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Crit Care Med. 2019 Jun;47(6):e470-e477. doi: 10.1097/CCM.0000000000003724.

Nebulized Amikacin and Fosfomycin for Severe Pseudomonas aeruginosa Pneumonia: An Experimental Study.

Author information

1
Department of Pulmonary and Critical Care Medicine, Hospital Clinic, Barcelona, Spain.
2
CIBER Enfermedades Respiratorias (CIBERES), Mallorca, Spain.
3
Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
4
Humanitas Clinical and Research Center, Rozzano, Milano, Italy.
5
Department of Surgical Sciences and Integrated Diagnostics (DISC), San Martino Policlinico Hospital - IRCCS for Oncology, Genova, Italy.
6
Department of Pathology, Hospital Clinic, Barcelona, Spain.
7
Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, Milan, Italy.
8
Instituto Federal Farroupilha, Santo Ângelo, Brazil.
9
Division of Pulmonary, Heart Institute (InCor), Hospital das Clinicas (HCFMUSP), Faculdade de Medicina da Universidade de Sao Paulo, São Paulo, Brazil.
10
Department of Anesthesiology, Hospital Clínic, Barcelona, Spain.
11
Critical Care Center, Sabadell Hospital, CIBER Enfermedades Respiratorias, Parc Tauli University Institute, Sabadell, Spain.
12
Center for Anti-Infective Research & Development, Hartford Hospital, Hartford, CT.
13
Catholic University of Rome - Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.
14
Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy.
15
Internal Medicine Department, Respiratory Unit and Adult Cystic Fibrosis Center Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico Milano, Milan, Italy.
16
CardeasPharma, Seattle, WA.

Abstract

OBJECTIVES:

Latest trials failed to confirm merits of nebulized amikacin for critically ill patients with nosocomial pneumonia. We studied various nebulized and IV antibiotic regimens in a porcine model of severe Pseudomonas aeruginosa pneumonia, resistant to amikacin, fosfomycin, and susceptible to meropenem.

DESIGN:

Prospective randomized animal study.

SETTING:

Animal Research, University of Barcelona, Spain.

SUBJECTS:

Thirty female pigs.

INTERVENTIONS:

The animals were randomized to receive nebulized saline solution (CONTROL); nebulized amikacin every 6 hours; nebulized fosfomycin every 6 hours; IV meropenem alone every 8 hours; nebulized amikacin and fosfomycin every 6 hours; amikacin and fosfomycin every 6 hours, with IV meropenem every 8 hours. Nebulization was performed through a vibrating mesh nebulizer. The primary outcome was lung tissue bacterial concentration. Secondary outcomes were tracheal secretions P. aeruginosa concentration, clinical variables, lung histology, and development of meropenem resistance.

MEASUREMENTS AND MAIN RESULTS:

We included five animals into each group. Lung P. aeruginosa burden varied among groups (p < 0.001). In particular, IV meropenem and amikacin and fosfomycin + IV meropenem groups presented lower P. aeruginosa concentrations versus amikacin and fosfomycin, amikacin, CONTROL, and fosfomycin groups (p < 0.05), without significant difference between these two groups undergoing IV meropenem treatment. The sole use of nebulized antibiotics resulted in dense P. aeruginosa accumulation at the edges of the interlobular septa. Amikacin, amikacin and fosfomycin, and amikacin and fosfomycin + IV meropenem effectively reduced P. aeruginosa in tracheal secretions (p < 0.001). Pathognomonic clinical variables of respiratory infection did not differ among groups. Resistance to meropenem increased in IV meropenem group versus amikacin and fosfomycin + meropenem (p = 0.004).

CONCLUSIONS:

Our findings corroborate that amikacin and fosfomycin alone efficiently reduced P. aeruginosa in tracheal secretions, with negligible effects in pulmonary tissue. Combination of amikacin and fosfomycin with IV meropenem does not increase antipseudomonal pulmonary tissue activity, but it does reduce development of meropenem-resistant P. aeruginosa, in comparison with the sole use of IV meropenem. Our findings imply potential merits for preemptive use of nebulized antibiotics in order to reduce resistance to IV meropenem.

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