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Antimicrobial Agents and Chemotherapy, September 2001, p. 2436-2440, Vol. 45, No. 9
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.9.2436-2440.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Pharmacokinetic and Pharmacodynamic Parameters for Antimicrobial Effects of Cefotaxime and Amoxicillin in an In Vitro Kinetic Model

I. Gustafsson,1,* E. Löwdin,2 I. Odenholt,2 and O. Cars2

Departments of Clinical Bacteriology1 and Infectious Diseases,2 University Hospital, Uppsala, Sweden

Received 25 September 2000/Returned for modification 25 February 2001/Accepted 5 June 2001

An in vitro kinetic model was used to study the relation between pharmacokinetic and pharmacodynamic (PK-PD) parameters for antimicrobial effect, e.g., the time above MIC (T>MIC), maximum concentration in serum (Cmax), and area under the concentration-time curve (AUC). Streptococcus pyogenes and Escherichia coli were exposed to cefotaxime, and the activity of amoxicillin against four strains of Streptococcus pneumoniae with different susceptibilities to penicillin was studied. The drug elimination rate varied so that the T>MIC ranged from 20 to 100% during 24 h, while the AUC and/or the initial concentration (Cmax) were kept constant. For S. pyogenes and E. coli, the maximal antimicrobial effect (Emax) at 24 h occurred when the antimicrobial concentration exceeded the MIC for 50 and 80% of the strains tested, respectively. The penicillin-susceptible pneumococci (MIC, 0.03 mg/liter) and the penicillin-intermediate strain (MIC, 0.25 mg/liter) showed maximal killing by amoxicillin at a T>MIC of 50%. For a strain for which the MIC was 2 mg/liter, Cmax needed to be increased to achieve the Emax. Under the condition that Cmax was 10 times the MIC, Emax was obtained at a T>MIC of 60%, indicating that Cmax, in addition to T>MIC, may be an important parameter for antimicrobial effect on moderately penicillin-resistant pneumococci. For the strain for which the MIC was 4 mg/liter, the reduction of bacteria varied from -0.4 to -3.6 log10 CFU/ml at a T>MIC of 100%, despite an initial antimicrobial concentration of 10 times the MIC. Our studies have shown that the in vitro kinetic model is a useful complement to animal models for studying the PK-PD relationship for antimicrobial effect of antibiotics.

* Corresponding author. Mailing address: Department of Clinical Bacteriology, Box 552, SE-751 22 Uppsala, Sweden. Phone: 46 (18) 611 39 11. Fax: 46 (18) 55 73 01. E-mail: ingegerd.gustafsson{at}medsci.uu.se.

Antimicrobial Agents and Chemotherapy, September 2001, p. 2436-2440, Vol. 45, No. 9
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.9.2436-2440.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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