Population Pharmacokinetic Assessment and Pharmacodynamic Implications of Pediatric Cefepime Dosing for Susceptible-Dose-Dependent Organisms.

The Clinical and Laboratory Standards Institute (CLSI) revised cefepime (CFP) breakpoints forEnterobacteriaceaein 2014, and MICs of 4 and 8 µg/ml were reclassified as susceptible-dose dependent (SDD). Pediatric dosing to provide therapeutic concentrations against SDD organisms has not been defined. CFP pharmacokinetics (PK) data from published pediatric studies were analyzed. Population PK parameters were determined using NONMEM, and Monte Carlo simulation was performed to determine an appropriate CFP dosage regimen for SDD organisms in children. A total of 664 CFP plasma concentrations from 91 neonates, infants, and children were included in this analysis. The median patient age was 1.0 month (interquartile range [IQR], 0.2 to 11.2 months). Serum creatinine (SCR) and postmenstrual age (PMA) were covariates in the final PK model. Simulations indicated that CFP dosing at 50 mg/kg every 8 h (q8h) (as 0.5-h intravenous [i.v.] infusions) will maintain free-CFP concentrations in serum of >4 and 8 µg/ml for >60% of the dose interval in 87.1% and 68.6% of pediatric patients (age, ≥30 days), respectively, and extending the i.v. infusion duration to 3 h results in 92.3% of patients with free-CFP levels above 8 µg/ml for >60% of the dose interval. CFP clearance (CL) is significantly correlated with PMA and SCR. A dose of 50 mg/kg of CFP every 8 to 12 h does not achieve adequate serum exposure for older children with serious infections caused by Gram-negative bacilli with a MIC of 8 µg/ml. Prolonged i.v. infusions may be useful for this population.

Longitudinal assessment of bone growth and development in a facility-based population of young adults with cerebral palsy.

AIM: Osteoporosis is a significant clinical problem in persons with moderate to severe cerebral palsy (CP), causing fractures with minimal trauma. Over the past decade, most studies examining osteoporosis and CP have been cross-sectional in nature, focused exclusively on children and adolescents and only involving one evaluation of bone mineral density (BMD). The purpose of this study was to assess BMD in a group including adults with CP, and changes in each individual's BMD over a 5- to 6-year period. METHOD: The study group included 40 residents of a long-term care facility aged 6 to 26 years at the time of their initial evaluation. Twenty-one patients (52.5%) were male, 35 (88%) were white, and 38 (95%) were in Gross Motor Function Classification System level V. BMD was assessed by dual-energy X-ray absorptiometry on the right and left distal femurs for three distinct regions of interest. RESULTS: Five residents had a fracture that occurred during the study period; this represented a fracture rate of 2.1% per year in the study group. Longitudinally, annualized change in the median BMD was 0.7% to 1.0% per year in the different regions of the distal femur, but ranged widely among the study group, with both increases and decreases in BMD. Increase in BMD over time was negatively correlated with age and positively correlated with change in weight. INTERPRETATION: Changes in BMD over time in profoundly involved persons with CP can range widely, which is important to recognize when evaluating potential interventions to improve BMD. Age and changes in body weight appear the most relevant factors.

Assessment of the clinical use of intravenous and oral N-acetylcysteine in the treatment of acute acetaminophen poisoning in children: a retrospective review.

BACKGROUND: N-acetylcysteine (NAC) is the most effective therapy for acetaminophen (APAP) toxicity and is currently available for oral and intravenous (IV) administration. Although both routes are effective, use of the IV formulation has been increasing since becoming available in the United States in 2004, raising questions about cost/benefit comparisons between the 2 formulations. Decreased length of treatment and hospital stay have been used to justify the use of IV NAC; however, some patients may receive extended therapy of either NAC regimen. OBJECTIVE: This retrospective review assessed the clinical use of oral and IV NAC in pediatric patients with APAP intoxication from June 1, 2004 through May 31, 2008. METHODS: Electronic medical charts for patients aged ≤21 years were identified with International Classification of Diseases, Ninth Revision (ICD-9) codes for APAP overdose. Descriptive statistics were used to describe the overall patient population and route of NAC administration. The primary outcome variable was the length of treatment with IV and oral NAC therapy. RESULTS: A total of 62 charts for patients with APAP toxicity were reviewed; 37 patients (60%) received IV NAC and 25 patients (40%) received oral NAC. The average lengths of treatment and stay for IV dosing were 23.5 hours (range, 17.6-54.9 hours) and 1.6 days (range, 1-3 days), respectively; those for oral dosing were 69.5 hours (range, 33-133 hours) and 1.95 days (range, 1-5 days), respectively. Of 16 patients who received oral NAC and were admitted for <3 days, 14 were transferred to an inpatient psychiatric unit and completed the 72-hour therapy. A total of 3 patients received extended NAC dosing-2 with IV dosing and 1 with oral dosing. CONCLUSIONS: Based on our review, the majority of patients received recommended dosing of NAC therapy; however, 3 patients received extended NAC therapy. Patient-specific factors should be considered when assessing whether NAC therapy should be extended and if one route of administration may be preferred. ClinicalTrials.gov identifier: NCT00725179.

Assessment of serum creatine kinase among adolescent patients following jimsonweed (Datura stramonium) and moonflower (Datura inoxia) ingestions: a review of 11 cases.

INTRODUCTION: Datura stramonium (DS) (jimsonweed) is well known for its abuse potential for hallucinogenic effects and Datura inoxia (DI) (moonflower) has been abused for similar effects. To our knowledge, only one case report describes rhabdomyolysis in association with DS or DI ingestion. CASE IDENTIFICATION AND DETAILS: Patient hospital charts were retrospectively screened from January 1, 2002 to December 31, 2007 to identify patients with qualifying ICD-9 codes for toxic plant ingestions. We report on 11 patient cases of DS/DI ingestions in which serum creatine kinase (CK) concentrations were monitored. These admissions occurred at our hospital over a 6-year period. Serum CK concentrations ranged from 72 to 70,230 U/L. Only three patients had serum CK concentrations greater than 1,000 U/L. One patient with a peak concentration of 70,230 U/L and a positive myoglobinuria was diagnosed with rhabdomyolysis. DISCUSSION: Based on our review of the literature and these cases, it is possible that serum CK concentrations may be elevated more frequently than previously realized. The clinical significance of this abnormal laboratory value is uncertain with the majority of patients remaining asymptomatic without any clinical evidence of rhabdomyolysis.

Explaining the poor bacteriologic eradication rate of single-dose ceftriaxone in group a streptococcal tonsillopharyngitis: a reverse engineering solution using pharmacodynamic modeling.

OBJECTIVE: To explore pharmacokinetic factors underlying the poor bacteriologic eradication rate with a single 500-mg dose of ceftriaxone for streptococcal tonsillopharyngitis and to identify the minimum ceftriaxone dose required for effective treatment. METHODS: Population modeling techniques were applied to pharmacokinetic data derived from paired plasma and tonsil samples from 153 children to assess the contribution of pharmacokinetic variability to patients' responses to ceftriaxone. In addition, a Monte Carlo simulation was performed to determine (1) the amount of time that free ceftriaxone concentrations must exceed the minimum inhibitory concentration (MIC) of group A Streptococcus to achieve bacteriologic eradication and (2) the ceftriaxone dose required to maintain free drug concentrations above the target MIC for the requisite amount of time. Ceftriaxone MICs for group A Streptococcus were obtained from a previous trial, in which all MICs (n = 115) were < or = 0.064 mg/L; 33.9% were susceptible at < or = 0.016 mg/L, 66.4% were susceptible at 0.032 mg/L, and 1.7% were susceptible at 0.064 mg/L. RESULTS: Mean population pharmacokinetic parameters and their variances reflected substantial variability of clearance and half-life in the target population. Tonsillar ceftriaxone protein binding was 89.1%. The proportions of 1000 simulated patients with free ceftriaxone concentrations that exceeded MICs of 0.016 mg/L, 0.032 mg/L, and 0.064 mg/L at 24 hours were 71.7%, 65.4%, and 57.2%, respectively, and at 48 hours were 41.8%, 35.8%, and 28.6%, respectively. The amount of time that free ceftriaxone concentrations need to exceed MIC to achieve bacteriologic success was estimated to be 36 hours. Using this time criterion, two 500-mg doses of ceftriaxone separated by 18 hours should achieve a bacteriologic cure rate of approximately 95%. CONCLUSIONS: Pharmacokinetic variability and high ceftriaxone tonsillar protein binding explain the high microbiologic failure rate for a single 500-mg dose of ceftriaxone in group A streptococcal tonsillopharyngitis. Monte Carlo simulation suggests that a second dose administered 18 hours after the first will be required to achieve an acceptable bacteriologic cure rate.