Tamara van Donge

Chapter 3 48 birth and increases over time, depending on the type of enzyme. These processes have an impact on exposure of antibiotics, and therefore dosing needs to be adjusted based on demographic characteristics of an individual neonate or infant. Microbiological response Pharmacodynamic, microbiological aspects (PD) focus on effects of a given drug on pathogen and body (Figure 3, C). In order to elicit an effect, antibiotics need to reach certain exposure levels to kill causative pathogens of a sepsis. Currently, the MIC-based approach is most frequently applied to link drug exposure to microbiological response (Figure 3, B-C). Understanding exposure profiles of antibiotics is necessary but not sufficient for optimizing and individualizing dosing strategies. It is essential to also understand characteristics and dynamics of the target (pathogen) as well. 27 It may be clear that the growth of the pathogen needs to be inhibited or, even better, stopped entirely by the antibiotic agent depending on the MIC breakpoint (Table 1). However, this is not a fixed value but rather changes over time. Furthermore, antibiotic resistance is partially responsible for the pathogen insensitivity to antibiotic treatment, which results in higher MIC breakpoints for pathogens over time. Table 1: Pharmacokinetic and pharmacodynamic indices for antimicrobial agents together with their target value and bactericidal characteristics. Cmax: maximum antibacterial concentration, MIC: minimal inhibitory concentration, AUC: area under the concentration-time curve, AUC24: area under the concentration time curve over 24 hours, fT > MIC: percentage of time for with the free fraction of drug remains above MIC. PK/PD indices and their target values Antimicrobial agents PK/PD index Target value for clinical antibacterial efficacy PK/PD properties Reference Aminoglycosides Gentamicin Amikacin Tobramycin Cmax/MIC ≥8 8-10 8-12 Concentration dependent killing (maximize drug concentration) 59 60 61 β-lactams Penicillins Carbapenems Cephalosporins fT > MIC T>MIC > 40% T>MIC > 50-60% T>MIC > 40-50% T>MIC > 60-70% Time dependent killing (maximize exposure time) 62 63 63 63 Lipopeptides Vancomycin Quinolones Levofloxacin Ciprofoxacin Fluoroquinolones AUC24/MIC AUC/MIC AUC/MIC AUC24/MIC 400 100 125 100-125 (Gram-negatives) 25-35 (Gram-positives) Time and concentration dependent killing (maximize daily amount of dose) 64 65 66 31