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Original Research: Critical Care |

A Randomized Trial of the Amikacin Fosfomycin Inhalation System for the Adjunctive Therapy of Gram-Negative Ventilator-Associated Pneumonia: IASIS Trial

Marin H. Kollef, MD; Jean-Damien Ricard, MD; Damien Roux, MD; Bruno Francois, MD; Eleni Ischaki, MD; Zsolt Rozgonyi, MD; Thierry Boulain, MD; Zsolt Ivanyi, MD; Gál János, MD; Denis Garot, MD; Firas Koura, MD; Epaminondas Zakynthinos, MD; George Dimopoulos, MD; Antonio Torres, MD; Wayne Danker, MD; A. Bruce Montgomery, MD
Author and Funding Information

FUNDING/SUPPORT: Dr Kollef was supported by the Barnes-Jewish Hospital Foundation.

aWashington University School of Medicine, Saint Louis, MO

bInserm, IAME, UMR 1137, University Paris Diderot, Sorbonne Paris Cité, Paris, France; AP-HP, Hopital Louis Mourier, Service de Reanimation Medico-Chirurgicale, Colombes, France

cInserm, CIC-1435 & UMR 1092, Réanimation Polyvalente, CHU, Limoges, France

dCritical Care Department, General Hospital of Athens “Evangelismos”, Athens, Greece

eOrszagos Koranyi TBC es Pulmonologiai Intezet, Budapest, Hungary

fHôpital de La Source, Orléans, France

gSemmelweis University, Budapest, Hungary

hCHRU Bretonneau, Tours, France

iKentucky Lung Clinic, Hazard, KY

jUniversity General Hospital of Larisa, Larisa, Greece

kNational and Kapodistrian University of Athens, Athens, Greece

lDepartment of Pulmonology, Hospital Clinic, IDIBAPS, CIBERES, University of Barcelona, Barcelona, Spain

mParexel Corp, Research Triangle Park, NC

nCardeas Pharma Corp, Seattle, WA

CORRESPONDENCE TO: Marin H. Kollef, MD, Division of Pulmonary and Critical Care Medicine, Washington University School of Medicine, 4523 Clayton Ave, Campus Box 8052, St. Louis, MO 63110


Copyright 2016, American College of Chest Physicians. All Rights Reserved.


Chest. 2017;151(6):1239-1246. doi:10.1016/j.chest.2016.11.026
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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

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