This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Woodnutt, G.
Right arrow Articles by Berry, V.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Woodnutt, G.
Right arrow Articles by Berry, V.

 Previous Article  |  Next Article 

Antimicrobial Agents and Chemotherapy, January 1999, p. 29-34, Vol. 43, No. 1
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Two Pharmacodynamic Models for Assessing the Efficacy of Amoxicillin-Clavulanate against Experimental Respiratory Tract Infections Caused by Strains of Streptococcus pneumoniae

Gary Woodnutt* and Valerie Berry

SmithKline Beecham Pharmaceuticals, Collegeville, Pennsylvania

Received 20 November 1997/Returned for modification 31 March 1998/Accepted 1 September 1998

Two models of respiratory tract infection were used to investigate the pharmacodynamics of amoxicillin-clavulanate against Streptococcus pneumoniae. Eight strains of S. pneumoniae were used in a mouse model in which the animals were infected intranasally and were then treated with a range of doses and dose intervals. The time that the plasma amoxicillin concentration remained above the MIC (T>MIC) correlated well with bacterial killing, such that if T>MIC was below 20% there was no effect on bacterial numbers in the lungs. As T>MIC increased, the response, in terms of decreased bacterial load, improved and at T>MICs of greater than 35 to 40% of the dosing interval, bacteriological cure was maximal. On the basis of equivalent T>MICs, these data would suggest that in humans a dosage of 500 mg three times daily (t.i.d.) should have efficacy equal to that of a dosage of 875 mg twice daily (b.i.d.). This hypothesis was evaluated in a rat model in which amoxicillin-clavulanate was given by computer-controlled intravenous infusion to achieve concentrations that approximate the concentrations achieved in the plasma of humans following oral administration of 500/125 mg t.i.d. or 875/125 mg b.i.d. Infusions continued for 3 days and bacterial numbers in the lungs 2 h after the cessation of the infusion were significantly reduced (P < 0.01) by both treatments in strains of S. pneumoniae for which amoxicillin MICs were below 2 µg/ml. When tested against a strain of S. pneumoniae for which the amoxicillin MIC was 4 µg/ml, the simulated 500/125-mg dose was ineffective but the 875/125-mg dose demonstrated a small but significant (P < 0.01) reduction in bacterial numbers. These data confirm the findings in the mouse and indicate that amoxicillin-clavulanate administered at 875/125 mg b.i.d. would be as effective clinically as amoxicillin-clavulanate administered at 500/125 mg t.i.d.

* Corresponding author. Mailing address: SmithKline Beecham Pharmaceuticals, 1250 South Collegeville Rd., P.O. Box 5089, Collegeville, PA 19426-0989. Phone: (610) 917-5567. Fax: (610) 917-7901. E-mail: Gary_Woodnutt{at}sbphrd.com.

Antimicrobial Agents and Chemotherapy, January 1999, p. 29-34, Vol. 43, No. 1
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


This article has been cited by other articles:

  • Abgueguen, P., Azoulay-Dupuis, E., Noel, V., Moine, P., Rieux, V., Fantin, B., Bedos, J.-P. (2007). Amoxicillin Is Effective against Penicillin-Resistant Streptococcus pneumoniae Strains in a Mouse Pneumonia Model Simulating Human Pharmacokinetics. Antimicrob. Agents Chemother. 51: 208-214 [Abstract] [Full Text]  
  • Berry, V., Hoover, J., Singley, C., Woodnutt, G. (2005). Comparative Bacteriological Efficacy of Pharmacokinetically Enhanced Amoxicillin-Clavulanate against Streptococcus pneumoniae with Elevated Amoxicillin MICs and Haemophilus influenzae. Antimicrob. Agents Chemother. 49: 908-915 [Abstract] [Full Text]  
  • Sethi, S., Breton, J., Wynne, B. (2005). Efficacy and Safety of Pharmacokinetically Enhanced Amoxicillin-Clavulanate at 2,000/125 Milligrams Twice Daily for 5 Days versus Amoxicillin-Clavulanate at 875/125 Milligrams Twice Daily for 7 Days in the Treatment of Acute Exacerbations of Chronic Bronchitis. Antimicrob. Agents Chemother. 49: 153-160 [Abstract] [Full Text]  
  • File, T. M. Jr., Lode, H., Kurz, H., Kozak, R., Xie, H., Berkowitz, E. (2004). Double-Blind, Randomized Study of the Efficacy and Safety of Oral Pharmacokinetically Enhanced Amoxicillin-Clavulanate (2,000/125 Milligrams) versus Those of Amoxicillin-Clavulanate (875/125 Milligrams), Both Given Twice Daily for 7 Days, in Treatment of Bacterial Community-Acquired Pneumonia in Adults. Antimicrob. Agents Chemother. 48: 3323-3331 [Abstract] [Full Text]  
  • MacGowan, A. P., Noel, A. R., Rogers, C. A., Bowker, K. E. (2004). Antibacterial Effects of Amoxicillin-Clavulanate against Streptococcus pneumoniae and Haemophilus influenzae Strains for Which MICs Are High, in an In Vitro Pharmacokinetic Model. Antimicrob. Agents Chemother. 48: 2599-2603 [Abstract] [Full Text]  
  • File, T. M. Jr, Garau, J., Blasi, F., Chidiac, C., Klugman, K., Lode, H., Lonks, J. R., Mandell, L., Ramirez, J., Yu, V. (2004). Guidelines for Empiric Antimicrobial Prescribing in Community-Acquired Pneumonia. Chest 125: 1888-1901 [Abstract] [Full Text]  
  • Brook, I., Gober, A. E. (2004). Eradication of Streptococcus pneumoniae in the Nasopharyngeal Flora of Children with Acute Otitis Media after Amoxicillin-Clavulanate Therapy. Antimicrob. Agents Chemother. 48: 1419-1421 [Abstract] [Full Text]  
  • Smith, C. (2003). Pharmacokinetic/Pharmacodynamic Considerations in Community-Acquired Lower Respiratory Tract Infections. Journal of Pharmacy Practice 16: 313-323 [Abstract]  
  • Tessier, P. R., Kim, M.-K., Zhou, W., Xuan, D., Li, C., Ye, M., Nightingale, C. H., Nicolau, D. P. (2002). Pharmacodynamic Assessment of Clarithromycin in a Murine Model of Pneumococcal Pneumonia. Antimicrob. Agents Chemother. 46: 1425-1434 [Abstract] [Full Text]  
  • Mouton, J. W., Punt, N. (2001). Use of the t > MIC to choose between different dosing regimens of {beta}-lactam antibiotics. J Antimicrob Chemother 47: 500-501 [Full Text]  
  • Nicolau, D. P., Onyeji, C. O., Zhong, M., Tessier, P. R., Banevicius, M. A., Nightingale, C. H. (2000). Pharmacodynamic Assessment of Cefprozil against Streptococcus pneumoniae: Implications for Breakpoint Determinations. Antimicrob. Agents Chemother. 44: 1291-1295 [Abstract] [Full Text]  
  • Butler, D. L., Gagnon, R. C., Miller, L. A., Poupard, J. A., Felmingham, D., Gruneberg, R. N. (1999). Differences between the activity of penicillin, amoxycillin, and co-amoxyclav against 5,252 Streptococcus pneumoniae isolates tested in the Alexander Project 1992- 1996. J Antimicrob Chemother 43: 777-782 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»