133 Impact of sepsis and antibiotics on the microbiome Introduction The gut microbiota – the microbes that collectively inhabit the human intestine– play a key role in protecting the body against potentially harmful compounds such as bacteria, toxins and antigens [1]. The interaction between sepsis and the microbiota can be regarded as a, not yet completely understood, bidirectional relationship. The disease state of sepsis has a disruptive effect on microbiota, but the interventions during clinical care for these critically ill patients are external modulators of the microbiota as well [2]. The rapid administration of appropriate antimicrobial therapy to patients with sepsis is vital and associated with both lower in-hospital and 30-day mortality when compared to inappropriate empiric antibiotics [3, 4]. The initial treatment of sepsis critically influences the clinical outcome of the patient. Empiric therapy regimens in critical illness often consist of multiple, broad-spectrum antimicrobial agents to ensure appropriate coverage of potential pathogens of concern. However, antibiotics are no longer considered only beneficial, but also potentially harmful agents, as multiple studies have shown that their use can have severe and long-lasting effects on the composition of the microbiota [5-7]. Duration of antimicrobial therapy has been independently associated with the development of Clostridium difficile infection (CDI)[8, 9]. Additionally, numerous studies have demonstrated the correlation of antimicrobial exposure and the impact on colonization and drug resistant pathogens [10-13]. For example, the proliferation of vancomycin-resistant Enterococcus (VRE) after antimicrobial exposure is also of concern as the high bacterial burden increases the risk of dissemination via translocation and can subsequently lead to bloodstream infections. The antibiotic-mediated depletion of commensal bacteria decreases intestinal RegIII gamma expression, which normally acts to resist colonization to VRE [14]. Furthermore, these disruptions in the microbiota may predispose a patient to recurrent infection and sepsis [15, 16]. Not surprisingly, microbiota-targeted therapies are being developed to prevent or treat sepsis [17, 18]. It remains to be seen to what extent these changes in the microbiota influence the clinical outcome of those who suffer from sepsis. One of the many challenges to understanding the association between antimicrobial administration and the effects on the microbiota in patients with sepsis is the varying level of antimicrobial exposure hospitalized patients receive, which is difficult to capture [10-12]. The spectrum of activity, dose received, route of administration, and the pharmacokinetic and pharmacodynamic properties of the antibiotic agent will all determine the extent of its effect on the microbiota [5, 6]. In addition, numerous other treatments given to patient with sepsis, such as proton pump inhibitors, enteral/parenteral feeding, anti-inflammatory drugs, sedatives, opioids and catecholamines, have all been described to impact the gut microbiota [18, 19]. The effects of medication on the microbiome remains significantly underexplored as demonstrated by recent in vitro screen testing of 1200 marketed drugs, which found 50% of non-bacterial anti-infectives and 25% of all human-targeted drugs inhibit at least one gut commensal [19]. As evidence continues to support a prime role of the importance of the microbiome in sepsis, knowledge on the interaction of the host and the causative microorganism, as well as the ecological impact of antimicrobial agents is of great clinical importance. In this review, we summarize data on the effect of sepsis and the effect of some of the empiric antibiotics utilized during sepsis on the composition of the gut microbiota. 6
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