title: Activities of moxifloxacin against, and emergence of resistance in, Streptococcus pneumoniae and Pseudomonas aeruginosa in an in vitro pharmacokinetic model.
abstract: The pharmacodynamics of moxifloxacin against Streptococcus pneumoniae and Pseudomonas aeruginosa were investigated in a pharmacokinetic infection model. Three strains of S. pneumoniae, moxifloxacin, and two strains of P. aeruginosa were used. Antibacterial effect and emergence of resistance were measured for both species over a 72-h period using an initial inoculum of about 10(8) CFU/ml. At equivalent area under the curve (AUC)/MIC ratios, S. pneumoniae was cleared from the model while P. aeruginosa was not. For S. pneumoniae, the area under the bacterial kill curve up to 72 h could be related to AUC/MIC ratio using an inhibitory maximum effect (E(max)) model (concentration required for 50% E(max) [EC(50)], 45 +/- 22; r(2), 0.97). For P. aeruginosa even at the highest AUC/MIC ratio (427), bacterial clearance was insufficient for the EC(50) to be calculated. Emergence of resistance occurred with P. aeruginosa but not to any significant extent with S. pneumoniae. Emergence of resistance in P. aeruginosa as measured by population analysis profile (PAP-AUC) was dependent on drug exposure and time of exposure. In weighted least-squares regression analysis AUC/MIC ratio was predictive of PAP-AUC. When emergence of resistance was measured by the time for the colony counts on media containing antibiotic to increase by 2 logs, again AUC/MIC was the best predictor of emergence of resistance. However, for both experiments using S. pneumoniae and P. aeruginosa the correlation between all the pharmacodynamic parameters was high. These data indicate that for a given fluoroquinolone the magnitude of the AUC/MIC ratio for antibacterial effect is dependent on the bacterial species. Emergence of resistance is dependent on (i) species, (ii) duration of drug exposure, and (iii) drug exposure. A single AUC/MIC ratio magnitude is not adequate to predict antibacterial effect or emergence of resistance for all bacterial species.
authors.affiliation: Bristol Centre for Antimicrobial Research and Evaluation, University of Bristol and North Bristol NHS Trust, Department of Medical Microbiology, Southmead Hospital, Westbury-on-Trym, United Kingdom. macgowan_a@southmead.swest.nhs.uk
authors.forename: Alasdair P
authors.initials: AP
authors.lastname: MacGowan
authors.forename: Chris A
authors.initials: CA
authors.lastname: Rogers
authors.forename: H Alan
authors.initials: HA
authors.lastname: Holt
authors.forename: Karen E
authors.initials: KE
authors.lastname: Bowker
mesh_terms: D000890:Anti-Infective Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D019540:Area Under Curve; D001372:Aza Compounds; D015169:Colony Count, Microbial; D003470:Culture Media; D024881:Drug Resistance, Bacterial; D024841:Fluoroquinolones; D006207:Half-Life; D008826:Microbial Sensitivity Tests; D000077266:Moxifloxacin; D011008:Pneumococcal Infections / Q000188:drug therapy* / Q000382:microbiology; D011552:Pseudomonas Infections / Q000188:drug therapy* / Q000382:microbiology; D011550:Pseudomonas aeruginosa / Q000187:drug effects*; D011804:Quinolines; D012044:Regression Analysis; D013296:Streptococcus pneumoniae / Q000187:drug effects*
chemical_list: D000890:Anti-Infective Agents; D001372:Aza Compounds; D003470:Culture Media; D024841:Fluoroquinolones; D011804:Quinolines; D000077266:Moxifloxacin