High-Dose Ceftriaxone for Bacterial Meningitis and Optimization of Administration Scheme Based on Nomogram.

High dosages of ceftriaxone are used to treat central nervous system (CNS) infections. Dosage adaptation according to the glomerular filtration rate is currently not recommended. Ceftriaxone pharmacokinetics (PK) was investigated by a population approach in patients enrolled in a French multicenter prospective cohort study who received high-dose ceftriaxone for CNS infection as recommended by French guidelines (75 to 100 mg/kg of body weight/day without an upper limit). Only those with suspected bacterial meningitis were included in the PK analysis. A population model was developed using Pmetrics. Based on this model, a dosing nomogram was developed, using the estimated glomerular filtration rate (eGFR) and total body weight as covariates to determine the optimal dosage allowing achievement of targeted plasma trough concentrations. Efficacy and toxicity endpoints were based on previous reports, as follows: total plasma ceftriaxone concentrations of ≥20 mg/liter in >90% of patients for efficacy and ≤100 mg/liter in >90% of patients for toxicity. Based on 153 included patients, a two-compartment model including eGFR and total body weight as covariates was developed. The median value of the unbound fraction was 7.57%, and the median value of the cerebral spinal fluid (CSF)/plasma ratio was 14.39%. A nomogram was developed according to a twice-daily regimen. High-dose ceftriaxone administration schemes, used to treat meningitis, should be adapted to the eGFR and weight, especially to avoid underdosing using current guidelines. (This study has been registered at ClinicalTrials.gov under identifier NCT01745679.).

Tolerability of high-dose ceftriaxone in CNS infections: a prospective multicentre cohort study.

BACKGROUND: Ceftriaxone is widely used to treat community-acquired CNS bacterial infections. French guidelines for meningitis in adults promote 75-100 mg/kg/day ceftriaxone without an upper limit for dosage, yet little is known about the pharmacology and tolerability of such regimens. PATIENTS AND METHODS: A multicentre prospective cohort study was conducted in adult patients to assess the adverse drug reactions (ADRs) of high-dose ceftriaxone (i.e. daily dosage ≥4 g or ≥75 mg/kg) in CNS infections and to analyse their related factors. Drug causality was systematically assessed by an expert committee who reviewed the medical charts of all included patients. RESULTS: A total of 196 patients were enrolled over a 31 month period. Median dosage and duration of ceftriaxone were 96.4 mg/kg/day (7 g/day) and 8 days, respectively. Nineteen ceftriaxone-related ADRs (mainly neurological) occurred in 17 patients (8.7%), with only one case of treatment discontinuation (biliary pseudolithiasis). In univariate analysis, older age, male gender, renal impairment and high trough ceftriaxone plasma concentration were associated with ceftriaxone-related ADRs. CONCLUSIONS: High-dose ceftriaxone for CNS infection administered as recommended by French guidelines in adults was well tolerated overall, suggesting these recommendations could be applied and generalized. In patients with advanced age or renal insufficiency, prescription should be done with caution and therapeutic drug monitoring could be useful.

Assessment of peri-extubation pain by visual analogue scale in the adult intensive care unit: a prospective observational study.

OBJECTIVE: This prospective observational study was undertaken in order to assess pain experienced by intensive care unit patients at the time of extubation and to identify factors associated with pain of at least moderate intensity. DESIGN: Prospective observational study. SETTING: Intensive care unit at a university hospital. PATIENTS: During a 1-year period the presence, severity and clinical predictors of orofacial and/or chest pain among patients undergoing removal of endotracheal tubes was assessed. MEASUREMENTS AND RESULTS: Pain was evaluated using a visual analogue scale (VAS). Of 332 extubated patients, 203 could be evaluated. During the peri-extubation period, pain was significantly associated with a SAPS II score more than 36 ( p=0.03) and duration of mechanical ventilation (MV) of 6 days or more ( p=0.002), whereas intubation in the operating room was associated with less pain ( p=0.001). Pain of at least moderate intensity (VAS score >30 mm) was reported by 73% of patients and pain of severe intensity (VAS score >50 mm) was reported by 45% of patients. MV duration of 6 days or more was the only independent risk factor for pain of at least moderate intensity (OR 2.4, 95% CI 1.03-5.4, p=0.04). We also observed that pain had resolved 1 h after extubation in the majority of patients. CONCLUSION: Our results suggest that, in intensive care unit patients, peri-extubation pain is frequent and should be considered for treatment, especially in patients with longer intubation.