Model-Informed Precision Dosing Guidance of Ethosuximide Developed from a Randomized Controlled Clinical Trial of Childhood Absence Epilepsy.

Ethosuximide was identified as the optimal option for new-onset childhood absence epilepsy (CAE) in a randomized, two-phase dose escalation comparative effectiveness trial of ethosuximide, lamotrigine, and valproic acid. However, 47% of ethosuximide initial monotherapy participants experienced short-term treatment failure. This study aimed to characterize the initial monotherapy ethosuximide exposure-response relationship and to propose model-informed precision dosing guidance. Dose titration occurred over a 16-20-week period until patients experienced seizure freedom or intolerable side effects. Subjects with initial monotherapy failure were randomized to one of the other two medications and dose escalation was repeated. A population pharmacokinetic model was created using plasma concentration data (n = 1,320), collected at 4-week intervals from 211 unique participants during both the initial and second monotherapy phases. A logistic regression analysis was performed on the initial monotherapy cohort (n = 103) with complete exposure-response data. Eighty-four participants achieved seizure freedom with a wide range of ethosuximide area under the curves (AUC) ranging from 420 to 2,420 µg·h/mL. AUC exposure estimates for achieving a 50% and 75% probability of seizure freedom were 1,027 and 1,489 µg·h/mL, respectively, whereas the corresponding cumulative frequency of intolerable adverse events was 11% and 16%. Monte Carlo Simulation indicated a daily dose of 40 and 55 mg/kg to achieve 50% and 75% probability of seizure freedom in the overall population, respectively. We identified the need for adjusted mg/kg dosing in different body weight cohorts. This ethosuximide proposed model-informed precision dosing guidance to achieve seizure freedom carries promise to optimize initial monotherapy success for patients with CAE.

An open-label, double tympanocentesis study of levofloxacin therapy in children with, or at high risk for, recurrent or persistent acute otitis media.

BACKGROUND: Levofloxacin has excellent activity against common respiratory pathogens and therefore is likely to be effective in treating children with persistent or recurrent otitis media. OBJECTIVE: The objective of this study was to assess the efficacy and safety of levofloxacin treatment in the eradication of bacterial pathogens from the middle ear fluid (MEF) of children with, or at high risk for, persistent or recurrent otitis media. METHODS: An open-label multicenter trial was conducted that involved tympanocentesis at entry and selectively 3 to 5 days after starting levofloxacin (10 mg/kg twice a day for 10 days). RESULTS: : Two hundred five children (80% < or =2 years) were enrolled. One child did not have a confirmed diagnosis of acute otitis media and did not return for follow-up visits. Of the remaining 204 children, 94 (46%) had bilateral infection and 63 (31%) were receiving antimicrobials immediately before entry. One hundred five isolates of Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis and Streptococcus. pyogenes were recovered in pure or mixed cultures. All isolates were susceptible to levofloxacin. During-treatment bacterial eradication from MEF occurred in 88% (78 of 89) of bacteriologically evaluable patients, including 90% (65 of 72) of children < or =24 months of age. Bacteria initially isolated from MEF were eradicated in 31 of 37 (84%) children infected with S. pneumoniae and in 54 of 54 (100%) children infected with H. influenzae. Overall, clinical success rate after therapy was 94% for the total study population and 92% for the bacteriologically evaluable population. Levofloxacin was well tolerated. Vomiting (4%) was the most common treatment-limiting adverse event. CONCLUSIONS: Levofloxacin was safe and effective in treating and eradicating common bacterial pathogens from MEF in children with, or at risk for, recurrent or persistent otitis media.

Developing strategies for psychopharmacological studies in preschool children.

OBJECTIVE: To identify the obstacles and special challenges-ethical, practical, scientific, and regulatory-faced by investigators who attempt to conduct psychopharmacological studies in preschoolers. METHOD: In a workshop held at the 47th Annual Meeting of the American Academy of Child and Adolescent Psychiatry, featuring interactive sessions designed to elicit discussion of the theory and feasibility of research in this young population, several key domains were identified: diagnosis and assessment, ethics, research design, special considerations for preschoolers, regulatory/industry issues, and education/training. RESULTS: A Pediatric Psychopharmacology Initiative is needed to consolidate recommendations from this and other workshops and current federal, research, and regulatory committees. A scholarly review and a guide for institutional review boards and investigators should be prepared on issues related to preschoolers. Developmental specialists provide valuable expertise that can strengthen studies of pediatric psychopharmacology. "N of 1" case studies can provide valuable information to clinicians. Only preschoolers with severe symptoms that occur in several interpersonal contexts should be entered into trials. Indications for the study of symptom complexes (e.g., aggression) rather than specific diagnoses should be examined and considered for regulatory activities. Psychopharmacology practice parameters for preschoolers are needed. CONCLUSIONS: With preschoolers being increasingly treated with psychopharmacological agents, the need for investigations to address the safety and efficacy of these medications is becoming a central issue for researchers from many disciplines.

Cefotaxime-resistant bacteria colonizing older people admitted to an acute care hospital.

OBJECTIVES: To determine the frequency of fecal colonization by cefotaxime-resistant gram-negative bacilli in older patients living in the community and in long-term care facilities (LTCFs) admitted to an acute care hospital. DESIGN: Case-control, point prevalence study. SETTING: Hospital. PARTICIPANTS: One hundred forty-three patients aged 65 and older. MEASUREMENTS: Rectal swab cultures, antibiotic drug sensitivity, beta lactamase isolation, and clonal identity. RESULTS: Of the 190 surveillance cultures obtained from 143 patients, 26 cefotaxime-resistant gram-negative isolates from 22 patients were recovered. The prevalence rate of cefotaxime-resistant isolates on admission was 13.3% (19/143). A logistic regression model using cefotaxime colonization as the dependent variable found that multiple comorbidities, admission to a surgical service, and having a diagnosis of infection on presentation and a transfusion history were factors associated with the presence of colonization. These four clinical items accurately classified 74% of patients colonized. Antibiotic use and nursing home residence were not associated with the presence of colonization by cefotaxime-resistant organisms. Twelve of the cefotaxime-resistant isolates (46%) were identified as Pseudomonas aeruginosa, and 14 (54%) were other gram-negative bacilli. In six of the 14 isolates that were not P. aeruginosa (36%), it was possible to demonstrate the presence of an AmpC beta-lactamase related to the CMY-2 beta-lactamase, a plasmid-borne cephalosporinase. CONCLUSION: These data raise awareness that there are community- and LTCF-dwelling older patients colonized with gram-negative enteric bacilli resistant to third-generation cephalosporins on admission to the hospital. The "reservoir of resistant bacteria" in older people is no longer confined to LTCFs.

Ciprofloxacin for the treatment of uncomplicated gonorrhea infection in adolescents: does the benefit outweigh the risk?

The highest rates of reported gonorrhea infections occur among adolescent females aged 15-19 years. Among the Centers for Disease Control and Prevention (CDC)-recommended single-dose gonorrhea treatment regimens, ciprofloxacin, a fluoroquinolone antibiotic, is approximately half the cost of other CDC-recommended oral treatment regimens. Fluoroquinolone use in patients aged <18 years has been limited because of irreversible articular cartilage damage demonstrated in large, weight-bearing joints of young animals. We reviewed the medical literature to assess whether the risks of a single 500-mg dose of ciprofloxacin to treat uncomplicated gonorrhea infection in adolescents appears to outweigh the benefits. We found no reports of irreversible cartilage toxicity or age-associated adverse events in 5236 human children and adolescents (aged 5 days-24 years) treated with a total of 5486 courses of fluoroquinolones.