A Randomized Trial of the Amikacin Fosfomycin Inhalation System for the Adjunctive Therapy of Gram-Negative Ventilator-Associated Pneumonia.
Kollef MH, Ricard, JD, Roux D, Francois B, Ischaki E, Rozgonyi, et al. A randomised trial of the amikacin fosfomycin inhalation system for the adjunctive therapy of Gram-negative ventilator-associated pneumonia: IASIS Trial. Chest 2016; epublished November 24th
Background & clinical question:
Ventilator Associated Pneumonia caused by gram negative bacteria is a major cause of mortality and morbidity in intensive care unit. Antibiotics administered intravenously may have poor lung penetration leading to treatment failure. Aerosolized antibiotics can attend higher lung concentration and can be an effective mode of therapy in addition to intravenous antibiotics.
This trial evaluated nebulized Amikacin and fosfomycin (Amikacin Fosfomycin Inhalation System AFIS) in gram negative ventilator associated pneumonia (VAP).
Multicenter randomized, phase-2, placebo control, double blind trial.
Setting (Population, Timeframe & Enrolment):
May 2013 and March 2016
18-80 years, men and non-pregnant, non-lactating women
Intubated and mechanically ventilated, with pneumonia defined as
New or progressive chest infiltrates with signs of infection
Fever>38 °C, WCC <4,00 or >12000/mm3, and hypoxia (PaO2/FiO2≤ 350 and APACHE II score >10 in the previous 24 hrs, and presence of a gram-negative organism in respiratory secretions within last 7 days.
AFIS group (Amikacin 300 mg + Fosfomycin 120 mg, 6ml volume) administered twice daily through (eFlow Inline System; PARI GmbH) run for 12 minutes. Intravenous antibiotic used was carbapenem and if resistant to carbapenem then Aminoglycoside other that Amikacin or Colistin or Polymyxin B was used. If patients were suitable for extubation then they are extubated and AFIS was stopped but the patients were analysed.
The control group received saline.
BAL or endotracheal aspirated were done prior to starting AFIS. Clinical Pulmonary Infection Score (CPIS) was done daily till day 14.
Primary end point was a change of baseline CPIS score during intervention period of 10days. A sample size of 140 patients provided 80% power to detect an effect size (difference in means/SDs) of 0.53 at any given time point (2-sided 0.05-level t test.
Secondary end points included
composite end point of mortality and time to clinical cure
composite end point of mortality and ventilator-free days
number of ventilator-free days
number of ICU days
microbiologic response rates at day 14
mortality, and clinical relapse rates after day 10
143 patients enrolled (AFIS 71 vs placebo 72). 143 patients received AFIS or placebo at least once, 65 patients received all 10 days of therapy (AFIS 36, placebo 29).
CPIS improvement did not differ between the groups. On pre-hoc analysis there was no difference in CPIS with respect to age, presence of multi-drug resistant organism (MDR).
There was no significant difference in any secondary outcome variables. The number of tracheal culture which were negative on day 3 & 7 were higher in AFIS group.
Post hoc analysis for patients with pan drug resistant (PDR) organism, AFIS had a significant ventilator free days and clinical cure rate at day 14, but the numbers included are very less (9 patients in AFIS and 4 in placebo group).
Amikacin and Fosfomycin inhalational treatment as an adjunct to routine intravenous antibiotics for proven gram negative VAP did not affect the clinical course, though it decreased the tracheal culture positivity.
Multicenter randomize trial.
Duration of intravenous antibiotic treatment prior to enrollment was far more than the pre-decided initial enrolment criteria (6 days in AFIS group vs 4 days in placebo group). So, the assessment of effectiveness is hard to interpret.
The authors interpreted that even if the AFIS treatment was given earlier than what realy happened in the study, the outcome would not have changed. This interpretation was based on the data of 32 patients evaluated in united states who received antibiotics for a median duration of 3 days prior to AFIS therapy. This finding cannot be generalized as it included 20.9% of the total sample.
As the study only evaluated Amikacin and Fofomycin, the conclusion cannot be generalized to all antibiotics used for gram negative VAP.
Relevance to current practice:
Literature before this study and basis of the current trial:
Multiple studies evaluated the following antibiotics in the treatment of pneumonia by the aerosolized method. Most of the studies are single center with low number of enrolled patients. The most common findings can be summarized as following: -
The drug concentration achieved was almost 100 times than that achieved by systemic antibiotics in the lungs.
Few of the antibiotics have been tested for aerosolization. Majority of the trials tested Amikacin and Colistin.
Most of the studies were conducted in patients with ventilator associated pneumonia (VAP) with multidrug resistant gram negative pathogens (MRD).
Most of the trials continued the appropriate intravenous (IV) antibiotics and used aerosolized antibiotics as adjuvant.
Most common results-
Aerosolized antibiotics were safe without any major side effect and were well tolerated.
Few of the studies only reported clinical benefit. Bacteriological clearance was better with aerosolized antibiotics in most of the studies.
No systemic adverse events or increased incidence of renal failure were demonstrated.
There is very less chances of development of resistance to antibiotics through aerosolization.
Summary of trials with aerosolised antibiotics for gram negative bacterial VAP
Aerosolized antibiotics cannot be recommended for routine use in intensive care unit for treatment of gram negative VAP.
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