Pharmacokinetic and pharmacodynamic parameters for antimicrobial effects of cefotaxime and amoxicillin in an in vitro kinetic model

Abstract

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 (C(max)), 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 (C(max)) were kept constant. For S. pyogenes and E. coli, the maximal antimicrobial effect (E(max)) 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, C(max) needed to be increased to achieve the E(max). Under the condition that C(max) was 10 times the MIC, E(max) was obtained at a T>MIC of 60%, indicating that C(max), 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 log(10) 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.

FIG. 1

Illustration of constant AUC with varied T>MIC and C_max.

FIG. 2

S. pyogenes exposed to cefotaxime. Values are presented as the change in the number of CFU per milliliter at 24 h with a constant AUC of 1.4 mg/liter · h and different T>MIC. Error bars, standard deviation.

FIG. 3

E. coli exposed to cefotaxime. Values are presented as the change in the number of CFU per milliliter at 24 h with a constant AUC of 4.8 mg/liter · h ± standard deviation/error bars. At 100% T>MIC, C_max was three times the MIC, giving an AUC of 5.5 mg/liter · h.

FIG. 4

The effect of amoxicillin at different T>MIC against S. pneumoniae. (A) PSP; (B) PIP; (C) PRP (MIC, 2 mg/liter), with an initial C_max of 10 times the MIC and 3 times the MIC at 90 and 100%, respectively; (D) PRP (MIC, 4 mg/liter), with an initial C_max of 10 times the MIC. Each dot represents an experiment, and the mean is shown as a line. The graphs illustrate change in number of bacterial CFU per milliliter at 24 h compared with the initial inoculum. Error bars, standard deviation.