The effectiveness of erythromycin has been validated by a large number of clinical studies in the last 15 years and seems to halve the fatality rate of legionnaires' disease compared with untreated cases. This first-choice drug has minimum inhibitory concentrations ranging from 0.125 to 0.5 g/ml. Its activity is rapidly reversed once the drug is removed. However, many clinical and bacteriological failures of erythromycin treatment have been reported, and may partly explain the fatality rates of 10 to 40 per cent under treatment, but no in vitro resistance has been reported.

The majority of the newer macrolides, such as josamycin, spiramycin, clarithromycin, and azithromycin, show better in vitro activity against Legionnella than erythromycin. The oral administration of 500 mg of clarithromycin twice daily has been associated with a 98 per cent success rate in an open study involving 46 patients with mild forms of the disease.

Rifampin is also very active against Legionella, with minimum inhibitory concentrations ranging from 0.001 to 0.125 g/ml. Rifampin penetrates intracellularly and reaches a high concentration in the lung. However, it should not be used as the sole therapy because of the theoretical possibility of emergence of resistance. There are no good clinical data demonstrating the superiority of combination therapy with rifampin and other agents over single-drug therapy without rifampin. However, anecdotal data show that the addition of rifampin to erythromycin therapy may improve outcome of immunosuppressed patients, and this treatment is preferred in severe patients with confirmed legionnaires' disease.

Tetracyclines are probably as effective as erythromycin. These agents were comparable with erythromycin in decreasing case fatality rate in the Philadelphia outbreak of 1976. Efficacy has been reported in patients in whom erythromycin therapy failed. However, failures of tetracycline treatment have also been described.

A wide variety of fluoroquinolones have been shown experimentally to be very active against Legionnella, achieving minimum inhibitory concentrations of less than 0.01 pg/ml. These drugs also very active against intracellular L. pneumophila, always being more active than erythromycin. Many of the fluoroquinolones kill, rather than inhibit, the intracellular bacterium. The activity of pefloxacin has been shown to be superior to that of ofloxacin and ciprofloxacin, partly because of a postantibiotic effect. However, no large prospective data exist which support the inclusion of fluoroquinolones in the first-choice treatment regimen.

On the basis of experimental data and open clinical studies, a fluoroquinolone or one of the newer macrolide azalide antimicrobials are probably more effective than erythromycin. In the intensive care unit (ICU), treatment of confirmed severe legionellosis with a fluoroquinolone or a combination of erythromycin and rifampin is presumably preferable. The duration of therapy is 2 to 3 weeks.

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