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The need to understand the mechanism of action of clarithromycin guided to the study of a model of experimental empyema by multidrug\u2010resistant <jats:italic>Pseudomonas aeruginosa<\/jats:italic> in 40 rabbits. Animals were randomized into controls (group A); treatment with clarithromycin (group B); treatment with piperacillin\/tazobactam (group C); and treatment with both agents (group D). Pleural fluid was collected at regular time intervals for quantitative culture, estimation of cell apoptosis and of concentrations of tumour necrosis factor\u2010alpha (<jats:styled-content style=\"fixed-case\">TNF<\/jats:styled-content>\u03b1). After 7\u00a0days, animals were euthanized for estimation of tissue growth. Bacterial growth in the pleural fluid of group D was significantly decreased compared with the other groups on day 5. Lung growth of group D was lower than group A. That was also the case of cytokine stimulation by pleural fluid samples on U937 monocytes. It is concluded that administration of clarithromycin enhanced the antimicrobial efficacy of piperacillin\/tazobactam and decreased bacterial growth in the pleural fluid and in tissues. 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