269 Towards precision medicine in sepsis Advances in the rapid molecular diagnosis of microbial pathogens will be essential for the further clinical development of highly specific therapeutics such as monoclonal antibodies, novel, narrow-spectrum antibiotics or bacteriophage therapies [75, 76]. Such therapeutics may be limited to a specific, targeted species [75-78], while others will require even more specific diagnostics such as targeted monoclonal antibodies specific to single species bacterial toxins, secretion apparatus, or serotype [75, 79, 80]. Further improvements in the rapid detection of microbial pathogens, susceptibility patterns, virulence factors and antigen detection instruments will be needed to fully implement precision medicine when treating septic patients in the future [31, 81, 82]. Challenges and limitations The successful uses of personalised medicine in oncology argue for testing precision medicine, a more targeted approach, in the management of sepsis. Identifying drugresponse phenotypes by examining interactions between phenotypes and sepsis therapies is a priority to optimise clinical trials. Adaptive trials (response-adaptive randomization) should be performed if endotypes are not available or when multiple endotypes (identified by measuring genomic, proteomic and microbiome markers) are present. Use of electronic health records should be explored to identify such endotypes. Replication of these endotypes in multiple data sets require big data with harmonisation across multiple sites. Also, validation studies will be required to determine the robustness of such endotypes for sepsis prognosis. However, a key limitation in observational studies is that results may be confounded. Several challenges lay ahead when applying precision medicine to acute critical illnesses such as sepsis, especially as management pathways are difficult to operationalise due to the fast evolving pathophysiology, multisystemic organ failure and high mortality risk (Table 3) [83]. Last but not least, the management of sepsis is complex and requires a multidisciplinary teamwork with strong expert leadership. Thus, a Road Map of Recommendations and Perspectives is detailed in Table 4. 11
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