Abstract
Controversy remains regarding the effect of dosing interval(τ) on the efficacy of antibiotics. Usually the antibiotic dose is based on static MIC/MBC determinations and dosing interval on pharmocokinetic data acquired through clinical studies. If smaller doses at more frequent intervals have equivalent bactericidal effect, high peak concentrations can be avoided. This study compares the effect of different τ's of chloramphenicol tested against a type b HI (MIC 0.8 μg/ml) in a dynamic in vitro dilution model. High dose (HD) and low dose (LD) simulations were compared using equivalent elimination half-life, area under the drug concentration vs. time curve, and drug concentration at steady state, but differing Cmax and τ(8.4 μg/ml q 6h or 4.8μg/ml q 2h in HD and 1.6 μg/ml q 6h or 0.98 μg/ml q 2h in LD). The HD simulations showed faster rate and greater total bacterial killing. For both HD and LD, total bacterial reduction and area under the bacterial concentration vs. time curve were comparable forτ=2h or τ=6h. Although total bacterial reduction in 12h was equivalent in LD, more bacteria were killed in the first 9h of study with LD q 6h in comparison to q 2h. These data suggest that total drug given, not Cmax or τ determine the maximum degree of bacterial killing, and that toxicity could be minimized with equal effect using dosage regimens with minimal concentration fluctuations. Animal studies are in progress to determine whether the in vitro data are reproducible in vivo.
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Greenfield, M., Toothaker, R. & Smith, A. INFLUENCE OF DOSAGE INTERVAL ON THE IN VITRO ACTIVITY OF CHLORAMPHENICOL AGAINST H. INFLUENZAE(HI). Pediatr Res 18 (Suppl 4), 276 (1984). https://doi.org/10.1203/00006450-198404001-01096
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DOI: https://doi.org/10.1203/00006450-198404001-01096