Safety and Pharmacokinetics of Multiple-Dose Metronidazole in Premature Infants

Evaluating the safety and dosing of metronidazole in premature infants for the treatment of serious infections.

 

This study evaluated the safety and pharmacokinetics (PK) of intravenous metronidazole in premature infants with suspected serious infection. Twenty-four participants, less than 32 weeks gestational age with suspected serious infection, participated in the study for up to 15 days at three centers. The Pediatric Trials Network generated PK data to guide dosing of metronidazole in premature infants using a simplified dosing regimen based on postmenstrual age.

Gregory Kearns, PharmD, PhD, of Children's Mercy Hospital Kansas City, discusses the PTN metronidazole study: clinical pharmacology in action.

Brian Smith, MD, MPH, of the Duke Clinical Research Institute, discusses the metronidazole in premature infants study.

Summary

Metronidazole is approved by the U.S. Food and Drug Administration for the treatment of adults with infections caused by anaerobic bacteria. Children and premature infants may be affected by these bacteria too; therefore, doctors frequently give metronidazole to infants who are suspected of having an infection caused by anaerobic bacteria. However, the appropriate dose of metronidazole in premature infants is not well-known.

We enrolled 24 babies <32 weeks gestational age with suspected serious infection and administered metronidazole for up to five days, measuring the levels of metronidazole in each baby. With this information, we were able to determine the appropriate dose of metronidazole in premature infants. Because metronidazole likely behaves differently in premature infants than it does in term infants, older children, and adults, this study meets a public health need for better evidence in the treatment of this vulnerable group.

Publications

 

OVERVIEW

Status:
Published; clinical study report submitted to FDA

ClinicalTrials.gov identifier:
NCT01222585

Principal Investigators:
Michael Cohen-Wolkowiez, MD, PhD and Daniel K. Benjamin, MD, PhD, MPH
Duke Health, Durham, NC

Results-at-a-Glance

Label Change

Intra-Abdominal Infections, including peritonitis, intra-abdominal abscess and liver abscess, caused by Bacteroides species including the B. fragilis group (B. fragilis, B. distasonis, B. ovatus, B. thetaiotaomicron, B. vulgatus), Clostridium species, Eubacterium species, Peptococcus species and Peptostreptococcus species in adults and pediatric patients less than 4 months of age.

  • The safety and effectiveness of Metronidazole Injection have been established for the treatment of intraabdominal infections in pediatric patients from birth to less than 4 months. Use of Metronidazole Injection in this age group is supported by evidence from data in adults with additional pharmacokinetic and safety data in pediatric patients from birth to less than 4 months of age.
  • A partially randomized, open-label, phase 2/3 study of intravenous Metronidazole Injection in combination with other intravenous antibacterial drugs was conducted in 62 preterm infants (≤ 33 weeks gestational age at birth, and postnatal age <121 days) and 55 late pre-term and term infants (≥ 34 weeks gestational age at birth, and postnatal age <121 days), with complicated intra-abdominal infections. The primary objective of this study was to evaluate the safety of metronidazole-containing regimens, which were administered for up to 10 days. The adverse reactions reported in patients receiving metronidazole-containing regimens were comparable to patients receiving other antibacterial regimens in the study and generally similar to adverse reactions described in adults.

Pediatric Patients Less than 4 Months of Age

  • The safety and effectiveness of Metronidazole Injection in pediatric patients less than 4 months of age have not been established for (1) the treatment of anaerobic infections other than intra-abdominal infections or for (2) prophylaxis for postoperative infections (see INDICATIONS AND USAGE, CLINICAL PHARMACOLOGY, Pediatric Patients and DOSAGE AND ADMINISTRATION).

Pediatric Patients 4 Months of Age and Older

  • The safety and effectiveness of Metronidazole Injection in pediatric patients 4 months of age and older have not been established.

The recommended dosage schedule for pediatric patients less than 4 months of age for the treatment of intra- abdominal infections is described in Table 2 of the label. These dosage schedules achieve drug exposures in pediatric patients similar to adults treated with Metronidazole Injection for this indication.

NEWS

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