Background: The Minimum Inhibitory Concentration (MIC) is a reference value for susceptibility testing of bacteria. However, the MIC is a net result of growth and killing after a certain duration of exposure under standardized favourable in vitro conditions. Killing and growth characteristics of a drug may yield more information on its activity and help to explain discrepancies between efficacy observed in vitro and in vivo. Methods: The MIC of meropenem was determined for P. aeruginosa ATCC 27853 both by microdilution and the E-test in dilutions of Mueller Hinton (MH) broth from 100% to 1%. Time-kill curves were obtained for twofold dilutions of meropenem. Growth rates and kill rates at each concentration and dilution were obtained by linear regression. The Hill equation was fit to the kill rates vs concentrations. Results: Growths rates decreased log linearly from 0.63/h at 100% to 0.29/h at 6% MH. Over the 100–6% MH dilution range, there was a log-linear decrease of the MIC of meropenem of both the E-test and microdilution. The EC50s decreased from 0.29 mg/L to 0.07 mg/L, which is in agreement with the MIC results. There was a log-linear relationship between MIC and EC50 for the various dilutions MH. Conclusions: The availability of nutritional factors is related to the MIC, and a lower availability is related to both a lower growth rate and higher kill rate. Since nutritional factors are less abundantly available in vivo as compared to in vitro, this should be taken into account when translating in vitro to in vivo pharmacodynamics.

Emax model, Hill equation, Meropenem, MIC, Modelling, Pharmacodynamics, Pseudomonas aeruginosa ATCC 29853,
European Journal of Pharmaceutical Sciences
Department of Medical Microbiology and Infectious Diseases

Mouton, J.W. (2018). Soup with or without meatballs: Impact of nutritional factors on the MIC, kill-rates and growth-rates. European Journal of Pharmaceutical Sciences, 125, 23–27. doi:10.1016/j.ejps.2018.09.008