Definitions of MIC and MPC

Several different designations of MIC exist. A standard procedure has been established for determination of MIC to enable comparison among clinical microbiology laboratories (refer to Box 2-1). For many bacterium-antibiotic combinations, MIC is defined as the minimal concentration that blocks growth or colony formation when 104 to 105 bacterial cells of a particular culture are tested. That value is designated as MIC without a following subscript. When the MIC of many different clinical isolates is measured, MIC99 is the value that exceeds the MIC for 99% of the isolates. (MIC90 is the number for 90% of the isolates.) This number is used to take into account differences among the isolates from different patients.

Because pathogen populations are heterogeneous, MIC, determined with 104 to 105 cells, need not be the same as the MIC measured with either more or fewer cells. Experimentally, the MIC for blocking the growth of 99% of the cells in a culture is usually lower than for blocking growth of 99.99% of the cells (standard MIC).111 In such a case, the standard MIC is not the minimal concentration that blocks growth. When nonstandard values of the MIC are used, terms must be defined.

MPC is the MIC of the least susceptible, single-step mutant subpopulation. With bacteria and most antibiotics, MPC can be estimated experimentally as the concentration that permits no growth (no colony) when 1010 (10 billion) cells are applied to drug-containing agar.

Because most bacterial infections contain fewer than 1010 bacterial cells, drug concentrations above MPC should severely restrict bacterial population growth, including mutant subpopulation growth. Determining MPC sometimes requires large numbers of agar plates or large liquid cultures.112- 113

The selection window hypothesis provides a general framework for thinking about the emergence of resistance, but like all hypotheses, it is only as good as its experimental support. For example, the window should be observed even when drug concentrations fluctuate, as during oral treatment regimens. (Drug concentrations rise soon after a dose is taken and then drop gradually.) When antibiotic concentration is adjusted in bacterial cultures to mimic human treatment, mutant enrichment does occur only when fluoroquinolone concentration is inside the selection window, not when concentration is below MIC or above MPC.114115 The same is true in animal infections.105 In Chapter 10, “Restricting Antibiotic Use and Optimizing Dosing,” we return to the window hypothesis when we discuss how to adjust dosing to restrict emergence of resistance.

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