A Phase 1 Pharmacokinetic and Safety Study of Extended-Duration, High-dose Cefixime for Cephalosporin-resistant Neisseria gonorrhoeae in the Pharynx.

BACKGROUND: There are no fully oral recommended treatment regimens for gonorrhea. Inadequately treated pharyngeal gonococcal infections are a likely reservoir for transmission and development of antimicrobial resistance. We sought to determine an oral cefixime dosing regimen that would theoretically treat pharyngeal infections by gonococci with minimum inhibitory concentrations 0.5 µg/mL. METHODS: We conducted an open-label, nonrandomized, phase I pharmacokinetic and safety study of cefixime in 25 healthy male and female volunteers divided into 4 dosing cohorts (cohort A, 400 mg; cohort B, 800 mg; cohort C, 1200 mg; and cohort D, 800 mg every 8 hours × 3 doses [total dose 2400 mg]) with a target serum concentration of at least 2.0 µg/mL for more than 20 hours. Cefixime concentrations from serum and pharyngeal fluid were determined with use of a validated liquid chromatography-tandem mass spectrometry assay. Safety measures included laboratories, physical examinations, and symptom diaries. RESULTS: None of the single-dose regimens attained the target concentration; however, 50% of subjects in cohort D attained the target concentration. Variation in absorption and protein binding contributed to differences in concentrations. Pharyngeal fluid concentrations were negligible. The single-dose regimens were well tolerated; the multidose regimen resulted in mild to moderate gastrointestinal symptoms in 43% of subjects. CONCLUSIONS: None of the dosing regimens achieved the target concentration. However, the proposed theoretical target was extrapolated from penicillin data; there are no empirically derived pharmacokinetic/pharmacodynamic criteria for pharyngeal gonorrhea. Under alternative cephalosporin-specific therapeutic goals, the multidose regimen may be effective, although the absence of cefixime in pharyngeal fluid is concerning. A clinical trial evaluating efficacy and defining pharmacokinetic/pharmacodynamic outcomes may be warranted.

Short-Term Propofol Infusion and Associated Effects on Serum Lactate in Pediatric Patients.

OBJECTIVES: This study aimed to determine if short-duration procedural sedation in children with propofol is related to an adverse metabolic stress response measured by serum lactate. Propofol infusion syndrome is associated with high-dose and long-duration infusion. It has not been studied with short-duration, outpatient propofol administration. METHODS: This was a prospective, longitudinal study that included 50 patients between the ages of 2 and 18 years who were undergoing outpatient procedural sedation with propofol at a pediatric sedation unit. Patients received bolus or bolus and continuous infusion doses of propofol. Serum lactate values were obtained before and after the patients' sedated procedures. RESULTS: The average length of procedure was 40.3 minutes, and the mean dose of propofol per patient was 8.2 mg/kg. The highest measured lactate value was 1.8 mmol/L. The average (SD) preprocedure and postprocedure lactate values were 1.0 (0.3) and 0.7 (0.2) mmol/L, respectively, resulting in an overall significant decrease in lactate of -0.3 (0.3) mmol/L (P < 0.001). There was a significant (P = 0.01) positive relationship between age and postprocedure lactate value, when controlling for the length of the procedure in a multivariable regression. No significant association was found between propofol dosage and length of the procedure with lactate values. CONCLUSION: In this study, we did not find a significant increase in metabolic stress, measured by serum lactate. Using propofol for short-duration procedural sedation may not carry similar risks for propofol infusion syndrome to those for long-duration/high-dose infusion therapy.

Effects of Vitamin D Supplementation on Bone Mineral Density and Bone Markers in HIV-Infected Youth.

BACKGROUND: Low bone mineral density (BMD) is a significant comorbidity in HIV. However, studies evaluating vitamin D supplementation on bone health in this population are limited. This study investigates changes in bone health parameters after 12 months of supplementation in HIV-infected youth with vitamin D insufficiency. METHODS: This is a randomized, active-control, double-blind trial investigating changes in bone parameters with 3 different vitamin D3 doses [18,000 (standard/control dose), 60,000 (moderate dose), and 120,000 IU/monthly (high dose)] in HIV-infected youth 8-25 years old with baseline serum 25-hydroxyvitamin D (25(OH)D) concentrations <30 ng/mL. BMD and bone turnover markers were measured at baseline and 12 months. RESULTS: One hundred two subjects enrolled. Over 12 months, serum 25(OH)D concentrations increased with all doses, but the high dose (ie, 120,000 IU/monthly) maintained serum 25(OH)D concentrations in an optimal range (≥30 or ≥20 ng/mL) throughout the study period for more subjects (85% and 93%, respectively) compared with either the moderate (54% and 88%, respectively) or standard dose (63% and 80%, respectively). All dosing groups showed some improvement in BMD; however, only the high-dose arm showed significant decreases in bone turnover markers for both procollagen type 1 aminoterminal propeptide (-3.7 ng/mL; P = 0.001) and Β-CrossLaps (-0.13 ng/mL; P = 0.0005). CONCLUSIONS: High-dose vitamin D supplementation (120,000 IU/mo) given over 12 months decreases bone turnover markers in HIV-infected youth with vitamin D insufficiency, which may represent an early, beneficial effect on bone health. High vitamin D doses are needed to maintain optimal serum 25(OH)D concentrations.