Ganciclovir population pharmacokinetics in neonates following intravenous administration of ganciclovir and oral administration of a liquid valganciclovir formulation.

Cytomegalovirus (CMV) is the most common viral congenital infection, producing both sensorineural hearing loss and mental retardation. Our objective was to assess the population pharmacokinetics of a research-grade oral valganciclovir solution in neonates with symptomatic congenital CMV disease. Twenty-four neonates received 6 weeks of antiviral therapy. Ganciclovir and valganciclovir were measured by liquid chromatography/tandem mass spectroscopy. NONMEM version VI beta was used for population analyses. All profiles were consistent with a one-compartment model. Postnatal age, body surface area, and gender did not improve the model fit after body weight was taken into account. The typical value of clearance (l/h), distribution volume (l), and bioavailability of ganciclovir were 0.146 x body weight (WT)(1.68), 1.15 x WT, and 53.6%, respectively. Although these results cannot be extrapolated to extemporaneously compounded valganciclovir preparations, they provide the foundation on which a commercial-grade valganciclovir oral solution may be a viable option for administration to neonates.

Human papillomavirus infection: the role of vaccination in pediatric patients.

Human papillomavirus (HPV) infection is the most common sexually transmitted infection among adolescents and adults in the United States. Given the prevalence of this infection and its relationship with the development of cervical cancer, HPV vaccine development has been a major public health initiative in the last decade. Despite extensive research in the development of these vaccines, there remain many unanswered questions in academic and public arenas regarding their administration and role in adolescent medicine.

Prevention of respiratory syncytial virus infection in high risk infants.

The incidence of serious RSV illness in premature infants and in infants with CLD can be reduced. Prophylaxis in infants with CHD and cystic fibrosis seem prudent as well, and clinical trials are currently under way to evaluate the use of Synagis in these high-risk groups. Synagis is preferred for most high-risk children because of its ease of administration, safety and effectiveness. The dose for Synagis is 15 mg/kg i.m. monthly during RSV season.

Impact of a waiting room videotape message on parent attitudes toward pediatric antibiotic use.

OBJECTIVE: To reduce the injudicious use of antibiotics, we developed an educational strategy that focused on parents of pediatric patients and their physicians. METHODS: This intervention was conducted in 5 pediatric practices in Arkansas during a 9-month period. Baseline data on parent attitudes about antibiotics and physician practice habits were measured by questionnaire. During the following 36 weeks, an educational videotape about the judicious use of antibiotics was played in waiting rooms. The videotape on antibiotics used a standard script based on the recommendations of the American Academy of Pediatrics. The physicians and staff at each site were actors in the videotape. During week 2 and week 36 of videotape use, parent attitudes were measured again. After the baseline week, the physicians and staff in each site were provided a standard in-service review of the American Academy of Pediatrics recommendations for judicious use of antibiotics. A study nurse recruited patients, administered questionnaires, and reviewed charts on-site. RESULTS: Parents who were exposed to the videotape were significantly less inclined to seek antibiotics for viral infections. Passively provided pamphlets were not read. No significant change in antibiotic prescribing by physicians was seen. CONCLUSION: Parent-focused passive education tools are effective at changing parent attitudes toward the use of antibiotics. Although physicians have blamed parent attitudes and demands for the overuse of antibiotics, changes in parent attitudes in this study were not associated with changes in prescribing rates. Changes in parent attitudes may be necessary but do not seem sufficient for changes in antimicrobial prescribing patterns.

Natural history of neonatal herpes simplex virus infections in the acyclovir era.

OBJECTIVE: During the 2 decades in which effective antiviral therapies have been available for neonatal herpes simplex virus (HSV) disease, changes have been documented not only in the outcomes of infected infants, but also in the natural history of the disease itself. Numerous studies previously have reported that early institution of antiviral therapy is beneficial to the outcome of the disease. The objective of this study was to provide an update of neonatal HSV disease to identify means by which future improvements in the management of HSV-infected neonates can be made. DESIGN/METHODS: Neonates enrolled in 2 studies of parenteral acyclovir for the treatment of neonatal HSV disease provided the data source. The National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group conducted the studies between 1981 and 1997. A total of 186 patients are summarized, all of whom were treated with acyclovir. Demographic and clinical characteristics of these patients are reported. RESULTS: Comparisons between patients treated in the periods between 1981-1988 and 1989-1997 according to extent of disease revealed that the mean time between the onset of disease symptoms and initiation of therapy has not changed significantly from the early 1980s to the late 1990s. Of all patients evaluated, 40% had fetal scalp monitors during the delivery process. A significant minority of patients did not have skin vesicles at the time of their presentation and did not develop them during the acute HSV disease (39% of patients with disseminated disease; 32% of patients with central nervous system [CNS] disease; and 17% of patients with skin, eye, and/or mouth disease). Among patients with CNS disease, mortality was associated with prematurity. Among patients with disseminated HSV disease treated with acyclovir at 30 mg/kg/d, mortality was associated with aspartate transaminase elevations of >/=10 times the upper limit of normal at the time of initiation of acyclovir therapy. Mortality was also associated with lethargy at initiation of antiviral therapy for patients with disseminated disease. Patients' morbidity status was associated with the extent of disease (skin, eye, and/or mouth disease vs CNS vs disseminated). For those patients with CNS disease, morbidity was also associated with seizures at initiation of antiviral therapy. CONCLUSION: Data presented in the current comparison of neonatal HSV disease over the 2 periods (1981-1988 vs 1989-1997) demonstrate that no progress has been made in decreasing the interval between onset of HSV symptoms and initiation of antiviral therapy. Additional strides in the improvement of disease outcome may occur only if the interval between onset of symptoms and initiation of therapy is shortened. The means by which this will be accomplished lie in increased consideration of neonatal HSV infections in acutely ill infants. Specific data and recommendations to facilitate this goal are contained within.

Safety and efficacy of high-dose intravenous acyclovir in the management of neonatal herpes simplex virus infections.

OBJECTIVE: The objective of this investigation was to establish the safety of high-dose (HD) acyclovir for the treatment of neonatal herpes simplex virus (HSV) disease. In addition, an estimate of therapeutic efficacy was sought, both with respect to mortality and to morbidity. Virologic efficacy of HD acyclovir was also assessed. PARTICIPANTS: Infants who were

Single dose pharmacokinetics of pleconaril in neonates. Pediatric Pharmacology Research Unit Network.

BACKGROUND: Pleconaril is an orally active, broad spectrum antipicornaviral agent with activity against nonpolio enteroviruses. Pleconaril phamacokinetics was evaluated in 16 neonates (16.4 +/- 8.7 days postnatal age) with suspected enteroviral infection. METHODS: Pleconaril (5 or 7.5 mg/kg) was administered orally to study subjects and plasma pleconaril concentrations quantified from serial blood samples obtained during 24 h after a single oral dose by gas chromatography with electrochemical detection. Pharmacokinetic parameter estimates were determined by noncompartmental methods and compared between doses and with similar data obtained from a previous study of pleconaril disposition in children (n = 18, 2 to 12 years). RESULTS: Pleconaril was well-tolerated in all neonates without discernible adverse events. Comparison between the 5.0- and 7.5-mg/kg doses revealed no significant differences in peak plasma concentration (Cmax 686.7 vs. 617.1 ng/ml), elimination half-life (t 1/2; 4.6 vs. 6.6 h), area under the plasma concentration vs. time curve (AUC; 5162.6 vs. 5523.9 ng/ml/h), apparent steady state volume of distribution (V(dss)/F; 9.3 vs. 17.1 liters/ kg) and apparent oral clearance (Cl/F; 1.3 vs. 1.7 liters/h/kg). In addition, no correlation was observed between postconceptional age and AUC, V(dss)/F, t 1/2 or Cl/F for pleconaril. Comparison of pleconaril pharmacokinetics between neonates and children suggested a significant difference in V(dss)/F (9.3 vs. 4.7 liters/kg), dose-normalized Cmax, (686.7 vs. 1272.5 ng(ml) and AUC (5125.6 vs. 8131.2 ng/ml/h). In contrast, the mean elimination t 1/2 between neonates and children was not appreciably different. CONCLUSIONS: The apparent age-dependent differences in the pharmacokinetics of pleconaril may in part be related to increased bioavailability of the drug in older children and adults than in neonates. Our data appear to support the use of a 5.0-mg/kg dose given every 8 to 12 h in future studies of pleconaril in neonatal patients with enteroviral infection.

Judicious use of antibiotics for common pediatric respiratory infections.

BACKGROUND: Antibiotic resistance among common respiratory infection-producing bacteria such as Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis has become a major global public health problem. The use of antibiotics, whether or not medically justified for a particular illness, contributes to the development of resistant bacteria. To help to contain the proliferation of drug-resistant bacteria, members of the CDC and the American Academy of Pediatrics (AAP) recently published principles for the judicious use of antibiotics in common pediatric respiratory infections including the common cold, otitis media, sinusitis and tonsillopharyngitis. This article reviews the CDC/AAP principles for management of these illnesses and describes results of clinical practice studies in which efforts to improve the judicious use of antibiotics were undertaken. CONCLUSIONS: The success of the CDC/AAP principles in containing the increase in antimicrobial resistance depends upon their being practiced. Results of clinical practice studies indicate that judicious use of antimicrobial therapy in pediatric respiratory infections can be realized through education and persistence. More widespread educational and behavior modification efforts are necessary to reduce unnecessary prescription of antibiotics and to curtail the still burgeoning problem of bacterial resistance.

Single dose pharmacokinetics of linezolid in infants and children.

BACKGROUND: Linezolid is an oxazolidinone antibiotic with excellent in vitro activity against a number of Gram-positive organisms including antibiotic-resistant isolates. The safety and pharmacokinetics of intravenously administered linezolid were evaluated in children and adolescents to examine the potential for developmental dependence on its disposition characteristics. METHODS: Fifty-eight children (3 months to 16 years old) participated in this study; 44 received a single 1.5-mg/kg dose and 14 received a single 10-mg/kg dose of linezolid administered by intravenous infusion. Repeated blood samples (n = 10 in children > or = 12 months; n = 8 in children 3 to 12 months) were obtained during 24 h after drug administration, and linezolid was quantitated from plasma by high performance liquid chromatography with mass spectrometry detection. Plasma concentration vs. time data were evaluated with a model independent approach. RESULTS: Linezolid was well-tolerated by all subjects. The disposition of linezolid appears to be age-dependent. A significant although weak correlation between age and total body clearance was observed. The mean (+/- SD) values for elimination half-life, total clearance and apparent volume of distribution were 3.0 +/- 1.1 h, 0.34 +/- 0.15 liter/h/kg and 0.73 +/- 0.18 liter/kg, respectively. Estimates of total body clearance and volume of distribution were significantly greater in children than historical values of adult data. As such maximum achievable linezolid plasma concentrations were slightly lower in children, and concentrations 12 h after a single 10-mg/kg dose were below the MIC90 for selected pathogens with in vitro susceptibility to the drug. CONCLUSION: Based on these data a linezolid dose of 10 mg/kg given two to three times daily would appear appropriate for use in pediatric therapeutic clinical trials of this agent.

Single-dose pharmacokinetics of a pleconaril (VP63843) oral solution in children and adolescents. Pediatric Pharmacology Research Unit Network.

Pleconaril is an orally active, broad-spectrum antipicornaviral agent which demonstrates excellent penetration into the central nervous system, liver, and nasal epithelium. In view of the potential pediatric use of pleconaril, we conducted a single-dose, open-label study to characterize the pharmacokinetics of this antiviral agent in pediatric patients. Following an 8- to 10-h period of fasting, 18 children ranging in age from 2 to 12 years (7.5 +/- 3.1 years) received a single 5-mg/kg of body weight oral dose of pleconaril solution administered with a breakfast of age-appropriate composition. Repeated blood samples (n = 10) were obtained over 24 h postdose, and pleconaril was quantified from plasma by gas chromatography. Plasma drug concentration-time data for each subject were fitted to the curve by using a nonlinear, weighted (weight = 1/Ycalc) least-squares algorithm, and model-dependent pharmacokinetic parameters were determined from the polyexponential parameter estimates. Pleconaril was well tolerated by all subjects. A one-compartment open-model with first-order absorption best described the plasma pleconaril concentration-time profile in 13 of the subjects over a 24-h postdose period. Pleconaril pharmacokinetic parameters (means +/- standard deviations) for these 13 patients were as follows. The maximum concentration of the drug in serum (Cmax) was 1,272.5 +/- 622.1 ng/ml. The time to Cmax was 4.1 +/- 1.5 h, and the lag time was 0.75 +/- 0.56 h. The apparent absorption rate constant was 0.75 +/- 0.48 1/h, and the elimination rate constant was 0.16 +/- 0.07 1/h. The area under the concentration-time curve from 0 to 24 h was 8,131.15 +/- 3,411.82 ng.h/ml. The apparent total plasma clearance was 0.81 +/- 0.86 liters/h/kg, and the apparent steady-state volume of distribution was 4.68 +/- 2.02 liters/kg. The mean elimination half-life of pleconaril was 5.7 h. The mean plasma pleconaril concentrations at both 12 h (250.4 +/- 148.2 ng/ml) and 24 h (137.9 +/- 92.2 ng/ml) after the single 5-mg/kg oral dose in children were higher than that from in vitro studies reported to inhibit > 90% of nonpolio enterovirus serotypes (i.e., 70 ng/ml). Thus, our data support the evaluation of a 5-mg/kg twice-daily oral dose of pleconaril for therapeutic trials in pediatric patients with enteroviral infections.

Treatment of tuberculous infection and disease in children: the North American perspective.

The standard preventive therapy for paediatric patients with tuberculous infection centres on isoniazid therapy. The chosen regimen of isoniazid therapy is based on individual patient factors. In the case of known or suspected resistance, combination therapy [e.g. isoniazid and rifampicin (rifampin)] or alternative therapies (e.g. pyrazinamide, a fluoroquinolone and/or ethambutol) should be employed. The goal of treatment of tuberculous disease is to achieve sterilisation in the shortest possible time. More intensive multiple drug combination regimens (e.g. isoniazid, rifampicin and pyrazinamide) have resulted in successful 6- and 9-month treatment regimens in children. If drug resistance is suspected then a fourth drug is added to the initial treatment regimen and the length of therapy may be extended to 18 months. The paediatric information available on the commonly used antituberculous agents (e.g. isoniazid, rifampicin, pyrazinamide and ethambutol) is reviewed in this article. Agents are described with an emphasis on their formulation availability, mechanism of action, pharmacokinetic properties (e.g. absorption, distribution, metabolism and elimination), adverse effects, and interactions (e.g. drug-drug, drug-food and drug-disease).

Cefpodoxime pharmacokinetics in children: effect of food.

BACKGROUND: Cefpodoxime, an oral third generation cephalosporin antibiotic, is used for the treatment of acute upper respiratory tract infection caused by susceptible bacteria in children 5 months to 12 years of age. We report the results of a randomized two-way crossover study designed to characterize the disposition of a single dose (10 mg/kg) of cefpodoxime proxetil oral suspension in children, under fed and fasted conditions. METHODS: Seventeen children (8.4 months to 12.2 years old, seven female) participated in this study. Each subject received a single 10-mg/kg dose of cefpodoxime proxetil oral suspension, after a predose fast and again coadministered with food. Repeated blood samples (n=10) were obtained during 12 h postdose and cefpodoxime was quantified from plasma by high performance liquid chromatography. Plasma concentration vs. time data were curve fit for each subject with a nonlinear weighted least squares algorithm, and pharmacokinetic parameters were determined from the polyexponential estimates. RESULTS: Cefpodoxime disposition was best characterized using a one-compartment open model with first order absorption. The area under the plasma concentration vs. time curve, Cmax and Ke were not significantly different between fed and fasted conditions. However, Tmax was significantly prolonged (fed=2.79+/-1.10 h vs. fasted=1.93+/-0.54 h) and Ka was significantly smaller (fed=0.42+/-0.14 h(-1) vs. fasted=0.81+/-0.72 h(-1)) in the fed state. CONCLUSIONS: Administration of cefpodoxime in the presence of food affected the rate but not the extent of absorption. Cefpodoxime proxetil oral suspension can be administered without regard to meals in children 6 months to 12 years of age.

A number-needed-to-treat analysis of the use of respiratory syncytial virus immune globulin to prevent hospitalization.

OBJECTIVES: To estimate how many infants in selected high-risk subgroups would require treatment with respiratory syncytial virus immune globulin (RSV-IG) to avoid 1 hospital admission and to determine whether this is economically justified. DESIGN: Cost-benefit analysis. Data from 3 randomized controlled trials of RSV-IG are used to estimate the number needed to treat to prevent 1 hospital admission for respiratory syncytial virus infection. The threshold number needed to treat is computed according to a formula incorporating costs and benefits of RSV-IG prophylaxis. Estimates of the willingness to pay were obtained from a sample of 39 health care providers (35 physicians and 4 nurses). MAIN OUTCOME MEASURES: The number needed to treat to prevent 1 hospital admission for respiratory syncytial virus infection. The threshold number needed to treat that would balance costs with benefits. RESULTS: More than 16 (95% confidence interval, 12.5-23.8) infants would need to be treated with RSV-IG to avoid 1 hospital admission for respiratory syncytial virus infection, ranging from 63 for premature infants without chronic lung disease to 12 (confidence interval, 6.3-100.0) for infants with bronchopulmonary dysplasia. A sensitivity analysis of the costs and values of hospital admission for respiratory syncytial virus infection and RSV-IG treatment resulted in a weak recommendation against the treatment of infants with bronchopulmonary dysplasia and strong recommendations that the costs and risks of RSV-IG treatment outweigh the benefits for the combined sample of infants and premature infants without lung disease. CONCLUSIONS: The number-needed-to-treat procedures offer a method to assess evidence of treatment effects and decision rules for whether to accept treatment recommendations. Under plausible assumptions, treatment with RSV-IG is not recommended for infants without lung disease. Institutions can examine cost and benefit assumptions that best fit their own practice setting.

Neonatal herpes simplex virus infections.

Neonatal herpes simplex virus (HSV) infection is one of the life-threatening infections of newborns. It affects approximately 1,500 to 2,200 infants per year in the United States. Changes in the presentation of neonatal HSV infection over the past two decades include an increase in the frequency of skin, eye, and mouth (SEM) disease with a relatively unchanged rate of central nervous system (CNS) disease, but a relative decline in disseminated infection. Although the mortality of neonatal HSV infections has declined with current antiviral therapy, the mortality rate in CNS disease (15%) and disseminated disease (57%) remains high. Morbidity has been seen most frequently in infants with CNS and disseminated disease, with seizures or infection with HSV-2 determined to be risk factors for poor outcome in survivors. In a multicenter, randomized, blinded study by the Collaborative Antiviral Study Group, no differences in outcome were seen between neonates treated with vidarabine and acyclovir. More recently, administration of oral acyclovir has been demonstrated to prevent cutaneous recurrences of HSV after neonatal SEM disease. Although promising, this investigational protocol requires further evaluation before a routine recommendation for prophylactic therapy with oral acyclovir can be made. The application of polymerase chain reaction to rapid diagnosis of neonatal HSV disease may provide additional information on which clinical decisions may be based, but its diagnostic utility outside the research setting is still unproven. Further clinical trials for prophylaxis of recurrent SEM disease, prophylactic therapy for the prevention of recurrences of CNS or disseminated disease, the appropriate use of rapid diagnostic testing, and future therapies that may include passive antibody plus antiviral therapy or higher dosage and longer duration of antiviral therapy need to be evaluated.

Bartonella henselae as a cause of prolonged fever and fever of unknown origin in children.

A prospective evaluation of 146 children with fever of unknown origin (FUO) and prolonged fever was performed from 1990 to 1996. FUO was defined as a documented daily temperature of > or = 38 degrees C for at least 14 days without diagnostic signs or symptoms. Prolonged fever was defined as fever for at least 14 days and no diagnosis at the time of referral for evaluation. An established diagnosis was made for 84 (57.5%) of 146 patients. The most common infectious disease diagnoses were Epstein-Barr virus infection (22 [15.1%] of 146), osteomyelitis (14 [9.6%] of 146), bartonellosis (7 [4.8%] of 146), and urinary tract infection (6 [4.1%] of 146). Three of seven patients with confirmed Bartonella henselae infection presented with FUO and no ultrasonographic findings compatible with hepatosplenic involvement; two patients presented with FUO and hepatosplenic involvement. The relatively common finding of acute bartonellosis in this population suggests that FUO and prolonged fever in children are other presentations of infection with B. henselae.

Human monocytic ehrlichiosis in children.

BACKGROUND: Much of what is known about human monocytic ehrlichiosis (HME) is based upon studies with adult patients. PURPOSE: To review our experience with HME to better understand the epidemiology, clinical manifestations, and outcome of this disease in children. METHODS: Demographic, clinical, and laboratory data were gathered after review of the medical records of patients identified with HME. RESULTS: Twelve patients with an median age of 7.4 years (range, 7 months to 13.7 years) were identified with HME; 10 were white, 7 were male, and 10 were from hometowns of <800 people. Eight patients presented from May through July, and 8 had a history of tick bites. Symptoms demonstrated by the patients during their illness included fever (100%), rash (67%), myalgias (58%), and vomiting, diarrhea, and headache (25%). On presentation, patients demonstrated thrombocytopenia (92%), elevated liver function tests (91%), lymphopenia (75%), hyponatremia (67%), leukopenia (58%), and anemia (42%) on the initial laboratory examination. Four patients presented in shock and 3 required blood pressure support and mechanical ventilation for a median of 10 days (8 to 37 days). These complicated patients required longer hospitalization (19.5 days vs 5. 5 days) and attained higher blood urea nitrogen levels (42.5 mg/dL vs 10 mg/dL) than the patients not presenting with shock. Morbidity associated with HME patients included a decrease in cognitive and neurologic performance. CONCLUSIONS: More information and long-term follow-up is required to understand the full spectrum of disease and morbidity associated with HME in children.