title: Exploration of the in-vitro pharmacodynamic activity of moxifloxacin for Staphylococcus aureus and Streptococci of lancefield groups A and G.
abstract: The serum concentrations associated with the oral administration of 400 mg moxifloxacin every 24 h over 48 h in man were simulated in an in-vitro dilutional, continuous bacterial culture model of infection. The initial inoculum was 5 x 10(7)-5 x 10(8) cfu/mL and all strains were tested on at least three occasions. Two strains of Staphylococcus aureus (one methicillin susceptible, the other resistant) with moxifloxacin MICs 0.14 mg/L and 0.06 mg/L and two strains of beta-haemolytic streptococci, Lancefield Group A, MIC 0. 16 mg/L and Group G, MIC 0.4 mg/L were used. In addition, two laboratory-generated mutants with raised moxifloxacin MICs were also employed: methicillin-sensitive S. aureus (MSSA) MIC 1.0 mg/L and Group A streptococcus MIC 1.8 mg/L. The antibacterial effect of moxifloxacin was judged by changes in viable count over time, and the area under the bacterial-kill curve (AUBKC) after 24 and 48 h. For S. aureus MIC 0.14 mg/L the AUBKC(24) (log cfu/mL.h) was 77.8 +/- 4.6 and AUBKC(48) 92.0 +/- 6.9. For its mutant, moxifloxacin MIC 1.0 mg/L, the AUBKC(24) was 116.1 +/- 15.6 and AUBKC(48) 211.9 +/- 23.1, indicating decreased killing. AUBKC(24) and AUBKC(48) values of 110.7 +/- 10.3 and 130.9 +/- 21.3, respectively, were noted for the MRSA strain. The Group A streptococcus, MIC 0.16 mg/L, had an AUBKC(24) of 91.4 +/- 19.4 and AUBKC(48) of 157.0 +/- 70.9. The mutant, MIC 1.8 mg/L, had an AUBKC(24) of 127.0 +/- 1.9 and AUBKC(48) of 205.1 +/- 6.4. Despite a lower MIC (0.4 mg/L) the single strain of Group G streptococcus tested was killed poorly, AUBKC(24) 139.9 +/- 3.6 and AUBKC(48) 252.3 +/- 18.6. The pharmacodynamic parameters AUC/MIC, T > MIC, (AUC > MIC)/MIC (AUC = area under the curve, T = time) and WAUC ((AUC/MIC) (T > MIC/100)) (WAUC = weighted area under the curve) were related to AUBKC(24) and AUBKC(48) using an inhibitory sigmoid E(max) model. T > MIC was poorly related to AUBKC (r = 0.36) while AUC/MIC, (AUC > MIC)/MIC and WAUC were strongly related to AUBKC(24) (r = 0.75-0.79) and AUBKC(48) (r = 0.78-0.84). The maximum antibacterial effect was achieved with an AUC/MIC ratio of 150-200. AUC-related pharmacodynamic parameters predicted antibacterial effect better than T > MIC.
authors.affiliation: Bristol Centre for Antimicrobial Research and Evaluation, North Bristol NHS Trust and University of Bristol, Department of Medical Microbiology, Southmead Hospital, Westbury-on-Trym, Bristol BS10 5NB, UK.macgowan_a@southmead.swest.nhs.uk
authors.forename: A P
authors.initials: AP
authors.lastname: MacGowan
authors.forename: K E
authors.initials: KE
authors.lastname: Bowker
authors.forename: M
authors.initials: M
authors.lastname: Wootton
authors.forename: H A
authors.initials: HA
authors.lastname: Holt
mesh_terms: D000890:Anti-Infective Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D001372:Aza Compounds; D015169:Colony Count, Microbial; D003470:Culture Media; D024841:Fluoroquinolones; D006801:Humans; D008826:Microbial Sensitivity Tests; D000077266:Moxifloxacin; D011804:Quinolines; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000254:growth & development; D013291:Streptococcus / Q000187:drug effects* / Q000254:growth & development; D013297:Streptococcus pyogenes / Q000187:drug effects* / Q000254:growth & development
chemical_list: D000890:Anti-Infective Agents; D001372:Aza Compounds; D003470:Culture Media; D024841:Fluoroquinolones; D011804:Quinolines; D000077266:Moxifloxacin