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Applying Pharmacodynamics for Susceptibility Breakpoint Selection 33now by several authors (2,63–71). An example is shown in Table 4 for two dosingregimens of ceftobiprole (BAL9141), a cephalosporin recently under clinicalinvestigation.The table shows the target-attainment rates of ceftobiprole for several valuesof T >MIC . For instance, the simulation shows that for the 750 mg every 12 hourregimen, a probability of target attainment of 100% is achieved at 40% fT >MIC formicroorganisms with an MIC of 4 mg/L. Since experimental studies have shownthat 40% fT >MIC results in adequate efficacy, it is inferred that infections caused bymicroorganisms with an MIC of 4 mg/L or lower should be adequately treatedwith this particular dosing regimen, at least if they are devoid of resistancemechanisms.The approach can be taken one step further by incorporating the frequencydistribution of MIC values of the target pathogen. By multiplying the targetattainmentrates and relative frequency of target pathogens, the fraction ofresponse is obtained at each MIC, and by cumulating these, the cumulativefraction of target attainment is obtained. In this fashion, not only is the variabilityin PK parameters considered, but also the variance in susceptibility in the targetpathogen population. The major drawback of this approach is that the MICfrequency distribution of the target microorganism population has to be unbiasedand this almost never is the case. The cumulative frequency of target attainmentcan be very useful, however, in the development phase of a drug to determinewhether the response is sufficiently adequate for further follow-up. For instance,Drusano et al. showed that the cumulative fraction target attainment for a 6 mg/kg dose of everninomycin would be 34% given the priors in the simulations, andthereby concluded that further development of the drug was not justified (2).After MCS has been performed, the results need to be interpreted. This is asomewhat gray area where opinions differ. Importantly, it should be realized thatMCS is a tool that can be used in the decision-making process and does not give afinal answer or outcome that cannot be reasonably disputed (see below). The firstand foremost question that can be asked is: what is the probability of cure thatone would hope to attain, given the susceptibility breakpoint? Ideally, the susceptibilitybreakpoint is set in such a way that MIC values at the susceptibilityTABLE 4 Probability of Target Attainment (%) for Two Dosing Regimens of Ceftobiprole UsingData from Human Volunteers a250 mg q12h 750 mg q12hDosing regimen(MIC mg/L) 30% 40% 50% 60% 30% 40% 50% 60%0.5 – – 100 100 – – – –1 – 100 99 71 – – – 1002 100 59 3 0 – – 100 994 0 0 0 – 100 100 78 158 – – – – 69 3 0 016 – – – – 0 0 – –32 – – – – – – – –PTA 100% 2 1 0.5 0.5 4 4 2 1a Probability of target attainments (PTA) are displayed for 30, 40, 50, and 60% fT >MIC .Abbreviations: MIC, minimum inhibitory concentration; T >MIC , duration of time the drug concentration remainsabove the MIC value.Source: Modified from Ref. 66.