Use of population pharmacokinetic modeling and Monte Carlo simulation to describe the pharmacodynamic profile of cefditoren in plasma and epithelial lining fluid.

Cefditoren is a broad-spectrum, oral cephalosporin that is highly active against clinically relevant respiratory tract pathogens, including multidrug-resistant Streptococcus pneumoniae. This study described its pharmacodynamic profile in plasma and epithelial lining fluid (ELF). Plasma and ELF pharmacokinetic data were obtained from 24 patients under fasting conditions. Cefditoren and urea concentrations were determined in plasma and bronchoalveolar lavage fluid by liquid chromatography-tandem mass spectrometry. Concentration-time profiles in plasma and ELF were modeled using a model with three disposition compartments and first-order absorption, elimination, and transfer. Pharmacokinetic parameters were identified in a population pharmacokinetic analysis (big nonparametric adaptive grid with adaptive gamma). Monte Carlo simulation (9,999 subjects) was performed with the ADAPT II program to estimate the probability of target attainment at which the free-cefditoren plasma concentrations (88%) protein binding and total ELF concentrations exceeded the MIC for 33% of the dosing interval for 400 mg cefditoren given orally every 12 h. After the Bayesian step, the overall fits of the model to the data were good, and plots of predicted versus observed concentrations for plasma and ELF showed slopes and intercepts very close to the ideal values of 1.0 and 0.0, respectively. In the plasma probability of target attainment analysis, the probability of achieving a time for which free, or unbound, plasma concentration exceeds the MIC of the organism for 33% of the dosing interval was <80% for a MIC of >0.06 mg/liter. Similar to plasma, the probability of achieving a time above the MIC of 33% was <80% for MIC of >0.06 mg/liter in ELF. Cefditoren was found to have a low probability of achieving a bacteriostatic effect against MICs of >0.06 mg/liter, which includes most S. pneumoniae isolates with intermediate susceptibility to penicillin, when given in the fasting state in both plasma and ELF.

[Abbreviated guidelines for prevention, diagnostics, and therapy of nosocomial pneumonia]. / Aktualisierte Kurzfassung der Leitlinien zur Prävention, Diagnostik und Therapie der nosokomial erworbenen Pneumonie.

BACKGROUND: Nosocomial pneumonia is a frequent nosocomial infection and the most common one in the intensive care unit. Nosocomial pneumonia is associated with a significant morbidity and mortality and therefore the outcome of patients with this complication becomes worse. Nosocomial infections are within the responsibility of predominantly the treating hospital after introduction of the DRGs also into the German health care system, and the occurrence of a nosocomial infection can also substantially stress the hospital budget. PURPOSE: Prevention, diagnosis and a severity-guided therapeutic approach are therefore inevitable parts of infectious concepts within the hospital. This abbreviated version of the German recommendations for prevention, diagnosis, and therapy of nosocomial pneumonia therefore aims at a larger readership and provides clinical pathways and worksheets to further improve health care and documentation of nosocomial pneumonia.

Intravenous/oral sequential therapy in patients hospitalised with community-acquired pneumonia: which patients, when and what agents?

Cost and pharmacoeconomic aspects are becoming more and more important in antibacterial therapy. Nevertheless, antibacterial therapy is curative and initial use of the right antibacterial with high activity and low resistance rates against the relevant pathogens can help to save costs. A new trend in antibacterial therapy is sequential therapy (intravenous/oral) in hospitalised patients with moderate to severe infections. Large studies comparing intravenous therapy with sequential therapy (intravenous/oral) have shown equivalence in clinical and bacteriological outcome. One main indication investigated is community-acquired pneumonia (CAP). CAP requires prompt and effective antibacterial treatment and conventional therapy for patients hospitalised with CAP has typically been parenteral antibacterial therapy for 7 to 10 days. However, clinical evidence shows that in most patients the objective and subjective indicators of infection are substantially improved within the first 2 to 3 days of treatment. Today a large number of clinical trials in patients with CAP have been undertaken and sequential therapy with appropriate antibacterials used in suitable patients has been proven as a treatment option. This demonstrates pharmacoeconomic benefits without compromising antibacterial efficacy. Recommended antibacterials for intravenous/oral sequential therapy in patients with CAP are second- and third- generation cephalosporins, aminopenicillins plus a beta-lactamase inhibitor, and new fluoroquinolones.