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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)
 
 
 
 
 

Enhancement of the in vitro and in vivo activities of clarithromycin against Haemophilus influenzae by 14-hydroxy-clarithromycin, its major metabolite in humans.

MICs of clarithromycin and its major human metabolite, 14-hydroxy-clarithromycin, for Haemophilus influenzae in combination were reduced two- to fourfold compared with the MICs of each compound alone. Serum reduced the MICs of the parent compound and metabolite two- to fourfold compared with the MICs in medium without serum. In serum spiked with clinically relevant concentrations of clarithromycin and 14-hydroxy-clarithromycin at a fixed ratio of 4:1, 15 of 16 strains (94%) were inhibited and killed by combinations containing 1.2 and 0.3 micrograms/ml, respectively. In time kill experiments, the combination of parent compound and metabolite at one-fourth and one-half of their individual MICs, respectively, reduced bacterial counts by greater than 5 log CFU. The postantibiotic effect of clarithromycin combined with 14-hydroxy-clarithromycin was twice that of clarithromycin when tested alone. When orally administered to gerbils with H. influenzae otitis media, the 14-hydroxy metabolite was significantly more active than clarithromycin in reducing bacterial counts from the middle ear. The in vivo activity of the two compounds in combination was synergistic or additive, depending on the level of H. influenzae present at the time treatment was initiated. Significant reductions in bacterial counts and increases in cure rates were observed when clarithromycin at 50 or 100 mg/kg of body weight was combined with 14-hydroxy-clarithromycin at 12 mg/kg or higher. Results from in vitro and in vivo combinations suggest that routine susceptibility tests and animal efficacy studies with clarithromycin alone may underestimate its potential efficacy against H. influenzae.[1]

References

  1. Enhancement of the in vitro and in vivo activities of clarithromycin against Haemophilus influenzae by 14-hydroxy-clarithromycin, its major metabolite in humans. Hardy, D.J., Swanson, R.N., Rode, R.A., Marsh, K., Shipkowitz, N.L., Clement, J.J. Antimicrob. Agents Chemother. (1990) [Pubmed]
 
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