title: Double blind placebo-controlled trial of pleconaril in infants with enterovirus meningitis.
abstract: BACKGROUND
  Enterovirus (EV) meningitis is common in infants and may have neurologic complications. Treatment of older children and adults with pleconaril has been associated with reduced severity and duration of symptoms. This study evaluated the pharmacokinetics, safety and efficacy of pleconaril in infants with EV meningitis.
  
  
  METHODS
  Infants < or =12 months old with suspected EV meningitis were randomized 2:1 to receive pleconaril, 5 mg/kg/dose orally three times a day or placebo for 7 days. Evaluations included pharmacokinetic determinations, safety laboratory testing, serial culture and PCR assays and clinical evaluations.
  
  
  RESULTS
  Of 21 evaluable subjects 20 were confirmed with EV infection (12 pleconaril, 8 placebo). Among pleconaril-treated subjects 26 of 29 peak and trough pleconaril levels exceeded the 90% inhibitory concentration for EVs. A median 3.5-fold drug accumulation occurred between Days 2 and 7. Pleconaril was well-tolerated, although twice as many adverse events occurred per subject in the pleconaril group. Serial cultures from the oropharynx, rectum and serum had low yield (< or =50%) and positivity generally persisted for <4 days in both groups. Serial PCR assays of culture-negative oropharyngeal and rectal specimens had high positivity rates (generally > or =50%) persisting through Day 14. No significant differences in duration of positivity by culture or PCR, hospitalization or symptoms were detected between groups.
  
  
  CONCLUSIONS
  The dose of pleconaril studied provided sufficient plasma levels and was well-tolerated; however, drug accumulation was evident. The low yields of serial viral cultures, relatively short and benign clinical courses and the small number of subjects enrolled precluded demonstration of efficacy. If this medication is to be prescribed in infants, surveillance for toxicity related to drug accumulation will be necessary.
authors.affiliation: Pediatric Infectious Disease, Department of Pediatrics, University of Colorado School of Medicine and The Children's Hospital, 1056 E. Nineteenth Avenue, Denver, CO 80218, USA. abzug.mark@tchden.org
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Abzug
authors.forename: Gretchen
authors.initials: G
authors.lastname: Cloud
authors.forename: John
authors.initials: J
authors.lastname: Bradley
authors.forename: Pablo J
authors.initials: PJ
authors.lastname: Sánchez
authors.forename: José
authors.initials: J
authors.lastname: Romero
authors.forename: Dwight
authors.initials: D
authors.lastname: Powell
authors.forename: Martha
authors.initials: M
authors.lastname: Lepow
authors.forename: Chitra
authors.initials: C
authors.lastname: Mani
authors.forename: Edmund V
authors.initials: EV
authors.lastname: Capparelli
authors.forename: Sharon
authors.initials: S
authors.lastname: Blount
authors.forename: Fred
authors.initials: F
authors.lastname: Lakeman
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Whitley
authors.forename: David W
authors.initials: DW
authors.lastname: Kimberlin
mesh_terms: D000284:Administration, Oral; D001682:Biological Availability; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D004769:Enterovirus Infections / Q000175:diagnosis / Q000188:drug therapy*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007223:Infant; D008297:Male; D008587:Meningitis, Viral / Q000175:diagnosis / Q000188:drug therapy*; D010069:Oxadiazoles / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D010080:Oxazoles; D011336:Probability; D012016:Reference Values; D018570:Risk Assessment; D012720:Severity of Illness Index; D016896:Treatment Outcome
chemical_list: D010069:Oxadiazoles; D010080:Oxazoles; C115201:pleconaril