Antibiotic-induced dysbiosis predicts mortality in an animal model ofClostridium difficileinfection

Abstract

AbstractBackgroundAntibiotic disruption of the intestinal microbiota favors colonization byClostridium difficile. Using a charcoal-based adsorbent to decrease intestinal antibiotic concentrations, we studied the relationship between antibiotic concentrations in feces and the intensity of dysbiosis, and quantified the link between this intensity and mortality.MethodsWe administered either moxifloxacin (n=70) or clindamycin (n=60) to hamsters by subcutaneous injection from day 1 (D1) to D5, and challenged them with aC. difficiletoxigenic strain at D3. Hamsters received various doses of a charcoal-based adsorbent, DAV131A, to modulate intestinal antibiotic concentrations. Gut dysbiosis was evaluated at D0and D3using diversity indices determined from 16S rRNA gene profiling. Survival was monitored until D16. We analyzed the relationship between fecal antibiotic concentrations and dysbiosis at the time ofC. difficilechallenge and studied their capacity to predict subsequent death of the animals.ResultsIncreasing doses of DAV131A reduced fecal concentrations of both antibiotics, lowered dysbiosis and increased survival from 0% to 100%. Mortality was related to the level of dysbiosis (p<10−5for the change of Shannon index in moxifloxacin-treated animals and p<10−9in clindamycin-treated animals). The Shannon diversity index and unweighted UniFrac distance best predicted death, with areas under the ROC curve of 0.89 [95%CI, 0.82;0.95] and 0.95 [0.90;0.98], respectively.ConclusionsAltogether, moxifloxacin and clindamycin disrupted the diversity of the intestinal microbiota with a dependency to the DAV131A dose; mortality afterC. difficilechallenge was related to the intensity of dysbiosis in a similar manner with the two antibiotics.