135 Impact of sepsis and antibiotics on the microbiome to other confounders (e.g. breastfeeding, overall health), treatment with meropenem, cefotaxime or ticarcillin/clavulanate is associated with significant reduction in species richness [42, 43]. This ‘resistome’ interaction with clinical infectious episodes is now the target of focused research. Studies in premature infants have also reported a proposed association between specific potential pathogens and an increased risk of necrotizing enterocolitis (NEC). Increased abundance of Enterobacteriaceae (shift towards Proteobacteria) together with reduced endogenous anaerobes and reduced microbial diversity preceding NEC onset support these findings [44]. Greater than 5 days of antimicrobial therapy for suspected early onset sepsis is associated with an increased risk of developing NEC and overall mortality [42]. Effects of the interventions during sepsis on microbiome The most detrimental effect on the microbiome is potentially caused by the widespread use of antibiotics [45]. A prospective, multicenter, point prevalence study (1-day) collecting data in 1265 ICUs worldwide showed that 71% of all patients received antibiotics [46]. Even macrolides that are sometimes utilized as prokinetics, notwithstanding direct antimicrobial effects on the microbiome, have alterations in gut transit time which has shown to cause a comparatively large effect size, accounting for ~5% of observed compositional variation [47]. As outlined above, aside from antimicrobial treatment, there are additional effects from non-antibiotic treatment for sepsis (or critical illness) on the microbiome, such as the impact of proton-pump inhibitors and nutritional support [17]. The clinical relevance of dysbiosis of the microbiome in sepsis remains poorly defined. However, this pathobiome appears highly unfavorable with potential links to sepsis-induced immunosuppression [17]. There are some strategies to modulate the microbiome during critical illness, such as the use of selective decontamination of the digestive tract (SDD) to prevent pathologic overgrowth [48, 49]. Despite the data on SDD in demonstrating a reduction in lower airway bloodstream infection, this has not translated into widespread clinical practice [50]. This may partly be due to fears of developing MDR bacteria, which is unfounded based on the majority of studies; with a caveat that they have largely been performed in ICUs with low baseline levels of antimicrobial resistance. Buelow et al. showed that in a small cohort, SDD only lead to the selection of four resistance genes and concluded the risks associated with antibiotic resistance is limited [23]. However, there was evidence to suggest that recolonization with MDR bacteria may occur on ICU discharge and cessation of SDD. Probiotics are already used as therapy in some ICUs, potentially decreasing the incidence of ventilator-associated pneumonia [51]. A recent randomized synbiotic trial suggested it could prevent sepsis in neonates in India [52]. Approximately 4500 healthy newborns were randomized to receive a 7-day course of either placebo or oral synbiotic preparation (Lactobacillus plantarum in fructooligosaccharide, chosen based on preclinical data showing superior gut colonization). The trial was terminated early after a 40% risk reduction of the primary outcome (death or sepsis) was shown in the treatment arm. What is more intriguing is the concomitant reduction in lower respiratory tract and skin and soft tissue site infections, suggesting a more systemic benefit of gut microbiome modulation. 6
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