An open randomized multicentre Phase 2 trial to assess the safety of DAV132 and its efficacy to protect gut microbiota diversity in hospitalized patients treated with fluoroquinolones.

BACKGROUND: DAV132 (colon-targeted adsorbent) has prevented antibiotic-induced effects on microbiota in healthy volunteers. OBJECTIVES: To assess DAV132 safety and biological efficacy in patients. PATIENTS AND METHODS: An open-label, randomized [stratification: fluoroquinolone (FQ) indication] multicentre trial comparing DAV132 (7.5 g, 3 times a day, orally) with No-DAV132 in hospitalized patients requiring 5-21 day treatment with FQs and at risk of Clostridioides difficile infection (CDI). FQ and DAV132 were started simultaneously, DAV132 was administered for 48 h more, and patients were followed up for 51 days. The primary endpoint was the rate of adverse events (AEs) independently adjudicated as related to DAV132 and/or FQ. The planned sample size of 260 patients would provide a 95% CI of ±11.4%, assuming a 33% treatment-related AE rate. Plasma and faecal FQ concentrations, intestinal microbiota diversity, intestinal colonization with C. difficile, MDR bacteria and yeasts, and ex vivo resistance to C. difficile faecal colonization were assessed. RESULTS: Two hundred and forty-three patients (median age 71 years; 96% with chronic comorbidity) were included (No-DAV132, n = 120; DAV132, n = 123). DAV132- and/or FQ-related AEs did not differ significantly: 18 (14.8%) versus 13 (10.8%) in DAV132 versus No-DAV132 patients (difference 3.9%; 95% CI: -4.7 to 12.6). Day 4 FQ plasma levels were unaffected. DAV132 was associated with a >98% reduction in faecal FQ levels (Day 4 to end of treatment; P < 0.001), less impaired microbiota diversity (Shannon index; P = 0.003), increased ex vivo resistance to C. difficile colonization (P = 0.0003) and less frequent FQ-induced VRE acquisition (P = 0.01). CONCLUSIONS: In FQ-treated hospitalized patients, DAV132 was well tolerated, and FQ plasma concentrations unaffected. DAV132 preserved intestinal microbiota diversity and C. difficile colonization resistance.

Incidence and predictive biomarkers of Clostridioides difficile infection in hospitalized patients receiving broad-spectrum antibiotics.

Trial enrichment using gut microbiota derived biomarkers by high-risk individuals can improve the feasibility of randomized controlled trials for prevention of Clostridioides difficile infection (CDI). Here, we report in a prospective observational cohort study the incidence of CDI and assess potential clinical characteristics and biomarkers to predict CDI in 1,007 patients ≥ 50 years receiving newly initiated antibiotic treatment with penicillins plus a beta-lactamase inhibitor, 3rd/4th generation cephalosporins, carbapenems, fluoroquinolones or clindamycin from 34 European hospitals. The estimated 90-day cumulative incidences of a first CDI episode is 1.9% (95% CI 1.1-3.0). Carbapenem treatment (Hazard Ratio (95% CI): 5.3 (1.7-16.6)), toxigenic C. difficile rectal carriage (10.3 (3.2-33.1)), high intestinal abundance of Enterococcus spp. relative to Ruminococcus spp. (5.4 (2.1-18.7)), and low Shannon alpha diversity index as determined by 16 S rRNA gene profiling (9.7 (3.2-29.7)), but not normalized urinary 3-indoxyl sulfate levels, predicts an increased CDI risk.

Microbiota-based markers predictive of development of Clostridioides difficile infection.

Antibiotic-induced modulation of the intestinal microbiota can lead to Clostridioides difficile infection (CDI), which is associated with considerable morbidity, mortality, and healthcare-costs globally. Therefore, identification of markers predictive of CDI could substantially contribute to guiding therapy and decreasing the infection burden. Here, we analyze the intestinal microbiota of hospitalized patients at increased CDI risk in a prospective, 90-day cohort-study before and after antibiotic treatment and at diarrhea onset. We show that patients developing CDI already exhibit significantly lower diversity before antibiotic treatment and a distinct microbiota enriched in Enterococcus and depleted of Ruminococcus, Blautia, Prevotella and Bifidobacterium compared to non-CDI patients. We find that antibiotic treatment-induced dysbiosis is class-specific with beta-lactams further increasing enterococcal abundance. Our findings, validated in an independent prospective patient cohort developing CDI, can be exploited to enrich for high-risk patients in prospective clinical trials, and to develop predictive microbiota-based diagnostics for management of patients at risk for CDI.

A Colon-Targeted Adsorbent (DAV132) Does Not Affect the Pharmacokinetics of Warfarin or Clonazepam in Healthy Subjects.

DAV132 is a novel colon-targeted adsorbent that prevents the deleterious impact of antibiotics on gut microbiota without modifying their systemic availability. A randomized, Latin-square crossover, open-label trial with 2 substudies in 18 and 24 healthy volunteers evaluated the pharmacokinetic (PK) bioequivalence of warfarin, a drug with a narrow therapeutic index (NTI), and clonazepam, both widely used for the treatment of chronic conditions, with or without coadministration of DAV132 7.5 g. PK parameters observed with single doses of 5 mg warfarin and 1 mg clonazepam when administered alone did not differ with the PK parameters when administered concomitantly with or 1 hour before DAV132. Geometric mean ratios (GMRs) for S-warfarin, R-warfarin, and clonazepam Cmax were 102.0, 102.8, and 91.9, respectively, after concomitant administration and 106.5, 107.5, and 95.0, respectively, when administered 1 hour before DAV132. After concomitant administration, GMRs for S-warfarin, R-warfarin, and clonazepam AUClast were 100.5, 100.2, and 94.9, respectively, and 101.9, 101.8, and 101.3, respectively, when administered 1 hour before DAV132. All GMR 90% confidence intervals fell within the prespecified 80% to 125% limit for bioequivalence, indicating a lack of drug-drug interaction. In conclusion, DAV132 did not affect the systemic exposure of 2 NTI drugs absorbed in the proximal intestine.

Modeling the Effect of DAV132, a Novel Colon-Targeted Adsorbent, on Fecal Concentrations of Moxifloxacin and Gut Microbiota Diversity in Healthy Volunteers.

To prevent antibiotic-induced perturbations on gut microbiota, DAV132, a novel colon-targeted adsorbent, which sequesters antibiotic residues in the lower gastrointestinal tract, was developed. We built an integrated pharmacological model of how DAV132 reduces fecal free moxifloxacin and preserves gut microbiota. We used plasma and fecal free moxifloxacin concentrations, and Shannon diversity index from 16S ribosomal RNA gene metagenomics analysis of fecal microbiota, of 143 healthy volunteers assigned randomly to receive moxifloxacin only, or with 10 DAV132 dose regimens, or to a control group. We modeled reduced fecal moxifloxacin concentrations using a transit model for DAV132 kinetics and a Michaelis-Menten model with an effect of the amount of activated charcoal on adsorption efficacy. Changes in moxifloxacin-induced perturbations on gut microbiota diversity were then quantified through a turnover model with the Emax model. With the developed model, the efficiency of pharmacokinetic antagonism and its consequences on gut microbiota diversity were quantified.

Protection of the Human Gut Microbiome From Antibiotics.

Background: Antibiotics are life-saving drugs but severely affect the gut microbiome with short-term consequences including diarrhea and selection of antibiotic-resistant bacteria. Long-term links to allergy and obesity are also suggested. We devised a product, DAV132, and previously showed its ability to deliver a powerful adsorbent, activated charcoal, in the late ileum of human volunteers. Methods: We performed a randomized controlled trial in 28 human volunteers treated with a 5-day clinical regimen of the fluoroquinolone antibiotic moxifloxacin in 2 parallel groups, with or without DAV132 coadministration. Two control goups of 8 volunteers each receiving DAV132 alone, or a nonactive substitute, were added. Results: The coadministration of DAV132 decreased free moxifloxacin fecal concentrations by 99%, while plasmatic levels were unaffected. Shotgun quantitative metagenomics showed that the richness and composition of the intestinal microbiota were largely preserved in subjects co-treated with DAV132 in addition to moxifloxacin. No adverse effect was observed. In addition, DAV132 efficiently adsorbed a wide range of clinically relevant antibiotics ex vivo. Conclusions: DAV132 was highly effective to protect the gut microbiome of moxifloxacin-treated healthy volunteers and may constitute a clinical breakthrough by preventing adverse health consequences of a wide range of antibiotic treatments. Clinical Trials Registration: NCT02176005.

Targeted adsorption of molecules in the colon with the novel adsorbent-based medicinal product, DAV132: A proof of concept study in healthy subjects.

During antibiotic treatments, active residuals reaching the colon profoundly affect the bacterial flora resulting in the emergence of resistance. To prevent these effects, we developed an enteric-coated formulated activated-charcoal based product, DAV132, meant to deliver its adsorbent to the ileum and neutralize antibiotic residues in the proximal colon. In a randomized, control, crossover study, the plasma pharmacokinetics of the probe drugs amoxicillin (500 mg) absorbed in the proximal intestine, and sulfapyridine (25 mg) metabolized from sulfasalazine in the cecum and rapidly absorbed, were compared after a single administration in 18 healthy subjects who had received DAV132, uncoated formulated activated charcoal (FAC) or water 16 and 8 hours before, concomitantly with the probe drugs, and 8 hours thereafter. The AUC0-96 h of amoxicillin was reduced by more than 70% when it was taken with FAC, but bioequivalent when it was taken with water or DAV132. By contrast, the AUC0-96 h of sulfapyridine was reduced by more than 90% when administered with either FAC or DAV132 in comparison with water. The results show that DAV132 can selectively adsorb drug compounds in the proximal colon, without interfering with drug absorption in the proximal small intestine, thereby constituting a proof of concept that DAV132 actually functions in humans.

Efficacy and safety of a phospholipid emulsion (GR270773) in Gram-negative severe sepsis: results of a phase II multicenter, randomized, placebo-controlled, dose-finding clinical trial.

OBJECTIVE: To assess the survival benefit and safety profile of low-dose (850 mg/kg) and high-dose (1350 mg/kg) phospholipid emulsion vs. placebo administered as a continuous 3-day infusion in patients with confirmed or suspected Gram-negative severe sepsis. Preclinical and ex vivo studies show that lipoproteins bind and neutralize endotoxin, and experimental animal studies demonstrate protection from septic death when lipoproteins are administered. Endotoxin neutralization correlates with the amount of phospholipid in the lipoprotein particles. DESIGN: A three-arm, randomized, blinded, placebo-controlled trial. SETTING: Conducted at 235 centers worldwide between September 2004 and April 2006. PATIENTS: A total of 1379 patients participated in the study, 598 patients received low-dose phospholipid emulsion, and 599 patients received placebo. The high-dose phospholipid emulsion arm was stopped, on the recommendation of the Independent Data Monitoring Committee, due to an increase in life-threatening serious adverse events at the fourth interim analysis and included 182 patients. MEASUREMENTS AND MAIN RESULTS: A 28-day all-cause mortality and new-onset organ failure. There was no significant treatment benefit for low- or high-dose phospholipid emulsion vs. placebo for 28-day all-cause mortality, with rates of 25.8% (p = .329), 31.3% (p = .879), and 26.9%, respectively. The rate of new-onset organ failure was not statistically different among groups at 26.3%, 31.3%, 20.4% with low- and high-dose phospholipid emulsion, and placebo, respectively (one-sided p = .992, low vs. placebo; p = .999, high vs. placebo). Of the subjects treated, 45% had microbiologically confirmed Gram-negative infections. Maximal changes in mean hemoglobin levels were reached on day 10 (-1.04 g/dL) and day 5 (-1.36 g/dL) with low- and high-dose phospholipid emulsion, respectively, and on day 14 (-0.82 g/dL) with placebo. CONCLUSIONS: Treatment with phospholipid emulsion did not reduce 28-day all-cause mortality, or reduce the onset of new organ failure in patients with suspected or confirmed Gram-negative severe sepsis.