About_editors 1..1 - Free

82 Griffith and DudleyTABLE 2 Summary of Metrics Used to Describe Rate and Extent of Bacterial Killing Under In Vivo ConditionsMetric(s) Typical units Description Comments Ref.Extent of bacterial killingChange in CFU Log CFU per tissueweight, organ, orvolumeArea under theCFU vs. timecurveStatic dose(exposure);EC-50, EC-90CFU hr/vol orweight of tissueLog CFU per tissueweight, organ, orvolumeShows change in total bacterial numbersat sentinel time compared to startinginoculum or untreated control animalsQuantifies the total burden of organismsover time by fitting function or by areaestimationStatic: No change in CFU over theduration of the experiment comparedto challenge inoculum. EC-50, EC-90:Corresponds to 50%, 90% ofmaximum effectsRate and duration of bacterial killingBactericidal rate Log CFU/(mLh) Depicts the rate of bacterial killing overTime to 99.9%decrease fromstarting inoculumEffective regrowthtimeFully parameterized methodsEstimates of growth,bacterial killingratestime by fitting slope to log CFU/mL vs.time curveHours Describes the time necessary for aregimen to produce a specified levelof reduction in CFUHours Determines the time needed for atreatment regimen to resume growthand return to CFU counts at the startof treatmentVarious parameters(e.g., kill rate,growth rate)Models using polynomials or (moreappropriately) parameterized forbacterial killing and regrowth phases.EC-50, EC-90: 50% or 90% effectiveconcentration, respectivelyMost easily used to determine effects whendestructive sampling is requiredComparisons assume similar starting inoculum(can correct by ratio of observation with startinginoculum to calculate survival fraction). Used todetermine the extent of anti-infective effectfollowing single or multiple dosesUsed for comparison of magnitude ofpharmacokinetic–pharmacodymanic parameterfor a given level of effect. Static dose observedto correlate with mortality in mice with someinfections (e.g., pneumonia)Need complete depiction of curve to estimateaccurate slope. Difficulty with simple modelswith data with biphasic killing pattern or bacterialregrowthChoice of endpoint (99.9% reduction) oftenarbitraryAdapted from in vitro PAE studies but may beapplied to animal model results. Studies need tobe prolonged to achieve a result. Evaluation ofmultiple dose regimens may not be possibleMost adapted from in vitro curves but can beapplied to results in animals. Many modelsunable to consider multiple doses. Limitedapplication outside models of infectionMany5–789, 10111213–15Abbreviation: CFU, colony-forming units; EC-50, 50% of maximum effective concentration; EC-90, 90% of maximum effective concentration.