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Antimicrob Agents Chemother. 2018 Sep 24;62(10). pii: e00925-18. doi: 10.1128/AAC.00925-18. Print 2018 Oct.

Antibiotic-Induced Dysbiosis Predicts Mortality in an Animal Model of Clostridium difficile Infection.

Author information

1
INSERM and Paris Diderot University, IAME, UMR 1137, Paris, France.
2
Department of Epidemiology, Biostatistic and Clinical Research, Bichat Hospital, Assistance Publique-Hopitaux de Paris, Paris, France.
3
Da Volterra, Paris, France.
4
GenoScreen, Lille, France.
5
University of North Texas Health Science Center, Fort Worth, Texas, USA.
6
Da Volterra, Paris, France gunzburg@davolterra.com.
#
Contributed equally

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.

KEYWORDS:

C. difficile infection; antibiotics; dysbiosis; hamster animal model; mortality; prevention

PMID:
30061286
PMCID:
PMC6153837
DOI:
10.1128/AAC.00925-18
[Indexed for MEDLINE]
Free PMC Article

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