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Acute respiratory tract infections are a key public health problem, and represent a major cause of death worldwide. The dramatic shortage of new antibiotics combined with the increasing number of antibiotic-resistant bacteria constitutes a worrisome threat for the global population and a critical challenge for healthcare institutions. Over recent years, a better understanding of bacterial growth, metabolism, and virulence has offered several potential targets for nonantibiotic antimicrobial therapies.Several leads have been investigated, targeting adhesion, communication, toxins, virulence factors, direct bacterial killing by bacteriophages, and vaccine strategies. Promising results have been obtained with these different targets, including inhibition of quorum sensing, use of pilicide compounds to inhibit bacterial adhesion, prevention and treatment of Pseudomonas aeruginosa pneumonia by bacteriophages, effective protection against P. aeruginosa lung infection with mucosal vaccination, use of anti-PcrV antibodies in P. aeruginosa-induced sepsis.Expectations are high regarding the translation of these experimental results into true clinical benefits for the patients. Importantly, clinical studies are ongoing in some areas, and promising preliminary results have already been obtained in some instances.