Choosing the right combination therapy in severe community-acquired pneumonia

In the past 5 years there has been a substantial shift in thinking regarding the optimal therapy of patients with severe community-acquired pneumonia (CAP), particularly with respect to pneumococcal disease. Observational studies by Mufson and Stanek [1], Waterer et al. [2], Martinez et al. [3], Baddour et al. [4] and Weiss et al. [5] have all identified significant mortality reductions in patients with bacteraemic pneumococcal pneumonia who received combination antibiotic therapy in comparison with patients who received monotherapy. Additional observational studies in more general CAP cohorts have also identified outcome benefits of combination therapy over monotherapy [6-9].Despite the limitations of these primarily retrospective observational studies, the similar findings in different populations makes it very likely that the association is real. However, it remains unclear whether there is a true survival advantage of combination therapy or whether there are common confounding factors related to patient selection, to the process, to quality or to care.In this issue, Mortensen et al. [10] demonstrate that, at least in their region, physicians have widely adopted combination therapy in patients with severe CAP. In contrast with previous studies, an important strength is that a large proportion of patients were intubated by severe respiratory failure. The findings of Mortensen et al. that fluoroquinolone/β-lactam combinations were associated with worse outcome than other combination regimens is both enlightening and disturbing.The most consistent finding across the retrospective studies favouring combination therapy is that it is the addition of a macrolide to a third-generation cephalosporin that has the best outcome [1-3,6,7,9]. What is not clear is the mechanism by which the addition of a macrolide is beneficial. Possible explanations include coverage of unrecognized co-infection with atypical pathogens, non-ribosomal anti-pneumococcal activity such as impairmen