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Springfield, MA
Dr. Granowitz is Assistant Professor of Medicine, and Dr. Brown is Professor of Medicine at Tufts University School of Medicine. Both are in the Infectious Disease Division at Baystate Medical Center.
Dr. Brown participates in the speakers’ bureaus of Cubist, Merck, Ortho-McNeil, Pfizer, and Roche.
Correspondence to: Richard B. Brown, MD, Infectious Diseases Division, Baystate Medical Center and Tufts University School of Medicine, 759 Chestnut St, Springfield, MA 01199; e-mail: richard.brown{at}bhs.org
In the preantibiotic era William Osler wrote that "(t)he most widespread and fatal of all acute diseases, pneumonia is now the ‘Captain of the Men of Death.’"1 At that time, the treatment of community-acquired pneumonia (CAP) consisted of bedrest and open drainage tubes for patients with empyema. Once penicillin became commercially available in the l940s, the most common identifiable cause of bacterial pneumonia, the pneumococcus, became amenable to pathogen-directed therapy. With the discovery and manufacture of broad-spectrum antibiotics, additional pulmonary pathogens such as Haemophilus influenzae became treatable. Atypical pneumonia, historically characterized by interstitial infiltrates and the inability to identify a pathogen on sputum Gram stain or culture was first described in the mid-1940s, but it was not until the l960s that it was recognized that some cases were due to tetracycline-susceptible mycoplasma.23 Legionella pneumophila was first identified as a cause of both atypical and typical CAP during a 1976 outbreak at an American Legion Convention. Mortality was 63% lower in patients treated with erythromycin compared to ß-lactams.4 Because of its activity against Streptococcus pneumoniae, Mycoplasma pneumoniae, Legionella species, and Chlamydia pneumoniae, erythromycin became a drug of choice for CAP. More recently, respiratory fluoroquinolones have been used empirically for the treatment of CAP because of their activity against the pneumococcus (including penicillin-resistant S pneumoniae), against most other bacterial causes of lobar pneumonia, and against the "atypicals." In the United States, it has been estimated that there are now at least 500,000 cases annually of CAP requiring hospitalization with 8,000 to 18,000 due to Legionella species, 20,000 to 100,000 due to M pneumoniae, and 5,000 to 50,000 due to C pneumonia.5
In 1993, the American Thoracic Society (ATS) first published guidelines for the management of adults with CAP.6 This statement advocated the use of a macrolide or tetracycline for young patients without comorbidities who could be treated outside the hospital and combination therapy with a macrolide and a broad-spectrum ß-lactam for patients who were older, had comorbidities, or required hospitalization. The most recent ATS guidelines categorize patients by whether they can be treated outside the hospital (groups I and II), require hospitalization on a regular medical floor (group III), or need intensive care (group IV).7 An advanced-generation macrolide, azalide, or doxycycline is recommended for outpatients without cardiovascular disease (group I). For most patients in groups II and III, monotherapy with an antipneumococcal quinolone or the combination of a broad-spectrum ß-lactam plus a macrolide or doxycycline is recommended. In ICUs, for patients who are not at risk for Pseudomonas aeruginosa the ATS guidelines suggest using a broad-spectrum ß-lactam plus either azithromycin or a fluoroquinolone. The Infectious Diseases Society of America (IDSA) made similar recommendations for treating CAP in its 2003 guidelines.8 In contrast to the ATS, the IDSA specifically addresses antimicrobial therapy for legionellosis recommending erythromycin, azithromycin, clarithromycin, a respiratory fluoroquinolone, or doxycycline. The next CAP guidelines are due to be published within the next year and will be a joint effort of the ATS and IDSA.
We believe that the authors of these upcoming guidelines should seriously reconsider the role of macrolides and azalides in treating CAP in general and legionellosis in particular. Recent data have shown that the adjusted rate of sudden death is twofold greater in patients receiving oral erythromycin compared to patients with similar illnesses who are treated with alternative antibiotics.9 This finding suggests that the risk/benefit ratio of erythromycin treatment may be unacceptably high. While erythromycin was traditionally the macrolide of choice for treating CAP, azithromycin is now the macrolide/azalide that is most commonly prescribed.
There is no question that azithromycin is effective in treating CAP patients who are mildly to moderately ill.1011 Recent data12 have shown that just a single dose of a new microsphere formulation of azithromycin results in clinical success in 92% of patients with CAP. There are even data1314 suggesting that severely ill patients with pneumococcal bacteremia who have been treated with both a ß-lactam and a macrolide have better outcomes than similar patients treated with a ß-lactam alone. In patients who have been hospitalized with legionellosis, an 8-day course of azithromycin results in an overall cure rate of 95%.15
There are also excellent data demonstrating the efficacy of respiratory fluoroquinolone monotherapy in patients with CAP.161718 In patients with mild-to-severe CAP, a 5-day course of levofloxacin resulted in a 92% clinical cure rate.19 Because of the relatively low morbidity and mortality associated with CAP caused by M pneumoniae and C pneumoniae, any differences in efficacy among a macrolide, azalide, tetracycline, or fluoroquinolone would probably have little clinical significance for these pathogens. Based on this information, some have argued that legionellosis was the last pathogen-specific reason to prefer macrolides or azalides to fluoroquinolones for the treatment of CAP. This argument became less compelling last year when Yu and colleagues20 published an article in CHEST demonstrating a 93% clinical cure rate for community-acquired legionellosis in patients who had been treated with a 5-day course of levofloxacin.
In this issue of CHEST (see page 1401), Sabria and coworkers21 report the results of a large prospective study comparing the efficacy of macrolides and fluoroquinolones in treating 130 patients with CAP who were admitted to one of three hospitals in Spain. In this observational study, patients with legionellosis were induced on the basis of a positive urinary antigen test for L pneumophila serogroup 1. Because others22 have found pulmonary copathogens in over one half of patients with CAP associated with atypicals, the authors did not include any patients with microbiological or serologic findings, suggesting the presence of a copathogen. Treatment was at the discretion of the patients’ physicians and consisted of erythromycin, clarithromycin, ofloxacin, or levofloxacin. The duration of therapy was at least 2 weeks for all patients. The investigators found no significant differences at study entry between the patients who received macrolides and those who received fluoroquinolones. The overall mortality rate was 7% and did not differ between the two groups. There was no significant difference in the risk of developing complications when comparing the groups. The time to defervescence was significantly shorter in the fluoroquinolone group compared to the macrolide group (43 vs 77 h, respectively). There was a trend toward a shorter hospital stay in the patients treated with fluoroquinolones.
The major limitation of the study is the lack of randomization to treatment. One could imagine local conditions resulting in more severely ill patients preferentially receiving one drug more frequently than the others. Additional limitations are the inclusion of some patients who received a potentially suboptimal dose of erythromycin (ie, 500 mg IV every 6 h), using a dose of levofloxacin (ie, 500 mg every 12 h) that exceeded standard dosing, the lack of patients treated with azithromycin, excluding patients who had been treated for < 14 days, including patients with incomplete data regarding the exclusion of copathogens (especially influenza), and the fact that the study was not designed to test for equivalence. Information regarding baseline chest radiographs and adverse events as well as a direct comparison of erythromycin-treated patients to clarithromycin-treated patients would have been interesting.
Two very recently published prospective, observational, nonrandomized studies of Spanish patients with community-acquired legionellosis also found no differences in mortality between macrolide-treated patients and fluoroquinolone-treated patients. The first study examined 120 patients from Barcelona and found no differences in mortality or the development of complications and faster times to defervescence and hospital discharge when comparing patients treated with levofloxacin to those treated with erythromycin or clarithromycin.23 In the second study, Garrido and coworkers24 described 292 patients with community-acquired legionellosis who were seen at a single hospital during an outbreak in Murcia. Notably, more than one half of the patients in the study by Sabria et al21 were also recruited during the same Murcia outbreak. Similar to the other two groups, Garrido et al24 observed no differences in mortality and a shorter hospitalization in patients treated with levofloxacin compared to those treated with clarithromycin or azithromycin.
We suspect that future head-to-head comparisons of macrolide, azalides, and respiratory fluoroquinolones for the treatment of CAP in general or legionellosis in particular are unlikely to yield much additional clinically important information on microbiological and clinical cure rates. The aforementioned studies on the duration of therapy indicate that in most cases of CAP both azithromycin and levofloxacin are effective when given as a single pill daily for 5 days. The costs of 5-day courses of azithromycin and levofloxacin are similar ($52 for the former and $58 for the latter at our hospital pharmacy). Both medications achieve effective tissue levels when administered orally. A cogent argument for choosing a macrolide rather than a respiratory fluoroquinolone is a desire to limit the growing problem of fluoroquinolone resistance in pneumococci25 and nosocomial aerobic Gram-negative bacilli.26 Choosing and using fluoroquinolones thoughtfully may be a better response to this problem than avoiding their use when clinically indicated.27 However, doing this may prove to be difficult.
Reasons for choosing a fluoroquinolone (rather than a macrolide or azalide) are numerous. First, if clinicians treat CAP in a manner that is consistent with the aforementioned ATS guidelines, the use of a respiratory fluoroquinolone allows monotherapy in almost all non-critically ill patients, pending microbiological and serological data. Such an approach simplifies decision making, saves money, and reduces the increased risk of adverse events seen with polypharmacy.28 Second, respiratory quinolones are very active against penicillin-resistant pneumococci compared to other antibiotics, including macrolides and azalides (although clinical failure with macrolides and azalides are rare). Finally, the aforementioned study showing increased mortality in patients treated with erythromycin10 should cause clinicians to pause prior to prescribing erythromycin when other simple alternatives are available. Whether there is an increased risk of death with the use of clarithromycin or azithromycin is unknown, but possibly is of concern. Whatever the reason, there is evidence that in recent years clinicians are writing more outpatient prescriptions for fluoroquinolones and fewer for macrolides in patients with CAP.29 Not surprisingly, fluoroquinolones are now the most commonly prescribed antibiotic class for adults in the United States, with 5% of these prescriptions being given for lower respiratory tract infections.30 As previously mentioned, this increasing use is associated with increasing resistance to these agents.
As infectious disease consultants who frequently see patients with CAP, we are most often asked "What’s the best drug?" While the choice of antimicrobial agents is obviously important, if clinicians follow credible treatment guidelines, the choice of one drug vs another is often just splitting hairs. Discordant antibiotic therapy is an infrequent cause of treatment failure in patients with CAP.31 Prompt diagnosis, the hospitalization of patients who are at risk for poor outcomes, the prompt institution of antibiotic therapy,32 and being alert for and appropriately managing complications such as hypoxemia, severe sepsis, and empyema are critical to improving patient outcomes. We strongly believe that, for now, CAP research should focus on the process of care, more rapid diagnosis, and developing novel antibiotics rather than choosing the "best" antibiotic.
References
This article has been cited by other articles:
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  Macrolides or Quinolones for Treatment of Legionnaires' Disease? Journal Watch Infectious Diseases, November 4, 2005; 2005(1104): 6 - 6. [Full Text]
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