Nebulized antibiotics in mechanically ventilated patients: a challenge for translational research from technology to clinical care

Abstract Nebulized antibiotic therapy directly targets airways and lung parenchyma resulting in high local concentrations and potentially lower systemic toxicities. Experimental and clinical studies have provided evidence for elevated lung concentrations and rapid bacterial killing following the administration of nebulized antibiotics during mechanical ventilation. Delivery of high concentrations of antibiotics to infected lung regions is the key to achieving efficient nebulized antibiotic therapy. However, current non-standardized clinical practice, the difficulties with implementing optimal nebulization techniques and the lack of robust clinical data have limited its widespread adoption. The present review summarizes the techniques and clinical constraints for optimal delivery of nebulized antibiotics to lung parenchyma during invasive mechanical ventilation. Pulmonary pharmacokinetics and pharmacodynamics of nebulized antibiotic therapy to treat ventilator-associated pneumonia are discussed and put into perspective. Experimental and clinical pharmacokinetics and pharmacodynamics support the use of nebulized antibiotics. However, its clinical benefits compared to intravenous therapy remain to be proved. Future investigations should focus on continuous improvement of nebulization practices and techniques. Before expanding its clinical use, careful design of large phase III randomized trials implementing adequate therapeutic strategies in targeted populations is required to demonstrate the clinical effectiveness of nebulized antibiotics in terms of patient outcomes and reduction in the emergence of antibiotic resistance

Effect of CYP4F2, VKORC1, and CYP2C9 in Influencing Coumarin Dose: A Single-Patient Data Meta-Analysis in More Than 15,000 Individuals

The CYP4F2 gene is known to influence mean coumarin dose. The aim of the present study was to undertake a meta-analysis at individual patients' level to capture the possible effect of ethnicity, gene-gene interaction or other drugs on the association and to verify if inclusion of CYP4F2*3 variant into dosing algorithms improves the prediction of mean coumarin dose. We asked the authors of our previous meta-analysis (30 articles) and of 38 new articles retrieved by a systematic review to send us individual patients' data. The final collection consists 15,754 patients split into a derivation and validation cohort. The CYP4F2*3 polymorphism was consistently associated with an increase in mean coumarin dose (+9% (95%CI 7-10%), with a higher effect in females, in patients taking acenocoumarol and in Whites. The inclusion of the CYP4F2*3 in dosing algorithms slightly improved the prediction of stable coumarin dose. New pharmacogenetic equations potentially useful for clinical practice were derived. This article is protected by copyright. All rights reserved