Clin Microbiol Infect 2013; 19: 257264 Abstract For patients hospitalized with pneumonia, guidelines provide empirical antibiotic recommendations and some studies suggest that macrolide/-lactam combinations are preferable. We hypothesized that guideline-concordant regimens, particularly macrolide/-lactams, would reduce mortality and ICU admissions. All patients hospitalized with pneumonia in Edmonton, Alberta, Canada, were managed according to a clinical pathway and enrolled in a population-based registry. Clinical data, Pneumonia Severity Index and treatments were collected. Guideline-concordant regimens were macrolides/-lactams or respiratory fluoroquinolone monotherapy. The main outcome was in-hospital mortality. The study included 3203 patients and most had severe pneumonia (63% PSI Class IV-V). Three hundred and twenty-one (10.0%) patients died, 306 (9.6%) were admitted to the ICU and 570 (17.8%) achieved the composite of death or ICU admission. Most (n=2506) patients received guideline-concordant antibiotics. Receipt of guideline-concordant antibiotics was not associated with a reduction in mortality alone (231 (9.2%) vs. 90 (12.9%); adjusted odds ratio (aOR), 0.82; 95% CI, 0.611.09; p0.16), but was associated with decreased death or ICU admission (14.7% vs. 29.0%; aOR, 0.44; 95% CI, 0.360.54; p<0.0001). Within guideline-concordant subgroups, there was no difference in mortality between macrolide/-lactams and respiratory fluoroquinolone monotherapy (22 (8.3%) vs. 209 (9.3%); aOR, 1.09; 95% CI, 0.661.81; p0.73) but macrolide/-lactams were associated with increased odds of death or ICU admission (17.4% vs. 14.4%; aOR, 1.58; 95% CI, 1.092.27; p0.01). In conclusion, guideline-concordant antibiotics were not associated with decreased mortality for patients hospitalized with pneumonia, but were associated with a decrease in the composite endpoint of death or ICU admission. Our findings do not support any clinical advantage of macrolide/-lactam compared with respiratory fluoroquinolone monotherapy.