Population pharmacokinetics of daptomycin in critically ill patients with various degrees of renal impairment.

Objectives: The objective of this study was to characterize the pharmacokinetics of unbound and total concentrations of daptomycin in infected ICU patients with various degrees of renal impairment. From these results, the probability of attaining antimicrobial efficacy and the risks of toxicity were assessed. Methods: Twenty-four ICU patients with various renal functions and requiring treatment of complicated skin and soft-tissue infections, bacteraemia, or endocarditis with daptomycin were recruited. Daptomycin (Cubicin®) at 10 mg/kg was administered every 24 h for patients with creatinine clearance (CLCR) ≥30 mL/min and every 48 h for patients with CLCR <30 mL/min. Total and unbound plasma concentrations and urine concentrations of daptomycin were analysed simultaneously following a population pharmacokinetic approach. Simulations were conducted to estimate the probability of attaining efficacy (unbound AUCu/MIC >40 or >80) or toxicity (Cmin >24.3 mg/L) targets. Results: Exposure to unbound daptomycin increased when the renal function decreased, thus increasing the probability of reaching the efficacy targets, but also the risk of toxicity. Modifications of the unbound fraction (fu) of daptomycin did not affect the pharmacokinetics of unbound daptomycin, but did affect the pharmacokinetics of total daptomycin. Conclusions: Daptomycin at 10 mg/kg q24h allowed efficacy pharmacokinetic/pharmacodynamic targets for ICU patients with CLCR ≥30 mL/min to be reached. For patients with CLCR <30 mL/min, halving the rate of drug administration, i.e. 10 mg/kg q48h, was sufficient to reach these targets. No adverse events were observed, but the toxicity of the 10 mg/kg q24h dosing regimen should be further assessed, particularly for patients with altered renal function.

Evaluation and comparison of epidural analgesia in labour related information on French and English-speaking websites.

OBJECTIVES: The medical information on the Internet is better in English than in other languages. The information about Epidural Analgesia In Labour (EAIL) available on French-speaking websites is of poor quality. The quality of the information about EAIL should be better in English, but there is no comparison available. This study has assessed and compared the quality of the information about EAIL available on French and English-speaking websites. METHOD: Keywords "epidural", "épidurale" and/or "péridurale" were used in the French, Canadian and American Google® and Yahoo® search engines. Two independent assessors assessed the 20 first websites for each engine search. They used an evaluation form created from French, Canadian and American recommendations. This form assessed the structure quality (Structure Score/25) and the medical information quality (Medical Information Score/30) of the websites. The addition of both scores gives the Global Score (/55). RESULTS: Seventy-one websites were assessed, 39 French-speaking and 32 English-speaking websites. Structure, Medical Information and Global Scores (expressed as mean (SD)) were respectively 11 (4), 13 (5), 24 (8) for the French-speaking websites and 11 (4), 12 (4), 23 (7) for the English-speaking websites. There was no statistical significant difference between both languages. CONCLUSION: Information about EAIL available on French and English-speaking websites is of poor quality and there is no difference in the information quality, whatever the language. A consideration on Internet medical information improvement is needed. A high quality dedicated website should be created and broadcasted.

A case-report of unpredictable and massive voriconazole intoxication in a patient with extensive CYP2C19 and CYP2C9 polymorphisms.

This case-report describes a massive voriconazole (VRZ) intoxication in a patient with a poor metabolizer profile, highlighted by low plasma main metabolite concentrations (N-oxide voriconazole), despite an extensive genetic profile for CYP2C19 and CYP2C9. The patient was treated with a therapeutic dose of VRZ but developed a neurotoxicity leading to hallucinations and coma while the plasma concentration of VRZ reached an exceptional level (20.0 µg/mL on day 10 of the treatment). Since neurological disorders diminished in parallel with the decrease of VRZ plasma concentrations, the coma was likely due to VRZ. The VRZ half-life, calculated to 58 h in this patient, was by far higher than the values reported in the literature. While VRZ concentrations slowly decreased, the N-oxide voriconazole concentrations slowly increased from day 15. Hypotheses for this lack of metabolization of VRZ are an inhibition of the metabolism by esomeprazole, a saturation of the metabolism or an enzymatic auto-inhibition of VRZ metabolism but none of these hypotheses have yet been explored. This case-report of unpredictable accumulation of VRZ in a patient without any genetic risk factor is an advocacy for systematic therapeutic drug monitoring of VRZ.