Rethinking Antibiotic Therapy for Mild-to-Moderate CAP

By Jacob Ufberg, MD Assistant Professor of Emergency Medicine, Residency Program Director, Department of Emergency Medicine, Temple University School of Medicine, Philadelphia, PA Dr. Ufberg discloses that he is a researcher for Pfizer Pharmaceuticals.

Source: Mills GD, et al. Effectiveness of beta-lactam antibiotics compared with antibiotics active against atypical pathogens in non-severe community acquired pneumonia: meta-analysis. BMJ 2005;330:456-460.

For more than 100 years, Streptococcus pneumoniae has been considered the major causative organism in community-acquired pneumonia (CAP); however, more recent microbiologic advances led to the discovery of Mycoplasma pneumoniae, Legionella pneumophilia, and Chlamydia pneumoniae — the so-called atypical pathogens. The distinguishing feature of the atypical pathogens is the lack of in vitro response to beta-lactam and sulfon-amide antibiotics, while clinical presentations are quite similar. Evidence for the need to cover atypical pathogens in CAP is weak, and published guidelines on the initial treatment of CAP vary. While the American Thoracic Society (ATS) supports the treatment of all CAP using agents with activity against atypical pathogens, the British Thoracic Society considers S pneumoniae the most important target of initial therapy and does not suggest targeting atypical pathogens in all cases.

This study was a meta-analysis of double-blind, randomized, controlled monotherapy trials comparing beta-lactam antibiotics with antibiotics active against atypical pathogens in adults with CAP. The primary outcome was failure to achieve improvement or clinical cure at the time of outcome assessment in each trial. The 18 trials identified for inclusion were performed in more than 30 countries between 1980 and 2000 and included 6749 participants. The trials used nine different fluoroquinolones, two macrolides, and one ketolide; the beta-lactams used were predominantly amoxicillin, amoxicillin/clavulanic acid, or cefaclor. Common exclusion criteria (although different in each trial) included hospital-acquired or aspiration pneumonia, immunocompromise, and major hepatic or renal dysfunction. The resulting patient mix in the trials was younger and had a better risk profile than observational pneumonia cohorts.

The overall rate of treatment failure for all trials was 18%. The authors found no significant heterogeneity between studies, and no significant difference between treatments in any study. In the combined analysis, the authors found no evidence that antibiotics active against atypical pathogens were superior to beta-lac-tam antibiotics (relative risk 0.97, 95% CI, 0.87 to 1.07). Separate analyses of studies using fluoro-quinolones (RR 0.99, 95% CI, 0.88 to 1.11) and macrolides and ketolides (0.81, 95% CI, 0.58 to 1.14) similarly showed no superiority of antibiotics active against atypical pathogens.

The overall mortality rate was 1.9%; this number is in keeping with the 1.5% mortality rate reported previously for mild-to-moderate pneumonia (i.e., class 1 to 3 by the prognostic index scoring developed by Fine and colleagues).1 The authors observed no difference in mortality between the study arms (RR 1.20, 95% CI, 0.84 to 1.71). In the 18 studies, 311 patients were diagnosed with M pneumoniae, 115 with C pneumoniae, and 75 with Legionella species. No treatment effect was found in patients with M pneumoniae (RR 0.60, 95% CI, 0.31 to 1.17) or C pneumoniae (RR 2.32, 95% CI, 0.67 to 8.03). The antibiotic failure rate for agents active against atypical pathogens was, however, statistically lower among patients diagnosed with CAP caused by Legionella species.

The authors concluded that their data did not support the need for antibiotics active against atypical pathogens in the initial management of adults with mild-to-moderate CAP. They stated that when antibiotics active against atypical pathogens were used, only Legionella pneumonia showed statistical improvement in outcome. They further stated that Legionella is sufficiently uncommon (<3%) in mild-to-moderate CAP, such that coverage for this possibility is not warranted in the initial management of non-severe CAP. The authors stated that this study provided the best evidence currently available regarding the need for antibiotics in non-severe CAP


This is a fascinating study that directly opposes the ATS guidelines for the outpatient treatment of mild-to-moderate CAP. While the ATS guidelines are based upon available evidence and expert opinion, this study provided contrary evidence. Physicians should feel comfortable in prescribing beta-lactam antibiotics in low-risk patients receiving outpatient treatment for CAP. Several issues will limit the extrapolation of these data to the community at large, however.

First, the patients in this study generally were younger and healthier (with less comorbidity) than the average cohort of CAP patients. It is important to note that these results should not be applied to patients with mild-to-moderate CAP who are being admitted for intravenous antibiotics, as almost all patients received oral therapy in this study. (Approximately half of pneumonia patients admitted to a hospital have mild-to-moderate pneumonia.) The exclusion criteria above also should be noted; these findings may not apply to the excluded patient groups.

Second, this study found a significant treatment difference among patients with Legionella pneumonia. While this subgroup is small, physicians should be aware of local differences in prevalence of pathogens causing CAP; these differences may affect prescribing patterns. Also, physicians should be aware of some of the common clinical and laboratory findings associated with Legionella, and expand antibiotic coverage on a case-by-case basis if Legionella seems more likely.

Third, physicians must be aware of local antibiotic susceptibility patterns for all relevant organisms, including S pneumoniae.