The role of PK/PD parameters to avoid selection and increase of resistance: mutant prevention concentration

The continuing escalation of antimicrobial resistant human pathogens and the limited number of new antimicrobial agents under development has dictated that our knowledge on the emergence of resistance and any potential strategies to slow the rate at which resistance occurs is of paramount importance. Investigations with fluoroquinolones resulted in the mutant prevention concentration (MPC) concept which represents a novel in vitro measurement of fluoroquinolone potency. In essence, the MPC defines the antimicrobial drug concentration threshold that would require an organism to simultaneously possess two resistance mutations for growth in the presence of the drug. An alternative definition is the drug concentration that prevents the growth of first-step resistant mutants or the minimal inhibitory concentration of the most resistant organism present in the heterogeneous bacterial population when tested against > or =10(9) organisms. From in vitro investigations, the new fluoroquinolones (gatifloxacin, gemifloxacin, moxifloxacin) were all found to have lower MPC values than did levofloxacin against clinical isolates of Streptococcus pneumoniae. Ciprofloxacin was found to have lower MPC values than levofloxacin against clinical isolates of Pseudomonas aeruginosa. When MPC data is applied to achievable and sustainable serum drug concentrations in the body, estimation of the time the serum drug concentration exceed both MIC and MPC values can be determined. This data along with kill data allows for an estimate of the amount of time drug concentration needs to exceed MIC/MPC values to not only result in significant kill but also to minimize resistance development. To date, MPC measurements have been determined in in vitro microbiological and pharmacological models and animal and human data are being investigated. The data summarized in this overview detail resistance issues for P. aeruginosa, S. pneumoniae and other pathogens. Also presented is a summary of the MPC concept and investigations completed to date. A brief summary of fluoroquinolone mechanisms of action and resistance is presented. Finally, some preliminary investigations with other classes of compounds are discussed. To date, very limited data is available to conclude if the MPC concept does or does not apply to other classes of antimicrobial agents.