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Antimicrobial Agents and Chemotherapy, November 2004, p. 4195-4199, Vol. 48, No. 11
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.11.4195-4199.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Pharmacodynamics of Pulse Dosing versus Standard Dosing: In Vitro Metronidazole Activity against Bacteroides fragilis and Bacteroides thetaiotaomicron

Khalid H. Ibrahim, Brent W. Gunderson, Elizabeth D. Hermsen, Laurie B. Hovde, and John C. Rotschafer*

Department of Experimental and Clinical Pharmacology, The University of Minnesota College of Pharmacy, Minneapolis, Minnesota

Received 18 December 2003/ Returned for modification 25 February 2004/ Accepted 8 July 2004

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 [Cmax] = 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 (Cmax = 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 log10 CFU/ml. The results of paired (Wilcoxon matched-pair signed-rank test) and nonpaired (Mann-Whitney test) statistical analyses conducted on time to 3 log10 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.

* Corresponding author. Mailing address: Department of Experimental and Clinical Pharmacology, University of Minnesota College of Pharmacy, 7-170 Weaver-Densford Hall, 308 Harvard St. SE, Minneapolis, MN 55455. Phone: (612) 624-2183. Fax: (612) 625-1140. E-mail: rotsc001{at}umn.edu.

Antimicrobial Agents and Chemotherapy, November 2004, p. 4195-4199, Vol. 48, No. 11
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.11.4195-4199.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Sun, H. K., Lee, S. Y., Banevicius, M. A., Du, X., Maglio, D., Nicolau, D. P. (2005). Efficacy of pulsatile amoxicillin and clarithromycin dosing alone and in combination in a murine pneumococcal pneumonia model. J Antimicrob Chemother 56: 559-565 [Abstract] [Full Text]  


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