DAV131A Protects Hamsters from Lethal Clostridioides difficile Infection Induced by Fluoroquinolones

Nathalie Saint-Lu; Charles Burdet; Frédérique Sablier-Gallis; Tanguy Corbel; Agathe Nevière; Sakina Sayah-Jeanne; Mark Pulse; William Weiss; Stéphanie Ferreira; Antoine Andremont; France Mentré; Jean de Gunzburg

doi:10.1128/AAC.01196-19

DOI: 10.1128/AAC.01196-19

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FIG 1
Survival rate (A), C. difficile counts (B), and free fecal antibiotic concentrations at D3 (C) in animals treated with LVX (left) and CIP (right) according to treatment group. In the “ABX/XXX” notation used in the legend, ABX is the antibiotic, and “XXX” is the unit dose of DAV131A (n = 10 for all groups except for CIP/600 group where n = 9). For the C. difficile counts, the mean and error bars representing the standard deviations are shown. For antibiotic concentrations, the boxes present the 25th and 75th percentiles, and the horizontal black bar reports the median value, while the whiskers indicate the 10th and 90th percentiles, and the outliers are also shown. Red asterisks represent adjusted P values of Wilcoxon tests comparing each group treated by antibiotic and DAV131A to the group treated by antibiotic alone (*, P < 0.05; **, P < 0.01; ***, P < 0.001; ****, P < 0.0001).
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FIG 2
Change of the Shannon index (α-diversity) (A) and unweighted UniFrac distance (β-diversity) (B) between D0 and D3 in animals treated with LVX (left) and CIP (right) according to the dose of DAV131A in each treatment group. The boxes present the 25th and 75th percentiles, and the horizontal black bar reports the median value, while the whiskers indicate the 10th and 90th percentiles, and the outliers are also shown. Asterisks represent adjusted P values of Wilcoxon tests comparing each group treated by antibiotic and DAV131A to the group treated by antibiotic alone (red stars) or to the untreated control group (gray star) (*, P < 0.05; **, P < 0.01; ***, P < 0.001; ****, P < 0.0001).
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FIG 3
Change of the Shannon index (α-diversity) (A) and unweighted UniFrac distance (β-diversity) (B) between D0 and D3 in animals treated with LVX (left) and CIP (right) according to survival or death measured at the end of the study (D16). Colored circles indicate the dose of DAV131A received by each animal. The boxes present the 25th and 75th percentiles, and the horizontal black bar reports the median value, while the whiskers indicate the 10th and 90th percentiles. Red asterisks represent P values of the Wilcoxon tests for the comparison of animal fates (***, P < 0.001; ****, P < 0.0001).
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FIG 4
Logistic models of mortality according to the change of Shannon index (A) (P < 10⁻¹⁵) and unweighted UniFrac distance (B) (P < 10⁻¹⁵) between D0 and D3 after pooling data from antibiotic-treated animals in the two studies performed with LVX and CIP, together with a previously published study with MXF (10). Red bars represent the mortality rates and their 95% confidence intervals of deciles of the observed diversity indices. The shaded areas represent the 95% confidence interval of the predicted probability of death.

TABLE 1
Mortality rates and fecal concentrations of active antibiotic at D3 according to treatment groups in the levofloxacin and ciprofloxacin studies^a
↵a The data are presented as n (%) or median (min, max) as appropriate. q values refer to the comparison of the corresponding treatment group with the antibiotic/0 group (LVX/0 or CIP/0) after Benjamini-Hochberg correction. P values for comparisons of all treatment groups using the Fisher exact or Kruskal-Wallis tests are reported in the “All groups” row. For concentration data, only antibiotic-treated groups were included.
TABLE 2
Change between D0 and D3 of the Shannon index and unweighted UniFrac distances according to treatment groups in the LVX and CIP studies^a
↵a The data are presented as n (%) or median (min; max) as appropriate. q values refer to the comparison of the corresponding treatment group with the relevant antibiotic/0 group (LVX/0 or CIP/0) (i) or control group (ii) after Benjamini-Hochberg correction. The P values for the comparison of all treatment groups using Fisher exact or Kruskal-Wallis tests are reported in the “All groups” row.
TABLE 3
Changes in microbiota diversity between D0 and D3^a
↵a According to the vital status at D16 in antibiotic-treated groups and their respective areas under the ROC curves for predicting occurrence of death by D16, after pooling data from antibiotic-treated animals in the two studies performed with LVX and CIP, together with a previously published study with MXF (10). The P values were determined using a nonparametric Wilcoxon test. 95% CI, 95% confidence interval.