Antibiotic-induced dysbiosis predicts mortality in an animal model of clostridium difficile infection

Charles Burdet, Sakina Sayah-Jeanne, Thu Thuy Nguyen, Perrine Hugon, Frédérique Sablier-Gallis, Nathalie Saint-Lu, Tanguy Corbel, Stéphanie Ferreira, Mark Pulse, William Weiss, Antoine Andremont, France Mentré, Jean De Gunzburg

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Antibiotic disruption of the intestinal microbiota favors colonization by Clostridium 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. We administered either moxifloxacin (n = 70) or clindamycin (n = 60) to hamsters by subcutaneous injection from day 1 (D1) to D5 and challenged them with a C. difficile toxigenic strain at D3. Hamsters received various doses of a charcoal-based adsorbent, DAV131A, to modulate intestinal antibiotic concentrations. Gut dysbiosis was evaluated at D0 and D3 using 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 of C. difficile challenge and studied their capacity to predict subsequent death of the animals. Increasing 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 <10-5 for the change of Shannon index in moxifloxacin-treated animals and P < 10-9 in clindamycin-treated animals). The Shannon diversity index and unweighted UniFrac distance best predicted death, with areas under the receiver operating curve (ROC) of 0.89 (95% confidence interval [CI], 0.82, 0.95) and 0.95 (0.90, 0.98), respectively. Altogether, moxifloxacin and clindamycin disrupted the diversity of the intestinal microbiota with a dependency on the DAV131A dose; mortality after C. difficile challenge was related to the intensity of dysbiosis in similar manners with the two antibiotics.

Original languageEnglish
Article numbere00925
JournalAntimicrobial agents and chemotherapy
Volume62
Issue number10
DOIs
StatePublished - Oct 2018

Fingerprint

Dysbiosis
Clostridium Infections
Clostridium difficile
Animal Models
Anti-Bacterial Agents
Mortality
Clindamycin
Charcoal
Cricetinae
Subcutaneous Injections
rRNA Genes
Feces
Confidence Intervals

Keywords

  • Antibiotics
  • C. difficile infection
  • Dysbiosis
  • Hamster animal model
  • Mortality
  • Prevention

Cite this

Burdet, C., Sayah-Jeanne, S., Nguyen, T. T., Hugon, P., Sablier-Gallis, F., Saint-Lu, N., ... De Gunzburg, J. (2018). Antibiotic-induced dysbiosis predicts mortality in an animal model of clostridium difficile infection. Antimicrobial agents and chemotherapy, 62(10), [e00925]. https://doi.org/10.1128/AAC.00925-18
Burdet, Charles ; Sayah-Jeanne, Sakina ; Nguyen, Thu Thuy ; Hugon, Perrine ; Sablier-Gallis, Frédérique ; Saint-Lu, Nathalie ; Corbel, Tanguy ; Ferreira, Stéphanie ; Pulse, Mark ; Weiss, William ; Andremont, Antoine ; Mentré, France ; De Gunzburg, Jean. / Antibiotic-induced dysbiosis predicts mortality in an animal model of clostridium difficile infection. In: Antimicrobial agents and chemotherapy. 2018 ; Vol. 62, No. 10.
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abstract = "Antibiotic disruption of the intestinal microbiota favors colonization by Clostridium 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. We administered either moxifloxacin (n = 70) or clindamycin (n = 60) to hamsters by subcutaneous injection from day 1 (D1) to D5 and challenged them with a C. difficile toxigenic strain at D3. Hamsters received various doses of a charcoal-based adsorbent, DAV131A, to modulate intestinal antibiotic concentrations. Gut dysbiosis was evaluated at D0 and D3 using 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 of C. difficile challenge and studied their capacity to predict subsequent death of the animals. Increasing 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 <10-5 for the change of Shannon index in moxifloxacin-treated animals and P < 10-9 in clindamycin-treated animals). The Shannon diversity index and unweighted UniFrac distance best predicted death, with areas under the receiver operating curve (ROC) of 0.89 (95{\%} confidence interval [CI], 0.82, 0.95) and 0.95 (0.90, 0.98), respectively. Altogether, moxifloxacin and clindamycin disrupted the diversity of the intestinal microbiota with a dependency on the DAV131A dose; mortality after C. difficile challenge was related to the intensity of dysbiosis in similar manners with the two antibiotics.",
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author = "Charles Burdet and Sakina Sayah-Jeanne and Nguyen, {Thu Thuy} and Perrine Hugon and Fr{\'e}d{\'e}rique Sablier-Gallis and Nathalie Saint-Lu and Tanguy Corbel and St{\'e}phanie Ferreira and Mark Pulse and William Weiss and Antoine Andremont and France Mentr{\'e} and {De Gunzburg}, Jean",
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Burdet, C, Sayah-Jeanne, S, Nguyen, TT, Hugon, P, Sablier-Gallis, F, Saint-Lu, N, Corbel, T, Ferreira, S, Pulse, M, Weiss, W, Andremont, A, Mentré, F & De Gunzburg, J 2018, 'Antibiotic-induced dysbiosis predicts mortality in an animal model of clostridium difficile infection', Antimicrobial agents and chemotherapy, vol. 62, no. 10, e00925. https://doi.org/10.1128/AAC.00925-18

Antibiotic-induced dysbiosis predicts mortality in an animal model of clostridium difficile infection. / Burdet, Charles; Sayah-Jeanne, Sakina; Nguyen, Thu Thuy; Hugon, Perrine; Sablier-Gallis, Frédérique; Saint-Lu, Nathalie; Corbel, Tanguy; Ferreira, Stéphanie; Pulse, Mark; Weiss, William; Andremont, Antoine; Mentré, France; De Gunzburg, Jean.

In: Antimicrobial agents and chemotherapy, Vol. 62, No. 10, e00925, 10.2018.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Antibiotic-induced dysbiosis predicts mortality in an animal model of clostridium difficile infection

AU - Burdet, Charles

AU - Sayah-Jeanne, Sakina

AU - Nguyen, Thu Thuy

AU - Hugon, Perrine

AU - Sablier-Gallis, Frédérique

AU - Saint-Lu, Nathalie

AU - Corbel, Tanguy

AU - Ferreira, Stéphanie

AU - Pulse, Mark

AU - Weiss, William

AU - Andremont, Antoine

AU - Mentré, France

AU - De Gunzburg, Jean

PY - 2018/10

Y1 - 2018/10

N2 - Antibiotic disruption of the intestinal microbiota favors colonization by Clostridium 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. We administered either moxifloxacin (n = 70) or clindamycin (n = 60) to hamsters by subcutaneous injection from day 1 (D1) to D5 and challenged them with a C. difficile toxigenic strain at D3. Hamsters received various doses of a charcoal-based adsorbent, DAV131A, to modulate intestinal antibiotic concentrations. Gut dysbiosis was evaluated at D0 and D3 using 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 of C. difficile challenge and studied their capacity to predict subsequent death of the animals. Increasing 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 <10-5 for the change of Shannon index in moxifloxacin-treated animals and P < 10-9 in clindamycin-treated animals). The Shannon diversity index and unweighted UniFrac distance best predicted death, with areas under the receiver operating curve (ROC) of 0.89 (95% confidence interval [CI], 0.82, 0.95) and 0.95 (0.90, 0.98), respectively. Altogether, moxifloxacin and clindamycin disrupted the diversity of the intestinal microbiota with a dependency on the DAV131A dose; mortality after C. difficile challenge was related to the intensity of dysbiosis in similar manners with the two antibiotics.

AB - Antibiotic disruption of the intestinal microbiota favors colonization by Clostridium 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. We administered either moxifloxacin (n = 70) or clindamycin (n = 60) to hamsters by subcutaneous injection from day 1 (D1) to D5 and challenged them with a C. difficile toxigenic strain at D3. Hamsters received various doses of a charcoal-based adsorbent, DAV131A, to modulate intestinal antibiotic concentrations. Gut dysbiosis was evaluated at D0 and D3 using 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 of C. difficile challenge and studied their capacity to predict subsequent death of the animals. Increasing 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 <10-5 for the change of Shannon index in moxifloxacin-treated animals and P < 10-9 in clindamycin-treated animals). The Shannon diversity index and unweighted UniFrac distance best predicted death, with areas under the receiver operating curve (ROC) of 0.89 (95% confidence interval [CI], 0.82, 0.95) and 0.95 (0.90, 0.98), respectively. Altogether, moxifloxacin and clindamycin disrupted the diversity of the intestinal microbiota with a dependency on the DAV131A dose; mortality after C. difficile challenge was related to the intensity of dysbiosis in similar manners with the two antibiotics.

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KW - C. difficile infection

KW - Dysbiosis

KW - Hamster animal model

KW - Mortality

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