oxadiazoles and Meningitis--Viral

Enteroviruses cause infections that present in diverse ways and affect people of all ages. Infections peak during summer and fall epidemics and cause 10 to 15 million symptomatic infections annually in the United States. The 70 enteroviral serotypes cause illness that ranges from nonspecific fevers and rashes to life-threatening myocarditis or central nervous system disease. These common infections create a significant burden on our society and healthcare system. New developments in rapid diagnosis of enterovirus infections using polymerase chain reaction (PCR) positively affect patient management and have the potential to reduce the healthcare impact of enterovirus infection. The future holds promise for effective antiviral drugs that can treat enterovirus infections and decrease their significant morbidity and mortality.

Topics: Adult; Antiviral Agents; Child; Clinical Trials as Topic; Enterovirus Infections; Humans; Meningitis, Viral; Oxadiazoles; Oxazoles; Polymerase Chain Reaction; Virus Replication

Enterovirus infections are common in both children and adults and range from benign short-lived febrile illnesses to life-threatening infections. Recent developments in nucleic acid amplification techniques now allow the rapid and sensitive diagnosis of enterovirus infections, which in turn can lead to improvements in patient management that shorten hospitalizations and reduce costs. New antiviral drugs have been developed that inhibit enterovirus replication, and early clinical trials of these compounds suggest that effective therapy for enterovirus infections is now possible.

Topics: Adolescent; Adult; Antiviral Agents; Child; Child, Preschool; Enterovirus Infections; Female; Humans; Infant; Infant, Newborn; Meningitis, Viral; Oxadiazoles; Oxazoles; Polymerase Chain Reaction; Pregnancy; Pregnancy Complications, Infectious; Sepsis

Topics: Antiviral Agents; Enterovirus; Humans; Meningitis, Viral; Oxadiazoles; Oxazoles; Picornaviridae Infections

Topics: Antiviral Agents; Child; Cost of Illness; Enterovirus; Enterovirus Infections; Humans; Meningitis, Viral; Oxadiazoles; Oxazoles; Polymerase Chain Reaction; Serologic Tests

Enteroviral meningitis causes appreciable morbidity in adults, including hospitalization, decreased activity, and headache. Limited data define the natural history of disease. No antiviral therapeutic agent has demonstrated improved outcome in controlled clinical trials. Pleconaril, an inhibitor of enterovirus replication, was tested in two placebo-controlled clinical trials. Of 607 randomized patients in a multicenter, double-blind placebo-controlled study of pleconaril (200 mg three times daily versus an identical-appearing placebo), 240 patients were confirmed to have enterovirus infection. The time to headache resolution was evaluated by using Kaplan-Meier survival methodology. A Cox regression model evaluated multivariate factors associated with disease resolution. Resolution of headache in patients with concomitant moderate to severe nausea at baseline occurred at a median of 9.5 days in the absence of therapy and was reduced to 7.0 days for pleconaril recipients (P = 0.009). For a headache score of > 5 alone, treated patients resolved headache significantly more rapidly (P = 0.005). Males resolved headache 50% faster than females. Regardless of randomization group, patients with a baseline headache score of 5 or greater resolved headache 50% more slowly than patients with a baseline headache score of 4. No differences in either clinical or laboratory adverse events were noted. Over 50% of untreated patients had a persistent headache that was greater than 1 week in duration. Pleconaril shortened the course of illness compared to placebo recipients, especially in the early disease course. However, the benefit was achieved only modestly in a subgroup analysis of patients with more severe disease after adjusting for confounding variables.

Topics: Adult; Antiviral Agents; Double-Blind Method; Enterovirus Infections; Female; Headache; Humans; Male; Meningitis, Viral; Multivariate Analysis; Oxadiazoles; Oxazoles; Treatment Outcome

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.. 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.. 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.. 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.

Topics: Administration, Oral; Biological Availability; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Enterovirus Infections; Female; Follow-Up Studies; Humans; Infant; Male; Meningitis, Viral; Oxadiazoles; Oxazoles; Probability; Reference Values; Risk Assessment; Severity of Illness Index; Treatment Outcome