Antibiotics for Neonatal Infections

(NANO Trial)

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

802 Participants Needed

Trial Summary

What is the purpose of this trial?

The goal of the NANO trial is to study the longstanding clinical practice of empirically administering intravenous antibiotics to extremely low birthweight (ELBW) infants in the first days of life. In this 802-subject multicenter placebo-controlled randomized clinical trial, the hypothesis to be tested is that the incidence of adverse outcomes is higher in babies receiving empiric antibiotics (EA) in the first week of life compared to babies receiving placebo. The study targets a population of ELBW infants in whom the clinical decision to use or not use EA is currently most challenging -- infants that are clinically stable that did not have a known exposure to intraamniotic infection and were not born preterm for maternal indications. The primary outcome is the composite outcome of late-onset sepsis (LOS), necrotizing enterocolitis (NEC), or death during the index hospitalization. Secondary safety outcomes will include total antibiotic days, days to full enteral feedings, and common morbidities in preterm infants that have previously been linked to EA, e.g. retinopathy of prematurity and bronchopulmonary dysplasia. Weight and length z-score, and head circumference, are standard measures to be collected weekly by clinical team per a standardized protocol.

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 data supports the effectiveness of the drug combination of ampicillin and sulbactam for neonatal infections?

Research shows that the combination of ampicillin and sulbactam is effective in treating serious infections in newborns, with a clinical cure and improvement rate of up to 100% in a study of 27 neonates. This combination is also effective in overcoming resistance in bacteria that produce beta-lactamase, an enzyme that usually makes them resistant to antibiotics like ampicillin. ^{1 2 3 4 5}

Is the combination of antibiotics like ampicillin and gentamicin safe for newborns?

Research shows that combinations like ampicillin and gentamicin are generally well-tolerated in newborns, with no significant harmful effects on blood, kidneys, or liver. Other studies also found that the combination of ampicillin and sulbactam is safe and effective for treating infections, with good tolerance in patients. ^{1 3 6 7 8}

How does the drug combination of Ampicillin and Gentamicin differ from other treatments for neonatal infections?

The combination of Ampicillin and Gentamicin is commonly used as an initial treatment for neonatal infections due to its effectiveness against a broad range of bacteria, and it is often preferred over other combinations like Ampicillin and Cefotaxime, which have been associated with worse outcomes and higher risks of resistant infections in critically ill neonates. ^{2 3 9 10 11}

Eligibility Criteria

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

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)

Treatment Details

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).

Participant Groups

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+

Findings from Research

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 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]

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 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 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]

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]

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 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 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]

References

1. Czech Republic pubmed.ncbi.nlm.nih.gov

[Unasyn in severe hospital infections]. [2013]

2. Netherlands pubmed.ncbi.nlm.nih.gov

Observations on oral Sultamicillin/Unasyn CP-45 899 therapy of neonatal infections. [2019]

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

Pharmacokinetic study of sulbactam and ampicillin administered concomitantly by intraarterial or intravenous infusion in the newborn. [2019]

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

Efficacy of sulbactam-ampicillin in the treatment of neonatal calf diarrhoea. [2019]

5. United States 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. [2019]

6. Canada pubmed.ncbi.nlm.nih.gov

Evaluation of three antibiotic programs in newborn infants. [2018]

7. Romania pubmed.ncbi.nlm.nih.gov

[Pharmacological studies of sulbactam and its association with semisynthetic beta-lactam antibiotics]. [2013]

8. Scotland pubmed.ncbi.nlm.nih.gov

Gentamicin use in neonates: should we have a change of practice? [2013]

9. France pubmed.ncbi.nlm.nih.gov

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

10. Switzerland 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. [2023]

11. England pubmed.ncbi.nlm.nih.gov

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