Pharmacokinetic (PK) and Safety Study of Meropenem in Young Infants With Intra-abdominal Infections

Study Overview
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Brief Summary
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Meropenem is an antibiotic that is commonly used to treat serious infections. Although it is used in premature and young infants, the correct dose is not known. The purpose of this study is to determine the correct dose and the safety of meropenem for the treatment of complicated intra-abdominal infections in these young babies.

Detailed Description
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This study will evaluate the safety, tolerability and Pharmacokinetics - Pharmacodynamics (PK-PD) of meropenem in infants <91 days of age with suspected and complicated intra-abdominal infections. The specific aims of this trial are: To characterize meropenem single-dose and multiple-dose PK in subjects with suspected and complicated intra-abdominal infections. To characterize the safety profile of meropenem in the treatment of suspected and complicated intra-abdominal infections. To assess collected efficacy data for meropenem for the treatment of suspected and complicated intra-abdominal infections.

Official Title
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Multiple Dose Pharmacokinetic Study of Meropenem in Young Infants (<91 Days) With Suspected or Complicated Intra-abdominal Infections

Conditions
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Necrotizing Enterocolitis, Intra-abdominal Infection

Intervention / Treatment
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* Drug: meropenem


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written permission from parent or legal guardian Age younger than 91 days Likely to survive beyond the first 48 hours after enrollment Sufficient intravascular access (either peripheral or central) to receive study drug. AND ONE OF THE FOLLOWING 1) Physical, radiological, and/or bacteriological findings of a complicated intra-abdominal infection. These include peritonitis, NEC (Necrotizing Enterocolitis) Grade II or higher by Bell's criteria, Hirschsprung's disease with perforation, spontaneous perforation, meconium ileus with perforation, bowel obstruction with perforation, as evidenced by free peritoneal air on abdominal radiograph, intestinal pneumatosis or portal venous gas on abdominal radiographic examination. OR 2) Possible NEC OR 3) Otherwise receiving meropenem per local standard of care Exclusion criteria: Renal dysfunction evidenced by urine output <0.5 mL/hr/kg over the prior 24 hours Serum creatinine >1.7 mg/dL History of clinical seizures or EEG (Electroencephalogram) confirmed seizures Concomitant treatment with another carbapenem (ertapenem or imipenem) at the time of informed consent Any condition which would make the subject or the caregiver, in the opinion of the investigator, unsuitable for 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: Meropenem<br>These Participants were subdivided into the following four groups based on Gestational Age (GA) and Postnatal Age (PNA): Group 1: GA at birth below 32 weeks - PNA <2 weeks; Group 2: GA at birth below 32 weeks - PNA ≥2 weeks and <91 days; Group 3: GA at birth 32 weeks or older - PNA <2 weeks; Group 4: GA at birth 32 weeks or older - PNA ≥2 weeks and <91 days. | Drug: meropenem<br>* Meropenem was administered concomitantly with compatible medications. Because an in-line filter is not appropriate due to drug binding, the 30 minute infusion was rate controlled by using appropriate infusion (syringe) pumps. Dosing and administration of other antimicrobial therapy (e.g., an aminoglycoside) was administered per local standard of care at the discretion of the infant's neonatologist. If there was a delay in the study drug shipment, sites were to use open-label meropenem to protect the safety of the participant. 20 mg/kg every 12 hours in infants <32 weeks GA and PNA < 2 weeks 20 mg/kg every 8 hours in infants <32 weeks GA and PNA ≥ 2 weeks 20 mg/kg every 8 hours in infants ≥32 weeks GA and PNA < 2 weeks 30 mg/kg every 8 hours in infants ≥32 weeks GA and PNA ≥ 2 weeks<br>* Other names: Merrem;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy Success (Alive at Efficacy Visit,Last Culture (if Obtained) From Sterile Body Fluid is Negative for Bacteria (Except Staphylococcus Species) From Start of Study Drug Until Efficacy Visit,Presumptive Clinical Cure Score(PCCS) >7 at Efficacy Visit) | The PCCS was derived by comparing clinical signs and symptoms prior to administration of the first dose of study drug and study Day 28.The elements of the PCCS include Mean BP,Temp,PaO2(mmHg)/FiO2,Lowest serum pH,seizures,Urine output,Cardiovascular inotrope support,C-reactive protein (CRP)and Abdominal girth. Score - Asymptomatic to Asymptomatic 1;Asymptomatic to Worsening 0;Symptomatic to Worsening 0;Symptomatic to No change 0;Symptomatic to Improved 1;Symptomatic to Asymptomatic 1 If 7 or more of 10 signs received a score of 1, then the infant was considered a presumptive clinical cure. GA stands for Gestational Age and PNA stands for Postnatal Age. | Average of 12 days (3 to 21 days) | 
| Deaths |  | Up to 51 days (Recorded from the time of informed consent until 72 hours following the last dose of study drug) | 
| Meropenem Clearance | Given the limited availability of blood for Pharmacokinetic (PK) assessments in this population a sparse sampling approach was utilized. Subjects were assigned to one of two Dose 1 sample collection schedules, PK-odd and PK-even based on birth date to ensure collection of PK data throughout the dose interval. In addition, PK samples were collected around approximately the 5th dose. Subjects that did not have Dose 1 PK samples could have steady-state (Dose 5) using the Dose 5 PK collection schedule. | Up to 7-8hrs post drug administration | 
| Key Safety Endpoints | Safety assessments included death, seizure documentation (including correlation of serum meropenem level and seizures), strictures, perforation, wound dehiscence, short gut, development of extended beta lactamase infection, development of candidiasis, antimicrobial therapy failure | Up to 51 days (Adverse Events (AEs) were recorded from the time of informed consent until 72 hours following the last dose of study drug) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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intra-abdominal infection, meropenem, infants, pharmacokinetics, safety