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In vitro resistance to antimicrobial agents is escalating among pathogens responsible for the most serious respiratory tract infections. Some reports have suggested that this has direct clinical implications. Because of penicillin and macrolide resistance in Streptococcus pneumoniae, current guidelines for the initial treatment of respiratory tract infections advocate less reliance on the use of either of these classes of drugs in single-agent therapy. Recent studies that have assessed the impact of β-lactam and macrolide resistance on clinical outcomes in community-acquired pneumonia fail to provide incontrovertible evidence for a direct link between in vitro resistance and treatment failure. However, there are anecdotal reports of breakthrough bacteremia due to macrolide-resistant pneumococci among patients receiving macrolide therapy, unlike the situation for β-lactams and penicillin-resistant pneumococci. Continued efforts, including in vitro surveillance, appropriate antibiotic use campaigns, and immunization programs, will be important in limiting the spread of drug-resistant S. pneumoniae.