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Antimicrobial Agents and Chemotherapy, December 2004, p. 4597-4605, Vol. 48, No. 12
0066-4804/04/$08.00+0 DOI: 10.1128/AAC.48.12.4597-4605.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.
Pharmacokinetics and Pharmacodynamics of Intravenous Levofloxacin at 750 Milligrams and Various Doses of Metronidazole in Healthy Adult Subjects
Kelly A. Sprandel,1 Christopher A. Schriever,1 Susan L. Pendland,1 John P. Quinn,2 Mark H. Gotfried,1,3,4 Suzanne Hackett,5 Mary Beth Graham,6 Larry H. Danziger,1,7 and Keith A. Rodvold1,7*Colleges of Pharmacy,1 Medicine, University of Illinois,7 Rush Medical College, Chicago, Illinois,2 School of Medicine, University of Arizona,3 Pulmonary Associates, Phoenix, Arizona,4 StatWorks, Inc., Chapel Hill, North Carolina,5 Division of Infectious Diseases, Medical College of Wisconsin, Milwaukee, Wisconsin6
Received 27 May 2004/ Returned for modification 25 July 2004/ Accepted 29 August 2004
The purpose of this investigation was to evaluate the steady-state pharmacokinetics, pharmacodynamics, and safety of intravenous levofloxacin at 750 mg administered once daily combined with three different dosages of intravenous metronidazole (500 mg every 8 h [q8h], 1,000 mg q24h, and 1,500 mg q24h). Eighteen healthy adult subjects received all three combinations in a randomized, crossover fashion. Serial blood and urine samples were collected on the third day of each study period. The 24-h areas under the inhibitory (AUIC0-24) and bactericidal (AUBC0-24) curves of these three combination regimens were determined against clinical isolates of Bacteroides fragilis, Bacteroides thetaiotaomicron, Peptostreptococcus asaccharolyticus, and Escherichia coli. The mean concentrations of levofloxacin were not different between study periods and were similar to those previously published. The mean (± standard deviation) areas under the metronidazole plasma concentration-time curve (AUC0-24) for 1,500-mg q24h (338 ± 105 mg · h/liter) and 500-mg q8h (356 ± 68 mg · h/liter) regimens were not different (P > 0.05), but both were significantly higher than the 1,000-mg q24h AUC0-24 (P < 0.05, 227 ± 57 mg · h/liter). Mean (± standard deviation) total body clearance and renal clearance values were similar among the 500-mg q8h, 1,000-mg q24, and 1,500-mg q24h regimens (62 ± 7, 67 ± 13, and 67 ± 14 and 11 ± 3, 12 ± 2, and 12 ± 5 ml/min/1.73 m2, respectively). Levofloxacin at 750 mg q24h plus metronidazole at 500 mg q8h or 1,500 mg q24h resulted in similar AUIC0-24 and AUBC0-24 values with one exception: the AUIC0-24 for the 1,500-mg q24h regimen against B. thetaiotamicron was significantly higher (P < 0.05) than those of the other regimens. Overall, the combination of levofloxacin at 750 mg once daily and metronidazole at 500 mg q8h or 1,500 mg q24h appeared to have greater AUIC0-24 and AUBC0-24 values than did the 1,000-mg q24h regimen. All combination regimens of levofloxacin and metronidazole were well tolerated, and no serious drug-related adverse effects were reported. The pharmacokinetic, safety, and pharmacodynamic data from our study suggest that a once-daily regimen of intravenous levofloxacin at 750 mg and metronidazole at 1,500 mg warrants further clinical investigation.
* Corresponding author. Mailing address: m/c 886, Pharmacy Practice, University of Illinois at Chicago, College of Pharmacy, Room 164, 833 South Wood St., Chicago, IL 60612. Phone: (312) 996-3341. Fax: (312) 413-1797. E-mail: kar{at}uic.edu.
Antimicrobial Agents and Chemotherapy, December 2004, p. 4597-4605, Vol. 48, No. 12
0066-4804/04/$08.00+0 DOI: 10.1128/AAC.48.12.4597-4605.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.
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