THE NON-ANTIBIOTIC MACROLIDE EM703 IMPROVES SURVIVAL IN A MODEL OF QUINOLONE-TREATED PSEUDOMONAS AERUGINOSA AIRWAY INFECTION [PublishAheadOfPrint]

Macrolide antibiotics are used as anti-inflammatory agents, e.g. for prevention of exacerbations in COPD and cystic fibrosis. Several studies have shown improved outcomes after addition of macrolides to beta-lactam antibiotics when treating severe community-acquired pneumonia. However, a beneficial effect of macrolides when treating Gram-negative bacterial airway infections, e.g. those caused by Pseudomonas aeruginosa, remains to be shown. Macrolide antibiotics have significant side effects, in particular motility-stimulating activity of the gastrointestinal tract and promotion of bacterial resistance. In this study, EM703, a modified macrolide lacking antibiotic and motility-stimulating activities, but with retained anti-inflammatory properties, was used as an adjunct treatment of experimental P. aeruginosa lung infection in combination with a conventional antibiotic. Airway infection in BALB/cJRj mice was induced by nasal instillation of P. aeruginosa. This was followed by treatment with the quinolone levofloxacin in the absence or presence of EM703. Survival, inflammatory responses, and cellular influx to the airways were monitored. Both pretreatment and simultaneous administration of EM703 dramatically improved survival in levofloxacin-treated mice with P. aeruginosa airway infection. In addition, EM703 reduced the levels of proinflammatory cytokines, increased the number of leukocytes in bronchoalveolar fluid, and reduced the number of neutrophils present in the lung tissue. In summary, the findings of this study show that the immunomodulatory properties of the modified macrolide EM703 can be important when treating Gram-negative pneumonia, as exemplified by P. aeruginosa infection in this study.

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