title: Pharmacodynamics of pulse dosing versus standard dosing: in vitro metronidazole activity against Bacteroides fragilis and Bacteroides thetaiotaomicron.
abstract: Pulse dosing is a novel approach to dosing that produces escalating antibiotic levels early in the dosing interval followed by a prolonged dose-free period. Antibiotic is frontloaded by means of four sequential bolus injections, after which antibiotic levels are allowed to diminish until the next dose. This study compares standard thrice-daily dosing and pulse dosing of metronidazole against Bacteroides spp. in an in vitro model. Two American Type Culture Collection Bacteroides fragilis isolates (metronidazole MIC for each organism = 1 mg/liter) were exposed to metronidazole for 48 or 96 h. Human pharmacokinetics were simulated for an oral 500-mg dose given every 8 h (maximum concentration of drug [C(max)] = 12 mg/liter; half-life = 8 h; area under the curve [AUC] = 294 mg . h/liter) and for pulse dosing. Pulses, each producing an increase in metronidazole concentration of 9 mg/liter, were administered at times 0, 2, 4, and 6 h of each 24-h cycle, with a targeted half-life of 8 h (AUC = 347 mg . h/liter). A metronidazole-resistant B. fragilis strain (metronidazole MIC = 32 mg/liter) was exposed to both dosing regimens and, additionally, to a regimen of 1,500 mg administered once daily (C(max) = 36 mg/liter; AUC = 364 mg . h/liter). Furthermore, regimens against one B. fragilis isolate and one B. thetaiotaomicron isolate corresponding to one-fourth and one-eighth of the thrice-daily and pulse dosing regimens, mimicking peak metronidazole concentrations achieved in abscesses, were simulated in 48-h experiments (metronidazole MIC = 1 mg/liter). Time-kill curves were generated for each experiment and analyzed for bactericidal activity, defined as a bacterial burden reduction >/= 3 log(10) CFU/ml. The results of paired (Wilcoxon matched-pair signed-rank test) and nonpaired (Mann-Whitney test) statistical analyses conducted on time to 3 log(10) kill data and area under the kill curve data from each of the thrice-daily dosing experiments versus each of the pulse dosing experiments were considered not significant for a given isolate-dosing regimen combination. The thrice-daily dosing, pulse dosing, and once-daily dosing regimens all exhibited bactericidal activity. Metronidazole administered in standard or pulse dosing fashion was highly active against both susceptible and resistant strains of Bacteroides spp.
authors.affiliation: Department of Experimental and Clinical Pharmacology, University of Minnesota College of Pharmacy, 7-170 Weaver-Densford Hall, 308 Harvard St. SE, Minneapolis, MN 55455, USA.
authors.forename: Khalid H
authors.initials: KH
authors.lastname: Ibrahim
authors.forename: Brent W
authors.initials: BW
authors.lastname: Gunderson
authors.forename: Elizabeth D
authors.initials: ED
authors.lastname: Hermsen
authors.forename: Laurie B
authors.initials: LB
authors.lastname: Hovde
authors.forename: John C
authors.initials: JC
authors.lastname: Rotschafer
mesh_terms: D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D019540:Area Under Curve; D001439:Bacteroides / Q000187:drug effects*; D001441:Bacteroides fragilis / Q000187:drug effects*; D002851:Chromatography, High Pressure Liquid; D015169:Colony Count, Microbial; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D006207:Half-Life; D006801:Humans; D007700:Kinetics; D008795:Metronidazole / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D008954:Models, Biological
chemical_list: D000900:Anti-Bacterial Agents; D008795:Metronidazole