Increase of in vitro amoxycillin bactericidal activity by clavulanic acid against Neisseria meningitis using time-kill curves.
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Biomedical subjects
Publications and source records attributed to L Alou.
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Pharmacodynamic in vitro models that simulate serum antimicrobial concentrations provide more information about the activity of an antibiotic than MICs or traditional time-kill methods. The aim of this study was to compare two pharmacodynamic simulation models using ATCC strains of five different species and five antibiotics. In the first model (Centriprep-10 system), a filtration-centrifugation process was used to eliminate the antibiotic; in the second model (microfiltration system) no centrifugation was necessary. The antibiotic concentrations tested were similar to those in serum after normal doses of cefuroxime, clarithromycin, ciprofloxacin, gentamicin and cefotaxime. No significant differences were observed in the killing rates between the models except in the case of Haemophilus influenzae and cefotaxime. The new microfiltration model had the following advantages: lack of the carry-over effect, the absence of centrifugation that could damage bacteria and the possibility of increasing the number of incubation periods to give a better fit of the kinetic profile of man.
The serum bactericidal activity against 2 Streptococcus pneumoniae strains (ciprofloxacin MIC 1 and 4 mg/l) was measured in 12 volunteers who received oral single doses of gemifloxacin 320 mg and trovafloxacin 200 mg in a crossover fashion. The 4-fold increase in ciprofloxacin MIC from the susceptible to the resistant strain resulted in a 2-fold increase in MIC (from 0.015 to 0.03 mg/l), a 2-fold decrease in C(max)/MIC (104 vs 52) and in AUC(0-24 h)/MIC (532 vs 266), but a 5.6-fold decrease in area under the bactericidal curve (AUBC: 168 vs 30) for gemifloxacin. Trovafloxacin showed a 4-fold higher MIC (0.25 vs 0.06 mg/l), a 4-fold lower C(max)/MIC (8.6 vs 36), a 4-fold lower AUC(0-24 h)/MIC (85 vs 356) and a 11-fold lower AUBCs (2 vs 22) against the resistant isolate compared with the susceptible one. Trovafloxacin serum bactericidal titres against the ciprofloxacin-resistant strain were measurable generally only at 1 h after dosing (median titre=2). Gemifloxacin showed similar ex vivo bactericidal activity against the ciprofloxacin-resistant strain to that of trovafloxacin against the ciprofloxacin-susceptible strain.
Sixty recent Streptococcus pneumoniae isolates with different susceptibilities to ciprofloxacin (14 with MIC 0.5 mg/L, 10 with MIC 1 mg/L, eight with MIC 2 mg/L, 11 with MIC 4 mg/L and 17 with MIC > or =8 mg/L) were tested against five new quinolones using Todd-Hewitt broth with and without 80% serum. The final inoculum was 5 x 10(5) cfu/mL. Gemifloxacin and clinafloxacin exhibited the lowest MIC90 values and resistance rates (percentage above and defined breakpoint) with and without serum for strains with a ciprofloxacin MIC of > or =4 mg/L. Other quinolones tested were less active against strains with reduced ciprofloxacin susceptibility. The presence of serum did not affect susceptibility to moxifloxacin, but increased the resistance rates to other new quinolones for strains with high ciprofloxacin MICs.
Analysis of the pulsed-field gel electrophoretic profiles of 82 pneumococcal isolates with reduced susceptibility to ciprofloxacin (RSC) and of 90 co-occurring susceptible isolates indicates a considerable genetic diversity among isolates with RCS and points to a close relation between the two groups. This finding suggests that pneumococci with RCS emerge through independent mutational events.
The in vitro susceptibility to trovafloxacin and gemifloxacin of Streptococcus pneumoniae strains exhibiting decreased susceptibility to ciprofloxacin (MIC > or =2 microg/ml; 30 strains with intermediate resistance [MIC 2 microg/ml] and 43 strains with complete resistance [MIC > or =4 microg/ml]) was determined. Seventy-three strains collected in a surveillance study carried out from May 1996 to April 1997 in Spain (prior to commercialisation of trovafloxacin and gemifloxacin) from patients with respiratory tract infections were tested. The antibacterial activity of gemifloxacin was affected to a lesser extent than that of trovafloxacin by the increase in the MIC of ciprofloxacin, with gemifloxacin showing significantly (P< or =0.001) better antibacterial activity than trovafloxacin in all ciprofloxacin MIC categories (MIC50/MIC90 values of 0.015/0.03, 0.015/0.06, 0.03/0.06 and 0.12/0.25 microg/ml for gemifloxacin vs. 0.12/0.12, 0.12/1, 0.25/0.5 and 2/4 microg/ml for trovafloxacin in the 2, 4, 8 and > or =16 microg/ml ciprofloxacin MIC categories, respectively). Nine (12.3%) of these 73 strains exhibited decreased susceptibility to trovafloxacin (> or =2 microg/ml), whereas all strains were inhibited by 0.25 microg/ml of gemifloxacin.
An in vitro model simulating trovafloxacin concentrations in human serum after standard doses was used to investigate the activity of this drug with time against Bacteroides fragilis, Escherichia coli, Enterococcus faecalis and Staphylococcus aureus. Antibiotic concentrations used for each incubation period were: 4.24 mg/l (0-1 h), 3.69 mg/l (1-3 h), 3.25 mg/l (3-6 h), 2.38 mg/l (6-8 h), 1.35 mg/l (8-24 h). A 99.9% initial inoculum reduction (> 3 log10 cfu/ml) was defined as bactericidal activity. Bactericidal activity against these organisms was obtained with trovafloxacin after the first hour of incubation, and similar activity was obtained against B. fragilis, E. faecalis and S. aureus after 3 h, when they were tested individually. When the strains were tested as mixed culture, there was bactericidal activity against E. coli after 1 h incubation and after 3 h for S. aureus. This activity was observed against B. fragilis and E. faecalis after 6 h incubation in the mixed culture assays and after 3 h when organisms were tested individually. Regrowth was not observed over a 24 h period. These data show that trovafloxacin might be effective in intraabdominal infections caused by mixed aerobic and anaerobic microorganisms.
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