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Antibacterial resistance was evaluated among Streptococcus pneumoniae (n=252) and Haemophilus influenzae (n=202) from two centres in Spain (Barcelona and Madrid) and two centres in Italy (Genoa and Catania) collected during 1999-2000 as part of the ongoing PROTEKT (Prospective Resistant Organism Tracking and Epidemiology for the Ketolide Telithromycin) international surveillance program. Pneumococcal nonsusceptibility to penicillin G was found to be considerably higher in Spain (53.4%) than in Italy (15.1%), whereas erythromycin A resistance was higher in Italy (42.9%) than in Spain (28.6%). Among macrolide-resistant isolates investigated for resistance genes, the prevalence of mefA was higher among isolates from Italy (20/51, 39.2%) than among Spanish isolates (2/38, 5.3%). All other macrolide-resistant isolates possessed ermB. Telithromycin possessed good anti-pneumococcal activity against isolates from both countries (MIC90 0.03 mg/L [Spain]; 0.25 mg/L [Italy]), irrespective of resistance to other antibacterials. Beta-lactamase production among H. influenzae was low: Spain, 10.9%; Italy, 1.8%. With the exception of ampicillin and co-trimoxazole, all H. influenzae isolates were highly susceptible to the antibacterials tested, and all were inhibited by telithromycin at a concentration of < or = 2 mg/L. The findings of PROTEKT 1999-2000 highlight the importance of local resistance patterns in guiding the choice of empirical antibacterials for community-acquired respiratory tract infections.