Antibiotics for Neonatal Infections

(NANO Trial)

Not currently recruiting at 13 trial locations

Overseen By Michael J Morowitz, MD

Age: < 18

Sex: Any

Trial Phase: Phase 4

Sponsor: Michael Morowitz

Must not be taking: Antibiotics

Disqualifiers: Maternal infection, Respiratory insufficiency, Hemodynamic instability, Major congenital anomalies, others

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

Compensation: Varies

Number of Visits: 1

Duration: 1 week

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial examines whether administering antibiotics to extremely low birthweight (ELBW) infants, who are stable and have not been exposed to infection, might cause more harm than benefit. Researchers aim to determine if these antibiotics could lead to late infections, serious gut problems, or even death. ELBW infants who are stable and have no known infection risks may qualify for this trial. Babies will receive either standard antibiotics (ampicillin and gentamycin) or a placebo, enabling researchers to compare outcomes. As a Phase 4 trial, this research focuses on understanding how an already FDA-approved treatment can benefit more patients.

Will I have to stop taking my current medications?

The trial information does not specify whether participants must stop taking their current medications. It is best to consult with the trial coordinators for specific guidance.

What is the safety track record for these treatments?

Research shows that the antibiotics ampicillin and gentamycin are often used together in newborns to prevent infections like early-onset sepsis. Most newborns tolerate these antibiotics well. For ampicillin, studies have found that administering two doses of 50 mg/kg to preterm infants provides good protection against bacteria while minimizing side effects. However, some cases may experience high blood pressure in the lungs (pulmonary hypertension) as a potential side effect.

For gentamycin, studies recommend its use for newborns at risk of early-onset sepsis, but information on its safety remains limited. Gentamycin may sometimes be ineffective if bacteria become resistant, though no specific safety concerns have been noted in the available research.

In summary, both antibiotics are generally well-tolerated in newborns, but like all medications, they carry some risks. The trial under consideration is in phase 4, indicating that the treatment is already in standard use and is considered relatively safe. ^{1 2 3 4 5}

Why are researchers enthusiastic about this study treatment?

Researchers are excited about these treatments for early-onset neonatal sepsis because they explore the effectiveness of standard antibiotics, ampicillin and gentamycin, in a structured setting. Unlike newer antibiotics that might target specific bacteria, ampicillin and gentamycin offer broad-spectrum coverage, which is essential for treating infections in newborns whose specific pathogens may not be immediately known. This trial also includes a placebo group, which is crucial for understanding the real impact and necessity of antibiotics in these early evaluations. By comparing these common antibiotics directly against a placebo, researchers aim to better understand their true efficacy and potential benefits in this vulnerable population.

What is the effectiveness track record for empiric antibiotics in treating neonatal infections?

Research has shown that using ampicillin and gentamycin together effectively combats most bacteria causing early-onset sepsis in newborns. For instance, a study in the UK found that these antibiotics could treat 95% of the bacteria in such infections. The World Health Organization also recommends this combination for newborn sepsis due to its effectiveness. In this trial, one group of infants will receive the standard antibiotic coverage of ampicillin and gentamycin. However, strong evidence does not support that this antibiotic pair is superior to other treatments for sepsis in young infants. The main point is its effectiveness in targeting common bacteria in newborns. ^{1 5 6 7 8}

Are You a Good Fit for This Trial?

The trial is for newborns born at 23-30 weeks gestation, who are clinically stable without signs of infection or severe respiratory issues. It excludes those with major congenital anomalies, infants expected not to survive beyond 72 hours, and babies whose mothers had infections like GBS disease or chorioamnionitis.

Inclusion Criteria

My newborn is between 23 and 30 weeks old.

Exclusion Criteria

My infant needs medicine or fluids to maintain blood pressure.

My previous child had a GBS infection.

My baby might be at high risk for sepsis based on their or my medical history.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

1 week

1 visit (in-person)

Treatment

Infants receive either empiric antibiotics or placebo while being evaluated for early-onset neonatal sepsis

1 week

Daily monitoring (in-person)

Sample Collection

Weekly fecal samples collected for microbiome analysis and a one-time blood draw for genetic analysis

8 weeks

Weekly visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessment of NEC, LOS, and death

Up to 50 weeks

Monthly visits (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• Ampicillin
• Gentamycin
• Normal saline

Trial Overview

This study tests whether giving antibiotics (Ampicillin and Gentamycin) to extremely low birthweight infants in their first week affects the rates of sepsis, necrotizing enterocolitis, or death compared to a placebo (Normal saline).

How Is the Trial Designed?

Group I: Empiric antibiotics Active Control 2 Interventions

Infants will receive standard antibiotic coverage of ampicillin and gentamycin at site approved dosing guidelines while completing an evaluation for early-onset neonatal sepsis.

Group II: Placebo Placebo Group 1 Intervention

Infants will receive a volume matched placebo of normal saline while completing an evaluation for early-onset neonatal sepsis.

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

Approved in United States as Ampicillin for:

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

Approved in European Union as Ampicillin for:

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

Approved in Canada as Ampicillin for:

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

Who Is Running the Clinical Trial?

Michael Morowitz

Lead Sponsor

Trials

1

Recruited

800+

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Collaborator

Trials

2,103

Recruited

2,760,000+

Published Research Related to This Trial

In a study of 16 patients with moderate to serious surgical and urogenital infections, the combination of ampicillin and sulbactam (Unasyn IM/IV) demonstrated a clinical cure rate of 69%, indicating its efficacy against infections, particularly those caused by ampicillin-resistant strains.

The treatment was well-tolerated, with excellent subjective and objective tolerance reported, suggesting that Unasyn IM/IV is a safe option for treating nosocomial infections in settings with rising beta-lactamase production.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Unasyn in severe hospital infections]. Sechser, T., Hatala, M., Svácek, J., et al.[2013]

In a study of 192 neonates, 43% exhibited elevated gentamicin levels, indicating a significant risk of potential toxicity, especially in preterm infants.

Preterm neonates, particularly those weighing less than 2.5 kg, showed a higher incidence of elevated gentamicin levels (61%), suggesting that dosage adjustments may be necessary to reduce toxicity in this vulnerable population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gentamicin use in neonates: should we have a change of practice? Krishnamoorthy, SS., Nair, A., Furness, J., et al.[2013]

In a study of 100 children aged 5 to 14 undergoing emergency appendectomy, the combination of sulbactam and ampicillin was found to be effective as prophylaxis against postoperative wound infections, with an overall infection rate of 8%.

There was no significant difference in infection rates between the sulbactam-ampicillin group and the metronidazole-cefotaxime group, indicating that sulbactam-ampicillin is a suitable alternative for preventing infections in pediatric appendicitis cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Perioperative prophylaxis with sulbactam and ampicillin compared with metronidazole and cefotaxime in the prevention of wound infection in children undergoing appendectomy. Foster, MC., Morris, DL., Legan, C., et al.[2019]

The combination of sulbactam and ampicillin was safely administered to 16 newborn infants, achieving satisfactory plasma concentrations with a dosage of 50 mg/kg every 12 hours, indicating it could be effective for treating infections in this population.

The pharmacokinetics showed longer elimination half-lives for both drugs in newborns compared to adults, but there was no evidence of drug accumulation, suggesting that the regimen is well tolerated and appropriate for further clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetic study of sulbactam and ampicillin administered concomitantly by intraarterial or intravenous infusion in the newborn. Sutton, AM., Turner, TL., Cockburn, F., et al.[2019]

In a study involving 60 newborns in an intensive care nursery, three antibiotic combinations were evaluated for safety and efficacy, showing that all combinations were well-tolerated without significant toxicity.

The aminoglycoside serum concentrations for gentamicin, tobramycin, and amikacin were within expected therapeutic ranges, indicating effective dosing without causing hematologic, renal, or hepatic toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation of three antibiotic programs in newborn infants. Marks, S., Marks, MI., Dupont, C., et al.[2018]

In a study involving over 300 neonatal calves, sulbactam-ampicillin significantly reduced mortality from 26.4% in untreated controls to 9.5%, demonstrating its efficacy against beta-lactam-resistant enterobacteria.

The combination treatment also decreased the probability of diarrhea from 50% in controls to 35%, highlighting its effectiveness in managing neonatal calf diarrhea compared to ampicillin alone, which had a lesser impact.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of sulbactam-ampicillin in the treatment of neonatal calf diarrhoea. Grimshaw, WT., Colman, PJ., Petrie, L.[2019]

In neonatal units, the most common initial treatment for suspected bacterial infections is a combination of ampicillin and gentamicin, particularly in cases of maternal or neonatal fever and other clinical signs of infection.

Treatment duration varies based on the presence of bacteria: typically around 10 days for identified pathogens and up to 20 days for confirmed meningitis, highlighting the importance of tailored antibiotic therapy in neonates.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Results of a national survey on the antibiotic therapy of neonatal bacterial infection due to materno-fetal contamination]. Bourrillon, A., Laik, P.[2015]

In a study of 1162 critically ill neonates on mechanical ventilation, those treated with ampicillin plus cefotaxime had worse outcomes compared to those receiving ampicillin plus gentamicin, including higher rates of late-onset sepsis and in-hospital mortality.

The use of ampicillin plus cefotaxime did not improve outcomes for neonates with early-onset sepsis and was linked to longer hospital stays, suggesting it should not be routinely used as empiric treatment in this population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Influences of Initial Empiric Antibiotics with Ampicillin plus Cefotaxime on the Outcomes of Neonates with Respiratory Failure: A Propensity Score Matched Analysis. Ou-Yang, MC., Hsu, JF., Chu, SM., et al.[2023]

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]

Sulbactame, a beta-lactamase inhibitor, demonstrated low toxicity with a lethal dose (DL50) in mice exceeding 4,000 mg/kg, indicating a strong safety profile when used alone or in combination with ampicillin or amoxicillin.

The combination of sulbactame with ampicillin or amoxicillin showed effective serum levels against tested bacteria, suggesting its therapeutic potential in treating infections caused by beta-lactamase producing germs, comparable to the established product Unasyn.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Pharmacological studies of sulbactam and its association with semisynthetic beta-lactam antibiotics]. Nechifor, M., Buiuc, D., Diaconu, E., et al.[2013]

In a study of 27 neonates with serious infections, oral Sultamicillin demonstrated high efficacy, achieving a clinical cure rate of 96.3% and a bacteriologic cure rate of 93.8% over an average treatment duration of 7.4 days.

The treatment was well-tolerated, with no serious side effects reported; only one infant experienced mild loose stools, indicating that Sultamicillin is a safe option for treating mild to moderate infections in newborns.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Observations on oral Sultamicillin/Unasyn CP-45 899 therapy of neonatal infections. Airede, AI., Jalo, I., Weerasinghe, HD., et al.[2019]

Citations

1.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC8127574/

Antibiotic regimens for early‐onset neonatal sepsis - PMC

For example, data from the UK showed that 95% of the identified pathogens were susceptible to the most used empirical antibiotic regimens of penicillin and ...

2.

publications.aap.org

publications.aap.org/pediatrics/article/154/Supplement%201/e2024066588F/198465/Efficacy-of-Antibiotic-Regimens-for-Sepsis-or

Efficacy of Antibiotic Regimens for Sepsis or Possible ...

We found limited evidence to support any single antibiotic regimen as superior to alternate regimens to treat young infant sepsis or PSBI.

3.

thelancet.com

thelancet.com/journals/laninf/article/PIIS1473-3099(21)00050-5/fulltext

Effects of antibiotic resistance, drug target attainment, ...

WHO advocates ampicillin–gentamicin as first-line therapy for the management of neonatal sepsis. In the BARNARDS observational cohort study of ...

4.

clinicaltrials.gov

clinicaltrials.gov/study/NCT00879190

Study Details | NCT00879190 | Ampicillin / Sulbactam vs. ...

When a participating patient is diagnosed with chorioamnionitis, she will be randomized in a blinded fashion to Arm 1 (Unasyn) or Arm 2 (ampicillin/gentamicin).

5.

academic.oup.com

academic.oup.com/jac/article/74/11/3150/5522501

Oral antibiotics for neonatal infections: a systematic review ...

Oral antibiotics administered to neonates are absorbed and result in adequate serum levels, judged by MICs of relevant pathogens, over time.

6.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC9262754/

Ampicillin Dosing in Premature Infants for Early-onset Sepsis

For EOS in preterm infants, two ampicillin doses (50mg/kg) provided optimal bactericidal exposures, while minimizing potential toxicity.

7.

healthcare.uiowa.edu

healthcare.uiowa.edu/marcom/uichildrens/neonatology-handbook/NICU-ABX-chart.pdf

Recommended Antimicrobial Dosage Schedules for ...

In the presence of GBS sepsis and the treatment with ampicillin or PenG, the bacteria will release a phospholipid that can cause pulmonary hypertension. Goal is ...

8.

labeling.pfizer.com

labeling.pfizer.com/ShowLabeling.aspx?id=12115

UNASYN IM/IV

Use in Children, Infants and Neonates. The dosage of sulbactam sodium/ampicillin sodium IM/IV for most infections in children, infants and neonates is 150 mg ...