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

Li Bassi, Gianluigi PhD1–4; Motos, Ana MSc1,3,4; Fernandez-Barat, Laia PhD1–4; Aguilera Xiol, Eli PhD1; Chiurazzi, Chiara MD5; Senussi, Tarek MD6; Saco, Maria A. MD7; Fuster, Carla MD7; Carbonara, Marco MD9; Bobi, Joaquim DVM1–3; Amaro, Rosanel MD, PhD1–3; De Rosa, Francesca MD1; Comaru, Talitha PhD10; Yang, Hua MD1; Ranzani, Otavio T. MD, PhD1–3,11; Marti, Joan-Daniel PT, PhD1–3; Rinaudo, Mariano MD, PhD1; Comino Trinidad, Oscar MD12; Rigol, Montserrat DVM, PhD1–4; Bringué, Josep MSc13; Ramirez, Jose MD, PhD7; Nicolau, David P. PharmaD14; Pelosi, Paolo MD6; Antonelli, Massimo MD8; Blasi, Francesco MD, PhD10,15,16; Artigas, Antonio MD, PhD13; Montgomery, A. Bruce MD17; Torres, Antoni MD, PhD, FERS1–4

doi: 10.1097/CCM.0000000000003724
Online Laboratory Investigations

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.

1Department of Pulmonary and Critical Care Medicine, Hospital Clinic, Barcelona, Spain.

2Faculty of Medicine, University of Barcelona, Barcelona, Spain.

3CIBER Enfermedades Respiratorias (CIBERES), Mallorca, Spain.

4Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.

5Humanitas Clinical and Research Center, Rozzano, Milano, Italy.

6Department of Surgical Sciences and Integrated Diagnostics (DISC), San Martino Policlinico Hospital - IRCCS for Oncology, Genova, Italy.

7Department of Pathology, Hospital Clinic, Barcelona, Spain.

8Catholic University of Rome – Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.

9Fondazione IRCCS Ca’ Granda - Ospedale Maggiore Policlinico, Milan, Italy.

10Instituto Federal Farroupilha, Santo Ângelo, Brazil.

11Division of Pulmonary, Heart Institute (InCor), Hospital das Clinicas (HCFMUSP), Faculdade de Medicina da Universidade de Sao Paulo, São Paulo, Brazil.

12Department of Anesthesiology, Hospital Clínic, Barcelona, Spain.

13Critical Care Center, Sabadell Hospital, CIBER Enfermedades Respiratorias, Parc Tauli University Institute, Sabadell, Spain.

14Center for Anti-Infective Research & Development, Hartford Hospital, Hartford, CT.

15Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy.

16Internal Medicine Department, Respiratory Unit and Adult Cystic Fibrosis Center Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico Milano, Milan, Italy.

17CardeasPharma, Seattle, WA.

*See also p. 880.

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Supported, in part, by Cardeas Ltd, the manufacturer of nebulized amikacin/fosfomycin combination.

Drs. Li Bassi’s and Torres’ institutions received funding from Cardeas Ltd, the manufacturer of nebulized amikacin/fosfomycin. Ms. Motos and Dr. Hua disclosed work for hire. Dr. Fernandez-Barat disclosed off-label product use of amikacin/fosfomycin combination from the manufacturer Cardeas Ltd. Dr. Antonelli received funding from Toray, Air Liquid, and Chiesi. Dr. Blasi received funding from AstraZeneca, Bayer, Guidotti, GlaxoSmithKline, Chiesi, Grifols, Insmed, Menarini, Novartis, Pfizer, Teva, and Zambon. Dr. Montgomery received funding from Cardeas Pharma (employee). The remaining authors have disclosed that they do not have any potential conflicts of interest.

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