The Nonantibiotic Macrolide EM703 Improves Survival in a Model of Quinolone-Treated Pseudomonas aeruginosa Airway Infection

Abstract

Macrolide antibiotics are used as anti-inflammatory agents, e.g., for prevention of exacerbations in chronic obstructive pulmonary disease and cystic fibrosis. Several studies have shown improved outcomes after the addition of macrolides to ␤-lactam antibiotics for treatment of severe community-acquired pneumonia. However, a beneficial effect of macrolides in 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 in 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 for experimental P. aeruginosa lung infection, in combination with a conventional antibiotic. Airway infections in BALB/cJRj mice were 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 infections. In addition, EM703 reduced the levels of proinflammatory cytokines, increased the numbers of leukocytes in bronchoalveolar lavage fluid, and reduced the numbers of neutrophils present in 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.KEYWORDS macrolide, EM703, host defense, anti-inflammatory, Pseudomonas aeruginosa M acrolide antibiotics (for example, erythromycin, azithromycin, and clarithromycin) have caught interest for use in the treatment of chronic airway inflammation (1). Reduction of pulmonary exacerbations has been demonstrated in cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD) (2, 3). Macrolides display broad biological responses, including bacteriostatic activity, stimulation of gastrointestinal motility, and anti-inflammatory properties (4-6). Each of these effects could be advantageous, depending on the clinical context; however, promotion of drug-resistant bacteria and diarrhea limit the clinical use of macrolides as anti-inflammatory agents.In severe community-acquired pneumonia, which is often caused by the Grampositive coccus Streptococcus pneumoniae, meta-analyses have shown that the addition of a macrolide antibiotic to a ␤-lactam has beneficial effects, reducing mortality rates (7-9). Pneumonia caused by Gram-negative bacteria, in particular, Pseudomonas aerugi-

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Azithromycin Inhibits Constitutive Airway Epithelial Sodium Channel Activation <i>in Vitro</i> and Modulates Downstream Pathogenesis <i>in Vivo</i>

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