Interferon-γ and Antibiotics Fail to Act Synergistically to KillLegionella pneumophilain Human Monocytes

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Abstract
Legionella pneumophila, the agent of Legionnaires' disease, is a gram-negative facultative intracellular bacterial pathogen that multiplies in human blood monocytes and alveolar macrophages. Interferon-γ (IFN-γ)-activated human monocytes inhibit the intracellular multiplication of L. pneumophila but fail to kill the organism. Similarly, erythromycin and rifampin, the drugs of choice in the treatment of Legionnaires' disease, inhibit the growth of L. pneumophila within monocytes without exerting a cidal effect. In this study, we examined the combined effects of IFN-γ and antibiotics (erythromycin, rifampin, and clindamycin) to determine whether these independently acting agents would synergistically mediate the killing of intracellular L. pneumophila. Each agent alone or in combination was effective in inhibiting the intracellular multiplication of L. pneumophila. However, IFN-γ and antibiotics together were unable to kill intracellular L. pneumophila, regardless of the sequence in which they were administered to monocytes. Like erythromycin and rifampin, clindamycin, which is highly concentrated in human alveolar macrophages, was capable of inhibiting the intracellular multiplication of L. pneumophila but failed to kill the bacteria in nonactivated or IFN-γ-activated monocytes. These results demonstrate that intracellular L. pneumophila are highly resistant to the bactericidal effects of both activated monocytes and antibiotics, alone or in combination.