-day treatment period without compromising efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A simple and more cost-effective antibiotic regimen for perforated appendicitis. St Peter, SD., Little, DC., Calkins, CM., et al.[2013]

Group B streptococci and Listeria monocytogenes are the main bacteria causing early-onset infections in neonates, while coagulase-negative staphylococci are common in late-onset infections, especially in high-risk infants.

Empirical treatment for early-onset infections typically involves a combination of ampicillin and an aminoglycoside, while late-onset infections may be treated with oxacillin and an aminoglycoside, with adjustments based on local bacterial patterns and microbiological results.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antibiotics in neonatal infections: a review. Fanos, V., Dall'Agnola, A.[2018]

A review of various antibiotics used to treat MRSA skin infections in lactating women found that older antibiotics like clindamycin and vancomycin are generally safe for breastfeeding infants, as the amounts transferred through breast milk are minimal.

Despite the overall low risk to infants, the limited data on newer antibiotics like linezolid and daptomycin highlights the importance of monitoring breastfed infants whose mothers are treated for MRSA infections.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Excretion of antimicrobials used to treat methicillin-resistant Staphylococcus aureus infections during lactation: safety in breastfeeding infants. Mitrano, JA., Spooner, LM., Belliveau, P.[2009]

Infections are more common in newborns than in any other age group, and antibiotics remain a crucial treatment for managing these infections, with specific classes like penicillins and cephalosporins being frequently used.

Due to rising antibiotic resistance in Neonatal Intensive Care Units (NICUs), there may be a shift towards using alternative antibiotics like quinolones and linezolid, highlighting the need for tailored antibiotic regimens based on local bacterial profiles.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antibiotics and antifungals in neonatal intensive care units: a review. Fanos, V., Cuzzolin, L., Atzei, A., et al.[2009]

In a study of 122 adult patients with intra-abdominal infections, the combination of cefepime and metronidazole was more effective than imipenem-cilastatin, with a clinical success rate of 87% compared to 72%.

Both treatment regimens achieved similar rates of microbiological eradication, but the cefepime + metronidazole combination showed a statistically significant improvement in clinical outcomes, suggesting it may be a preferable option for treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A randomized prospective study of cefepime plus metronidazole with imipenem-cilastatin in the treatment of intra-abdominal infections. Garbino, J., Villiger, P., Caviezel, A., et al.[2018]

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 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]

A new antibiotic combination of ceftriaxone, clarithromycin, and metronidazole was found to significantly improve perinatal outcomes in preterm premature rupture of membranes (PROM) compared to the standard regimen of ampicillin and/or cephalosporins, as shown in a study of 314 patients.

Patients receiving the new regimen had lower rates of acute histologic chorioamnionitis and funisitis, as well as significantly reduced incidences of intra-ventricular hemorrhage and cerebral palsy, indicating better safety and efficacy for neonatal health.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A new anti-microbial combination prolongs the latency period, reduces acute histologic chorioamnionitis as well as funisitis, and improves neonatal outcomes in preterm PROM. Lee, J., Romero, R., Kim, SM., et al.[2022]

In a study of 147 women with preterm premature rupture of membranes, the antibiotic regimen of ampicillin-sulbactam followed by oral amoxicillin + clavulanate did not increase the risk of necrotizing enterocolitis in newborns compared to the cefazolin and erythromycin regimen.

Both antibiotic protocols showed similar outcomes in terms of latency period, gestational age at delivery, and route of delivery, indicating that both regimens are effective for prolonging latency without significant differences in safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A retrospective review of ampicillin-sulbactam and amoxicillin + clavulanate vs cefazolin/cephalexin and erythromycin in the setting of preterm premature rupture of membranes: maternal and neonatal outcomes. Ehsanipoor, RM., Chung, JH., Clock, CA., et al.[2013]

In a study of 102 women with preterm premature rupture of membranes (PPROM), the combination of cefazolin with either erythromycin or clarithromycin did not show significant differences in neonatal morbidity or neurological outcomes compared to cefazolin alone.

However, the use of clarithromycin was associated with a significantly lower degree of histological funisitis, suggesting it may offer some benefits over erythromycin in managing PPROM.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The efficacy of cefazolin plus macrolide (erythromycin or clarithromycin) versus cefazolin alone in neonatal morbidity and placental inflammation for women with preterm premature rupture of membranes. Kwak, HM., Shin, MY., Cha, HH., et al.[2013]

New beta-lactam antibiotics, including cephem and carbapenem classes, show strong effectiveness against multidrug-resistant organisms like MRSA and PRSP by targeting PBP 2a, which is crucial for bacterial cell wall synthesis.

AM-112, a novel beta-lactamase inhibitor, demonstrates potent activity against various classes of beta-lactamases, enhancing the efficacy of existing antibiotics against resistant strains.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Recent trend for the development of new antibacterial agents]. Nishino, T.[2011]

Vancomycin is the preferred treatment for methicillin-resistant Staphylococcus aureus (MRSA) infections, as beta-lactam antibiotics are ineffective due to the mechanism of resistance.

While investigational antibiotics like teicoplanin and daptomycin are related to vancomycin, they have not shown superior efficacy in clinical trials at lower doses, and ongoing trials are testing their effectiveness at higher doses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of infection and colonization caused by methicillin-resistant Staphylococcus aureus. Chambers, HF.[2019]

In a study analyzing 124 MRSA strains from hospitalized patients, all strains were found to be susceptible to the tested antibiotics, indicating effective treatment options are available.

Dalbavancin demonstrated the lowest minimum inhibitory concentration (MIC), making it the most effective antimicrobial against MRSA in this study, while vancomycin had the highest MIC value.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

In vitro analysis of the minimal inhibitory concentration values of different generations of anti-methicillin-resistant Staphylococcus aureus antibiotics. Guzek, A., Rybicki, Z., Tomaszewski, D.[2023]

The study found that combining vancomycin (VCM) with low concentration beta-lactam antibiotics, such as flomoxef and ampicillin, significantly reduced survival rates in mice with infections caused by beta-lactam antibiotic-induced vancomycin resistant MRSA (BIVR), indicating an antagonistic effect.

In contrast, combining imipenem/cilastatin with teicoplanin (TEIC) resulted in improved survival rates and reduced bacterial load in mice, demonstrating a synergistic effect, which suggests that not all combinations of antibiotics are equally effective against BIVR.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Combined effect of vancomycin or teicoplanin plus a beta-lactam antibiotic in mouse infection models caused by beta-lactam antibiotec-induced vancomycin resistant MRSA (BIVR)]. Hatano, K., Yokota, Y., Hanaki, H., et al.[2019]

References

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

A simple and more cost-effective antibiotic regimen for perforated appendicitis. [2013]

2. New Zealand pubmed.ncbi.nlm.nih.gov

Antibiotics in neonatal infections: a review. [2018]

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

Excretion of antimicrobials used to treat methicillin-resistant Staphylococcus aureus infections during lactation: safety in breastfeeding infants. [2009]

4. England pubmed.ncbi.nlm.nih.gov

Antibiotics and antifungals in neonatal intensive care units: a review. [2009]

5. Germany pubmed.ncbi.nlm.nih.gov

A randomized prospective study of cefepime plus metronidazole with imipenem-cilastatin in the treatment of intra-abdominal infections. [2018]

6. Germany pubmed.ncbi.nlm.nih.gov

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

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

Transcervical amnioinfusion of antibiotics: a basic study for managing premature rupture of membranes. [2019]

8. England pubmed.ncbi.nlm.nih.gov

A new anti-microbial combination prolongs the latency period, reduces acute histologic chorioamnionitis as well as funisitis, and improves neonatal outcomes in preterm PROM. [2022]

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

A retrospective review of ampicillin-sulbactam and amoxicillin + clavulanate vs cefazolin/cephalexin and erythromycin in the setting of preterm premature rupture of membranes: maternal and neonatal outcomes. [2013]

10. Netherlands pubmed.ncbi.nlm.nih.gov

The efficacy of cefazolin plus macrolide (erythromycin or clarithromycin) versus cefazolin alone in neonatal morbidity and placental inflammation for women with preterm premature rupture of membranes. [2013]

11. Japan pubmed.ncbi.nlm.nih.gov

[Recent trend for the development of new antibacterial agents]. [2011]

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

Treatment of infection and colonization caused by methicillin-resistant Staphylococcus aureus. [2019]

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

In vitro analysis of the minimal inhibitory concentration values of different generations of anti-methicillin-resistant Staphylococcus aureus antibiotics. [2023]

14. Japan pubmed.ncbi.nlm.nih.gov

[Combined effect of vancomycin or teicoplanin plus a beta-lactam antibiotic in mouse infection models caused by beta-lactam antibiotec-induced vancomycin resistant MRSA (BIVR)]. [2019]