부산대학교 도서관

Summary Background Staphylococcus aureus remains a common cause of ventilator-associated pneumonia, with little change in incidence over the past 15 years. We aimed to evaluate the efficacy of suvratoxumab, a monoclonal antibody targeting the [alpha] toxin, in reducing the incidence of S aureus pneumonia in patients in the intensive care unit (ICU) who are on mechanical ventilation. Methods We did a multicentre, randomised, double-blind, placebo-controlled, parallel-group, phase 2 pilot trial at 31 hospitals in Belgium, the Czech Republic, France, Germany, Greece, Hungary, Portugal, Spain, and Switzerland. Eligible patients were in the ICU, aged [greater than or equal to]18 years, were intubated and on mechanical ventilation, were positive for S aureus colonisation of the lower respiratory tract, as assessed by quantitative PCR (qPCR) analysis of endotracheal aspirate, and had not been diagnosed with new-onset pneumonia. Patients were excluded if they had confirmed or suspected acute ongoing staphylococcal disease; had received antibiotics for S aureus infection for more than 48 h within 72 h of randomisation; had a Clinical Pulmonary Infection Score of 6 or higher; had an acute physiology and chronic health evaluation II score of 25 or higher with a Glasgow coma scale (GCS) score of more than 5, or an acute physiology and chronic health evaluation II score of at least 30 with a GCS score of 5 or less; had a Sequential Organ Failure Assessment score of 9 or higher; or had active pulmonary disease that would impair the ability to diagnose pneumonia. Colonised patients were randomly assigned (1:1:1), by use of an interactive voice or web response system, to receive either a single intravenous infusion of suvratoxumab 2000 mg, suvratoxumab 5000 mg, or placebo. Randomisation was done in blocks of size four, stratified by country and by whether patients had received systemic antibiotics for S aureus infection. Patients, investigators, and study staff involved in the treatment or clinical evaluation of patients were masked to patient assignment. The primary efficacy endpoint was the incidence of S aureus pneumonia at 30 days, as determined by a masked independent endpoint adjudication committee, in all patients who received their assigned treatment (modified intention-to-treat [ITT] population). Primary safety endpoints were the incidence of treatment-emergent adverse events at 30 days, 90 days, and 190 days after treatment, and the incidence of treatment-emergent serious adverse events, adverse events of special interest, and new-onset chronic disease at 190 days after treatment. All primary safety endpoints were assessed in the modified ITT population. This trial is registered with ClinicalTrials.gov (NCT02296320) and the EudraCT database (2014-001097-34). Findings Between Oct 10, 2014, and April 1, 2018, 767 patients were screened, of whom 213 patients with confirmed S aureus colonisation of the lower respiratory tract were randomly assigned to the suvratoxumab 2000 mg group (n=15), the suvratoxumab 5000 mg group (n=96), or the placebo group (n=102). Two patients in the placebo group did not receive treatment after randomisation because their clinical conditions changed and they no longer met the eligibility criteria for dosing. As adjudicated by the data monitoring committee at an interim analysis, the suvratoxumab 2000 mg group was discontinued on the basis of predefined pharmacokinetic criteria. At 30 days after treatment, 17 (18%) of 96 patients in the suvratoxumab 5000 mg group and 26 (26%) of 100 patients in the placebo group had developed S aureus pneumonia (relative risk reduction 31*9% [90% CI -7*5 to 56*8], p=0*17). The incidence of treatment-emergent adverse events at 30 days were similar between the suvratoxumab 5000 mg group (87 [91%]) and the placebo group (90 [90%]). The incidence of treatment-emergent serious adverse events at 30 days were also similar between the suvratoxumab 5000 mg group (36 [38%]) and the placebo group (32 [32%]). No significant difference in the incidence of treatment-emergent adverse events between the two groups at 90 days (89 [93%] in the suvratoxumab 5000 mg group vs 92 [92%] in the placebo group) and at 190 days (93 [94%] vs 93 [93%]) was observed. 40 (40%) patients in the placebo group and 50 (52%) in the suvratoxumab 5000 mg group had a serious adverse event at 190 days. In the suvratoxumab 5000 mg group, one (1%) patient reported at least one treatment-emergent serious adverse event related to treatment, two (2%) patients reported an adverse event of special interest, and two (2%) reported a new-onset chronic disease. Interpretation In patients in the ICU receiving mechanical ventilation with qPCR-confirmed S aureus colonisation of the lower respiratory tract, the incidence of S aureus pneumonia at 30 days was not significantly lower following treatment with 5000 mg suvratoxumab than with placebo. Despite these negative results, monoclonal antibodies still represent one promising therapeutic option to reduce antibiotic consumption that require further exploration and studies. Funding AstraZeneca, with support from the Innovative Medicines Initiative Joint Undertaking. Author Affiliation: (a) ICU Department, Inserm CIC-1435 and UMR-1092, CRICS-TRIGGERSEP Network, CHU Dupuytren, Limoges, France (b) BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, USA (c) Institut de Cardiologie, Service de Réanimation Médicale, Groupe Hospitalier Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris, France (d) Department of Critical Care, Hospital Clínico San Carlos, Madrid, Spain (e) Department of Critical Care, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland (f) CHRU de Tours, Service de Médecine Intensive Réanimation, Inserm CIC 1415 and UMR-1100, and CRICS-TRIGGERSEP Network, Tours, France (g) Centre Hospitalier Jolimont-Lobbes, La Louvière, Belgium (h) Hospital Universitario Central de Asturias, Asturias, Spain (i) Centre Hospitalier Régional d'Orléans, Médecine Intensive Réanimation, Orleans, France (j) Service de Soins Intensifs-Pneumologie, Hôpital Guillaume et René Laennec, Nantes, France (k) Département d'Anesthésiologie, Pharmacologie, Soins Intensifs et Urgences, Université de Genève, Geneva, Switzerland (l) Intensive Care Department, Hospital Universitari Mutua de Terrassa, Terrassa, Spain (m) CHU Limoges and Inserm UMR-1092, Limoges, France (n) Department of Medical Microbiology, University Medical Center Utrecht, Utrecht, Netherlands (o) Department of Medical Microbiology and Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, Netherlands (p) Laboratory of Medical Microbiology, Vaccine and Infectious Disease Institute, Antwerp University Hospital, Antwerp, Belgium (q) Intensive Care Unit, Université Catholique de Louvain, Louvain-la-Neuve, Belgium * Correspondence to: Dr Bruno François, ICU Department, Inserm CIC-1435 and UMR-1092, CRICS-TRIGGERSEP Network, CHU Dupuytren, Limoges 87042, France (footnote)* Contributed equally (footnote)[Dagger] Study group members are listed in the ) Byline: Bruno François, MD [b.francois@unilim.fr] (a), Hasan S Jafri, MD [hasan.jafri.md@gmail.com] (b), Prof Jean Chastre, MD (c), Miguel Sánchez-García, MD (d), Philippe Eggimann, MD (e), Prof Pierre-François Dequin, MD (f), Vincent Huberlant, MD (g), Lucia Viña Soria, MD (h), Thierry Boulain, MD (i), Cédric Bretonnière, MD (j), Jérôme Pugin, MD (k), Josep Trenado, MD (l), Ana Catalina Hernandez Padilla, MD (m), Omar Ali, PhD (b), Kathryn Shoemaker, MS (b), Pin Ren, PhD (b), Frank E Coenjaerts, PhD (n), Alexey Ruzin, PhD (b), Olivier Barraud, PharmD (m), Leen Timbermont, PhD (p), Christine Lammens, BS (p), Vadryn Pierre, PharmD (b), Yuling Wu, PhD (b), Julie Vignaud, MLT (m), Susan Colbert, RN (b), Terramika Bellamy, MS (b), Mark T Esser, PhD (b), Filip Dubovsky, MD (b), Prof Marc J Bonten, MD (o), Prof Herman Goossens, MD (p), Prof Pierre-François Laterre, MD (q), Didier Chochrad, Alain Dive, Frédéric Foret, Marc Simon, Herbert Spapen, Jacques Creteur, Yves Bouckaert, Patrick Biston, Marc Bourgeois, Martin Novacek, Tomas Vymazal, Petr Svoboda, Jan Pachl, Vladimir Sramek, Michal Hanauer, Tomas Hruby, Martin Balik, Tomas Suchy, Alain Lepape, Laurent Argaud, Frédéric Dailler, Arnaud Desachy, Christophe Guitton, Alain Mercat, Ferhat Meziani, Jean-Christophe Navellou, Rene Robert, Bertrand Souweine, Jean-Marc Tadie, Adel Maamar, Djillali Annane, Fabienne Tamion, Antoine Gros, Saad Nseir, Carole Schwebel, Gilles Francony, Jean-Yves Lefrant, Francis Schneider, Matthias Gründling, Johann Motsch, Lorenz Reill, Caroline Rolfes, Tobias Welte, Oliver Cornely, Frank Bloos, Maria Deja, Katrin Schmidt, Frank Wappler, Andreas Meier-Hellmann, Apostolos Komnos, Vasileios Bekos, Vasilios Koulouras, Ioanna Soultati, Georgios Baltopoulos, Georgios Filntisis, Epaminondas Zakynthinos, Spyros Zakynthinos, Ioannis Pnevmatikos, Ildikó Krémer, Zoltán Szentkereszty, Agnes Sarkany, Zsuzsa Marjanek, Pedro Moura, Maria Consuelo Pintado Delgado, Juan Carlos Montejo González, Paula Ramirez, Antonio Torres Marti, Juan Carlos Valia, Jose Lorente, Ana Loza Vazquez, Raúl De Pablo Sanchez, Dolores Escudero, Ricard Ferrer Roca, Jean-Luc Pagani, Marco Maggiorini