A convenient assay for estimating the possible involvement of efflux of fluoroquinolones by Streptococcus pneumoniae and Staphylococcus aureus: evidence for diminished moxifloxacin, sparfloxacin, and trovafloxacin efflux.
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We developed a simplified assay for estimating efflux by measuring the effect of reserpine on the growth of Streptococcus pneumoniae and Staphylococcus aureus over 7 h. Reserpine enhanced ciprofloxacin and levofloxacin 17 to 68%. The hydrophobic drug trovafloxacin and the drug moxifloxacin, with a bulky C-7 substituent but hydrophilicity similar to that of levofloxacin, showed little (0 to 11%) reserpine-enhancing effect. The ease of resistant mutant strain selection correlated with efflux susceptibility. (+info)
Comparative in vitro activities of ciprofloxacin, gemifloxacin, grepafloxacin, moxifloxacin, ofloxacin, sparfloxacin, trovafloxacin, and other antimicrobial agents against bloodstream isolates of gram-positive cocci.
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The in vitro activity of gemifloxacin against 316 bloodstream isolates of staphylococci, pneumococci, and enterococci was compared with the activities of six fluoroquinolones and three other antimicrobial agents. Of the antimicrobial agents tested, gemifloxacin was the most potent against penicillin-intermediate and -resistant pneumococci, methicillin-susceptible and -resistant Staphylococcus epidermidis isolates, and coagulase-negative staphylococci. (+info)
Intracellular targets of moxifloxacin: a comparison with other fluoroquinolones.
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The in vitro activity of the novel 8-methoxyquinolone, moxifloxacin, against Streptococcus pneumoniae was evaluated, and the intracellular targets of this agent were studied. Analysis of mutant strains selected with moxifloxacin demonstrated that first-step mutants bore amino acid substitutions at position 81 in the GyrA subunit of DNA gyrase. This suggests that, unlike older fluoroquinolone agents such as ciprofloxacin and levofloxacin, but similar to other C-8 substituted quinolones like sparfloxacin and gatifloxacin, moxifloxacin targets the GyrA subunit of DNA gyrase as an initial lethal event. Such a mechanism results in high activity against increasingly common S. pneumoniae strains bearing substitutions in DNA topoisomerase IV. Moxifloxacin was active with an MIC of Phe/Tyr substitution in ParC. The moxifloxacin MIC for strains with mutations in the structural genes for both DNA gyrase subunit GyrA and DNA topoisomerase IV subunit ParC did not exceed 2 mg/L, a level within clinically achievable serum concentrations for this agent. We also found that moxifloxacin is a poor substrate for active efflux in S. pneumoniae. Therefore, the high activity of moxifloxacin against S. pneumoniae appears to be a result of both enhanced activity against DNA gyrase and topoisomerase IV, and reduced efflux from the bacterial cell. (+info)
Trans-epithelial intestinal elimination of moxifloxacin in rabbits.
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The intestinal trans-epithelial elimination of moxifloxacin was measured in the jejunum, ileum, caecum and in the bile in a rabbit model. Over a 120 min period following a single parenteral administration of moxifloxacin 15 mg/kg, peak serum concentration was 3.1 (+/- 1.1) mg/L. The elimination constants were: 0.019 (+/- 0. 017) microg/cm(2)/min, 0.011 (+/- 0.014) microg/cm(2)/min and 0.002 (+/- 0.002) microg/cm(2)/min in the jejunum, ileum and caecum, respectively. Per loop, over 120 min, the respective eliminated quantities were: 9.59 (+/- 9.37) microg, 8.26 (+/- 6.74) microg and 1.92 (+/- 1.86) microg. Biliary moxifloxacin concentrations varied between 1.30 and 5.16 mg/L and exceeded serum levels from 45 min onwards. Intestinal concentrations paralleled serum moxifloxacin levels. Altogether, approximately 4.5% of the moxifloxacin dose was eliminated trans-epithelially in the digestive tract over the 120 min experimental period. (+info)
Comparative in vitro activities of linezolid, quinupristin-dalfopristin, moxifloxacin, and trovafloxacin against erythromycin-susceptible and -resistant streptococci.
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The in vitro activities of the new agents linezolid, quinupristin-dalfopristin, moxifloxacin, and trovafloxacin were determined and compared with those of penicillin, clindamycin, and four macrolides against 53 erythromycin-resistant Streptococcus pneumoniae, 117 S. pyogenes (64 erythromycin-susceptible and 53 -resistant), and 101 S. agalactiae (53 erythromycin-susceptible and 48 -resistant) isolates. Differentiation of macrolide resistance phenotypes was performed by the double-disk method. The genetic basis for macrolide resistance in 52 strains was also determined. The M phenotype was found in 84.9, 6.3, and 1.9% of S. pyogenes, S. agalactiae, and S. pneumoniae isolates, respectively. These strains were susceptible to miocamycin and clindamycin. Strains with the inducible phenotype accounted for 27.1% of S. agalactiae isolates and 9.4% each of S. pyogenes and S. pneumoniae isolates. All erythromycin-resistant isolates were also resistant to the 14- and 15-membered macrolides tested. Strains with all three phenotypes were susceptible to +info)
Assessment of different antibacterial effect measures used in in vitro models of infection and subsequent use in pharmacodynamic correlations for moxifloxacin.
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A dilutional culture in vitro pharmacodynamic model of infection was used to assess the best measure of antibacterial effect for moxifloxacin at simulated human doses of 400 mg 24 hourly for 48 h. This was then related to two pharmacodynamic parameters, the drug area under curve: MIC ratio (AUC/MIC) and the length of time that the drug concentration remained above the MIC of the bacterium (T > MIC). Twenty-one bacterial strains (Streptococcus pneumoniae n = 6; Haemophilus influenzae n = 6; Moraxella catarrhalis n = 3; beta-haemolytic streptococci n = 3; Staphylococcus aureus n = 3; MIC range 0.06-3.6 mg/L) were tested in 69 individual simulations. The measures or parameters of antibacterial effect considered were log change in viable count in the initial inoculum at 12 h (triangle up12), 24 h (triangle up24), 36 h (triangle up36), 48 h (triangle up48), maximum reduction in count (triangle up(max)); time for bacterial counts to reduce by 100-fold from the initial density (T99) or 1,000-fold (T99.9); and area under the bacterial kill curve from 0 to 24 h (AUBKC(24)) or from 0 to 48 h (AUBKC(48)). triangle up12, triangle up24, triangle up36, triangle up48, triangle up(max), T99, T99.9 did not vary over the complete range of MICs; at high MICs, especially with Gram-positive bacteria the T99 and T99.9 values were >48 h while at low MICs, especially with Gram-negative bacteria, bacterial counts were reduced below the limit of detection with triangle up12, triangle up24, triangle up36, triangle up48 and triangle up(max) exceeding >6.5 log reduction. AUBKC(24) and AUBKC(48) varied more completely over the range of MICs and more importantly had the best within-strain reproducibility (median percentage coefficient of variation <15%). The relationship between the transformed AUBKC(24) and AUC/MIC could be described by a sigmoid Emax model but the relationship with T > MIC could not. Use of weighted least squares regression to examine the combined effect of AUC/MIC and T > MIC on AUBKC(24) indicated that AUC/MIC provided a good fit to the data (r(2) = 0.94) and adding T > MIC did not improve the model fit. Cox proportional hazards regression indicated that AUC/MIC was predictive of T99 and in a multivariate model although AUC/MIC predicted outcome after fitting AUC/MIC, T > MIC was not significant. AUBKC was thus shown to be the optimum measure of antibacterial effect to use in pharmacodynamic studies of moxifloxacin and AUC/MIC the best predictor of antibacterial effect as measured by AUBKC(24) or T99. These results are in good agreement with animal data on moxifloxacin pharmacodynamics and human data for some other fluoroquinolones. (+info)
In vitro potency of moxifloxacin, clinafloxacin and sitafloxacin against 248 genetically defined clinical isolates of Staphylococcus aureus.
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The in vitro potency of three newer fluoroquinolones, moxifloxacin, clinafloxacin and sitafloxacin was tested against 248 genetically defined Staphylococcus aureus isolates, comprising 116 unrelated S. aureus, seven heterogeneous intermediate vancomycin-resistant S. aureus strains as well as 125 clonally related methicillin-resistant S. aureus. All strains were susceptible to clinafloxacin and sitafloxacin based on an investigational breakpoint of 1 mg/L and were less influenced by mutations within the grl and gyr gene loci. In one-quarter to one-third of the strains tested, reserpine decreased slightly the MICs of moxifloxacin, clinafloxacin and sitafloxacin. Compared with moxifloxacin, clinafloxacin and sitafloxacin showed a significantly increased anti-staphylococcal potency. (+info)
New azasteroidal antifungal antibiotics from Geotrichum flavo-brunneum. III. Biological activity.
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The A25822 antibiotic complex consists of seven biologically active factors. A comparative study of these factors determined that factor B possessed the greatest antifungal activity. The minimal inhibitory concentration of A25822B against isolates of Candida albicans was less than 0.3 similar to 5.0 mug/ml, Trichophyton mentagrophytes was inhibited at less than 0.0312 mug/ml. Other pathogenic fungi such as Cryptococcus neoformans, Histoplasma capsulatum, Blastomyces dermatitidis, Sporotrichum schenckii, and Microsporium gypseum were very susceptible to A25822B. Only limited antibacterial activity of A25822B was found. Parenteral or oral administration of 50 mg/kg of A25822B significantly extended the average survival time of mice infected with C. albicans. Doses of 20 mg/kg of A25822B caused a greater than ten-fold reduction in the number of Candida cells recovered from kidneys of infected mice. A solution of 0.5% or 0.25% A25822B applied topically was effective against an experimental dermatophyte infection on guinea pigs. A peak blood level of 3 mug/ml was achieved in mice following a 100 mg/kg dose of A25822B. Combination of A25822B with a polyene antibiotic in vitro showed antagonism. (+info)