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The Alexander Project is a continuing surveillance study, begun in 1992, examining the susceptibility of pathogens involved in adult community-acquired respiratory tract infections (CARTI) to a range of antimicrobial agents.This study tested the susceptibility of isolates of Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis collected between 1998 and 2000 to 23 antimicrobials. Minimum inhibitory concentrations of agents were determined using the broth microdilution method and interpreted according to NCCLS and pharmacokinetic/pharmacodynamic (PK/PD) breakpoints.In total, 8882 isolates of S. pneumoniae, 8523 isolates of H. influenzae and 874 isolates of M. catarrhalis were collected during 1998–2000 from centres in 26 countries. The world-wide prevalence of penicillin resistance (penicillin MICs ≥ 2 mg/L) in isolates of S. pneumoniae was 18.2% over the study period, and the prevalence of macrolide resistance (erythromycin MICs ≥ 1 mg/L) in this pathogen was 24.6%. Over the study period, macrolide resistance exceeded penicillin resistance in 19 of the 26 countries included in the study. Of the non-fluoroquinolone agents, the only oral agents to which over 90% of S. pneumoniae isolates were susceptible at both NCCLS and PK/PD breakpoints were amoxicillin (95.1%) and co-amoxiclav (95.5–97.9%). The prevalence of fluoroquinolone-resistant S. pneumoniae (ofloxacin MICs ≥ 8 mg/L) was 1.1%. Gemifloxacin was the most potent fluoroquinolone tested against S. pneumoniae (99.9% susceptible). In isolates of H. influenzae, β-lactamase production was 16.9%, whereas the prevalence of β-lactamase-negative, ampicillin-resistant strains was low (0.2%). β-Lactamase production in M. catarrhalis world-wide remained high over the period studied (92.1%). Using PK/PD breakpoints, the most active non-fluoroquinolone agents against H. influenzae were ceftriaxone (100% susceptible), cefixime (99.8%) and co-amoxiclav (98.1–99.6%). Co-amoxiclav, cefdinir and cefixime (100%) were the most active β-lactams against M. catarrhalis. Both H. influenzae and M. catarrhalis were highly susceptible to the fluoroquinolones.These data demonstrate the continued evolution of and geographical variation in bacterial resistance and highlight the need for appropriate prescribing of antimicrobials in CARTI, using agents with adequate activity, based on local susceptibility profiles and PK/PD parameters.