The choice of antibiotic therapy in respiratory tract infections is usually empirical. However, this choice is complicated by the increasing prevalence of resistant strains among the major bacterial pathogens involved in these infections, particularly Streptococcus pneumoniae. The aim of antimicrobial therapy in respiratory tract infections should be bacterial eradication, which is necessary to maximize clinical cure and minimize the development and spread of resistance. An increase in antimicrobial resistance reduces the probability of achieving eradication and increases the probability of clinical failure. Recent reports have demonstrated the clinical relevance of respiratory bacterial resistance to macrolides and some fluoroquinolones and betalactams. Unlike macrolide and fluoroquinolone resistance, penicillin resistance in Streptococcus pneumoniae can be overcome by increasing the dose, and hence increasing the time during which serum concentrations are above the MIC. Pharmacokinetic/pharmacodynamic (PK/PD) parameters can be used to establish breakpoints predictive of bacterial eradication. From the viewpoint of PK/PD, in Spain only high-doses of amoxicillin/clavulanic acid (875/125 mg tid and 2000/125 mg bid) and levofloxacin, among the oral antibiotics considered, achieve optimal coverage against S. pneumoniae and Haemophilus influenzae.