Tamara van Donge

Chapter 3 50 Time dependency The effect of time dependent antibiotics relies on the length of time that the antibiotic is in contact with causative pathogen. These antibiotics are concentration independent, meaning that after a finite point higher peak concentrations (and thus higher doses) will not improve the killing capacity and clinical outcome. 18 For β-lactams the antibacterial effect is considered to be time dependent and therefore the PK/PD index Time/MIC is used (Figure 3, B-C). Regularly this index is transformed to fT>MIC; this reflects the percentage of time for which the free fraction of drug concentration remains above the MIC (Table 1). For β-lactams (penicillin’s, cephalosporins, carbapenems) it has been proposed that dosing schedules should maintain plasma concentrations above MIC for at least 50% of the dosing interval. The efficacy of β-lactams is therefore enhanced with longer exposure times. The post antibiotic effect is limited for β-lactams with an exception for carbapenems. 32 Since β-lactams are concentration independent, increased exposure does not influence the bacterial killing effect and therefore the PAE is considered short or nonexistent. 32 Continuous infusions can potentially improve target attainment for fT>MIC, they may, however, be impractical in many settings. 39 Several studies have shown the importance of a third index, namely AUC/MIC (Figure 3, B-C). 40,41 AUC reflects the area under the concentration-time curve and represents the antibiotic exposure over time. This parameter is often used for concentration independent antibiotics with extended post antibiotic effects, such as vancomycin. Bacterial regrowth is inhibited, even when the concentration falls below MIC, but the effect is not dependent on the peak concentration. 31 Imminent challenges to overcome Although tremendous progress has been made in decreasing mortality and morbidity rate caused by sepsis, it is not yet sufficient. Today, there are still numerous challenges to overcome and knowledge gaps to close (Table 2). A clear and uniform sepsis definition is still lacking. Although definitions have been established, there are still discrepancies between the diagnostic criteria for sepsis and the diagnosis made by a physician. 15 Despite the high burden of sepsis, robust and reliable diagnostics, in particular relating to microbiological diagnosis, are largely still lacking. 42 Quick, sensitive and selective biomarkers are a prerequisite in order to provide a correct diagnosis. Furthermore, concentration measurements are often collected from plasma since these are relatively easy to obtain, although these levels appear to be a poor descriptor of the activities of the drug at site of action in individual patients.