No abstract

Two multicenter, open-label, single-arm, two-phase studies evaluated single-dose pharmacokinetics and single-and multiple-dose safety of a pediatric oral famciclovir formulation (prodrug of penciclovir) in children aged 1 to 12 years with suspicion or evidence of herpes simplex virus (HSV) or varicella-zoster virus (VZV) infection. Pooled pharmacokinetic data were generated after single doses in 51 participants (ϳ12.5 mg/kg of body weight [BW] for children weighing <40 kg and 500 mg for children weighing >40 kg). The average systemic exposure to penciclovir was similar (6-to 12-year-olds) or slightly lower (1-to <6-year-olds) than that in adults receiving a 500-mg dose of famciclovir (historical data). The apparent clearance of penciclovir increased with BW in a nonlinear manner, proportional to BW 0.696 . An eight-step weight-based dosing regimen was developed to optimize exposure in smaller children and was used in the 7-day multiple-dose safety phases of both studies, which enrolled 100 patients with confirmed/suspected viral infections. Twenty-six of 47 (55.3%) HSV-infected patients who received famciclovir twice a day and 24 of 53 (45.3%) VZV-infected patients who received famciclovir three times a day experienced at least one adverse event. Most adverse events were gastrointestinal in nature. Exploratory analysis following 7-day famciclovir dosing regimen showed resolution of symptoms in most children with active HSV (19/21 [90.5%]) or VZV disease (49/53 [92.5%]). Famciclovir formulation (sprinkle capsules in OraSweet) was acceptable to participants/caregivers. In summary, we present a weight-adjusted dosing schedule for children that achieves systemic exposures similar to those for adults given the 500-mg dose.Intravenous and high-dose oral acyclovir has been the gold standard for many children requiring treatment and/or prevention of herpes simplex virus (HSV) and varicella-zoster virus (VZV) infections (3,14,15,25). However, intravenous acyclovir requires hospitalization, and oral acyclovir has limited bioavailability, necessitating frequent dosing, and may not provide maximum therapeutic benefit especially in immunocompromised hosts requiring higher plasma drug levels (22). It is therefore desirable to identify more pharmacokinetically appealing therapies for children with conditions caused by HSV or VZV infections. Alternative therapies for treating herpesvirus infections have become available over the last decade, including valacyclovir and famciclovir (5, 18), but only acyclovir is currently approved for pediatric use in many countries.Penciclovir, a nucleoside analogue, possesses potent in vitro antiviral activity against HSV types 1 and 2 and VZV (21). Famciclovir, the oral prodrug of penciclovir, is currently approved for the treatment of herpes zoster and herpes labialis, treatment or suppression of genital herpes in immunocompetent adult patients, and treatment of HSV infections and herpes zoster in immunocompromised adults. Although pharmacokinetic and safety data for famciclovir have been rep...

Sensorineural deafness occurs in 20%-30% of children after Streptococcus pneumoniae meningitis. An infant rat model of S. pneumoniae meningitis was developed to study the pathogenesis of inner ear invasion by S. pneumoniae. S. pneumoniae type 6 was administered intraperitoneally (inoculum: 1-10 x 10(8) cfu) every 24 h for 3 days to 5-day-old rats. Bacteremia (12 [50%] of 24) and meningitis (11 [46%] of 24) were detected most frequently 4 days after the three doses. The mean cerebrospinal fluid (CSF) white blood count for rats with positive CSF cultures was 7271/mm3 (range, 81-20,475). Hematoxylin-eosin-stained brain tissue from the 11 rats with positive CSF cultures showed inflammation in the meninges and scala tympani in 9 each (82%), and scala vestibuli in 6 (55%), but none in the scala media. Gram's-stained brain and inner ear sections from the same 11 rats showed organisms in the meninges in 5 (45%) and scala tympani or vestibuli in 2 (18%). Perilymphatic inflammation occurred significantly (P less than .001) more than did endolymphatic inflammation.