title: A Randomized Trial of the Amikacin Fosfomycin Inhalation System for the Adjunctive Therapy of Gram-Negative Ventilator-Associated Pneumonia: IASIS Trial.
abstract: Clinical failures in ventilator-associated pneumonia (VAP) caused by gram-negative bacteria are common and associated with substantial morbidity, mortality, and resource utilization.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  ClinicalTrials.gov; No.: NCT01969799; URL: www.clinicaltrials.gov.
authors.affiliation: Washington University School of Medicine, Saint Louis, MO. Electronic address: kollefm@wustl.edu.
authors.forename: Marin H
authors.initials: MH
authors.lastname: Kollef
authors.affiliation: Inserm, IAME, UMR 1137, University Paris Diderot, Sorbonne Paris Cité, Paris, France; AP-HP, Hopital Louis Mourier, Service de Reanimation Medico-Chirurgicale, Colombes, France.
authors.forename: Jean-Damien
authors.initials: JD
authors.lastname: Ricard
authors.affiliation: Inserm, IAME, UMR 1137, University Paris Diderot, Sorbonne Paris Cité, Paris, France; AP-HP, Hopital Louis Mourier, Service de Reanimation Medico-Chirurgicale, Colombes, France.
authors.forename: Damien
authors.initials: D
authors.lastname: Roux
authors.affiliation: Inserm, CIC-1435 & UMR 1092, Réanimation Polyvalente, CHU, Limoges, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Francois
authors.affiliation: Critical Care Department, General Hospital of Athens "Evangelismos", Athens, Greece.
authors.forename: Eleni
authors.initials: E
authors.lastname: Ischaki
authors.affiliation: Orszagos Koranyi TBC es Pulmonologiai Intezet, Budapest, Hungary.
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Rozgonyi
authors.affiliation: Hôpital de La Source, Orléans, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Boulain
authors.affiliation: Semmelweis University, Budapest, Hungary.
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Ivanyi
authors.affiliation: Semmelweis University, Budapest, Hungary.
authors.forename: Gál
authors.initials: G
authors.lastname: János
authors.affiliation: CHRU Bretonneau, Tours, France.
authors.forename: Denis
authors.initials: D
authors.lastname: Garot
authors.affiliation: Kentucky Lung Clinic, Hazard, KY.
authors.forename: Firas
authors.initials: F
authors.lastname: Koura
authors.affiliation: University General Hospital of Larisa, Larisa, Greece.
authors.forename: Epaminondas
authors.initials: E
authors.lastname: Zakynthinos
authors.affiliation: National and Kapodistrian University of Athens, Athens, Greece.
authors.forename: George
authors.initials: G
authors.lastname: Dimopoulos
authors.affiliation: Department of Pulmonology, Hospital Clinic, IDIBAPS, CIBERES, University of Barcelona, Barcelona, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Torres
authors.affiliation: Parexel Corp, Research Triangle Park, NC.
authors.forename: Wayne
authors.initials: W
authors.lastname: Danker
authors.affiliation: Cardeas Pharma Corp, Seattle, WA.
authors.forename: A Bruce
authors.initials: AB
authors.lastname: Montgomery
mesh_terms: D018806:APACHE; D000280:Administration, Inhalation; D000328:Adult; D000368:Aged; D000583:Amikacin / Q000008:administration & dosage*; D000900:Anti-Bacterial Agents / Q000008:administration & dosage*; D017024:Chemotherapy, Adjuvant; D004311:Double-Blind Method; D005260:Female; D005578:Fosfomycin / Q000008:administration & dosage*; D016905:Gram-Negative Bacterial Infections / Q000188:drug therapy*; D006801:Humans; D008297:Male; D008875:Middle Aged; D053717:Pneumonia, Ventilator-Associated / Q000188:drug therapy*; D016896:Treatment Outcome
chemical_list: D000900:Anti-Bacterial Agents; D005578:Fosfomycin; D000583:Amikacin
keywords: aerosols; antibiotics; pneumonia