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Applying Pharmacodynamics for Susceptibility Breakpoint Selection 29and aminoglycosides, concentrations in the extracellular compartment will beunderestimated by concentrations in tissue homogenates, while concentrationsin extracellular fluid of drugs, which are taken up by cells to a relatively low(fluoroquinolones) or high (macrolides, azithromycin) extent, are overestimated bytissue homogenates. Most antibiotics have been shown to reach the extracellularfluid rapidly, and concentrations in extracellular fluid to be comparable to thenon–protein-bound concentration in serum or plasma (51,52), although there seemto be some exceptions such as cerebrospinal fluid (CSF) and epithelial lining fluid(ELF) concentrations (53). Methods by which extracellular concentrations havebeen determined include suction blisters (54), inflammatory blisters (55), andthreads (49). Recently, microdialysis techniques that measure only unbound-drugconcentrations are increasingly being used to obtain concentration–time profiles ininterstitial fluid (56–58). Thus, the strong relationship between unbound-drugconcentrations in serum or plasma and those in extracellular fluid explains thegood correlation found between unbound serum concentrations and in vivo effectsand the lack of correlation of these effects with tissue concentrations obtained inhomogenates. For intracellular infections, it is much less clear which concentrationscorrelate with effect. Drugs may be bound or trapped within the cell, whilethe activity of a drug intracellularly can also be distinctly different from thatobserved extracellularly (59).In conclusion, except for some intracellular infections, CSF infections, andsome lung infections where ELF concentrations are much higher than in serum orplasma, it is the free fraction of the drug in serum or plasma that correlates bestwith measures of in vivo efficacy. It should be emphasized that concentrationsmeasured locally at sites of infection cannot be used to establish breakpoints sincethe quantitative relationship between local concentrations and effect is largelyunknown.ONE SIZE DOES NOT FIT ALL: VARIATIONS IN MIC AND PKSIn the discussion above, the AUC:MIC ratio of 100 was used as a reference value todetermine tentative PK–PD susceptibility breakpoints for quinolones. However, theAUC values used to calculate the susceptibility breakpoint were mean values of thepopulation, and within the population, there is variability in PK profiles. Thus,approximately half the population will have AUCs lower than this value (forinstance, because of a higher than average clearance) and the other half will have ahigher value, the extent being described by the variance. In a similar fashion, the MICmeasurement has a certain margin of error, and in general is at least one twofolddilution. Both these variations result in PI values that will differ for each specific caseand should be accounted for when determining susceptibility breakpoint values.THE MICFor over 50 years, no agreement could be reached over a standard methodologyfor MIC testing. In the earlier mentioned reference of Ericsson and Sherris (5),there appeared to be some consensus on using twofold dilutions and on includingthe concentration 1.0 mg/L. However, the medium, incubation times, volume,temperature, and other variables were still a matter of debate. In addition, becausenot all bacteria grow in standard media, numerous variations have been listed forvarious microorganisms. These methods are described in various countries by