Tamara van Donge

Key components for antibiotic dose optimization 49 3 An increase in MIC breakpoints should ultimately result in dose adjustments to ensure efficacious exposure. This requires that dosing guidelines should be regularly updated and amended. It is necessary that these new recommendations and revised guidelines should be applied in clinical setting, not only to improve the patient care but also to diminish antibiotic resistance. Unfortunately, implementation of revised guidelines still happens far too little. 28 Understanding the relationship between key components With a limited pipeline of new antibiotics, relying on proper use and understanding the link between antibiotic exposure (PK) and microbiological response (PD) is a key issue concerning dosing optimization of the presently available antibiotics. 27 In order to describe relationships between drug exposure and microbiological effects, exposure-response parameters are used. A PK/PD index is defined as the quantitative relationship between an exposure-related parameter (e.g. plasma concentration) and a microbiological parameter (e.g. MIC breakpoint). 29,30 Antibiotic classes are characterized by different properties, some pathogens are killed when a high concentration of antibiotics are reached (peak concentration dependent antibiotics). For others, the growth will be inhibited when drug exposure is associated with a long period of time above a certain MIC value (time dependent antibiotics). The optimal target index is frequently identified based on animal dose fractionation studies. 31 Already in the early 1950s Eagle et al. noticed the time dependent properties of penicillin, and realized that penicillin’s are best administered as continuous infusions, whereas a concentration dependent agent is better given as an intravenous bolus to achieve high maximum concentrations. 32,33 Concentration dependency The bacterial killing rate of concentration dependent antibiotics increases at high levels of the antibiotic; this applies to aminoglycosides and fluoroquinolones. For aminoglycosides, the antibacterial effect is related to the peak concentration ( C max /MIC ). C max /MIC ratios of 8-12 resemble efficacious response. 34-36 Depending on the antibiotic class, different ratios apply (Table 1). The post antibiotic effect (PAE) is defined as the suppression of bacterial growth after the exposure of bacteria to an antibiotic (even in absence of host defense mechanisms). 37 The magnitude of the peak concentration is often associated with the bacterial killing efficiency (hit hard and hit fast paradigm). 32,38 Shifts in MIC can lead to a situation where dosing recommendations need to be revised to achieve optimal treatment. For gentamicin, for example, an increase in MIC breakpoints from 0.5 to 1.0 mg/L means that, in order to achieve similar efficacy (similar ratio of C max /MIC ), the dose should be increased from 5 mg/kg to 7.5 mg/kg. 8