Antibiotics for Neonatal Infections (NANO Trial)
Palo Alto (17 mi)Age: < 18
Sex: Any
Travel: May be covered
Time Reimbursement: Varies
Trial Phase: Phase 4
Recruiting
Sponsor: Michael Morowitz
Prior Safety Data
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.
What safety data is available for antibiotics used in neonatal infections?The safety data for antibiotics used in neonatal infections includes several studies:
1. Sulbactam, when combined with ampicillin or amoxicillin, shows low toxicity and good local tolerance, similar to Unasyn.
2. A study on newborns using combinations like gentamicin-ampicillin showed no hematologic, renal, or hepatic toxicity, and the combinations were well tolerated.
3. In a pharmacokinetic study, sulbactam and ampicillin were well tolerated in newborns, with no significant drug accumulation.
4. Unasyn, a combination of ampicillin and sulbactam, was effective and safe in treating severe hospital infections, with excellent tolerance.
5. Gentamicin, commonly used in neonates, has potential toxicity, but specific incidence rates were not detailed in the provided data.123410
Do I have to stop taking my current medications for the trial?The trial protocol does not specify whether participants must stop taking their current medications. However, infants who have received antibiotics prior to randomization are excluded from the trial.
What data supports the idea that Antibiotics for Neonatal Infections is an effective treatment?The available research shows that the combination of ampicillin and sulbactam, known as Unasyn, is effective in treating neonatal infections. In a study of 27 newborns with serious infections, the clinical cure and improvement rates were 96.3% and 100%, respectively, with significant improvement seen within 48 hours. This suggests that the drug is highly effective in treating infections in newborns. Additionally, in a study involving neonatal calf diarrhea, the combination of sulbactam and ampicillin significantly reduced mortality and the likelihood of diarrhea compared to ampicillin alone or no treatment, indicating its superior effectiveness. These findings support the use of this antibiotic combination as an effective treatment for infections.34569
Is the drug combination of Ampicillin and Gentamicin promising for treating neonatal infections?Yes, the combination of Ampicillin and Gentamicin is promising for treating neonatal infections. It is frequently prescribed for newborns with suspected bacterial infections and has shown better outcomes compared to other antibiotic combinations, such as Ampicillin and Cefotaxime. This combination is effective in treating infections and is commonly used in neonatal care.478911
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.
I am a mother and I am under 18 years old.
My baby was born by C-section without labor induction or signs of maternal infection.
My infant needs a breathing machine and extra oxygen.
My infant has received antibiotics before being chosen for the study.
Treatment Details
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).
2Treatment groups
Active Control
Placebo Group
Group I: Empiric antibioticsActive Control2 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: PlaceboPlacebo Group1 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:
πΊπΈ Approved in United States as Ampicillin for:
- Bacterial infections
- Urinary tract infections
- Respiratory tract infections
- Skin and soft tissue infections
- Gastrointestinal infections
πͺπΊ Approved in European Union as Ampicillin for:
- Bacterial infections
- Urinary tract infections
- Respiratory tract infections
- Skin and soft tissue infections
- Gastrointestinal infections
π¨π¦ Approved in Canada as Ampicillin for:
- Bacterial infections
- Urinary tract infections
- Respiratory tract infections
- Skin and soft tissue infections
- Gastrointestinal infections
Find a clinic near you
Research locations nearbySelect from list below to view details:
Penn State Medical CollegeHershey, PA
Pennsylvania Hospital/The Children's Hospital of PhiladelphiaPhiladelphia, PA
USA Children's and Women's HospitalMobile, AL
University of South Flordia HealthTampa, FL
More Trial Locations
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Who is running the clinical trial?
Michael MorowitzLead Sponsor
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)Collaborator
References
Evaluation of three antibiotic programs in newborn infants. [2018]Emergence of gram-negative bacteria resistnant to a number of antibiotics in intensive care nurseries for neonates emphasizes the need for alternatives in antibiotic combinations. One commonly used combination, gentamicin-ampicillin, and two newer combinations, tobramycin-cephalothin and amikacinampicillin, were evaluated prospectively in 60 newborns in such a nursery. Subjects were randomly assigned to one of the above therapy groups. Dosages in mg/kg.d were 100 for ampicillin and cephalothin, 6 for gentamicin and tobramycin and 15 for amikacin. Aminoglycoside serum concentrations, clinical tolerance and toxicity were monitored. Aminoglycoside concentrations after intravenous administration of the drugs were within the expected range (gentamicin and tobramycin 4 to 6 microgram/mL and amikacin 15 to 20 microgram/mL). There was no hematologic, renal or hepatic toxicity attributable to antibiotic therapy and the combinations were tolerated equally; no bilirubin displacement was detected in vitro or in vivo.
[Pharmacological studies of sulbactam and its association with semisynthetic beta-lactam antibiotics]. [2013]The acute toxicity, local tolerance and pharmacokinetic properties of sulbactame manufactured by the IaΕi Antibiotic Investigation Centre, alone or in association with ampicillin or amoxicillin were tested. Some tests were made comparatively with the product Unasyn--Pfizer. The obtained data show that this beta-lactamase inhibitor has a low toxicity--DL50 i.p. in mice over 4,000 mg/kg, both alone or associated with the two semisynthetic beta-lactamic antibiotics. The local tolerance is good and the serum levels of the above mentioned associations are above towards the tested bacteria and are similar or very close to those of Unasyn. It is believed that the therapeutical use of the association sulbactame + ampicillin or sulbactame + amoxicillin is very useful in the beta-lactamase producing germs infection.
[Unasyn in severe hospital infections]. [2013]A total 16 patients with moderate and serious surgical and urogenital infections were treated intravenously with the Unasyn IM/IV inj., combination of ampicillin and sulbactam, which is a beta-lactamase inhibitor. In this combination, sulbactam saves the ampicillin against the effects of beta-lactamases and extends the susceptibility to ampicillin of previously ampicillin-resistant strains. Clinical cure was observed in 69% of the patients, improvement in 19%, and failure in 12%. Microbiological elimination was proved in 50% of the patients, persistence in 6%, a in the rest of the patients (44%) were microbiological response unevaluable. The evaluation of subjective and objective tolerance of Unasyn IM/IV inj. was excellent. It follows from this study that the combination of ampicillin with sulbactam can be considered an effective and safe treatment of nosocomial infections, especially in the departments with an increasing rate of ampicillin-resistant strains due to production of the beta-lactamases.
Pharmacokinetic study of sulbactam and ampicillin administered concomitantly by intraarterial or intravenous infusion in the newborn. [2019]The combination of sulbactam and ampicillin was administered to 16 newborn infants, 15 preterm and one term, who required umbilical arterial or venous catheterization and prophylactic antibiotics. The aims were to determine an appropriate dosage regimen and to study the pharmacokinetics. Satisfactory plasma concentrations were achieved with administration of a bolus injection of 50 mg of each drug/kg every 12 hr (mean concentrations: sulbactam, 110 mg/liter; ampicillin, 87 mg/liter 3 hr after dosing; and sulbactam, 105 and 135 mg/liter; ampicillin, 320 and 310 mg/liter 30 min after dosing in two infants. Mean elimination half-lives were longer than those in adults (sulbactam, 7.9 hr; ampicillin, 9.4 hr), and urinary excretion over 12 hr varied considerably (range: sulbactam, 7%-91%; ampicillin, 5%-132%), rates reflecting the immature renal function in the newborn and the relative oliguria characteristic of preterm infants with idiopathic respiratory distress syndrome. There was little evidence of accumulation of either drug, and both were well tolerated. This combination and dosage should be suitable for a trial of therapy for infection in the newborn.
Perioperative prophylaxis with sulbactam and ampicillin compared with metronidazole and cefotaxime in the prevention of wound infection in children undergoing appendectomy. [2019]Sulbactam is a beta-lactamase inhibitor, which when administered with ampicillin, increases the latter agents antibacterial activity against beta-lactamase producing organisms. One hundred children between the ages of 5 and 14 undergoing emergency appendectomy were entered into a prospective randomized trial comparing sulbactam and ampicillin (SA) with metronidazole and cefotaxime (MC) as prophylaxis against postoperative wound infection. Patients in whom the appendix was perforated or gangrenous received a 72-hour course of antibiotics, others received a single dose only. The overall wound infection rate was 8% (14% in patients with perforation or gangrene and 4% in those without). There was no difference in infection rate between the two antibiotic groups; there were three wound infections and one subphrenic abscess in patients receiving SA and four wound infections in patients receiving MC. SA, therefore, appears to be a suitable antibiotic combination for use as prophylaxis in appendicitis in children.
Efficacy of sulbactam-ampicillin in the treatment of neonatal calf diarrhoea. [2019]Sulbactam-ampicillin is a combination of sulbactam, a beta-lactamase inhibitor, and ampicillin, a broad spectrum beta-lactam antibiotic. The efficacy of sulbactam-ampicillin was evaluated in the treatment of neonatal calf diarrhoea under conditions where a major proportion of the calves were excreting enterobacteria which were resistant to beta-lactam antibiotics. In a series of six studies with a common experimental design, three treatments (sulbactam-ampicillin, ampicillin alone and untreated control) were compared in over 300 Friesian and Ayrshire calves aged between three and 10 days and of known immunological status as determined by their zinc sulphate turbidity values. A mortality rate of 26.4 per cent in the negative control calves was reduced to 14.0 per cent with ampicillin alone and 9.5 per cent with sulbactam-ampicillin. The probability of diarrhoea subsequent to initiation of treatment was reduced from 0.50 in the negative control calves to 0.44 with ampicillin alone and 0.35 with sulbactam-ampicillin. The differences in mortality and diarrhoea observed between the calves treated with sulbactam-ampicillin and the calves in each of the other treatment groups were statistically significant. The superior efficacy of sulbactam-ampicillin is explained by the inhibitory effect of sulbactam on the beta-lactamases produced by resistant bacteria, thus rendering them susceptible to the ampicillin in the combination.
[Results of a national survey on the antibiotic therapy of neonatal bacterial infection due to materno-fetal contamination]. [2015]The aim of the study was to overview the antibiotic treatments usually prescribed in the different neonatal units and NICU's for neonatal primary bacterial infections. Maternal or neonatal fever, shock, respiratory distress, leuconeutropenia, hyperfibrinemia as well as an increased level in C-Reactive Protein appeared to be the best clinical diagnosis criteria. Before isolation of the bacteria, the most frequently prescribed treatment was a combination of ampicillin and gentamicin. When no bacteria grew up, the treatment was usually discontinued after a few days. When a presumably pathogenic bacteria was found either in blood, or CSF or urine or peripheral cultures, the treatment lasted around 10 days. However, in proved meningitis, the treatment lasted around 20 days. In case of Streptococcus type B and Listeria monocytogenes, ampicillin (100-200 mg/kg/day) was often used in combination with gentamicin (3-4 mg/kg/day), in spite of the recent availability of new aminoglycosides. When the isolated E. coli was ampicillin-resistant, Cefotaxime was frequently used in combination.
Antibiotics and antifungals in neonatal intensive care units: a review. [2009]The incidence of infections is higher in the neonatal period than at any time of life. The basic treatment of infants with infection has not changed substantially over the last years. Antibiotics (with or without supportive care) are one of the most valuable resources in managing sick newborn babies. Early-onset (ascending or transplacental) or late-onset (hospital acquired) infections present different chronology, epidemiology, physiology and outcome. Some classes of antibiotics are frequently used in the neonatal period: penicillins, cephalosporins, aminoglycosides, glycopeptides, monobactams, carbapenems. Other classes of antibiotics (chloramphenicol, cotrimoxazole, macrolides, clindamycin, rifampicin and metronidazole) are rarely used. Due to emergence of resistant bacterial strains in Neonatal Intensive Care Units (NICU), other classes of antibiotics such as quinolones and linezolid will probably increase their therapeutic role in the future. Although new formulations have been developed for treatment of fungal infections in infants, amphotericin B remains first-line treatment for systemic Candida infection. Prophylactic antibiotic therapy is almost always undesirable. Challenges from pathogens and antibiotic resistance in the NICU may warrant modification of traditional antibiotic regimens. Knowledge of local flora and practical application of different antibiotic characteristics are key to an effective and safe utilization of antibiotics and antifungals in critical newborns admitted to the NICU, and especially in very low birth weight infants.
Observations on oral Sultamicillin/Unasyn CP-45 899 therapy of neonatal infections. [2019]The use of an effective antimicrobial remains a problem in the neonate, thereby necessitating empiric combinations of parenteral agents. We therefore studied oral Sultamicillin's (Unasyn CP-45 899) efficacy and tolerability (dose = 50 mg/kg per day) in the treatment of serious infections in 27 neonates over an 18 month period. The study cohort comprised newborns with suspected or confirmed infections in the Special Care Baby Unit of a referral hospital. The infants with overwhelming/severe infections or proven/suspected renal, hepatic or hematologic disease; or known hypersensitivity to penicillins or any beta-lactams were excluded. There were 12 babies with skin and soft-tissue infections, although pneumonia [11] was most predominant in our series. Bacterial isolates were mainly Staphylococcus aureus, Escherichia Coli and Klebsiella pneumoniae with a beta-lactamase production rate of 88%. The clinical cure and improvement rates were 96.3 and 100%, respectively and the evaluable bacteriologic cure-rate was 93.8%. The mean (S.D.) duration of therapy was 7.4 (2.6) days (range, 4-14) with significant resolution of features occurring within a 48 h period (24 27 , P
Gentamicin use in neonates: should we have a change of practice? [2013]Gentamicin, one of the most commonly used antibiotics in neonates, has potential toxicity. This study was performed to determine the incidence of potential toxicity of gentamicin in term and preterm neonates.
Influences of Initial Empiric Antibiotics with Ampicillin plus Cefotaxime on the Outcomes of Neonates with Respiratory Failure: A Propensity Score Matched Analysis. [2023]Background: Empiric antibiotics are often prescribed in critically ill and preterm neonates at birth until sepsis can be ruled out. Although the current guideline suggests narrow-spectrum antibiotics, an upgrade in antibiotics is common in the neonatal intensive care unit. The impacts of initial broad-spectrum antibiotics on the outcomes of critically ill neonates with respiratory failure requiring mechanical intubation have not been well studied. Methods: A total of 1162 neonates from a tertiary level neonatal intensive care unit (NICU) in Taiwan who were on mechanical ventilation for respiratory distress/failure at birth were enrolled, and neonates receiving ampicillin plus cefotaxime were compared with those receiving ampicillin plus gentamicin. Propensity score-matched analysis was used to investigate the effects of ampicillin plus cefotaxime on the outcomes of critically ill neonates. Results: Ampicillin plus cefotaxime was more frequently prescribed for intubated neonates with lower birth weight, higher severity of illness, and those with a high risk of early-onset sepsis. Only 11.1% of these neonates had blood culture-confirmed early-onset sepsis and/or congenital pneumonia. The use of ampicillin plus cefotaxime did not significantly contribute to improved outcomes among neonates with early-onset sepsis. After propensity score-matched analyses, the critically ill neonates receiving ampicillin plus cefotaxime had significantly worse outcomes than those receiving ampicillin plus gentamicin, including a higher risk of late-onset sepsis caused by multidrug-resistant pathogens (11.2% versus 7.1%, p = 0.027), longer duration of hospitalization (median [IQR], 86.5 [47-118.8] days versus 78 [45.0-106.0] days, p = 0.002), and a significantly higher risk of in-hospital mortality (14.2% versus 9.6%, p = 0.023). Conclusions: Ampicillin plus cefotaxime should not be routinely prescribed as the empiric antibiotics for critically ill neonates at birth because they were associated with a higher risk of infections caused by multidrug-resistant pathogens and final worse outcomes.