Treatment of Legionnaires Disease

Abstract & Commentary

Stan Deresinski, MD, FACP, Clinical Professor of Medicine, Stanford; Associate Chief of Infectious Diseases, Santa Clara Valley Medical Center, is Editor for Infectious Disease Alert

Synopsis: Levofloxacin was at least as effective as macrolide therapy in the management of Legionnaire's disease.

Sources: Mykietiuk A, et al. Clinical Outcomes for Hospitalized Patients with Legionella pneumonia in the Antigenuria Era: The Influence of Levofloxacin Therapy. Clin Infect Dis. 2005;40:794-799; Blazquez Garrido RMB, et al. Antimicrobial Chemotherapy for Legionnaires Disease: Levofloxacin vs Macrolides. Clin Infect Dis. 2005;40:800-806.

Mykietiuk and colleagues report that 139 (7.2%) of 1934 prospectively evaluated adults without severe immunocompromise admitted over an approximately 8-year period to a university hospital in Barcelona because of community-acquired pneumonia (CAP) had evidence of Legionella infection. According to hospital guidelines, patients with CAP received empiric therapy with a lactam with or without a macrolide or, as an alternative allowed from 1998 on, levofloxacin alone. Of those with a urine antigen test positive for L. pneumophila serogroup, 1 received specific therapy with either a macrolide with or without rifampin or with levofloxacin.

Appropriate therapy was administered to 120 patients with legionellosis, including 40 who received levofloxacin (500 mg daily) and 80 treated with either erythromycin (1gm IV 6 hourly) or clarithromycin (500mg IV 12 hourly). Approximately one-fourth of patients in each group also received corticosteroids. The case fatality rate was 2.5% in levofloxacin recipients and 5% in those given macrolides (P = NS), and complications occurred in 25% in each group. Levofloxacin therapy was, however, associated with a shorter time to defervescence (2.0 vs 4.5 days; P <.001 and clinical stability vs days>P = .002), as well as median time to discharge (8 days vs 10 days; P = .518).

In a second report, Blazquez Garrido and colleagues describe the results of therapy in another observational, prospective, nonrandomized study of patients with Legionnaires disease in a setting of a community outbreak in Murcia. Antibiotic therapy was chosen by the clinicians attending the patients. Of the 292 patients included in this analysis, 65 received clarithromycin or azithromycin and 143 received levofloxacin, with 45 of the latter also receiving rifampin.

All but one patient, a levofloxacin recipient, survived. While there was no difference in outcome between treatment groups in patients with mild-to-moderate infection (Fine groups I-III), the frequency of complications was higher in macrolide than in levofloxacin recipients (27.1% vs 3.4%; P = .02), and the duration of hospitalization was longer (11.3 days vs 5.5 days; P = .04). A comparison of 45 patients who received levofloxacin alone, with 45 who received it in combination with rifampin, found that the latter group had more complications, as well as a longer duration of fever and of hospital stay.

Comment by Stan Deresinski, MD, FACP

Although both of these studies were prospective, neither randomly assigned the antibiotic treatment, making the results potentially corrupted by confounding. For instance, in the experiment reported by Mykietiuk et al, all the patients given levofloxacin received it in the latter years of the study, and it is possible that other changes in management introduced at the same time may have improved outcomes. Thus, strictly speaking, the results can only be used to generate hypotheses for future randomized trials. Since, however, results of such trials are not likely to be available for quite a while, if ever, we are left to make the best use of this information for our patients that we can.

Perhaps the most interesting thing about these results is the extraordinarily low mortality in these patients with Legionella infection, a disease previously associated with mortality rates of 5% to 25% in immunocompetent patients. This apparent improvement in outcome is likely related, at least in part, to the routine inclusion of antibiotics with activity against this organism in published guideline recommendations for the empirical management of CAP, as well as other changes in practice that have occurred over time. In addition, the availability of the urine antigen test for the detection of infection due to L. pneumophila serogroup 1 has probably allowed for the diagnosis of less severe cases than in the past.

These studies suggest that levofloxacin therapy of Legionellosis is at least as effective as treatment with a macrolide. In fact, while ultimate cure rates are similar, levofloxacin therapy may be associated with a lower incidence of complications and more rapid clinical improvement, including more rapid derfervescence. However, it is possible that not all macrolides have similar efficacy in this infection; only a minority of patients given a macrolide received azithromycin. A recent publication reported that a favorable outcome was achieved in 22 of 23 patients with Legionella pneumophila infection treated with azithromycin for a mean duration of 8 days.1 Also of note, is the finding by Blazquez Garrido et al of lack of evidence for benefit from the addition of rifampin to levofloxacin therapy. The addition of rifampin, in fact, may have had a negative effect.

The rank order of in vitro activity against L. pneumophila serogroup 1 is reported to be fluoroquinolones > ketolides > macrolides, whether using broth dilution susceptibility testing or examining intracellular efficacy.2 All the available respiratory fluoroquinolones are active in vitro against L. pneumophila, and each is likely to be effective in the treatment of pneumonia due to this organism. None, however, have as much published clinical experience available to demonstrate this efficacy as does levofloxacin. In addition to the studies discussed here, a compilation of cases from clinical trials found that there were no deaths among 75 patients with legionellosis treated with levofloxacin.3 Of note, is that treatment with 750 mg for 5 days appeared to be as efficacious as 500mg for 7-14 days; in a trial comparing 750 for 5 days and 500 for 10 days, 11 of 11 of the former and 3 of 3 of the latter were cured.4

References

  1. Plouffe JF, et al. Azithromycin in the Treatment of Legionella pneumonia Requiring Hospitalization. Clin Infect Dis. 2003;37:1475-1480.
  2. Stout JE , et al. Comparative Activity of Quinolones, Macrolides and Ketolides Against Legionella Species Using In Vitro Broth Dilution and Intracellular Susceptibility Testing. Int J Antimicrob Agents. 2005; 25:302-307.
  3. Yu VL, et al. Levofloxacin Efficacy in the Treatment of Community-Acquired Legionellosis. Chest. 2004; 125:2135-2139.
  4. Dunbar LM, et al. High-Dose, Short-Course Levofloxacin for Community-Acquired Pneumonia: A New Treatment Paradigm. Clin Infect Dis. 2003;37:752-760.