Tamara van Donge

Key components for antibiotic dose optimization 45 3 Distinction between two treatment phases In a clinical setting, there is generally no time to wait for the result from microbiologic samples when there is suspected sepsis. Treatment can therefore be viewed as having two phases, namely an initial, empirical treatment phase followed by a targeted treatment phase once sepsis is confirmed (Figure 2). Both phases are time-related, and antibiotic treatment optimization may focus on either efficacy or safety, respectively. Empirical treatment phase In the first hours to days of treatment, during the initial empirical treatment phase, the primary focus is to deliver efficacious treatment with a lesser focus on safety or toxicity (Figure 2). During this period, mortality associated with sepsis is high, and it is therefore essential for administered treatment to be efficacious. As the causative organism remains unknown, selection of the antibiotic regimen needs to take into account the overall epidemiology of sepsis in the age group of the patient. Initial antibiotic doses administered in the empirical treatment phase are therefore mainly based on population-level data. A key parameter describing susceptibility to antibiotics and used in dose-finding is the minimal inhibitory concentration, or MIC, which reflects the lowest antibiotic concentration needed to inhibit visible growth of the pathogen. 18 MIC breakpoints for pathogens are established based on various in vitro tests and are applied to an entire population. During the empirical treatment phase, the benefits (e.g. high probability that causative pathogens are killed) outweigh the risks (e.g. development of renal toxicity) and therefore a certain trade-off in dosing regimen to achieve relatively high exposures in relation to non-pathogen specific MIC may be acceptable. Targeted treatment phase After an initial empirical treatment there are two possible outcomes. Treatment may be discontinued because the clinical picture of sepsis cannot be microbiologically confirmed and an alternative diagnosis emerges. On the other hand, the microbiological cause confirming the diagnosis of sepsis may be identified. In the latter case treatment will be continued and adapted if necessary. During this second treatment phase antibiotic treatment will be optimized and individualized to achieve an optimal efficacy and safety balance (Figure 2). For example, when β-lactams are administered over a prolonged period of time, there is a risk of accumulation and toxicity (e.g. seizures). 19 In case of aminoglycosides such as gentamicin, extended treatment and accumulation appear to be associated with nephrotoxicity and ototoxicity, rather than with high peak concentrations. 8,20,21 Considerations may therefore shift from a focus on efficacious treatment to a balance targeted and safe treatment in order to limit drug related adverse events, especially if there has been a satisfying clinical response (Figure 2).