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

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

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.

Study Overview

• Status: Completed
• Conditions: Necrotizing Enterocolitis; Intra-abdominal Infection
• Intervention / Treatment: Drug: meropenem

Detailed Description

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:

1. To characterize meropenem single-dose and multiple-dose PK in subjects with suspected and complicated intra-abdominal infections.
2. To characterize the safety profile of meropenem in the treatment of suspected and complicated intra-abdominal infections.
3. To assess collected efficacy data for meropenem for the treatment of suspected and complicated intra-abdominal infections.

• Study Type: Interventional
• Enrollment (Actual): 200
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
      • University Of Alabama
  • California
    • Oakland, California, United States, 94609
      • Children's Hospital of Oakland
    • Orange, California, United States, 92868
      • Children's Hospital of Orange County
    • San Diego, California, United States, 92117
      • University of California Medical Center
    • San Diego, California, United States, 92123
      • Sharp-Mary Birch Hospital for Women
  • Connecticut
    • New Haven, Connecticut, United States, 06510
      • Yale New Haven Hospital
  • District of Columbia
    • Washington, District of Columbia, United States, 20010
      • Children's National Medical Center
  • Florida
    • Gainesville, Florida, United States, 32610
      • University of Florida
  • Hawaii
    • Honolulu, Hawaii, United States, 96826
      • Kapiolani Medical Center for Women and Children
  • Illinois
    • Evanston, Illinois, United States, 60056
      • Evanston Northwestern Healthcare
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University - Riley Hospital for Children
  • Kentucky
    • Louisville, Kentucky, United States, 40202
      • University of Louisville
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan
  • Missouri
    • Kansas City, Missouri, United States, 64108
      • Kansas City Children's Mercy Hospital
  • New York
    • Albany, New York, United States, 12208
      • Albany Medical Center
    • Brooklyn, New York, United States, 11203
      • SUNY Downstate Medical Center
  • North Carolina
    • Durham, North Carolina, United States, 27708
      • Duke University Medical Center
    • Durham, North Carolina, United States, 27715
      • Duke University
  • Ohio
    • Akron, Ohio, United States, 44308
      • Akron Children's Hospital
    • Cleveland, Ohio, United States, 44106
      • Case Western Reserve, RB&C, UHCMC
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Children's Hospital of Philadelphia
    • Pittsburgh, Pennsylvania, United States, 15213
      • Magee Women's Hospital
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt Children's Hospital
  • Texas
    • Dallas, Texas, United States, 75390
      • University of Texas Southwestern Medical Center
    • Houston, Texas, United States, 77030
      • Baylor College of Medicine
  • Utah
    • Salt Lake City, Utah, United States, 84108
      • University of Utah Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 2 months (Child)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Written permission from parent or legal guardian
2. Age younger than 91 days
3. Likely to survive beyond the first 48 hours after enrollment

4. Sufficient intravascular access (either peripheral or central) to receive study drug.

   AND ONE OF THE FOLLOWING

5. 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:

1. Renal dysfunction evidenced by urine output <0.5 mL/hr/kg over the prior 24 hours
2. Serum creatinine >1.7 mg/dL
3. History of clinical seizures or EEG (Electroencephalogram) confirmed seizures
4. Concomitant treatment with another carbapenem (ertapenem or imipenem) at the time of informed consent
5. Any condition which would make the subject or the caregiver, in the opinion of the investigator, unsuitable for the study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Meropenem; 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; 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; Other Names: Merrem

What is the study measuring?

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)

Collaborators and Investigators

• Sponsor: The Emmes Company, LLC
• Collaborators: The Emmes Company, LLC
• Investigators: Principal Investigator: Danny Benjamin, MD, PhD, MPH, Duke University

Publications and helpful links

General Publications

• Cohen-Wolkowiez M, Poindexter B, Bidegain M, Weitkamp JH, Schelonka RL, Randolph DA, Ward RM, Wade K, Valencia G, Burchfield D, Arrieta A, Mehta V, Walsh M, Kantak A, Rasmussen M, Sullivan JE, Finer N, Rich W, Brozanski BS, van den Anker J, Blumer J, Laughon M, Watt KM, Kearns GL, Capparelli EV, Martz K, Berezny K, Benjamin DK Jr, Smith PB; Meropenem Study Team. Safety and effectiveness of meropenem in infants with suspected or complicated intra-abdominal infections. Clin Infect Dis. 2012 Dec;55(11):1495-502. doi: 10.1093/cid/cis758. Epub 2012 Sep 5.

Study record dates

Study Major Dates

• Study Start: June 1, 2008
• Primary Completion (Actual): October 1, 2009
• Study Completion (Actual): October 1, 2009

Study Registration Dates

• First Submitted: February 20, 2008
• First Submitted That Met QC Criteria: February 20, 2008
• First Posted (Estimate): February 22, 2008

Study Record Updates

• Last Update Posted (Actual): April 25, 2023
• Last Update Submitted That Met QC Criteria: March 30, 2023
• Last Verified: March 1, 2023

More Information

Terms related to this study

• Keywords: safety; pharmacokinetics; infants; meropenem; intra-abdominal infection
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Disease Attributes; Gastrointestinal Diseases; Gastroenteritis; Intestinal Diseases; Infections; Communicable Diseases; Intraabdominal Infections; Enterocolitis; Enterocolitis, Necrotizing; Anti-Infective Agents; Anti-Bacterial Agents; Meropenem
• Other Study ID Numbers: HHSN267200700051C (Other Identifier: NICHD)