Pilar Martínez-Olondris

Efficacy of linezolid compared to vancomycin in an experimental model of pneumonia induced by methicillin-resistant Staphylococcus aureus in ventilated pigs.

Objective:To assess the efficacy of linezolid compared with vancomycin in an experimental model of pneumonia induced by methicillin-resistant Staphylococcus aureus (MRSA) in ventilated pigs. Methods:Forty pigs (30 kg) were intubated and challenged via bronchoscopy with a suspension of 106 colony forming units of MRSA into every lobe. Afterwards, pigs were ventilated up to 96 hours. Twelve hours after bacterial inoculation, the animals were randomized into 4 groups of treatment: group 1, control; group 2, vancomycin twice daily; group 3, continuous infusion of vancomycin; and group 4, linezolid. Clinical and laboratory parameters were monitored throughout the study. Bacterial cultures of bronchoalveolar lavage fluid and lung tissue samples were performed at the end of the study. Measurements of histopathology derangements of lung samples and studies of intrapulmonary drug penetration were performed. Results:A total of 34 animals completed the study. No differences in clinical and laboratory parameters were observed. The percentage of bronchoalveolar lavage fluid and lung tissue samples with positive cultures for MRSA in controls and groups 2, 3, and 4 was respectively 75%, 11%, 11%, and 0% (p < .01); 52%, 9%, 24%, and 2.5% (p < .01). Histopathology studies demonstrated signs of pneumonia in 95%, 69%, 58%, and 57% and signs of severe pneumonia in 48%, 29%, 22%, and 0% of controls and groups 2, 3, and 4, respectively (p < .01). In addition, pharmacokinetics/pharmacodynamics profile in serum and lung tissue showed better results for linezolid compared with both vancomycin treatments. Conclusions:In this animal model of MRSA pneumonia, linezolid showed a better efficacy than vancomycin showed because of a better pharmacokinetics/pharmacodynamics index.

Punción transbronquial aspirativa en el estudio de las adenopatías mediastínicas: rentabilidad y coste-beneficio

Objetivo Existe controversia sobre el papel de las diferentes tecnicas diagnosticas en la estadificacion del mediastino en pacientes con sospecha de cancer de pulmon. El objetivo del estudio ha sido analizar la rentabilidad diagnostica y el coste-beneficio de la puncion transbronquial aspirativa (PTA) en la estadificacion mediastinica del cancer de pulmon, en pacientes evaluados en un hospital de tercer nivel. Pacientes y metodos Se ha realizado un estudio observacional retrospectivo, en el que se han analizado los resultados de las PTA practicadas a pacientes con sospecha de cancer de pulmon y adenopatias mediastinicas patologicas. Tambien se ha evaluado el coste-beneficio de la aplicacion sistematica de esta tecnica. Resultados Se evaluo a 194 pacientes (un 85% varones y un 15% mujeres), en 157 de los cuales (81%) se confirmo el diagnostico de cancer de pulmon. La muestra citologica que se obtuvo de la PTA fue adecuada en 147 de los 194 casos (76%). Cuando se analizaron las muestras adecuadas, la sensibilidad de la PTA fue del 88%, la especificidad del 100%, el valor predictivo positivo del 100%, el valor predictivo negativo del 64% y el valor global del 90%. En 44 de los 127 casos (34%) con cancer de pulmon no microcitico localizado se evito la realizacion de una mediastinoscopia, lo que represento un ahorro economico estimado de 119.456 €. Conclusiones La PTA es una tecnica con una elevada rentabilidad diagnostica que puede evitar la realizacion de una mediastinoscopia en un porcentaje significativo de pacientes, con las consiguientes implicaciones terapeuticas y economicas que ello conlleva.

Linezolid limits burden of methicillin-resistant Staphylococcus aureus in biofilm of tracheal tubes.

Objective: To evaluate the effects of systemic treatment with linezolid compared with vancomycin on biofilm formation in mechanically ventilated pigs with severe methicillin-resistant Staphylococcus aureus–induced pneumonia. Design: Prospective randomized animal study. Setting: Departments of Pneumology, Microbiology, and Pharmacy of the Hospital Clínic, Barcelona, and Scientific and Technological Services of the University of Barcelona. Subjects: We prospectively analyzed 70 endotracheal tube samples. Endotracheal tubes were obtained from pigs either untreated (controls, n = 20), or treated with vancomycin (n = 32) or linezolid (n = 18). Interventions: The endotracheal tubes were obtained from a previous randomized study in tracheally intubated pigs with methicillin-resistant Staphylococcus aureus severe pneumonia, and mechanically ventilated for 69 ± 16 hrs. Measurements and Main Results: Distal and medial hemisections of the endotracheal tube were assessed to quantify methicillin-resistant Staphylococcus aureus burden, antibiotic biofilm concentration by high-performance liquid chromatography or bioassay, and biofilm thickness through scanning electron microscopy. We found a trend toward a significant variation in biofilm methicillin-resistant Staphylococcus aureus burden (log colony-forming unit/mL) among groups (p = .057), and the lowest bacterial burden was found in endotracheal tubes treated with linezolid (1.98 ± 1.68) in comparison with untreated endotracheal tubes (3.72 ± 2.20, p = .045) or those treated with vancomycin (2.97 ± 2.43, p = .286). Biofilm linezolid concentration was 19-fold above the linezolid minimum inhibitory concentration, whereas biofilm vancomycin concentration (1.60 ± 0.91 µg/mL) was consistently below or close to the vancomycin minimum inhibitory concentration. Biofilm was thicker in the vancomycin group (p = .077). Conclusions: Systemic treatment with linezolid limits endotracheal tube biofilm development and methicillin-resistant Staphylococcus aureus burden. The potential clinical usefulness of linezolid in decreasing the risk of biofilm-related respiratory infections during prolonged tracheal intubation requires further investigation.

An experimental model of pneumonia induced by methicillin-resistant Staphylococcus aureus in ventilated piglets

The objectives of the study were to validate a model of methicillin-resistant Staphylococcus aureus (MRSA) pneumonia in ventilated piglets and to study the time-course of biological markers and histopathological changes. 12 piglets were intubated and inoculated with 15 mL of a suspension of 106 colony forming units of MRSA in every lobe through the bronchoscope channel. The piglets were ventilated for 12 h (n = 6) and 24 h (n = 6). Clinical parameters were assessed every 6 h and pro-inflammatory cytokines were measured in serum and in bronchoalveolar lavage (BAL) at baseline and sacrifice. Histopathology of each lobe and cultures from blood, lungs and BAL were performed. Animals developed histopathological evidence of pneumonia at necropsy. At 12 h, pneumonia was present in all animals and was severe pneumonia at 24 h. Microbiological studies confirmed the presence of MRSA. A significant increase in interleukin (IL)-6, IL-8 and tumour necrosis factor-&agr; values was seen in BAL at 24 h and IL-6 at 12 h. In serum, only IL-6 levels had increased significantly at 24 h. In ventilated piglets, bronchoscopic inoculation of MRSA induces pneumonia at 12 h and severe pneumonia at 24 h. This severity was associated with a corresponding increase in systemic and local inflammatory response.

What lessons have been learnt from animal models of MRSA in the lung

Staphylococcus aureus is one of the most common causes of nosocomial pneumonia contributing to significant morbidity and mortality. Therapeutic options for patients with methicillin-resistant S. aureus (MRSA) infection are limited. In addition, little is known about the S. aureus virulence factors that may influence the presentation and prognosis of severe lower respiratory tract infections. Animal models of severe pneumonia allow investigators to control and exclude potential confounders and to examine the influence of comorbid conditions. Therefore, these models may improve our knowledge of the intimate pathophysiological mechanisms affecting pharmacodynamics, pharmacokinetics and efficacy of therapy. So far, animal research studies on MRSA and vancomycin-resistant S. aureus, performed both in small and large animal models, have improved knowledge of the mechanisms of disease, which may lead to a better treatment for this severe and complex infection in humans.

Development and validation of a high performance liquid chromatography method to determine linezolid concentrations in pig pulmonary tissue.

Abstract Background: Linezolid is the first synthetic compound of a new group of antimicrobials, the oxazolidinones, which inhibit protein synthesis. It shows a broad spectrum of activity against Gram positive organisms. With respect to its pharmacokinetics, linezolid shows a relatively high volume of distribution and good penetration into inflammatory fluids, bone, fat and muscle. Methods: A reversed-phase isocratic high-performance liquid chromatographic method for linezolid analysis in piglet pulmonary tissue is described. Tissue samples and controls were prepared in 1×TBE (1 M Tris, 0.9 M boric acid, 0.01 M EDTA). The mobile phase consisted of 20% ultrafiltered water and 80% of (A) 15 mM potassium monohydrogen phosphate buffer (pH=5) with (B) acetonitrile (80%/20%; v/v). Samples were homogenized and precipitated with HClO4 3% (1/1, v/v). The injection volume was 100 μL. Ofloxacin was used as an internal standard. Results: The assay was linear over a linezolid concentration range: 1.6–100 μg/mL. The method provided good validation data (n=15): inaccuracy (3.6%), intra and inter-day variability (4.2% and 5.2%, respectively), recovery (91.8%), limit of detection (0.8 μg/mL) and quantitation (1.6 μg/mL) and acceptable stability within 24 h in the auto-sampler. Conclusions: The method offers a fast and simple approach to determine linezolid in pulmonary tissue which could be of use in pharmacokinetic studies. Clin Chem Lab Med 2010;48:391–8.

Discontinuing noninvasive ventilation in severe chronic obstructive pulmonary disease exacerbations: a randomised controlled trial

We assessed whether prolongation of nocturnal noninvasive ventilation (NIV) after recovery from acute hypercapnic respiratory failure (AHRF) in chronic obstructive pulmonary disease (COPD) patients with NIV could prevent subsequent relapse of AHRF. A randomised controlled trial was performed in 120 COPD patients without previous domiciliary ventilation, admitted for AHRF and treated with NIV. When the episode was resolved and patients tolerated unassisted breathing for 4 h, they were randomly allocated to receive three additional nights of NIV (n=61) or direct NIV discontinuation (n=59). The primary outcome was relapse of AHRF within 8 days after NIV discontinuation. Except for a shorter median (interquartile range) intermediate respiratory care unit (IRCU) stay in the direct discontinuation group (4 (2–6) versus 5 (4–7) days, p=0.036), no differences were observed in relapse of AHRF after NIV discontinuation (10 (17%) versus 8 (13%) for the direct discontinuation and nocturnal NIV groups, respectively, p=0.56), long-term ventilator dependence, hospital stay, and 6-month hospital readmission or survival. Prolongation of nocturnal NIV after recovery from an AHRF episode does not prevent subsequent relapse of AHRF in COPD patients without previous domiciliary ventilation, and results in longer IRCU stay. Consequently, NIV can be directly discontinued when the episode is resolved and patients tolerate unassisted breathing. NIV can be directly discontinued when a COPD exacerbation is resolved and patients tolerate unassisted breathing http://ow.ly/fJCY30bYfme

[Transbronchial needle aspiration in the study of mediastinal lymph nodes: yield and cost-effectiveness].

OBJECTIVE The role of different techniques for mediastinal staging in patients with suspected lung cancer is a subject of debate. The aim of this study was to analyze the diagnostic yield and cost-effectiveness of transbronchial needle aspiration in the mediastinal staging of lung cancer in patients being evaluated in a tertiary hospital. PATIENTS AND METHODS This was a retrospective, observational study of the results of transbronchial needle aspiration in patients with suspected lung cancer and mediastinal lymph node involvement. A cost-effectiveness analysis of the systematic use of this technique was also performed. RESULTS One-hundred ninety-four patients (85% men, 15% women) were evaluated. The diagnosis of lung cancer was confirmed in 157 (81%). Cytology samples obtained by transbronchial needle aspiration were adequate in 147 (76%) of the 194 cases. When only the adequate samples were included in the analysis, transbronchial needle aspiration showed a sensitivity of 88%, specificity of 100%, positive predictive value of 100%, negative predictive value of 64%, and efficiency of 90%. Mediastinoscopy was avoided in 44 (34%) of the 127 patients with localized non-small cell lung cancer, with an estimated saving of euro 119,456. CONCLUSIONS Transbronchial needle aspiration has a high diagnostic yield and obviates the need for mediastinoscopy in a significant percentage of cases. This finding is of diagnostic and economic significance.