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Respiratory tract infections account for more than 116 million office visits and an estimated 3 million visits to hospital EDs annually. Patients presenting at EDs with symptoms suggestive of lower respiratory tract infections of suspected bacterial etiology are often severely ill, thus requiring a rapid presumptive diagnosis and empiric antimicrobial treatment. Traditionally, clinicians have relied on β-lactam or macrolide antibiotics to manage community-acquired lower respiratory tract infections. However, the emerging resistance of Streptococcus pneumoniae to β-lactams and/or macrolides may affect the clinical efficacy of these agents. Inappropriate use of antibiotics and use of agents with an overly broad spectrum of antimicrobial activity have contributed to the emergence of antibiotic resistance. When treating respiratory infections, clinicians need to prescribe antimicrobial agents only for those individuals with infections of suspected bacterial etiology; to select agents with a targeted spectrum of activity that ensures coverage against typical S pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis strains, including antibiotic-resistant strains and atypical pathogens; and to consider agents with specific chemical properties that limit the development of antimicrobial resistance and that achieve concentrations at sites of infection that exceed those required for bactericidal activity. Newer classes of antimicrobial agents, such as the oxazolidinones and ketolides, will likely play a significant role in this era of antimicrobial resistance.