title: A Randomized, Double-Blind, Placebo-Controlled Trial of Pleconaril for the Treatment of Neonates With Enterovirus Sepsis.
abstract: BACKGROUND
  Neonatal enterovirus sepsis has high mortality. Antiviral therapy is not available.
  
  
  METHODS
  Neonates with suspected enterovirus sepsis (hepatitis, coagulopathy, and/or myocarditis) with onset at ≤15 days of life were randomized 2:1 to receive oral pleconaril or placebo for 7 days. Serial virologic (oropharynx, rectum, urine, serum), clinical, pharmacokinetic, and safety evaluations were performed.
  
  
  RESULTS
  Sixty-one subjects were enrolled (43 treatment, 18 placebo), of whom 43 were confirmed enterovirus infected (31 treatment, 12 placebo). There was no difference in day 5 oropharyngeal culture positivity (primary endpoint; 0% in both groups). However, enterovirus-infected subjects in the treatment group became culture negative from all anatomic sites combined faster than placebo group subjects (median 4.0 versus 7.0 days, P = .08), and fewer subjects in the treatment group remained polymerase chain reaction (PCR)-positive from the oropharynx when last sampled (23% versus 58%, P = .02; median, 14.0 days). By intent to treat, 10/43 (23%) subjects in the treatment group and 8/18 (44%) in the placebo group died (P = .02 for 2-month survival difference); among enterovirus-confirmed subjects, 7/31 (23%) in the treatment group died versus 5/12 (42%) in the placebo group (P = .26). All pleconaril recipients attained concentrations greater than the IC90 after the first study day, but 38% were less than the IC90 during the first day of treatment. One subject in the treatment group and three in the placebo group had treatment-related adverse events.
  
  
  CONCLUSIONS
  Shorter times to culture and PCR negativity and greater survival among pleconaril recipients support potential efficacy and warrant further evaluation.
authors.affiliation: Department of Pediatrics, University of Colorado School of Medicine and Children's Hospital Colorado, Aurora.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Abzug
authors.affiliation: Children's Hospital, Pittsburgh of University of Pittsburgh Medical Center.
authors.forename: Marian G
authors.initials: MG
authors.lastname: Michaels
authors.affiliation: University of Wisconsin, Milwaukee.
authors.forename: Ellen
authors.initials: E
authors.lastname: Wald
authors.affiliation: University of Arkansas for Medical Sciences, Little Rock.
authors.forename: Richard F
authors.initials: RF
authors.lastname: Jacobs
authors.affiliation: University of Nebraska School of Medicine, Omaha, and University of Arkansas for Medical Sciences, Little Rock.
authors.forename: José R
authors.initials: JR
authors.lastname: Romero
authors.affiliation: University of Texas Southwestern, Dallas, and Nationwide Children's Hospital-The Ohio State University, Columbus.
authors.forename: Pablo J
authors.initials: PJ
authors.lastname: Sánchez
authors.affiliation: Vanderbilt University, Nashville, Tennessee.
authors.forename: Gregory
authors.initials: G
authors.lastname: Wilson
authors.affiliation: University of California, Los Angeles.
authors.forename: Paul
authors.initials: P
authors.lastname: Krogstad
authors.affiliation: Washington University, St. Louis, Missouri.
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Storch
authors.affiliation: University of Florida, Gainesville.
authors.forename: Robert
authors.initials: R
authors.lastname: Lawrence
authors.affiliation: Cooks Children Hospital, Ft. Worth, Texas.
authors.forename: Mark
authors.initials: M
authors.lastname: Shelton
authors.affiliation: University of Mississippi Medical Center, Jackson.
authors.forename: April
authors.initials: A
authors.lastname: Palmer
authors.affiliation: University of Alberta, Canada.
authors.forename: Joan
authors.initials: J
authors.lastname: Robinson
authors.affiliation: Hasbro Children's Hospital, Providence, Rhode Island.
authors.forename: Penelope
authors.initials: P
authors.lastname: Dennehy
authors.affiliation: North Shore LIJ Health System, New York.
authors.forename: Sunil K
authors.initials: SK
authors.lastname: Sood
authors.affiliation: University of Alabama at Birmingham.
authors.forename: Gretchen
authors.initials: G
authors.lastname: Cloud
authors.affiliation: University of Alabama at Birmingham.
authors.forename: Penelope
authors.initials: P
authors.lastname: Jester
authors.affiliation: University of Alabama at Birmingham.
authors.forename: Edward P
authors.initials: EP
authors.lastname: Acosta
authors.affiliation: University of Alabama at Birmingham.
authors.forename: Richard
authors.initials: R
authors.lastname: Whitley
authors.affiliation: University of Alabama at Birmingham.
authors.forename: David
authors.initials: D
authors.lastname: Kimberlin
mesh_terms: D000998:Antiviral Agents / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000652:urine; D004311:Double-Blind Method; D004770:Enterovirus / Q000187:drug effects* / Q000235:genetics / Q000302:isolation & purification; D004769:Enterovirus Infections / Q000097:blood / Q000150:complications* / Q000188:drug therapy* / Q000652:urine; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D000071074:Neonatal Sepsis / Q000097:blood / Q000188:drug therapy* / Q000652:urine / Q000821:virology*; D009960:Oropharynx / Q000821:virology; D010069:Oxadiazoles / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000652:urine; D010080:Oxazoles; D012007:Rectum / Q000821:virology
chemical_list: D000998:Antiviral Agents; D010069:Oxadiazoles; D010080:Oxazoles; C115201:pleconaril
keywords: enterovirus; hepatitis; neonatal; pleconaril; sepsis