Tamara van Donge

Key components for antibiotic dose optimization 47 3 Pharmacokinetics Pharmacodynamics Targets Pathogens Dose Exposure Response A D M E A Parameters: Cmax, AUC Parameters: MIC Drug properties Administration route - Intravenous - Oral - Intramuscular - Subcutaneous Chemical properties - Molecular mass - pH - Log P Gram positive Gram negative Miscellaneous Enzymes Transporters Ion channels Receptors Figure 3: General overview illustrating pharmacological key components. (A) Dose: drug properties and administration routes. (B) Exposure: Pharmacokinetic processes and parameters, A: Absorption (e.g. intestines), D: Distribution (e.g. blood circulation), M: Metabolism (e.g. liver), E: Excretion (e.g. kidneys), Cmax: peak concentration, AUC: area under the concentration-time curve. (C) Response: Pharmacodynamics, targets and pathogens, MIC: minimal inhibitory concentration. T > MIC: time above MIC. Exposure to antibiotic treatment The relationship between dose and drug exposure is governed by pharmacokinetics, defined by the kinetic processes abbreviated as ADME, which defines the absorption, distribution, metabolism and excretion of a drug (Figure 3, B). Due to dynamic maturation processes neonates and infants have marked differences compared to adults in terms of physiology affecting the different pharmacokinetic stages. 22,23 Concerning the absorption phase, delayed gastric emptying time, decreased intestinal motility, reduction in bile acid synthesis, and increased gastric pH can affect the absorption of orally administered drugs. 24 The total body water in infancy is decreasing over time (80-90% compared to 55-60% in adults), which influences the distribution of water soluble drugs such as gentamicin. Drug eliminating organs such as liver and kidney are immature at birth. During the first two weeks of life glomerular filtration rate increases rapidly reaching adult values within 1 to 2 years. 25,26 The metabolic capacity is determined by the ontogeny of metabolizing enzymes (a majority of them located in liver). Generally, the rate of hepatic metabolism is low at