fidaxomicin and Disease-Models--Animal

To investigate the effect of vancomycin and fidaxomicin on the diversity of intestinal microbiota in a mouse model of Clostridioides difficile infection.. Mice were divided into 11 models (4 mice per model): 6 uninoculated models and 5 models inoculated with C. difficile BI/NAP1/027. Inoculated models were prepared using intraperitoneal clindamycin followed by inoculation with C. difficile BI/NAP1/027. Uninoculated and C. difficile-inoculated mice received 2 or 7 days' vancomycin or fidaxomicin. Clostridium butyricum MIYAIRI 588 probiotic and lactoferrin prebiotic were administered for 10 days to uninoculated mice. Intestinal microbiome composition was investigated by sequence analyses of bacterial 16S rRNA genes from faeces, and microbiota diversity estimated.. In uninoculated, untreated ('normal') mice, Clostridia (57.8%) and Bacteroidia (32.4%) accounted for the largest proportions of gut microbiota. The proportion of Clostridia was numerically reduced in C. difficile-inoculated versus normal mice. Administration of vancomycin to C. difficile-inoculated mice reduced the proportions of Bacteroidia and Clostridia, and increased that of Proteobacteria. Administration of fidaxomicin to C. difficile-inoculated mice reduced the proportion of Clostridia to a lesser extent, but increased that of Bacteroidia. Microbiota diversity was lower in C. difficile-inoculated versus normal mice (164.5 versus 349.1 operational taxonomic units (OTUs), respectively); treatment of C. difficile-inoculated mice with 7 days' vancomycin reduced diversity to a greater extent than did 7 days' fidaxomicin treatment (26.2 versus 134.2 OTUs, respectively).. Both C. difficile inoculation and treatment with vancomycin or fidaxomicin reduced microbiota diversity; however, dysbiosis associated with fidaxomicin was milder than with vancomycin.

Topics: Animals; Anti-Bacterial Agents; Clostridioides difficile; Clostridium Infections; Disease Models, Animal; Feces; Fidaxomicin; Gastrointestinal Microbiome; Humans; Mice; Microbiota; RNA, Ribosomal, 16S; Vancomycin

The aim of this study was to test whether the perioperative composition of intestinal microbiota can contribute to variable outcomes following vertical sleeve gastrectomy (VSG).. Although bariatric surgery is the most effective treatment for obesity, metabolic outcomes are variable.. Diet-induced obese mice were randomized to VSG or sham surgery, with or without exposure to antibiotics that selectively suppress mainly gram-positive (fidaxomicin, streptomycin) or gram-negative (ceftriaxone) bacteria on postoperative days (POD) 1-4. Fecal microbiota was characterized before surgery and on POD 7 and 28. Mice were metabolically characterized on POD 30-32 and euthanized on POD 35.. VSG resulted in weight loss and shifts in the intestinal microbiota composition relative to sham-operated mice. Antibiotic exposure resulted in sustained reductions in alpha (within-sample) diversity of microbiota and shifts in its composition. All antibiotic treatments proved to be detrimental to metabolic VSG outcomes, regardless of antimicrobial specificity of antibiotics. These effects involved functionally distinct pathways. Specifically, fidaxomicin and streptomycin markedly altered hepatic bile acid signaling and lipid metabolism, while ceftriaxone resulted in greater reduction of key antimicrobial peptides. However, VSG mice exposed to antibiotics, regardless of their specificity, had significantly increased subcutaneous adiposity and impaired glucose homeostasis without changes in food intake relative to control VSG mice.. Dysbiosis induced by brief perioperative antibiotic exposure attenuates weight loss and metabolic improvement following VSG. Potential mechanisms include disruption of bile acid homeostasis and reduction in the production of gut antimicrobial peptides. Results of this study implicate the intestinal microbiota as an important contributor to metabolic homeostasis and a potentially modifiable target influencing clinical outcomes following VSG.

Topics: Animals; Anti-Bacterial Agents; Ceftriaxone; Disease Models, Animal; Fidaxomicin; Gastrectomy; Gastrointestinal Microbiome; Male; Mice; Mice, Inbred C57BL; Obesity; Streptomycin; Treatment Failure; Weight Loss

To establish the role of specific, non-synonymous SNPs in the RNA polymerase β subunit (rpoB) gene in reducing the susceptibility of Clostridium difficile to fidaxomicin and to explore the potential in vivo significance of rpoB mutant strains.. Allelic exchange was used to introduce three different SNPs into the rpoB gene of an erythromycin-resistant derivative (CRG20291) of C. difficile R20291. The genome sequences of the created mutants were determined and each mutant analysed with respect to growth and sporulation rates, toxin A/B production and cytotoxicity against Vero cells, and in competition assays. Their comparative virulence and colonization ability was also assessed in a hamster infection model.. The MIC of fidaxomicin displayed by three mutants CRG20291-TA, CRG20291-TG and CRG20291-GT was substantially increased (>32, 8 and 2 mg/L, respectively) relative to that of the parent strain (0.25 mg/L). Genome sequencing established that the intended mutagenic substitutions in rpoB were the only changes present. Relative to CRG20291, all mutants had attenuated growth, were outcompeted by the parental strain, had lower sporulation and toxin A/B production capacities, and displayed diminished cytotoxicity. In a hamster model, virulence of all three mutants was significantly reduced compared with the progenitor strain, whereas the degree of caecum colonization was unaltered.. Our study demonstrates that particular SNPs in rpoB lead to reduced fidaxomicin susceptibility. These mutations were associated with a fitness cost in vitro and reduced virulence in vivo.

Topics: Animals; Anti-Bacterial Agents; Bacterial Toxins; Cell Survival; Chlorocebus aethiops; Clostridioides difficile; Clostridium Infections; Disease Models, Animal; DNA-Directed RNA Polymerases; Drug Resistance, Bacterial; Epithelial Cells; Female; Fidaxomicin; Genetic Fitness; Mesocricetus; Microbial Sensitivity Tests; Mutation, Missense; Spores, Bacterial; Vero Cells; Virulence; Whole Genome Sequencing

Topics: Animals; Anti-Bacterial Agents; Clostridioides difficile; Clostridium Infections; Cross Infection; Disease Models, Animal; Feces; Female; Fidaxomicin; Gastrointestinal Microbiome; Mice; Mice, Inbred C57BL; RNA, Ribosomal, 16S; Vancomycin

SMT19969 is a novel narrow-spectrum antimicrobial under development for the treatment of Clostridium difficile infection (CDI). The objectives were to assess the relative efficacies of SMT19969, vancomycin and fidaxomicin in the hamster model of CDI.. Hamsters were infected with either C. difficile BI1 (ribotype 027) or C. difficile 630 (ribotype 012) prior to treatment with vehicle, SMT19969, fidaxomicin or vancomycin for 5 days. Animals were further monitored through to day 28 and survival recorded. Plasma and gastrointestinal concentrations of SMT19969 following single and repeat administration in infected hamsters were determined.. Following infection with C. difficile BI1, treatment with SMT19969, vancomycin and fidaxomicin resulted in 100% survival during the 5 day dosing period, with 90%-100% of animals receiving SMT19969 and fidaxomicin surviving during the post-dosing follow-up period. Whilst protective during treatment, onset of mortality was observed on day 11 in animals treated with vancomycin, with a 10% survival recorded by day 28. Similar results were observed for SMT19969 and vancomycin following infection with C. difficile 630, with day 28 survival rates of 80%-100% and 0%, respectively. Fidaxomicin protected animals infected with C. difficile 630 from mortality during dosing, although day 28 survival rates varied from 0% to 40% depending on dose. Plasma levels of SMT19969 were typically below the limit of quantification, but levels in the gastrointestinal tract remained far in excess of the MIC.. These data show that SMT19969 is highly effective at treating both acute infection and preventing recurrent disease and support continued investigation of SMT19969 as a potential therapy for CDI.

Topics: Aminoglycosides; Animals; Anti-Bacterial Agents; Benzimidazoles; Clostridioides difficile; Clostridium Infections; Disease Models, Animal; Fidaxomicin; Gastrointestinal Tract; Mesocricetus; Microbial Sensitivity Tests; Plasma; Pyridines; Recurrence; Survival Analysis; Treatment Outcome; Vancomycin

Clostridium difficile infection (CDI) is a serious diarrheal disease that often develops following prior antibiotic usage. One of the major problems with current therapies (oral vancomycin and metronidazole) is the high rate of recurrence. Nitazoxanide (NTZ), an inhibitor of pyruvate:ferredoxin oxidoreductase (PFOR) in anaerobic bacteria, parasites, Helicobacter pylori, and Campylobacter jejuni, also shows clinical efficacy against CDI. From a library of ∼250 analogues of NTZ, we identified leads with increased potency for PFOR. MIC screens indicated in vitro activity in the 0.05- to 2-μg/ml range against C. difficile. To improve solubility, we replaced the 2-acetoxy group with propylamine, producing amixicile, a soluble (10 mg/ml), nontoxic (cell-based assay) lead that produced no adverse effects in mice by oral or intraperitoneal (i.p.) routes at 200 mg/kg of body weight/day. In initial efficacy testing in mice treated (20 mg/kg/day, 5 days each) 1 day after receiving a lethal inoculum of C. difficile, amixicile showed slightly less protection than did vancomycin by day 5. However, in an optimized CDI model, amixicile showed equivalence to vancomycin and fidaxomicin at day 5 and there was significantly greater survival produced by amixicile than by the other drugs on day 12. All three drugs were comparable by measures of weight loss/gain and severity of disease. Recurrence of CDI was common for mice treated with vancomycin or fidaxomicin but not for mice receiving amixicile or NTZ. These results suggest that gut repopulation with beneficial (non-PFOR) bacteria, considered essential for protection against CDI, rebounds much sooner with amixicile therapy than with vancomycin or fidaxomicin. If the mouse model is indeed predictive of human CDI disease, then amixicile, a novel PFOR inhibitor, appears to be a very promising new candidate for treatment of CDI.

Topics: Aminoglycosides; Animals; Anti-Bacterial Agents; Benzamides; Clostridioides difficile; Clostridium Infections; Disease Models, Animal; Enzyme Inhibitors; Fidaxomicin; Mice; Microbial Sensitivity Tests; Nitro Compounds; Pyruvate Synthase; Thiazoles; Treatment Outcome; Vancomycin

RELEVANCE TO ETHNOPHARMACOLOGY: Tongxinluo capsule is a compound preparation formulated on the basis of the meridian theory of traditional Chinese medicine and is officially approved for the treatment of angina pectoris and ischemic stroke in China.. To test the hypothesis that the Chinese traditional medicine tongxinluo in capsule form has similar effects as simvastatin in lowering serum lipid levels and stabilizing vulnerable plaques.. Thirty New Zealand white rabbits underwent balloon-induced abdominal aortic endothelial injury and were fed a diet of 1% cholesterol for 8 weeks. The rabbits were then randomly divided into three groups (n=10 each) for daily doses of tongxinluo capsule (1 g/kg), simvastatin (5 mg/kg) or no drugs for 12 weeks. At the end of week 20, plaque rupture was induced by pharmacological triggering. Serological, ultrasonographic, pathologic, immunohistochemical, and gene expression studies were performed.. The incidence of plaque rupture with tongxinluo and simvastatin treatment was significantly lower than that with control treatment (0% for both drug treatments vs. 56.0%; P<0.05). Values of serum lipid profile, inflammatory markers, and pathological and immunohistological assays were significantly improved in the tongxinluo- and simvastatin-treated groups than in the control group. The simvastatin-treated group showed lower serum lipid levels than the tongxinluo-treated group.. Treatment with the Chinese medicine tongxinluo was as effective as simvastatin in lowering serum lipid levels, inhibiting plaque inflammation and preventing vulnerable plaques from rupture and may provide an alternative therapy for atherosclerosis.

Topics: Aminoglycosides; Animals; Anti-Inflammatory Agents; Aorta, Abdominal; Cholesterol; Cholesterol, LDL; Diet; Disease Models, Animal; Drugs, Chinese Herbal; Endothelium, Vascular; Fidaxomicin; Hypolipidemic Agents; Magnoliopsida; Rabbits; Random Allocation; Simvastatin; Triglycerides; Tunica Intima