In this pragmatic, cluster-randomized, crossover trial, a strategy of preferred empirical treatment with beta-lactam monotherapy was noninferior to strategies of treatment with beta-lactam–macrolide combination therapy and with fluoroquinolone monotherapy among patients with suspected CAP who were admitted to non-ICU wards. Moreover, there were no clinically relevant differences among treatment strategies in the length of hospital stay or in reported complications. The median time to starting oral treatment was shorter with the fluoroquinolone strategy, mainly because more patients during those strategy periods started with oral empirical treatment at admission, but this did not result in a decreased length of hospital stay.

Our approach differs from those of previous studies in four aspects. First, this study addressed treatment strategies, rather than individual antibiotics, in the treatment of patients hospitalized with a clinical suspicion of CAP. To reflect daily medical practice, we allowed for deviations from the assigned therapy for medical reasons. To minimize confounding, all the patients were included in the intention-to-treat analysis. Although deviations and switches reduced the differences among treatment strategies, empirical atypical coverage was reduced by 67% during the beta-lactam strategy periods as compared with the beta-lactam–macrolide strategy periods and by 69% during the beta-lactam strategy periods as compared with the fluoroquinolone strategy periods. The number of in-hospital days with atypical coverage was also reduced during the beta-lactam strategy periods, by 57% and 62%, respectively. In the post hoc analysis of the strategy-adherent and antibiotic-adherent populations, the beta-lactam strategy remained noninferior to the beta-lactam–macrolide strategy. In the crude analysis of the antibiotic-adherent population, the lower limit of the confidence interval crossed −3 percentage points for the comparison between beta-lactam and fluoroquinolone monotherapy; however, after adjustment for confounders, the lower limit of the confidence interval fell within the defined margins of noninferiority.

Second, we used a cluster-randomized design that allowed for an immediate start of the assigned empirical treatment strategy. The crossover component increased the efficiency of the trial by allowing comparisons of the effect of the strategies within each cluster and ensuring that all hospitals used all three strategies, a design that minimized the possibility of confounding. Despite the risk of selection bias that is inherent to cluster-randomized studies, the baseline characteristics of the patients were similar among strategies, and statistical adjustment for potential confounders changed the findings only minimally. Differential inclusion of patients across treatment groups was unlikely, given the similar age patterns for nonincluded patients and similar enrollment rates. We were not allowed to collect data on other characteristics of the patients who were not included. The pathogens found were similar among strategy groups, but the resistance of pathogens to the actual treatment was highest during the beta-lactam strategy periods. This did not appear to lead to a worse outcome, possibly because not all were proven causative pathogens and because of antibiotic switches.

Third, all patients for whom the antibiotic strategy might have been used in daily practice were eligible for enrollment, which increases the generalizability of the results. Although this could increase the heterogeneity of the population and the potential for bias toward noninferiority, the effect estimates were similar in the sensitivity analysis that included only patients with radiologically confirmed CAP.

Finally, the primary end point was 90-day all-cause mortality, because CAP is associated with high long-term mortality and this is a patient-relevant outcome that is not susceptible to observation bias.17,29,30 An unplanned sensitivity analysis with 30-day mortality as the outcome yielded similar results. Among the secondary outcomes, complications, which were extracted from the medical records, might have been misclassified and subject to observation bias.

The noninferiority of the beta-lactam strategy to the beta-lactam–macrolide strategy was apparent in all analyses. These findings, together with the slightly longer length of hospital stay with the latter strategy, reported associations with the development of resistance,7,8 and possible increased risks of cardiac events,31,32 indicate that the addition of macrolides for empirical treatment of CAP should be reconsidered. In a recent randomized, controlled trial, the noninferiority of beta-lactam monotherapy to beta-lactam–macrolide combination therapy with respect to clinical stability at day 7 could not be shown, although superiority of the beta-lactam–macrolide combination therapy was not shown, either. Moreover, 30-day and 90-day all-cause mortality and length of hospital stay were similar with the two therapies.33 Differences between that study and the current study include the strict criteria for eligibility and for switching therapy in cases of clinical deterioration in that study.

Some aspects of our study require explanation. In the noninferiority design, we used one-sided testing with an alpha significance level of 0.05. With 95% confidence intervals — that is, an alpha level of 0.025 — the noninferiority of beta-lactams to fluoroquinolones was not shown (Figure 2); however, there was no clear trend toward superiority for fluoroquinolones in any of the other adjusted analyses.

Differences in the numbers of eligible patients per strategy resulted from cluster randomization. The beta-lactam and fluoroquinolone strategies were assigned more frequently during the 2011–2012 and 2012–2013 winter seasons, respectively, and more patients were hospitalized during 2012–2013 winter months. However, the proportions of patients included were similar throughout the seasons and among strategies (Figure 1, and Fig. S2 in the Supplementary Appendix). Although a low incidence of atypical infections during the 2011–2012 winter season could have favored the beta-lactam strategy, national surveillance data showed a higher incidence of Mycoplasma pneumoniae infections, mostly CAP, during that period,34 for which the beta-lactam strategy might have been less effective. The outbreak of Q fever in the Netherlands ended before the start of the current study,35 and the distribution of pathogens was similar to those in other studies that have relied on routine microbiologic testing.36-38

Regional differences in microbial causes could reduce the generalizability of our findings. However, resistance of S. pneumoniae to penicillin,39 which rarely occurs in the Netherlands, is unlikely to influence the outcome in patients with pneumonia treated with beta-lactam antibiotics.40 The prevalence of S. pneumoniae resistance to macrolides was 4.2% in the Netherlands in 2011.39 The incidence of legionella in this study was less than 1%. A higher incidence could influence the effectiveness of empirical treatment with beta-lactam monotherapy, which stresses the importance of rapid testing in patients with risk factors for Legionnaires’ disease. In the current study, rapid urinary antigen testing for legionella was performed in 492 patients (75%) during the beta-lactam strategy periods; 5 of the patients (1%) tested positive, 2 of whom received ciprofloxacin empirically because of a high clinical suspicion. For the other 3 patients, antibiotic therapy was adjusted after test results became available. All 5 patients had a good clinical outcome. Higher incidences of community-acquired Pseudomonas aeruginosa or methicillin-resistant Staphylococcus aureus infections would require the adaptation of all three treatment strategies.

In conclusion, among patients with suspected CAP who were admitted to non-ICU wards, we found that a strategy of preferred empirical treatment with beta-lactam monotherapy that allowed for deviations for medical reasons was noninferior to strategies with beta-lactam–macrolide combination therapy or fluoroquinolone monotherapy in terms of 90-day all-cause mortality. In addition, beta-lactam monotherapy was not associated with a longer length of hospital stay or a higher incidence of complications.