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Two ketolides, three macrolides, and one azalide were tested in vitro against 17 isolates of the B. burgdorferi s.l. complex. As measured in micrograms per milliliter, activity was highest for cethromycin (MIC at which 90% of the tested isolates were inhibited [MIC(90)], 0.0019 micro g/ml) and telithromycin (MIC(90), 0.0078 micro g/ml). Electron-microscope analysis and time-kill studies also supported enhanced effectiveness of both ketolides.