Pharmacokinetic and pharmacodynamic models of the antistaphylococcal effects of meropenem and cloxacillin in vitro and in experimental infection.

The efficacies of meropenem (MPM) and cloxacillin (CLC) against two Staphylococcus aureus strains were established in vitro. A pharmacodynamic model equation, based on the concept that the killing rate depends on concentration and time, was fitted to the numbers of CFU. The parameters of the equation are maximum killing rate, time point of maximum killing, and 50% effective concentration (EC50). The EC50s for the two strains were 0.047 and 0.040 mg/liter, respectively, for MPM and 0.105 and 0.121 mg/liter, respectively, for CLC. Calculated values of the parameters were used to predict the numbers of CFU at exponentially decreasing concentrations in vitro as well as in an experimental infection model. The prediction for in vitro conditions gave a satisfactory fit (R2, between 0.862 and 0.894). In vivo the numbers were predicted with the assumption that killing rate in vivo is proportional to that in vitro (R2, between 0.731 and 0.973). The proportionality factor ranged between 0.23 and 0.42; this variation was due mainly to covariation with growth rates in control animals, without other significant differences between antibiotics or strains.

Comparison of the antibacterial efficacies of ampicillin and ciprofloxacin against experimental infections with Listeria monocytogenes in hydrocortisone-treated mice.

The efficacies of ciprofloxacin and ampicillin against Listeria monocytogenes in an immunosuppressed mouse model of listeriosis were compared. Immunosuppression was achieved by administration of 2.5 mg of hydrocortisone acetate daily. Both ciprofloxacin and ampicillin were effective in reducing the number of viable L. monocytogenes cells in the liver and spleen. After treatment with 100 mg of ampicillin per kg of body weight every 6 h for 3 days, virtually no L. monocytogenes could be recovered from the livers and spleens of the mice. In contrast, after treatment with 100 mg of ciprofloxacin per kg every 6 h for 3 days, a geometric mean of 5 x 10(4) CFU of L. monocytogenes was recovered from the spleens and 1 x 10(5) CFU was recovered from the livers of the mice. Results of the study show that the antibacterial efficacy of ampicillin is far superior to that of ciprofloxacin in our animal model of listeriosis.

Modulation of the intestinal flora of mice by treatment with aztreonam and tigemonam.

Oral and parenteral administration of aztreonam and oral administration of tigemonam to conventional mice caused a decrease in the number of aerobic gram-negative rods in the feces. Oral treatment with high doses of aztreonam (greater than or equal to 25 mg/kg/day) and tigemonam (100 mg/kg/day) adversely influenced colonization resistance, whereas oral treatment with lower doses of the monobactams or parenteral treatment with aztreonam did not.

Comparison of the effects of aztreonam and tigemonam against Escherichia coli and Klebsiella pneumoniae in vitro and in vivo.

A study was performed to investigate the pharmacodynamics of aztreonam and tigemonam against Escherichia coli and Klebsiella pneumoniae in vitro and in vivo. The in vitro concentration-effect relationships were determined in short-term growth experiments. The in vivo dose-effect relationships were determined in an experimental thigh muscle infection in irradiated mice. In this model, E. coli was injected into one thigh muscle and K. pneumoniae was injected into the other. Throughout these experiments aztreonam was administered subcutaneously and tigemonam was administered orally. For analysis of the antibacterial pharmacodynamics, the following parameters were determined: the maximum effect as a parameter for efficacy, the 50% effective concentration (or dose) as a parameter for potency, and the slope of the concentration-effect relationship. To assess the relationship between the concentration of the antibiotic and the antibacterial effect in vivo, the pharmacokinetics of the two drugs in the plasma of mice were determined as well. The maximum in vitro and in vivo effects of aztreonam and tigemonam against both bacteria did not differ substantially. However, both drugs killed E. coli more effectively than K. pneumoniae, indicating that the maximum in vitro effect of these drugs against E. coli was higher than that against K. pneumoniae. The maximum in vivo effect of both drugs against E. coli was similar to that against K. pneumoniae. Furthermore, in vitro aztreonam was about twice as potent as tigemonam, but in vivo the reverse was the case. These findings were explained by pharmacokinetic differences between subcutaneously administered aztreonam and orally administered tigemonam, because concentrations of tigemonam in plasma remained at microbiologically active concentrations longer than those of aztreonam did.