Metronidazole Pharmacokinetics (PK) in Premature Infants

Study Overview
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Brief Summary
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Yearly in the United States over 500,000 newborns are delivered prematurely. This population is at high risk of catastrophic bowel disease known as necrotizing enterocolitis. Infants with necrotizing enterocolitis are at high risk of death, and survivors are at increased risk of mental retardation. Metronidazole is an antibiotic that is often administered to infants with suspected or confirmed necrotizing enterocolitis. Unfortunately, the appropriate dose of metronidazole in premature infants has not been established and it is likely to be different from older children and adults. The investigators will investigate the appropriate metronidazole dose in very premature infants by: 1) determining how premature infants eliminate metronidazole from the body and 2) determining the safest and most effective dose of metronidazole in premature infants. The investigators hypothesis are: 1) The rate of removal of metronidazole will increase with infant maturity and 2) an appropriate metronidazole dosing regimen will result in necessary drug levels to treat bacteria involved in necrotizing enterocolitis.

Official Title
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Safety and Pharmacokinetics of Multiple Dose Metronidazole in Premature Infants

Conditions
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Serious Systemic Infections, Necrotizing Enterocolitis

Intervention / Treatment
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* Drug: Metronidazole


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Gestational age <32 weeks at the time of enrollment. Postnatal age <91 days at the time of enrollment. Sufficient venous access to permit administration of study medication. Infant suspected to have a serious infection and from whom a blood culture has been obtained within 96 hours of study entry. Exclusion Criteria: History of anaphylaxis to metronidazole or other nitroimidazole derivatives (e.g., tinidazole). Previous exposure to metronidazole in the week prior to study. Previous participation in the study.

Ages Eligible for Study
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Maximum Age: 90 Days

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment<br>Intravenous metronidazole loading dose 15 mg/kg followed by 7.5 mg/kg every 12-24 hours | Drug: Metronidazole<br>* Metronidazole will be administered intravenously to premature infants as a 15 mg/kg loading dose followed by maintenance doses of 7.5 mg/kg every 12 hours for infants with >=14 postnatal days and every 24 hours for infants <14 postnatal days.<br>* Other names: Flagyl;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Curve at Steady State | Area under the curve at steady state (AUCss) | pre-dose: 30 min; post-dose:10 min, 3-4,6-8, 12-13, 24-25, 36-37, 48-49, 72-73 hours post dose | 
| Loading Dose Maximum Concentration | Loading Dose Maximum concentration (Cmax) | 2-5 days of study drug administration | 
| Loading Dose Minimum Concentration | Loading Dose Minimum Concentration (mg/L) | 2-5 days of study drug administration | 
| Multiple Dose Maximum Concentration | Multiple Dose Maximum Concentration (mg/L) | 2-5 days of study drug administration | 
| Multiple Dose Minimum Concentration | Multiple Dose Minimum Concentration (mg/L) | 2-5 days of study drug administration | 
| Clearance | Clearance (L/h/kg) | 2-5 days of study drug administration | 
| Volume of Distribution | Volume of Distribution (L/kg) | 2-5 days of study drug administration | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Metronidazole, Neonate, Premature, Sepsis, Necrotizing enterocolitis