With an established role in cystic fibrosis and bronchiectasis, nebulized antibiotics are increasingly being used to treat respiratory infections in critically ill invasively mechanically ventilated adult patients. Although there is limited evidence describing their efficacy and safety, in an era when there is a need for new strategies to enhance antibiotic effectiveness because of a shortage of new agents and increases in antibiotic resistance, the potential of nebulization of antibiotics to optimize therapy is considered of high interest, particularly in patients infected with multidrug-resistant pathogens. This Position Paper of the European Society of Clinical Microbiology and Infectious Diseases provides recommendations based on the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology regarding the use of nebulized antibiotics in invasively mechanically ventilated adults, based on a systematic review and meta-analysis of the existing literature (last search July 2016). Overall, the panel recommends avoiding the use of nebulized antibiotics in clinical practice, due to a weak level of evidence of their efficacy and the high potential for underestimated risks of adverse events (particularly, respiratory complications). Higher-quality evidence is urgently needed to inform clinical practice. Priorities of future research are detailed in the second part of the Position Paper as guidance for researchers in this field. In particular, the panel identified an urgent need for randomized clinical trials of nebulized antibiotic therapy as part of a substitution approach to treatment of pneumonia due to multidrug-resistant pathogens.

Nebulized antibiotics have an established role in patients with cystic fibrosis or bronchiectasis. Their potential benefit to treat respiratory infections in mechanically ventilated patients is receiving increasing interest. In this consensus statement of the European Society of Clinical Microbiology and Infectious Diseases, the body of evidence of the therapeutic utility of aerosolized antibiotics in mechanically ventilated patients was reviewed and resulted in the following recommendations: Vibrating-mesh nebulizers should be preferred to jet or ultrasonic nebulizers. To decrease turbulence and limit circuit and tracheobronchial deposition, we recommend: (a) the use of specifically designed respiratory circuits avoiding sharp angles and characterized by smooth inner surfaces, (b) the use of specific ventilator settings during nebulization including use of a volume controlled mode using constant inspiratory flow, tidal volume 8 mL/kg, respiratory frequency 12 to 15 bpm, inspiratory:expiratory ratio 50%, inspiratory pause 20% and positive end-expiratory pressure 5 to 10 cm H2O and (c) the administration of a short-acting sedative agent if coordination between the patient and the ventilator is not obtained, to avoid patient's flow triggering and episodes of peak decelerating inspiratory flow. A filter should be inserted on the expiratory limb to protect the ventilator flow device and changed between each nebulization to avoid expiratory flow obstruction. A heat and moisture exchanger and/or conventional heated humidifier should be stopped during the nebulization period to avoid a massive loss of aerosolized particles through trapping and condensation. If these technical requirements are not followed, there is a high risk of treatment failure and adverse events in mechanically ventilated patients receiving nebulized antibiotics for pneumonia.

Adopting a unique Spanish perspective, this study aims to assess healthcare resource utilization (HCRU) and the costs of treating nosocomial pneumonia (NP) produced by methicillin-resistant Staphylococcus aureus (MRSA) in hospitalized adults using linezolid or vancomycin. An evaluation is also made of the renal failure rate and related economic outcomes between study groups. An economic post hoc evaluation of a randomized, double-blind, multicenter phase 4 study was carried out. Nosocomial pneumonia due to MRSA in hospitalized adults. The modified intent to treat (mITT) population comprised 224 linezolid- and 224 vancomycin-treated patients. Costs and HCRU were evaluated between patients administered either linezolid or vancomycin, and between patients who developed renal failure and those who did not. Analysis of HCRU outcomes and costs. Total costs were similar between the linezolid- (€17,782 ± €9,615) and vancomycin-treated patients (€17,423 ± €9,460) (P = .69). The renal failure rate was significantly lower in the linezolid-treated patients (4% vs. 15%; P < .001). The total costs tended to be higher in patients who developed renal failure (€19,626 ± €10,840 vs. €17,388 ± €9,369; P = .14). Among the patients who developed renal failure, HCRU (days on mechanical ventilation: 13.2 ± 10.7 vs. 7.6 ± 3.6 days; P = .21; ICU stay: 14.4 ± 10.5 vs. 9.9 ± 6.6 days; P = .30; hospital stay: 19.5 ± 9.5 vs. 16.1 ± 11.0 days; P = .26) and cost (€17,219 ± €8,792 vs. €20,263 ± €11,350; P = .51) tended to be lower in the linezolid- vs. vancomycin-treated patients. There were no statistically significant differences in costs per patient-day between cohorts after correcting for mortality (€1000 vs. €1,010; P = .98). From a Spanish perspective, there were no statistically significant differences in total costs between the linezolid and vancomycin pneumonia cohorts. The drug cost corresponding to linezolid was partially offset by fewer renal failure adverse events. Analizar la utilización de recursos sanitarios (URS) y los costes de la neumonía nosocomial por Staphylococcus aureus resistente a meticilina en adultos hospitalizados tratados con linezolid o vancomicina. También se evaluó el porcentaje de fallo renal entre dichos pacientes. Análisis post-hoc de un ensayo clínico fase iv multicéntrico, aleatorizado, doble ciego. Pacientes adultos, hospitalizados con neumonía nosocomial por Staphylococcus aureus resistente a meticilina. Pacientes tratados con linezolid (224) o vancomicina (224). Desde la perspectiva española se compararon costes y URS entre pacientes tratados con linezolid o vancomicina y entre los que desarrollaron fallo renal y los que no. Análisis de costes y URS. Los costes totales fueron similares (p = 0,69) en los pacientes tratados con linezolid (17.782 ± 9.615 €) o vancomicina (17.423 ± 9.460 €). La tasa de fallo renal fue significativamente menor en los tratados con linezolid (4 vs. 15%, p < 0,001). Los costes totales fueron mayores en aquellos que desarrollaron fallo renal (19.626 ± 10.840 € vs. 17.388 ± 9.369 €, p = 0,14). La URS (días de ventilación mecánica: 13,2 ± 10,7 vs. 7,6 ± 3,6, p = 0,21; días en UCI: 14,4 ± 10,5 vs. 9,9 ± 6,6, p = 0,30; días de hospitalización: 19,5 ± 9,5 vs. 16,1 ± 11,0, p = 0,26) y los costes totales (17.219 ± 8.792 € vs. 20.263 ± 11.350 €, p = 0,51) tendieron a ser inferiores en los pacientes tratados con linezolid que desarrollan fallo renal. Tras corregir el análisis por mortalidad, los costes diarios por paciente fueron similares (1.000 vs. 1.010 €; p = 0,98). Desde la perspectiva española, no hubo diferencias en la URS y los costes entre los pacientes con neumonía tratados con linezolid o vancomicina. El coste de linezolid fue contrarrestado por la menor incidencia de fallo renal.

P001 - Sepsis impairs the capillary response within hypoxic capillaries and decreases erythrocyte oxygen-dependent ATP efflux

Parmi les mesures préventives proposées pour réduire l’incidence des pneumonies acquises sous ventilation mécanique (PAVM), les soins pluriquotidiens d’hygiène oropharyngés sont régulièrement inclus dans les ventilator care bundles. Ces soins correspondent à des rinçages de bouche avec des solutions antiseptiques, principalement à base de chlorhexidine, utilisées à différentes concentrations, et au brossage des dents, et sont associés aux aspirations oropharyngées itératives. Le rationnel de leur utilisation se fonde sur la physiopathologie des PAVM. Les micro-organismes à l’origine des PAVM proviennent principalement de la flore oropharyngée et de la plaque dentaire: les soins à base d’antiseptique et le brossage diminuent la charge des bactéries potentiellement pathogènes présentes à ce niveau. Si les essais randomisés ont montré des résultats positifs en chirurgie cardiaque, les résultats dans les autres populations de malades de réanimation se sont montrés discordants. Les méta-analyses ont globalement confirmé ces résultats en retenant un effet des rinçages à la chlorhexidine sur la prévention des PAVM probable mais modeste, l’absence d’effet additionnel du brossage des dents, l’absence d’impact de ces soins sur la mortalité, la durée de ventilation mécanique ou la durée de séjour. Ce sont donc avant tout des soins de confort et de propreté de base, ne jouant qu’un rôle mineur dans la prévention des PAVM.

Nebulized antimicrobial agents are increasingly administered for treatment of respiratory infections in mechanically ventilated (MV) patients. A structured online questionnaire assessing the indications, dosages and recent patterns of use for nebulized antimicrobial agents in MV patients was developed. The questionnaire was distributed worldwide and completed by 192 intensive care units. The most common indications for using nebulized antimicrobial agent were ventilator-associated tracheobronchitis (VAT; 58/87), ventilator-associated pneumonia (VAP; 56/87) and management of multidrug-resistant, Gram-negative (67/87) bacilli in the respiratory tract. The most common prescribed nebulized agents were colistin methanesulfonate and sulfate (36/87, 41.3% and 24/87, 27.5%), tobramycin (32/87, 36.7%) and amikacin (23/87, 26.4%). Colistin methanesulfonate, amikacin and tobramycin daily doses for VAP were significantly higher than for VAT (p < 0.05). Combination of parenteral and nebulized antibiotics occurred in 50 (86%) of 58 prescriptions for VAP and 36 (64.2%) of 56 of prescriptions for VAT. The use of nebulized antimicrobial agents in MV patients is common. There is marked heterogeneity in clinical practice, with significantly different in use between patients with VAP and VAT. Randomized controlled clinical trials and international guidance on indications, dosing and antibiotic combinations to improve clinical outcomes are urgently required.

Unfortunately, the original version of this supplement [1] contained errors in two of the abstracts; P037 and P127. Please see details below.

L’extracorporeal membrane oxygenation veinoartérielle périphérique (ECMO-VAP) est devenue le traitement de première ligne des patients souffrant de choc cardiogénique réfractaire. Implantée au lit du malade, elle permet la correction rapide des dysfonctions cardiocirculatoires et/ou respiratoires. De plus, le développement d’unités mobiles d’assistance circulatoire permet l’accessibilité de cette technique à un nombre grandissant de malades. L’efficacité de l’ECMO-VAP comme thérapeutique de sauvetage a été rapportée dans de nombreuses situations cliniques avec une bonne qualité de vie chez les survivants. Le pronostic des patients traités par ECMO-VAP varie cependant très fortement selon l’indication. La myocardite aiguë, la dysfonction primaire du greffon cardiaque, la dysfonction myocardique réfractaire au cours du choc septique et certaines intoxications médicamenteuses ont un pronostic favorable, avec un taux d’explantation et de survie élevé (>70 %). Le choc cardiogénique à la phase aiguë de l’infarctus du myocarde, la décompensation de myocardiopathie dilatée et le choc cardiogénique en postopératoire de chirurgie cardiaque semblent avoir un pronostic intermédiaire, avec un taux de survie entre 40 et 50 %. Dans ces situations, le sevrage des malades est plus difficile et un certain nombre d’entre eux nécessiteront un « bridge » vers une assistance de longue durée ou une transplantation cardiaque. Enfin, en cas d’arrêt cardiaque extrahospitalier réfractaire, les résultats sont décevants (survie entre 0 et 15 %), remettant en cause l’indication de l’assistance circulatoire chez un grand nombre de ces patients. De nouvelles études sont actuellement en cours pour mieux sélectionner les patients et mieux définir le moment opportun de l’implantation de l’ECMO-VAP dans chacune de ces indications.

Le choc cardiogénique, secondaire à une myocardite adrénergique de type Takotsubo, dans le phéochromocytome est une complication rarissime. L’oxygénation par membrane extracorporelle (ECMO) est un système d’assistance circulatoire extracorporelle. Une cinquantaine de cas de phéochromocytome ayant eu recours à l’ECMO sont décrits dans la littérature. Nous décrivons neuf cas de choc cardiogénique sévère révélant un phéochromocytome ou un paragangliome. Ces patients n’avaient aucun antécédent notable, une seule patiente avait une neurofibromatose de type 1. L’âge moyen était de 41 ans. La pression artérielle (PA) était normale, voire élevée, pendant le choc. Les dérivés méthoxylés étaient supérieurs à 10 fois la normale. Le choc hémodynamique était réfractaire aux thérapeutiques usuelles et l’implantation de l’ECMO a permis de soutenir la phase initiale d’asystolie. En moyenne, l’ECMO était retirée au quatrième jour et la chirurgie avait lieu 6 semaines après la réanimation. Trois patients sont décédés de défaillance multiviscérale avant la chirurgie. Six patients ont survécu et ont eu une surrénalectomie par cœlioscopie différée, après contrôle de l’état hémodynamique par un alpha-bloquant. Les patients ont été définitivement sevrés des traitements antihypertenseurs après la chirurgie. Aucune mutation génétique n’a été identifiée. La myocardite adrénergique du phéochromocytome est rare mais devrait être rapidement suspectée devant un état de choc cardiogénique résistant aux amines vasopressives. L’assistance circulatoire par ECMO a révolutionné la prise en charge initiale de ces patients en grande détresse vitale. Après sevrage de l’ECMO, le traitement médicamenteux permet d’attendre la récupération de la cardiomyopathie et de réaliser une surrénalectomie différée.

We evaluated 13 transsexual men who were hospitalized for symptoms resulting from illicit subcutaneous injections of silicone. Patients with acute silicone pneumonitis were admitted because of fever, bilateral pulmonary infiltrates, and hypoxemia (mean PaO2, 58 +/- 14 mm Hg). Most patients in this group had received new silicone injections within hours of admission, but one presented with the same clinical syndrome a few hours after a brawl. The alveolitis of acute silicone pneumonitis was characterized by increased numbers of alveolar macrophages, neutrophils, and eosinophils (p less than 0.05 compared with those in normal persons with a similar smoking history). Evidence of alveolar hemorrhage was also present in some cases. Alveolar macrophages contained large, pleomorphic, cytoplasmic inclusions, which were identified as silicone by atomic absorption and infrared spectrometry. Patients with latent silicone pneumonitis underwent clinical study at much longer times after the silicone fluid injections because they developed local inflammatory phenomena at the sites of previous injections. Pulmonary function studies usually showed slight restrictive changes, and bronchoalveolar lavage disclosed abnormalities similar to those found in patients with acute silicone pneumonitis, although to a lesser degree. Thus, illicit silicone fluid injection carries a serious respiratory risk since it can induce pneumonitis, followed in some patients by respiratory failure.

The fully human anti-lipopolysaccharide (LPS) immunoglobulin M (IgM) monoclonal antibody panobacumab was developed as an adjunctive immunotherapy for the treatment of O11 serotype Pseudomonas aeruginosa infections. We evaluated the potential clinical efficacy of panobacumab in the treatment of nosocomial pneumonia. We performed a post-hoc analysis of a multicenter phase IIa trial (NCT00851435) designed to prospectively evaluate the safety and pharmacokinetics of panobacumab. Patients treated with panobacumab (n = 17), including 13 patients receiving the full treatment (three doses of 1.2 mg/kg), were compared to 14 patients who did not receive the antibody. Overall, the 17 patients receiving panobacumab were more ill. They were an average of 72 years old [interquartile range (IQR): 64–79] versus an average of 50 years old (IQR: 30–73) (p = 0.024) and had Acute Physiology and Chronic Health Evaluation II (APACHE II) scores of 17 (IQR: 16–22) versus 15 (IQR: 10–19) (p = 0.043). Adjunctive immunotherapy resulted in an improved clinical outcome in the group receiving the full three-course panobacumab treatment, with a resolution rate of 85 % (11/13) versus 64 % (9/14) (p = 0.048). The Kaplan–Meier survival curve showed a statistically significantly shorter time to clinical resolution in this group of patients (8.0 [IQR: 7.0–11.5] versus 18.5 [IQR: 8–30] days in those who did not receive the antibody; p = 0.004). Panobacumab adjunctive immunotherapy may improve clinical outcome in a shorter time if patients receive the full treatment (three doses). These preliminary results suggest that passive immunotherapy targeting LPS may be a complementary strategy for the treatment of nosocomial O11 P. aeruginosa pneumonia.

Les objectifs du contrôle glycémique en réanimation se sont complexifiés depuis la première étude de Louvain [1] mettant en évidence une réduction de mortalité associée au seul respect d’une cible glycémique stricte (4,4–6,1 mmol/L). Au-delà de la controverse concernant la cible glycémique qui s’en est suivie, hypoglycémie et variabilité glycémique élevée seraient associées à un pronostic défavorable [2]. Le but de l’étude est de vérifier si ces associations existent dans le collectif de patients inclus dans l’étude multicentrique CGAO-REA visant à comparer l’impact sur la mortalité à J90 d’un contrôle glycémique informatisé strict (4,4–6,1 mmol/L) à un contrôle glycémique conventionnel (< 10 mmol/L) [3]. Pour chacun des 2556 patients (parmi les 2648 randomisés analysables de l’étude CGAO-REA) pour lesquels les données de monitorage glycémique étaient disponibles, nous avons déterminé, pour l’ensemble du séjour en réanimation, la glycémie minimale Gmin, la glycémie maximale Gmax, la différence Gmax–Gmin, et la glycémie moyenne. La division en quintiles de la distribution de ces paramètres descriptifs du contrôle glycémique a permis de construire 5 groupes de patients pour chaque paramètre. La mortalité à J90 a été déterminée dans chacun des groupes et comparée à l’aide d’un test Chi2 à la mortalité attendue. Parmi les 2556 patients, 835 sont décédés à J90 (mortalité attendue 32,7 %). Les 4 graphiques suivants indiquent la mortalité dans chacun des quintiles pour chaque paramètre (Fig. 1) L’analyse des patients inclus dans l’étude CGAO-REA semble confirmer l’association entre hypoglycémie et variabilité glycémique et pronostic défavorable.

Objectives: This study was designed to assess the effects on macrocirculation and microcirculation of adding an intra-aortic balloon pump to peripheral venoarterial extracorporeal membrane oxygenation in patients with severe cardiogenic shock and little/ no residual left ventricular ejection.Design: A prospective, single-center, observational study where macrocirculation and microcirculation were assessed with clinical-, Doppler echocardiography-, and pulmonary artery-derived hemodynamic variables and also cerebral and thenar eminence tissue oxygenation and side-stream dark-field imaging of sublingual microcirculation.Setting: A 26-bed tertiary ICU in a university hospital.Patients: We evaluated 12 consecutive patients before and 30 minutes after interrupting and restarting intra-aortic balloon pump.Interventions: Measurements were performed before, and 30 minutes after interrupting and restarting intra-aortic balloon pump.Measurements and Main Results: Stopping intra-aortic balloon pump was associated with higher pulmonary artery-occlusion pressure (19 +/- 10 vs 15 +/- 8 mm Hg, p = 0.01), increased left ventricular end-systolic (51 +/- 13 vs 50 +/- 14 mm, p = 0.05) and end-diastolic (55 +/- 13 vs 52 +/- 14 mm, p = 0.003) dimensions, and decreased pulse pressure (15 +/- 13 vs 29 +/- 22 mm Hg, p = 0.02). Maximum pulmonary artery-occlusion pressure reduction when the intra-aortic balloon pump was restarted was observed in the seven patients whose pulmonary artery-occlusion pressure was more than 15 mm Hg when intra-aortic balloon pump was off (-6.6 +/- 4.3 vs -0.6 +/- 3.4 mm Hg, respectively). Thenar eminence and brain tissue oxygenation and side-stream dark-field-assessed sublingual microcirculation were unchanged by stopping and restarting intra-aortic balloon pump.Conclusions: Restoring pulsatility and decreasing left ventricular afterload with intra-aortic balloon pump was associated with smaller left ventricular dimensions and lower pulmonary artery pressures but did not affect microcirculation variables in cardiogenic shock patients with little/no residual left ventricular ejection while on peripheral venoarterial extracorporeal membrane oxygenation.

To determine the incremental cost-effectiveness of linezolid versus vancomycin using data from a clinical trial assessing treatment of nosocomial pneumonia due to MRSA in hospitalized adults. A cost-effectiveness analysis from the U.S. hospital-payer perspective was piggybacked onto a phase 4, randomized, double-blind, multicenter trial (Wunderink et al, Clin Infect Dis 2012) in nosocomial pneumonia patients with culture-proven MRSA [microbiologic confirmed intent-to-treat (mITT) cohort]. Efficacy was measured by treatment success (defined as Cure+Improvement) at the end of study (i.e., 7-30 days after the end of treatment). Direct medical costs (USD, 2011 values) were calculated from the health care resources used, including study medication, hospitalization, mechanical ventilation, and dialysis. Nonparametric bootstrapping was conducted to calculate confidence intervals (CI) for costs, efficacy, and incremental cost-effectiveness ratios (ICER). One-way sensitivity analyses were conducted to evaluate the uncertainty and cost drivers. Data from 391 patients (186 linezolid, 205 vancomycin) were analyzed. A greater proportion of linezolid patients achieved treatment success versus vancomycin patients [mean (95% CI)]: 55% (48.3%-61.9%) versus 45% (38%-52.3%). Total costs per linezolid patient were $48,929 ($45,375-$52,483) compared to $46,665 ($43,201-$50,128) per vancomycin patient. The point estimate for the ICER of linezolid versus vancomycin was $16,516. The median ICER from bootstrapping was $16,219 (95% percentile: $100,487). Of the 10,000 bootstrap simulations, 73% had greater efficacies and higher costs (positive ICERs) for linezolid, 24% had greater efficacies and lower costs for linezolid (linezolid dominated vancomycin), and <2% had greater efficacies and lower costs for vancomycin (vancomycin dominated linezolid). Key cost drivers included number of ICU and general ward days in each treatment group. Addition of empirical treatment had a relatively small impact on ICER. In this clinical trial population, linezolid appears to be cost-effective compared to vancomycin in treating patients with nosocomial pneumonia due to MRSA.