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Several medical-specialty professional societies have suggested that combination therapy with a β-lactam plus a macrolide or doxycycline or monotherapy with a “respiratory quinolone” (i.e., levofloxacin, gatifloxacin, moxifloxacin, or gemifloxacin) are optimal first-line therapy for patients hospitalized with community-acquired pneumonia. These recommendations are based predominantly on retrospective studies that suggest improved rates of morbidity and mortality and hospital length of stay among patients treated in such a fashion. Well-designed, prospective, randomized studies confirming this tenet of therapy have not been published, although numerous prospective studies have provided indirect confirmation. The biological rationale for such a differential response (i.e., favoring combination therapy or fluoroquinolone therapy) includes the immunomodulatory effects of macrolides or more-optimal treatment of primary infection or coinfection with atypical pathogens. Well-designed, prospective, randomized trials are required to best define the effectiveness of combination therapy with a β-lactam plus macrolide or doxycycline or with a respiratory quinolone in hospitalized patients with community-acquired pneumonia.