267 Towards precision medicine in sepsis A recent large observational study confirmed that source control, predominately abdominal, urinary or soft-tissue infection, is an important prognostic factor in patients with sepsis [49]. Time to source control was not significantly associated with survival, but this finding may reflect the limitations of the dataset. Local antimicrobial resistance data are important, and should be taken into account when the initial antibiotic regimen is prescribed, especially as such decision making is likely to be empirical. In addition to the factors outlined above, the presence of co-morbidities and drug use should be evaluated before starting antimicrobial treatment. To optimize the initial dosing regimen, physicians should, preferably in the near future, be assisted by computer algorithms identifying a dosage that considers patient weight, concomitant medication for drug interactions, renal and hepatic function, allergy history, pharmacogenetics, etc. Suboptimal dosages of antibiotics are common in patients with sepsis, especially in critically ill patients, because of hyperdynamic shock, large distribution volume, low albumin level, and diuretic use [50]. However, over-dosing could be observed in patients with advanced age, and/or renal failure. Therefore, attention to therapeutic drug monitoring of antibiotics is needed in patients with sepsis, and especially in those with fluctuating organ function, to optimise efficacy and prevent the harmful effects of over-dosing. Particular attention is required for antibiotics with narrow therapeutic indices, such as vancomycin and aminoglycosides. Acute kidney injury is an ominous complication in patients with sepsis. The use of continuous renal replacement therapy, or extracorporeal membrane oxygenation increases antibiotic clearance, and so higher doses of antibiotics should be given in patients receiving these interventions [51]. Immunosuppression is a well-known risk factor for viral, fungal, and other opportunistic infections [52]. Investigations aiming at diagnosing these infections should be routinely performed in immunocompromised patients. COPD patients are at increased risk for respiratory infections related to Pseudomonas aeruginosa, or Aspergillus spp. when inhaled or systemic corticosteroids are prescribed, and pulmonary function is severely altered [53] Antimicrobial stewardship is now an established practice to improve the quality of antimicrobial use. Active antimicrobial stewardship teams can indeed improve patient outcomes in hospitals, as well as reduce adverse events, costs and bacterial resistance rates [54]. Prescribing antibiotics in the ambulance has not been associated with improved outcomes [55]. Moreover, implementing bundles of immediate antibiotics in sepsis has been associated with increased risk of C. difficile infection [56]. Antimicrobial stewardship teams thereby represent an important opportunity for the successful implementation of precision medicine in sepsis. A notably controversial issue, which may become more relevant as antimicrobial stewardship evolves, is how antibiotic diversity (that is, heterogeneous antibiotic use by varied use of antibiotic regimens to ensure a balanced use of different agents) should influence individualized prescribing decisions. Diversity of prescribing in an intensive care setting can be associated with reduced rates of resistance [57, 58]. However, conventional institutional antibiotic policies tend to drive the use of a limited number of antibiotics, and often just one or two agents for any particular infection. Specialist input, or feasibly use of information technology, in making prescribing decisions could be used to increased antibiotic diversity, whilst still optimizing the therapeutic choice for each patient. 11
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