RESUMEN
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.
Asunto(s)
Carbón Orgánico/administración & dosificación , Clonazepam/administración & dosificación , Warfarina/administración & dosificación , Adulto , Área Bajo la Curva , Carbón Orgánico/farmacocinética , Clonazepam/farmacocinética , Estudios Cruzados , Interacciones Farmacológicas , Femenino , Voluntarios Sanos , Humanos , Masculino , Persona de Mediana Edad , Equivalencia Terapéutica , Warfarina/farmacocinética , Adulto JovenRESUMEN
BACKGROUND: Aminopenicillins with or without a ß-lactamase inhibitor are widely used in both human and veterinary medicine. However, little is known about their differential impact on the gut microbiota and development of antimicrobial resistance. OBJECTIVES: To investigate changes in the faecal microbiota of dogs treated with amoxicillin or amoxicillin/clavulanic acid. METHODS: Faeces collected from 42 dogs (21 per treatment group) immediately before, during and 1 week after termination of oral treatment with amoxicillin or amoxicillin/clavulanic acid were analysed by culture and 16S rRNA gene sequence analysis. RESULTS: In both groups, bacterial counts on ampicillin selective agar revealed an increase in the proportion of ampicillin-resistant Escherichia coli during treatment, and an increased occurrence and proportion of ampicillin-resistant enterococci during and after treatment. 16S rRNA gene analysis showed reductions in microbial richness and diversity during treatment followed by a return to pre-treatment conditions approximately 1 week after cessation of amoxicillin or amoxicillin/clavulanic acid treatment. While no significant differences were observed between the effects of amoxicillin and amoxicillin/clavulanic acid on microbial richness and diversity, treatment with amoxicillin/clavulanic acid reduced the abundance of taxa that are considered part of the beneficial microbiota (such as Roseburia, Dialister and Lachnospiraceae) and enriched Escherichia, although the latter result was not corroborated by phenotypic counts. CONCLUSIONS: Our results suggest a limited effect of clavulanic acid on selection of antimicrobial resistance and microbial richness when administered orally in combination with amoxicillin. However, combination with this ß-lactamase inhibitor appears to broaden the spectrum of amoxicillin, with potential negative consequences on gut health.
Asunto(s)
Combinación Amoxicilina-Clavulanato de Potasio , Amoxicilina , Perros/microbiología , Microbiota , Amoxicilina/farmacología , Amoxicilina/uso terapéutico , Combinación Amoxicilina-Clavulanato de Potasio/farmacología , Combinación Amoxicilina-Clavulanato de Potasio/uso terapéutico , Animales , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Heces/microbiología , Pruebas de Sensibilidad Microbiana , Microbiota/efectos de los fármacos , ARN Ribosómico 16S/genética , Resistencia betalactámica , beta-Lactamasas/genéticaRESUMEN
Fluoroquinolone treatments induce dysbiosis of the intestinal microbiota, resulting in loss of resistance to colonization by exogenous bacteria such as Clostridioides difficile that may cause severe diarrhea in humans and lethal infection in hamsters. We show here that DAV131A, a charcoal-based adsorbent, decreases the intestinal levels of the fluoroquinolone antibiotics levofloxacin and ciprofloxacin in hamsters, protects their intestinal microbiota, and prevents lethal infection by C. difficile.
Asunto(s)
Carbón Orgánico/administración & dosificación , Clostridioides difficile , Infecciones por Clostridium/prevención & control , Administración Oral , Adsorción , Animales , Antibacterianos/efectos adversos , Antibacterianos/farmacocinética , Ciprofloxacina/efectos adversos , Ciprofloxacina/farmacocinética , Clostridioides difficile/patogenicidad , Modelos Animales de Enfermedad , Disbiosis/inducido químicamente , Disbiosis/metabolismo , Disbiosis/prevención & control , Fluoroquinolonas/efectos adversos , Fluoroquinolonas/farmacocinética , Microbioma Gastrointestinal/efectos de los fármacos , Levofloxacino/efectos adversos , Levofloxacino/farmacocinética , Masculino , MesocricetusRESUMEN
Quantitative data on fecal shedding of antimicrobial-resistant bacteria are crucial to assess the risk of transmission from dogs to humans. Our first objective was to investigate the prevalence of quinolone/fluoroquinolone-resistant and beta-lactam-resistant Enterobacteriaceae in dogs in France and Spain. Due to the particular concern about possible transmission of extended-spectrum cephalosporin (ESC)-resistant isolates from dogs to their owners, we characterized the ESBL/pAmpC producers collected from dogs. Rectal swabs from 188 dogs, without signs of diarrhea and that had not received antimicrobials for 4 weeks before the study, were quantified for total and resistant Enterobacteriaceae on selective media alone or containing relevant antibiotic concentrations. Information that might explain antibiotic resistance was collected for each dog. Extended-spectrum cephalosporin-resistant isolates were subjected to bacterial species identification (API20E), genetic lineage characterization (MLST), ESBL/pAmpC genes identification (sequencing), and plasmid characterization (pMLST). Regarding beta-lactam resistance, amoxicillin- (AMX) and cefotaxime- (CTX) resistant Enterobacteriaceae were detected in 70 and 18% of the dogs, respectively, whereas for quinolone/fluoroquinolone-resistance, Nalidixic acid- (NAL) and ciprofloxacin- (CIP) resistant Enterobacteriaceae were detected in 36 and 18% of the dogs, respectively. Medical rather than preventive consultation was a risk marker for the presence of NAL and CIP resistance. CTX resistance was mainly due to a combination of specific ESBL/pAmpC genes and particular conjugative plasmids already identified in human patients: bla CTX-M-1/IncI1/ST3 (n = 4), bla CMY-2/IncI1/ST12 (n = 2), and bla CTX-M-15/IncI1/ST31 (n = 1). bla SHV-12 (n = 3) was detected in various plasmid lineages (InI1/ST3, IncI1/ST26, and IncFII). ESBL/pAmpC plasmids were located in different genetic lineages of E. coli, with the exception of two strains in France (ST6998) and two in Spain (ST602). Our study highlights dogs as a potential source of Q/FQ-resistant and ESBL/pAmpC-producing bacteria that might further disseminate to humans, and notably a serious risk of future acquisition of CTX-M-1 and CMY-2 plasmids by the owners of dogs.
RESUMEN
BACKGROUND: Of the various drug therapies that influence gastrointestinal (GI) physiology, one of the most important are the acid-reducing agents (ARAs). Because changes in GI physiology often influence the pharmacokinetics of drugs given orally, there is a need to identify in vitro methods with which such effects can be elucidated. OBJECTIVE: Literature concerning the effects of ARAs (antacids, H2-receptor antagonists, and proton pump inhibitors [PPIs]) on GI physiology are reviewed with the aim of identifying conditions under which drugs are released after oral administration in the fasted state. In vitro dissolution tests to mimic the effects in the stomach were designed for H2-receptor antagonists and PPIs. CONCLUSIONS: The impact of ARAs on GI physiology depends on the type, duration, and amount of ARA administered as well as the location in the GI tract, with greatest impact on gastric physiology. While ARAs have a high impact on the gastric fluid pH and composition, changes in volume, viscosity, surface tension, and gastric emptying appear to be less profound. The proposed dissolution tests enable a ready comparison between dosage form performance in healthy adults and those receiving PPIs or H2-receptor antagonists.
Asunto(s)
Antiácidos/farmacología , Antiácidos/uso terapéutico , Tracto Gastrointestinal/efectos de los fármacos , Tracto Gastrointestinal/fisiología , Administración Oral , Animales , Vaciamiento Gástrico/efectos de los fármacos , Vaciamiento Gástrico/fisiología , Humanos , Solubilidad/efectos de los fármacosRESUMEN
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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Antibacterianos/efectos adversos , Infecciones por Clostridium/tratamiento farmacológico , Infecciones por Clostridium/mortalidad , Disbiosis/inducido químicamente , Animales , Antibacterianos/uso terapéutico , Clindamicina/uso terapéutico , Clostridioides difficile/efectos de los fármacos , Clostridioides difficile/patogenicidad , Cricetinae , Disbiosis/mortalidad , Microbioma Gastrointestinal/efectos de los fármacos , Masculino , Mesocricetus , Moxifloxacino/uso terapéuticoRESUMEN
Lowering the gut exposure to antibiotics during treatments can prevent microbiota disruption. We evaluated the effects of an activated charcoal-based adsorbent, DAV131A, on the fecal free moxifloxacin concentration and mortality in a hamster model of moxifloxacin-induced Clostridium difficile infection. A total of 215 hamsters receiving moxifloxacin subcutaneously (day 1 [D1] to D5) were orally infected at D3 with C. difficile spores. They received various doses (0 to 1,800 mg/kg of body weight/day) and schedules (twice a day [BID] or three times a day [TID]) of DAV131A (D1 to D8). Moxifloxacin concentrations and C. difficile counts were determined at D3, and mortality was determined at D12 We compared mortality rates, moxifloxacin concentrations, and C. difficile counts according to DAV131A regimen and modeled the links between DAV131A regimen, moxifloxacin concentration, and mortality. All hamsters that received no DAV131A died, but none of those that received 1,800 mg/kg/day died. Significant dose-dependent relationships between DAV131A dose and (i) mortality, (ii) moxifloxacin concentration, and (iii) C. difficile count were evidenced. Mathematical modeling suggested that (i) lowering the moxifloxacin concentration at D3, which was 58 µg/g (95% confidence interval [CI] = 50 to 66 µg/g) without DAV131A, to 17 µg/g (14 to 21 µg/g) would reduce mortality by 90%; and (ii) this would be achieved with a daily DAV131A dose of 703 mg/kg (596 to 809 mg/kg). In this model of C. difficile infection, DAV131A reduced mortality in a dose-dependent manner by decreasing the fecal free moxifloxacin concentration.
Asunto(s)
Clostridioides difficile/patogenicidad , Infecciones por Clostridium/inducido químicamente , Disbiosis/inducido químicamente , Enterocolitis Seudomembranosa/inducido químicamente , Fluoroquinolonas/efectos adversos , Microbioma Gastrointestinal/efectos de los fármacos , Tracto Gastrointestinal/efectos de los fármacos , Animales , Carbón Orgánico/farmacología , Infecciones por Clostridium/tratamiento farmacológico , Cricetinae , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Enterocolitis Seudomembranosa/tratamiento farmacológico , Enterocolitis Seudomembranosa/mortalidad , Fluoroquinolonas/farmacología , Tracto Gastrointestinal/microbiología , MoxifloxacinoRESUMEN
Alzheimer's disease (AD) is a neurodegenerative condition that leads to neuronal death and memory dysfunction. In the past, specific peroxisome proliferator-activated receptor (PPAR)γ-agonists, such as pioglitazone, have been tested with limited success to improve AD pathology. Here, we investigated the therapeutic efficacy of GFT1803, a novel potent PPAR agonist that activates all the three PPAR isoforms (α/δ/γ) in the APP/PS1 mouse model in comparison to the selective PPARγ-agonist pioglitazone. Both compounds showed similar brain/plasma partitioning ratios, although whole body and brain exposure to GFT1803 was significantly lower as compared to pioglitazone, at doses used in this study. Oral treatment of APP/PS1 mice with GFT1803 decreased microglial activation, amyloid ß (Aß) plaque area, Aß levels in sodium dodecyl sulfate- and formic acid-soluble fractions in a concentration-dependent manner. With a single exception of Aß38 and Aß40 levels, measured by ELISA, these effects were not observed in mice treated with pioglitazone. Both ligands decreased glial fibrillary acidic protein (GFAP) expression to similar extent and did not affect ApoE expression. Finally, GFT1803 increased insulin-degrading enzyme expression. Analysis of spatial memory formation in the Morris water maze demonstrated that both compounds were able to partially revert the phenotype of APP/PS1 mice in comparison to wild-type mice with GFT1803 being most effective. As compared to pioglitazone, GFT1803 (pan-PPAR agonist) produced both quantitatively superior and qualitatively different therapeutic effects with respect to amyloid plaque burden, insoluble Aß content, and neuroinflammation at significantly lower whole body and brain exposure rates.
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Precursor de Proteína beta-Amiloide , Trastornos del Conocimiento/prevención & control , PPAR gamma/agonistas , PPAR gamma/fisiología , Placa Amiloide/prevención & control , Presenilina-1 , Precursor de Proteína beta-Amiloide/genética , Animales , Células COS , Chlorocebus aethiops , Trastornos del Conocimiento/genética , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Pioglitazona , Placa Amiloide/genética , Presenilina-1/genética , Tiazolidinedionas/farmacología , Tiazolidinedionas/uso terapéutico , Resultado del TratamientoRESUMEN
Antibiotics excreted into the intestinal tract, such as broad-spectrum cephalosporins, disrupt the indigenous microflora, affect colonization resistance (CR), and promote intestinal colonization by resistant bacteria. We tested whether oral DAV131, a charcoal-based adsorbent, would prevent colonization by a cefotaxime (CTX)-resistant Klebsiella pneumoniae strain (PUG-2) in CTX-treated mice. Mice received CTX, saline, CTX and DAV131, or saline and DAV131 for 3 days before oral challenge with 10(6) CFU of PUG-2. The fecal CTX concentrations and counts of PUG-2 were assayed. Fecal CTX disappeared when DAV131 was given concomitantly with CTX (P < 0.05), and the area under the curve of PUG-2 fecal density was significantly reduced (P < 0.01). In conclusion, reducing intestinal antibiotic exposure with DAV131 may reduce colonization by resistant strains during treatment compared to treatment with CTX only. This might open new possibilities for decreasing the impact of antibiotics on the intestinal microbiota during treatments.
Asunto(s)
Antibacterianos/farmacología , Cefotaxima/farmacología , Carbón Orgánico/farmacología , Intestinos/efectos de los fármacos , Infecciones por Klebsiella/tratamiento farmacológico , Klebsiella pneumoniae/efectos de los fármacos , Resistencia betalactámica , Administración Oral , Adsorción , Animales , Área Bajo la Curva , Recuento de Colonia Microbiana , Sinergismo Farmacológico , Heces/microbiología , Femenino , Intestinos/microbiología , Infecciones por Klebsiella/microbiología , Klebsiella pneumoniae/crecimiento & desarrollo , RatonesRESUMEN
OBJECTIVE: The adaptive mechanisms in response to excess energy supply are still poorly known in humans. Our aims were to define metabolic responses and changes in gene expression in skeletal muscle of healthy volunteers during fat overfeeding. RESEARCH METHODS AND PROCEDURES: Eight lean young healthy men were given a diet rich in saturated fat with an excess of approximately 550 kcal/d for 4 weeks. Using oligonucleotide microarrays, gene expression changes in skeletal muscle were analyzed at Day 0, Day 14, and Day 28. RESULTS: Fat overfeeding led to an increase in body weight (1.0 +/- 0.3 kg) and waist circumference (2.2 +/- 0.5 cm, p = 0.005) and a significant decrease in fasting non-esterified fatty acid plasma levels (-29 +/- 5%, p = 0.028). Respiratory quotient was significantly increased (0.84 +/- 0.01 to 0.88 +/- 0.02, p = 0.034) and lipid oxidation rate tended to decrease. The expression of 55 genes was modified in skeletal muscle. The main pathways indicated a coordinated stimulation of triacylglycerol synthesis, inhibition of lipolysis, reduction of fatty acid oxidation, and development of adipocytes. Promoter analysis of the regulated genes suggests that sterol regulatory element binding proteins might be important players of the short-term adaptation to fat overfeeding in human skeletal muscle. DISCUSSION: This combined metabolic and genomic investigation shows that fat overfeeding for 28 days promotes the storage of the excess energy in lean men and demonstrates the usefulness of a transcriptomic approach to a better understanding of the metabolic adaptation to changes in nutritional behavior in human.