New concepts in antimicrobial susceptibility testing: the mutant prevention concentration and mutant selection window approach

Current measurements of antimicrobial susceptibility or resistance utilize a standardized bacterial inoculum (10(5) cfu/mL) exposed to varying drug concentrations in a test tube. Following incubation under ideal conditions, the lowest drug concentration inhibiting growth is the minimum inhibitory concentration (MIC). When the MIC exceeds the amount of drug that can be safely achieved in the body, we call these microorganisms resistant; established breakpoints for various 'bug-drug' combinations are used to categorize microorganisms as susceptible, intermediate or resistant. MIC testing has been used for decades to guide antimicrobial therapy and remains an important measurement for infectious diseases. More recently, the mutant prevention concentration (MPC) has been described as a novel measurement of in vitro susceptibility or resistance and is based on the testing of larger bacterial inocula, i.e. >= 10(9) cfu/mL - such as those associated with some infections in humans and animals. MPC defines the lowest drug concentration required to block the growth of the least susceptible cell present in high density bacterial populations. MPC testing applies to microorganisms considered susceptible to the drug by MIC testing. The mutant selection window (MSW) defines the 'danger zone' for therapeutic drug concentrations. Minimizing the length of time the drug concentration remains in the MSW may reduce the likelihood for resistance selection during therapy. The MSW is bordered by the MIC and MPC values and the drug concentration range between the measured MIC and MPC values defines the MSW. MPC values, when considered with drug pharmacology, may allow prediction on the probability of resistance selection when bacteria are exposed to antimicrobial agents during therapy for infectious diseases. In today's environment, resistance prevention should be a goal of antimicrobial therapy.