Marin H Kollef1, Jean-Damien Ricard2, Damien Roux2, Bruno Francois3, Eleni Ischaki4, Zsolt Rozgonyi5, Thierry Boulain6, Zsolt Ivanyi7, Gál János7, Denis Garot8, Firas Koura9, Epaminondas Zakynthinos10, George Dimopoulos11, Antonio Torres12, Wayne Danker13, A Bruce Montgomery14. 1. Washington University School of Medicine, Saint Louis, MO. Electronic address: kollefm@wustl.edu. 2. Inserm, IAME, UMR 1137, University Paris Diderot, Sorbonne Paris Cité, Paris, France; AP-HP, Hopital Louis Mourier, Service de Reanimation Medico-Chirurgicale, Colombes, France. 3. Inserm, CIC-1435 & UMR 1092, Réanimation Polyvalente, CHU, Limoges, France. 4. Critical Care Department, General Hospital of Athens "Evangelismos", Athens, Greece. 5. Orszagos Koranyi TBC es Pulmonologiai Intezet, Budapest, Hungary. 6. Hôpital de La Source, Orléans, France. 7. Semmelweis University, Budapest, Hungary. 8. CHRU Bretonneau, Tours, France. 9. Kentucky Lung Clinic, Hazard, KY. 10. University General Hospital of Larisa, Larisa, Greece. 11. National and Kapodistrian University of Athens, Athens, Greece. 12. Department of Pulmonology, Hospital Clinic, IDIBAPS, CIBERES, University of Barcelona, Barcelona, Spain. 13. Parexel Corp, Research Triangle Park, NC. 14. Cardeas Pharma Corp, Seattle, WA.
Abstract
BACKGROUND: Clinical failures in ventilator-associated pneumonia (VAP) caused by gram-negative bacteria are common and associated with substantial morbidity, mortality, and resource utilization. METHODS: We assessed the safety and efficacy of the amikacin fosfomycin inhalation system (AFIS) for the treatment of gram-negative bacterial VAP in a randomized double-blind, placebo-controlled, parallel group, phase 2 study between May 2013 and March 2016. We compared standard of care in each arm plus 300 mg amikacin/120 mg fosfomycin or placebo (saline), delivered by aerosol twice daily for 10 days (or to extubation if < 10 days) via the investigational eFlow Inline System (PARI GmbH). The primary efficacy end point was change from baseline in the Clinical Pulmonary Infection Score (CPIS) during the randomized course of AFIS/placebo, using the subset of patients with microbiologically proven baseline infections with gram-negative bacteria. RESULTS: There were 143 patients randomized: 71 to the AFIS group, and 72 to theplacebo group. Comparison of CPIS change from baseline between treatment groups was not different (P = .70). The secondary hierarchical end point of no mortality and clinical cure at day 14 or earlier was also not significant (P = .68) nor was the hierarchical end point of no mortality and ventilator-free days (P = .06). The number of deaths in the AFIS group was 17 (24%) and 12 (17%) in the placebo group (P = .32). The AFIS group had significantly fewer positive tracheal cultures on days 3 and 7 than placebo. CONCLUSIONS: In this trial of adjunctive aerosol therapy compared with standard of care IV antibiotics in patients with gram-negative VAP, the AFIS was ineffective in improving clinical outcomes despite reducing bacterial burden. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01969799; URL: www.clinicaltrials.gov.
RCT Entities:
BACKGROUND: Clinical failures in ventilator-associated pneumonia (VAP) caused by gram-negative bacteria are common and associated with substantial morbidity, mortality, and resource utilization. METHODS: We assessed the safety and efficacy of the amikacin fosfomycin inhalation system (AFIS) for the treatment of gram-negative bacterial VAP in a randomized double-blind, placebo-controlled, parallel group, phase 2 study between May 2013 and March 2016. We compared standard of care in each arm plus 300 mg amikacin/120 mg fosfomycin or placebo (saline), delivered by aerosol twice daily for 10 days (or to extubation if < 10 days) via the investigational eFlow Inline System (PARI GmbH). The primary efficacy end point was change from baseline in the Clinical Pulmonary Infection Score (CPIS) during the randomized course of AFIS/placebo, using the subset of patients with microbiologically proven baseline infections with gram-negative bacteria. RESULTS: There were 143 patients randomized: 71 to the AFIS group, and 72 to the placebo group. Comparison of CPIS change from baseline between treatment groups was not different (P = .70). The secondary hierarchical end point of no mortality and clinical cure at day 14 or earlier was also not significant (P = .68) nor was the hierarchical end point of no mortality and ventilator-free days (P = .06). The number of deaths in the AFIS group was 17 (24%) and 12 (17%) in the placebo group (P = .32). The AFIS group had significantly fewer positive tracheal cultures on days 3 and 7 than placebo. CONCLUSIONS: In this trial of adjunctive aerosol therapy compared with standard of care IV antibiotics in patients with gram-negative VAP, the AFIS was ineffective in improving clinical outcomes despite reducing bacterial burden. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01969799; URL: www.clinicaltrials.gov.
Authors: María Díez-Aguilar; María Isabel Morosini; Emin Köksal; Antonio Oliver; Miquel Ekkelenkamp; Rafael Cantón Journal: Antimicrob Agents Chemother Date: 2017-12-21 Impact factor: 5.191
Authors: Marin H Kollef; Matteo Bassetti; Bruno Francois; Jason Burnham; George Dimopoulos; Jose Garnacho-Montero; Jeffrey Lipman; Charles-Edouard Luyt; David P Nicolau; Maarten J Postma; Antonio Torres; Tobias Welte; Richard G Wunderink Journal: Intensive Care Med Date: 2017-02-04 Impact factor: 17.440
Authors: Garyphallia Poulakou; Dimitrios K Matthaiou; David P Nicolau; Georgios Siakallis; George Dimopoulos Journal: Drugs Date: 2017-09 Impact factor: 9.546
Authors: Owen R Albin; Oryan Henig; Twisha S Patel; Thomas S Valley; Jason M Pogue; Lindsay A Petty; John P Mills; Adamo Brancaccio; Emily T Martin; Keith S Kaye Journal: Clin Infect Dis Date: 2020-12-15 Impact factor: 9.079
Authors: Su Young Jung; Seung Hee Lee; Soo Young Lee; Seungwon Yang; Hayeon Noh; Eun Kyoung Chung; Jangik I Lee Journal: Crit Care Date: 2017-12-20 Impact factor: 9.097