Pharmacokinetic/pharmacodynamic parameters were used to interpret susceptibility data for the oral agents tested in a clinically meaningful way. Among S pneumoniae isolates, >99% were susceptible to respiratory fluoroquinolones, 91.6% to amoxicillin, 92.1% to amoxicillin/clavulanic acid (95.2% at the extended-release formulation breakpoint), 90.6% to clindamycin, 80.4% to doxycycline, 71.0% to azithromycin, 72.3% to clarithromycin, 71.8% to cefprozil and cefdinir, 72.6% to cefuroxime axetil, 66.3% to cexime, 63.7% to trimethoprim/sulfamethoxazole, and 19.7% to cefaclor. Among H influenzae isolates, 28.6% were b-lactamase positive, but virtually all were susceptible to amoxicillin/clavulanic acid (98.3%, with 99.8% at the extended-release formulation breakpoint), cexime (100%), and uoroquinolones (99.8%), whereas 93.5% were susceptible to cefdinir, 82.8% to cefuroxime axetil, 78.1% to trimethoprim/sulfamethoxazole, 70.2% to amoxicillin, 25.1% to doxycycline, 23.2% to cefprozil, and 5% to cefaclor, azithromycin and clarithromycin. Most isolates of M catarrhalis were resistant to amoxicillin, cefaclor, cefprozil, and trimethoprim/sulfamethoxazole. Thus significant b-lactam and macrolide/azalide resistance in Streptococcus pneumoniae and b-lactamase production and trimethoprim/sulfamethoxazole resistance in untypeable Haemophilus influenzae are still present. The results of this study should therefore be applied to clinical practice based on the clinical presentation of the patient, the probability of the patient's having a bacterial rather than a viral infection, the natural history of the disease, the potential of pathogens to be susceptible to various oral antimicrobial agents, the potential for cross-resistance between agents with S pneumoniae, and the potential for pathogens to develop further resistance. Antibiotics should be used judiciously to maintain remaining activity and chosen carefully based on activity determined by pharmacokinetic/pharmacodynamic-based breakpoints to avoid these bacteria developing further resistance, particularly to fluoroquinolones.