Community-acquired pneumonia (CAP) is one of the leading causes of mortality [1–4]. This disease can be caused by a variety of pathogens, including typical and atypical bacteria. The most common typical bacteria causing CAP are Streptococcus pneumoniae and Haemophilus influenzae. The need to include empiric coverage for atypical bacteria, such as Mycoplasma pneumoniae, Chlamydophila pneumoniae and Legionella spp., for all hospitalized adult patients is controversial. Adding antibiotics to cover atypical bacteria might increase the likelihood of adverse effects, bacterial resistance, and cost; However, routine empiric atypical coverage is recommended by the current major guidelines for CAP [1–4].

Prior meta-analyses of randomized clinical trials (RCTs) of atypical coverage for CAP have not demonstrated the benefit of empiric atypical coverage in the treatment of hospitalized adults with CAP. It should be noted, however, that these meta-analyses had major limitations despite including a large number of trials [5–7]. The two meta-analyses that found mortality benefit of empiric atypical coverage were based mainly on observational studies [8, 9].

The primary objective of this meta-analysis was to evaluate the impact of atypical coverage on rates of clinical failure with guideline-recommended antibiotic regimens. Rates of mortality, bacteriologic failure, and adverse events were evaluated as secondary outcomes. The meta-analysis was limited to RCTs comparing treatments with atypical coverage (a fluoroquinolone or combination of a macrolide/doxycycline with a β-lactam) to a regimen without atypical antibiotic coverage (β-lactam monotherapy).

The meta-analysis was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (Additional file 1: Table S1).

Our meta-analysis of RCTs confirms the benefit of empiric atypical bacteria coverage in hospitalized adult patients with CAP, unlike the other meta-analyses. This meta-analysis provides support for the current major guideline recommendations, including U.S guidelines of Infectious Diseases Society of America as well as European guidelines [1–4], using studies that used regimens recommended by these guidelines. The principal finding of our meta-analysis is that including empiric atypical coverage reduced the rates of clinical failure by approximately 15%. It should be noted that no single trial in our meta-analysis reported a statistically significant difference in the efficacy outcome, though there was a favorable trend in all 5 trials. However, the non-inferiority study by Garin et al., in which the empiric non-atypical bacterial coverage arm failed to meet the pre-specified non-inferiority threshold [14]. It is worth mentioning that a significant difference in clinical cure was found in previous meta-analyses favoring empiric atypical coverage in patients who had Legionella pneumonia [5, 6].

Our meta-analysis did not find a significant difference in mortality rates, which is consistent with other meta-analyses of RCTs [5–7]. Regimens that provided atypical coverage did not result in significantly more adverse events; however, adverse events were assessed in the studies involving respiratory fluoroquinolones and not in the macrolide-β-lactam combination study. The individual studies were not powered to detect differences in mortality and were not focused on adverse events. It remains unclear if adding empiric atypical coverage with a macrolide or doxycycline to a β-lactam increases the rate of adverse events. Future RCTs should evaluate benefits in terms of efficacy and potential harm in terms of adverse events and increased cost.

Our meta-analysis differs from prior meta-analyses of RCTs [5–7]. These meta-analyses included some studies of non-recommended comparators. For example, the inclusion of ciprofloxacin as monotherapy would be inappropriate due to poor activity against S. pneumoniae. The use of macrolide monotherapy may be inappropriate for the same reason and depending on the selected macrolide, coverage of H. influenzae may be poor. Studies of agents that have been withdrawn from the market, such as temafloxacin, have been included in these meta-analysis. Another limitation of prior meta-analyses is a focus on longer term outcomes (e.g. at 30 day follow up) and, therefore, any observed benefit could be attributed to confounding factors. The inclusion of studies that permitted adding empiric atypical coverage to the arm the should have lacked atypical coverage could bias the results against the benefit of including atypical coverage because it makes the two groups more similar and reduce our ability to assess the true benefit of empiric atypical coverage.

The stringent inclusion criteria make our meta-analysis unique, increases its clinical relevance, and addresses antibiotic regimens recommended in major CAP guidelines. Published studies including non-recommended and withdrawn antibiotics for hospitalized CAP adults were excluded to provide results that are relevant to clinical practice. In addition, we preferred clinical failure rates that were reported earlier rather than at the final assessment at post therapy follow up. Using outcomes collected at around day 30 post treatment allows for accumulation of confounding events including changes in therapy and evolution of underlying illness. For example, clinical failure rates in the Petitpretz et al. study [12] were 46/200 (23%) vs. 44/208 (21.2%) in two meta-analyses [5, 6] because they reported the rates during follow-up; the rates were 27/200 (12.2%) vs 37/208 (17.8%) in one meta-analysis [8] as well as ours when using rates reported at the end of therapy (rates difference, 1.8% vs 5.6%, respectively). RCTs should embrace early clinical outcome as an endpoint since this provides the most direct information about antimicrobial efficacy and improves discrimination of differences between treatments. The Food and Drug Administration’s 2014 guidance for developing drugs for treatment of community-acquired bacterial pneumonia stated that the time points at 36–48 h and 48–72 h after starting therapy demonstrate the greatest treatment effect of clinical recovery [17]. The guidance calls for a primary endpoint assessment on day 3 to day 5 of treatment.

Only five RCTs were found that meet our inclusion criteria. Despite the relatively small number of studies, subgroup analyses were performed for completeness and are available in the Additional file 1. Exclusion by language of publication can introduce bias and affects the results. However, only one study was excluded because of language in our meta-analysis [16]. Given the fact that the results of this study were available in an English abstract, we verified that including this study would not have altered the conclusions of our meta-analysis. Unfortunately, most RCTs have not reported detailed information about resistance rates, which is important to consider in studies of infectious diseases. Amoxicillin was used for typical coverage in one of the studies that we included and the coverage that this agent provides coverage that is inferior to that of moxifloxacin against S. pneumoniae, H. influenzae and M. catarrhalis. However, only one study included amoxicillin, in which all patients had their H. influenzae eradicated except three patients [13]. Amoxicillin is one of the recommended antibiotics per major guidelines and it is preferred over other excluded agents such as ciprofloxacin. Since moxifloxacin provides atypical coverage and better typical coverage, the treatment effect is not limited to the additional atypical coverage. Two of the studies included amoxicillin/clavulanate for typical bacterial coverage. The only deficiency here would be in coverage of penicillin non-susceptible S. pneumoniae; however, the incidence of these isolates in CAP studies is typically low [18–20]. In fact, this coverage deficit could be a problem when comparing any beta-lactam other than ceftaroline to a respiratory fluoroquinolone. If the goal is to evaluate impact of atypical coverage, then confounding factors need to be minimized. Therefore, a trial of ceftaroline versus ceftaroline plus a macrolide or respiratory fluoroquinolone would be valuable to sort out the effect of atypical coverage.

Etiologic diagnosis has evolved so that the pathogen can be identified in almost 90% of CAP cases [21]. In one study, atypical pathogens were detected in just over 4% of CAP cases [21]; however, there are outbreaks of Legionella spp. and areas with higher endemic incidence [22]. Given this low incidence, it is unlikely that any single RCT will ever be able to demonstrate the effect of atypical coverage for CAP. A better approach would be to include empiric atypical coverage for hospitalized (sicker) patients with CAP and then streamline therapy if the etiology is identified.

Our restricted but targeted meta-analysis of RCTs was able to define a significant reduction (approximately 15%) in clinical failure with the inclusion of atypical coverage in hospitalized adults with CAP. No significant differences were found in terms of secondary outcomes including mortality, bacteriologic failure and adverse events. Our meta-analysis provides supports for the current recommendations of the major CAP guidelines. However, some of the difference noted may be due to differences in typical coverage between treatment arms.