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Pleconaril in Infants with Enterovirus Meningitis
Abstract & Commentary
Synopsis: A study of pleconaril in infants with enterovirus meningitis showed good oral availability, but the limited virus shedding and benign course of enterovirus meningitis in infants precluded identifying virological or clinical benefit.
Source: Abzug MJ, et al. Double blind placebo-controlled trial of pleconaril in infants with enterovirus meningitis. Pediatr Infect Dis J. 2003;22:335-341.
A multicenter, double-blind, placebo-controlled study of 21 infants (children younger than 12 months of age) was conducted as part of the National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group. Enterovirus was identified by culture or PCR. Of the 21 infants, all but 1 had proven (8 pleconaril vs 7 placebo), probable (1 placebo), or possible (4 pleconaril) enterovirus infection of the central nervous system. Subjects were randomized 2:1 in a double-blind manner to receive pleconaril 5 mg/kg/dose orally 3 times a day for 7 days or an identical placebo lacking the active agent. All but 3 of the 29 pleconaril drug concentrations obtained were > 70 ng/mL, a concentration that inhibits 90% of enterovirus isolates in vitro. Plasma trough concentrations showed that almost all of the day 2 trough and 2-hour postdose values were in the predicted range, whereas all of the day 7 trough values were at the upper limit of or greater than the expected range.
Pleconaril was well tolerated with no significant differences in adverse events between the 2 groups. Adverse events that occurred in > 2 subjects included diarrhea (4 of 12 in the pleconaril group vs 2 of 9 in the placebo group), rash (3 of 12 vs 1 of 9), fever (2 of 12 vs 0 of 9), vomiting (3 of 12 vs 1 of 9), and neutropenia (1 of 12 vs 1 of 9). Of the 20 infants with enterovirus infection (all specimens were negative by both culture and PCR in 1 patient in the placebo group), only 8 cultures from the oropharynx and 10 cultures from the rectum were positive on day 1. From the 12 subjects in whom an enterovirus was cultured from any body site, serotyping showed that 8 were Coxsackie B viruses, 2 were echoviruses, and 2 were indeterminate. Virus was rarely recovered from any site after the second day of the study. PCR of cerebrospinal fluid was positive in all subjects with proven enterovirus meningitis; none of the 6 cerebrospinal fluids negative by PCR was culture positive. Fever, irritability, anorexia, and lethargy were common among all infants but were infrequent beyond day 4. There were no significant differences in clinical manifestations or duration of hospitalization between the 2 groups.
Comment by Hal B. Jenson, MD, FAAP
Pleconaril has in vitro activity against enteroviruses, and in some studies of enteroviral meningitis has shown reduction in intensity and duration of symptoms. The results of this study indicate significant differences of enteroviral meningitis in adults and older children compared to infants, the age group with the highest incidence of enterovirus disease. Virus shedding was considerably shorter than the more typical range of several days to 3-4 weeks from the oropharynx and up to 6-8 weeks from the rectum that usually follows enterovirus infections. As expected, PCR was more sensitive than culture for mucosal, cerebrospinal, and serum specimens. Serial cultures had low yield (< 50%) with positive cultures for < 4 days in both groups, whereas serial PCR of culture-negative specimens had high positive rates (> 50%) persisting through day 14. There was an approximately 3.5-fold accumulation of pleconaril between day 2 and day 7, although the pleconaril was generally well tolerated.
In this small study, there was no demonstrable effect of pleconaril on enterovirus shedding, either by culture or PCR. The course of enterovirus meningitis in these infants was relatively short and benign, with virus shedding generally limited to 2 days and clinical symptoms for only 3-4 days. This benign virological and clinical course is contrasted with the more protracted illness in adolescents and adults with enterovirus meningitis. Although pleconaril remains potentially valuable for enterovirus infections, especially for chronic enterovirus meningoencephalitis in immunocompromised patients, it may be difficult to prove efficacy for infants with enterovirus meningitis. The pharmaceutical sponsor (ViroPharma, Inc., Exton, Pa) has decided not to pursue an enterovirus meningitis indication for pleconaril.
Dr. Jenson is Chair, Department of Pediatrics, Director, Center of Pediatric Research, Eastern Virginia Medical School and Children's Hospital of King's Daughters, Norfolk, VA.