RESUMEN
Microbial communities play a significant role in maintaining ecosystems in a healthy homeostasis. Presently, in the human gastrointestinal tract, there are certain taxonomic groups of importance, though there is no single species that plays a keystone role. Bacteroides spp. are known to be major players in the maintenance of eubiosis in the human gastrointestinal tract. Here we review the critical role that Bacteroides play in the human gut, their potential pathogenic role outside of the gut, and their various methods of adapting to the environment, with a focus on data for B. fragilis and B. thetaiotaomicron. Bacteroides are anaerobic non-sporing Gram negative organisms that are also resistant to bile acids, generally thriving in the gut and having a beneficial relationship with the host. While they are generally commensal organisms, some Bacteroides spp. can be opportunistic pathogens in scenarios of GI disease, trauma, cancer, or GI surgery, and cause infection, most commonly intra-abdominal infection. B. fragilis can develop antimicrobial resistance through multiple mechanisms in large part due to its plasticity and fluid genome. Bacteroidota (formerly, Bacteroidetes) have a very broad metabolic potential in the GI microbiota and can rapidly adapt their carbohydrate metabolism to the available nutrients. Gastrointestinal Bacteroidota species produce short-chain fatty acids such as succinate, acetate, butyrate, and occasionally propionate, as the major end-products, which have wide-ranging and many beneficial influences on the host. Bacteroidota, via bile acid metabolism, also play a role in in colonization-resistance of other organisms, including Clostridioides difficile, and maintenance of gut integrity.
Asunto(s)
Microbioma Gastrointestinal , Microbiota , Humanos , Bacteroides/genética , Tracto Gastrointestinal , Ácidos y Sales Biliares/farmacologíaRESUMEN
OBJECTIVES: In the US, Clostridioides difficile (C. difficile) infection (CDI) is the 8th leading cause of hospital readmission and 7th for mortality among all gastrointestinal (GI) disorders. Here, we investigated GI dysfunction post-CDI in humans and mice post-acute infection. MATERIALS AND METHODS: From March 2020 to July 2021, we reviewed the clinical records of 67 patients referred to the UVA Complicated C. difficile clinic for fecal microbiota transplantation (FMT) eligibility. C57BL/6 mice were infected with C. difficile and clinical scores were determined daily. Stool samples from mice were collected to measure the shedding of C. difficile and myeloperoxidase (MPO) levels. On day 21 post-infection, Evans's blue and FITC-70kDa methods were performed to evaluate GI motility in mice. RESULTS: Of the 67 patients evaluated at the C. difficile clinic, 40 patients (59.7%) were confirmed to have CDI, and 22 patients (32.8%) with post-CDI IBS (diarrhea-type, constipation-type, and mixed-type). In infected mice, levels of MPO in stools and clinical score were higher on day 3. On day 21, mice recovered from body weight loss induced by CDI, and fecal MPO was undetectable. The total GI transit time (TGITT) and FITC-70kDa levels on the proximal colon were increased in infected mice (p = 0.002), suggesting a constipation phenotype post-acute phase of CDI. A positive correlation intestinal inflammation on day 3 and TGITT on day 21 was observed. CONCLUSION: In conclusion, post-infection intestinal dysfunction occurs in humans and mice post-CDI. Importantly, we have validated in the mouse model that CDI causes abnormal GI transit in the recovery phase of the disease, indicating the potential utility of the model in exploring the underlying mechanisms of post-infectious IBS in humans.
Asunto(s)
Clostridioides difficile , Infecciones por Clostridium , Ratones Endogámicos C57BL , Animales , Humanos , Infecciones por Clostridium/microbiología , Infecciones por Clostridium/fisiopatología , Ratones , Clostridioides difficile/patogenicidad , Femenino , Masculino , Persona de Mediana Edad , Modelos Animales de Enfermedad , Heces/microbiología , Enfermedades Gastrointestinales/microbiología , Enfermedades Gastrointestinales/fisiopatología , Anciano , Trasplante de Microbiota Fecal , Adulto , Peroxidasa/metabolismoRESUMEN
This case series and propensity-matched cohort study on the use of tigecycline in Clostridioides difficile infection (CDI) evaluated the effect of tigecycline on 30-day mortality. Adjusted for ATLAS Score, hypotension, treatment time period, and serum lactate, tigecycline did not significantly improve 30-day mortality (odds ratio: 0.89; 95% confidence interval: 0.25-3.12; P = 0.853). A randomized controlled trial is needed to determine efficacy and safety of tigecycline in severe or refractory CDI.
Asunto(s)
Clostridioides difficile , Infecciones por Clostridium , Tigeciclina , Antibacterianos/uso terapéutico , Infecciones por Clostridium/tratamiento farmacológico , Humanos , Estudios Retrospectivos , Tigeciclina/uso terapéuticoRESUMEN
Clostridioides difficile is the leading health care-associated pathogen, leading to substantial morbidity and mortality; however, there is no widely accepted model to predict C. difficile infection severity. Most currently available models perform poorly or were calibrated to predict outcomes that are not clinically relevant. We sought to validate six of the leading risk models (Age Treatment Leukocyte Albumin Serum Creatinine (ATLAS), C. difficile Disease (CDD), Zar, Hensgens, Shivashankar, and C. difficile Severity Score (CDSS)), guideline severity criteria, and PCR cycle threshold for predicting C. difficile-attributable severe outcomes (inpatient mortality, colectomy/ileostomy, or intensive care due to sepsis). Models were calculated using electronic data available within ±48 h of diagnosis (unavailable laboratory measurements assigned zero points), calibrated using a large retrospective cohort of 3,327 inpatient infections spanning 10 years, and compared using receiver operating characteristic (ROC) and precision-recall curves. ATLAS achieved the highest area under the ROC curve (AuROC) of 0.781, significantly better than the next best performing model (Zar 0.745; 95% confidence interval of AuROC difference 0.0094-0.6222; P = 0.008), and highest area under the precision-recall curve of 0.232. Current IDSA/SHEA severity criteria demonstrated moderate performance (AuROC 0.738) and PCR cycle threshold performed the worst (0.531). The overall predictive value for all models was low, with a maximum positive predictive value of 37.9% (ATLAS cutoff ≥9). No clinical model performed well on external validation, but ATLAS did outperform other models for predicting clinically relevant C. difficile-attributable outcomes at diagnosis. Novel markers should be pursued to augment or replace underperforming clinical-only models.
Asunto(s)
Clostridioides difficile , Infecciones por Clostridium , Clostridioides , Humanos , Valor Predictivo de las Pruebas , Curva ROC , Estudios RetrospectivosRESUMEN
Clostridioides difficile infection (CDI) is the fifth leading cause of death from nonmalignant gastrointestinal disease in the United States. The contribution of resistance to C. difficile-active antibiotics to the outcomes of CDI is unclear. We evaluated the antimicrobial susceptibility of C. difficile isolates in a U.S. hospital and determined associations of clinical variables and binary toxin positivity with antibiotic resistance. C. difficile spores were cultured from fecal specimens of adult patients with CDI for genotyping and antimicrobial susceptibility assay (for clindamycin [CLI], fidaxomicin [FDX], metronidazole [MTZ], moxifloxacin [MXF], tigecycline [TGC], and vancomycin [VAN]). Electronic medical records were reviewed for clinical data extraction. Ninety-seven of 130 (75%) fecal samples grew toxigenic C. difficile in culture. Most of the isolates were tcdA+ tcdB+ cdtB- (80.4%), and 18.6% and 1% were tcdA+ tcdB+ cdtB+ and tcdA-tcdB+ cdtB+, respectively. Susceptibility to VAN, MTZ, FDX, TGC, MXF, and CLI was 96%, 94%, 100%, 100%, 8%, and 79%, respectively. Six isolates, all cdtB positive and belonging to the 027 ribotype, were resistant to VAN and/or MTZ. Higher MICs were found in isolates with a mutation in the VAN-related resistance gene vanR, but not vanS. In addition, cdtB+ isolates exhibited higher MICs of VAN, MTZ, TGC, CLI, and MXF compared to cdtB- strains. Patients with greater intestinal inflammation or severe disease were more likely to be infected with cdtB+ strains. Decreased susceptibility to antibiotics is not directly associated with either severe or recurrent CDI. However, antimicrobial susceptibility of C. difficile is decreased in strains positive for the binary toxin gene.
Asunto(s)
Toxinas Bacterianas , Clostridioides difficile , Infecciones por Clostridium , Adulto , Antibacterianos/farmacología , Toxinas Bacterianas/genética , Clostridioides , Clostridioides difficile/genética , Infecciones por Clostridium/tratamiento farmacológico , Fidaxomicina , Humanos , Metronidazol/farmacología , Pruebas de Sensibilidad Microbiana , Moxifloxacino , Índice de Severidad de la Enfermedad , Tigeciclina , Vancomicina/farmacologíaRESUMEN
Trichomoniasis is a sexually transmitted infection in humans caused by the protozoan Trichomonas vaginalis, the leading causative agent of vaginitis in women and urethritis in men worldwide. Metronidazole is the standard treatment for trichomoniasis, with tinidazole as the second line. There are currently no FDA-approved non-nitroimidazole alternative treatments for resistant strains. This study compares the efficacy of a newly synthesized non-nitroimidazole oral drug, amixicile, to that of both metronidazole and the synthetic precursor of amixicile, nitazoxanide with in vitro sensitivity testing. One standard strain from ATCC and three patient-isolated strains of T. vaginalis were used to compare treatments under anaerobic conditions. The minimum inhibitory concentration for metronidazole, nitazoxanide, and amixicile were 12.5 µM, 100 µM, and 6.25 µM, respectively. These results suggest that amixicile may be highly active against T. vaginalis and warrants further investigation as a potential alternative to metronidazole in the treatment of trichomoniasis.
Asunto(s)
Tricomoniasis , Vaginitis por Trichomonas , Trichomonas vaginalis , Benzamidas , Resistencia a Medicamentos , Femenino , Humanos , Masculino , Metronidazol/farmacología , Metronidazol/uso terapéutico , Tiazoles , Tricomoniasis/tratamiento farmacológico , Vaginitis por Trichomonas/tratamiento farmacológicoRESUMEN
PURPOSE OF REVIEW: Clostridioides difficile infection (CDI) is a significant burden on the health system, especially due to high recurrence rates. Since the beginning of the CDI epidemic in early 2000s, many strategies for combatting recurrence have been explored, with moderate success so far. This review will focus on the most recent developments in recurrent CDI prevention and treatment. RECENT FINDINGS: There are two main mechanisms of CDI recurrence: alteration in microbiome and poor antibody response. Development of new antibiotics aims to minimize damage to the microbiome. Fecal transplant or other microbiome replacement therapies seek to replenish the missing elements in the microbiome. Fecal microbiota transplant is the most effective treatment for prevention of CDI recurrenceso far, but is difficult to standardize and regulate, leading to efforts to develop microbiome-derived therapeutics. A deficiency in developing antibodies to C. difficile toxins is another mechanism of recurrence. Active immunization using toxoid vaccines or passive immunization using mAbs address this aspect. SUMMARY: There are promising new treatments for recurrent CDI in development. Fecal microbiota transplant remains the most effective therapy for multiply recurrent CDI. New antibiotics, microbiome-derived therapeutics, and immunologic therapies are in development.
Asunto(s)
Infecciones por Clostridium/prevención & control , Infecciones por Clostridium/terapia , Antibacterianos/uso terapéutico , Trasplante de Microbiota Fecal/métodos , Humanos , Probióticos/uso terapéutico , Recurrencia , Prevención Secundaria/métodos , Resultado del TratamientoRESUMEN
Background: Clostridium difficile infection (CDI) is a serious threat for an aging population. Using an aged mouse model, we evaluated the effect of age and the roles of innate immunity and intestinal microbiota. Methods: Aged (18 months) and young (8 weeks) mice were infected with C difficile, and disease severity, immune response, and intestinal microbiome were compared. The same experiment was repeated with intestinal microbiota exchange between aged and young mice before infection. Results: Higher mortality was observed in aged mice with weaker neutrophilic mobilization in blood and intestinal tissue and depressed proinflammatory cytokines in early infection. Microbiota exchange improved survival and early immune response in aged mice. Microbiome analysis revealed that aged mice have significant deficiencies in Bacteroidetes phylum and, specifically, Bacteroides, Alistipes, and rc4-4 genera, which were replenished by cage switching. Conclusions: Microbiota-dependent alteration in innate immune response early on during infection may explain poor outcome in aged host with CDI.
Asunto(s)
Infecciones por Clostridium/inmunología , Infecciones por Clostridium/patología , Microbioma Gastrointestinal , Inmunidad Innata , Factores de Edad , Animales , Citocinas/metabolismo , Modelos Animales de Enfermedad , Intestinos/inmunología , Intestinos/patología , Masculino , Ratones Endogámicos C57BL , Neutrófilos/inmunología , Análisis de SupervivenciaRESUMEN
BACKGROUND: The elderly host is highly susceptible to severe disease and treatment failure in Clostridium difficile infection (CDI). We investigated how treatment with vancomycin in the aged host influences systemic and intestinal humoral responses and select intestinal microbiota. METHODS: Young (age, 2 months) and aged (age, 18 months) C57BL/6 mice were infected with VPI 10463 after exposure to broad-spectrum antibiotics. Vancomycin was given 24 hours after infection, and treatment was continued for 5 days. At select time points, specimens of serum and intestinal tissue and contents were collected for histopathologic analysis, to measure antibody levels and the pathogen burden, and to determine the presence and levels of select intestinal microbiota and C. difficile toxin. RESULTS: Levels of disease severity, relapse, and mortality were increased, and recovery from infection was slower in aged mice compared to young mice. Serum levels of immunoglobulin M, immunoglobulin A, and immunoglobulin G against C. difficile toxin A were depressed in aged mice, and vancomycin treatment reduced antibody responses in both age groups. While baseline levels of total bacterial load, Bacteroidetes, Firmicutes, and Enterobacteriaceae were mostly similar, aged mice had a significant change in the Firmicutes to Bacteroidetes ratio with vancomycin treatment. CONCLUSIONS: Vancomycin treatment decreases the systemic humoral response to CDI. Increased mortality from and recurrence of CDI in the aged host are associated with an impaired humoral response and a greater susceptibility to vancomycin-induced alteration of intestinal microbiota.
Asunto(s)
Antibacterianos/uso terapéutico , Clostridioides difficile/efectos de los fármacos , Infecciones por Clostridium/tratamiento farmacológico , Microbioma Gastrointestinal/efectos de los fármacos , Inmunidad Humoral/efectos de los fármacos , Vancomicina/uso terapéutico , Factores de Edad , Animales , Humanos , Ratones Endogámicos C57BL , Modelos AnimalesRESUMEN
The role of leptin in the mucosal immune response to Clostridium difficile colitis, a leading cause of nosocomial infection, was studied in humans and in a murine model. Previously, a mutation in the receptor for leptin (LEPR) was shown to be associated with susceptibility to infectious colitis and liver abscess due to Entamoeba histolytica as well as to bacterial peritonitis. Here we discovered that European Americans homozygous for the same LEPR Q223R mutation (rs1137101), known to result in decreased STAT3 signaling, were at increased risk of C. difficile infection (odds ratio, 3.03; P = 0.015). The mechanism of increased susceptibility was studied in a murine model. Mice lacking a functional leptin receptor (db/db) had decreased clearance of C. difficile from the gut lumen and diminished inflammation. Mutation of tyrosine 1138 in the intracellular domain of LepRb that mediates signaling through the STAT3/SOCS3 pathway also resulted in decreased mucosal chemokine and cell recruitment. Collectively, these data support a protective mucosal immune function for leptin in C. difficile colitis partially mediated by a leptin-STAT3 inflammatory pathway that is defective in the LEPR Q223R mutation. Identification of the role of leptin in protection from C. difficile offers the potential for host-directed therapy and demonstrates a connection between metabolism and immunity.
Asunto(s)
Clostridioides difficile , Infecciones por Clostridium , Colitis/microbiología , Leptina/fisiología , Receptores de Leptina/genética , Animales , Quimiocinas/metabolismo , Clostridioides difficile/genética , Clostridioides difficile/inmunología , Infecciones por Clostridium/genética , Infecciones por Clostridium/inmunología , Colitis/genética , Citocinas/metabolismo , Modelos Animales de Enfermedad , Citometría de Flujo , Predisposición Genética a la Enfermedad , Mucosa Intestinal/inmunología , Intestinos/microbiología , Leptina/inmunología , Modelos Logísticos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Oportunidad Relativa , Polimorfismo Genético , Receptores de Leptina/deficiencia , Factor de Transcripción STAT3 , Transducción de Señal/fisiología , Tirosina/genéticaRESUMEN
Amixicile shows efficacy in the treatment of Clostridium difficile infections (CDI) in a mouse model, with no recurrence of CDI. Since amixicile selectively inhibits the action of a B vitamin (thiamine pyrophosphate) cofactor of pyruvate:ferredoxin oxidoreductase (PFOR), it may both escape mutation-based drug resistance and spare beneficial probiotic gut bacteria that do not express this enzyme. Amixicile is a water-soluble derivative of nitazoxanide (NTZ), an antiparasitic therapeutic that also shows efficacy against CDI in humans. In comparative studies, amixicile showed no toxicity to hepatocytes at 200 µM (NTZ was toxic above 10 µM); was not metabolized by human, dog, or rat liver microsomes; showed equivalence or superiority to NTZ in cytochrome P450 assays; and did not activate efflux pumps (breast cancer resistance protein, P glycoprotein). A maximum dose (300 mg/kg) of amixicile given by the oral or intraperitoneal route was well tolerated by mice and rats. Plasma exposure (rats) based on the area under the plasma concentration-time curve was 79.3 h · µg/ml (30 mg/kg dose) to 328 h · µg/ml (100 mg/kg dose), the maximum concentration of the drug in serum was 20 µg/ml, the time to the maximum concentration of the drug in serum was 0.5 to 1 h, and the half-life was 5.6 h. Amixicile did not concentrate in mouse feces or adversely affect gut populations of Bacteroides species, Firmicutes, segmented filamentous bacteria, or Lactobacillus species. Systemic bioavailability was demonstrated through eradication of Helicobacter pylori in a mouse infection model. In summary, the efficacy of amixicile in treating CDI and other infections, together with low toxicity, an absence of mutation-based drug resistance, and excellent drug metabolism and pharmacokinetic metrics, suggests a potential for broad application in the treatment of infections caused by PFOR-expressing microbial pathogens in addition to CDI.
Asunto(s)
Antibacterianos/farmacocinética , Benzamidas/farmacocinética , Infecciones por Helicobacter/tratamiento farmacológico , Helicobacter pylori/efectos de los fármacos , Tiazoles/farmacocinética , Animales , Antibacterianos/sangre , Antibacterianos/farmacología , Área Bajo la Curva , Benzamidas/sangre , Benzamidas/farmacología , Disponibilidad Biológica , Línea Celular , Supervivencia Celular/efectos de los fármacos , Perros , Evaluación Preclínica de Medicamentos , Semivida , Infecciones por Helicobacter/sangre , Infecciones por Helicobacter/microbiología , Helicobacter pylori/crecimiento & desarrollo , Helicobacter pylori/metabolismo , Hepatocitos/citología , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Humanos , Masculino , Pruebas de Sensibilidad Microbiana , Microbiota/efectos de los fármacos , Microbiota/fisiología , Microsomas Hepáticos/efectos de los fármacos , Piruvato-Sintasa/metabolismo , Ratas , Tiamina Pirofosfato/metabolismo , Tiazoles/sangre , Tiazoles/farmacologíaRESUMEN
Clostridium difficile (C. difficile) infection (CDI) rates have exhibited a steady rise worldwide over the last two decades and the infection poses a global threat due to the emergence of antibiotic resistant strains. Interstrain antagonistic interactions across the host microbiome form an important strategy for controlling the emergence of CDI. The current diagnosis method for CDI, based on immunoassays for toxins produced by pathogenic C. difficile strains, is limited by false negatives due to rapid toxin degradation. Furthermore, simultaneous monitoring of nontoxigenic C. difficile strains is not possible, due to absence of these toxins, thereby limiting its application toward the control of CDI through optimizing antagonistic interstrain interactions. Herein, we demonstrate that morphological differences within the cell wall of particular C. difficile strains with differing S-layer proteins can induce systematic variations in their electrophysiology, due alterations in cell wall capacitance. As a result, dielectrophoretic frequency analysis can enable the independent fingerprinting and label-free separation of intact microbials of each strain type from mixed C. difficile samples. The sensitivity of this contact-less electrophysiological method is benchmarked against the immunoassay and microbial growth rate methods for detecting alterations within both, toxigenic and nontoxigenic C. difficile strains after vancomycin treatment. This microfluidic diagnostic platform can assist in the development of therapies for arresting clostridial infections by enabling the isolation of individual strains, optimization of antibiotic treatments and the monitoring of microbiomes.
Asunto(s)
Clostridioides difficile/aislamiento & purificación , Electroforesis/métodos , Adhesión Bacteriana , Línea Celular , Clostridioides difficile/clasificación , Clostridioides difficile/fisiología , Ensayo de Inmunoadsorción Enzimática , Humanos , Mucosa Intestinal/microbiología , Microscopía Electrónica de Transmisión , Especificidad de la EspecieAsunto(s)
Infecciones por Clostridium/mortalidad , Infecciones por Clostridium/psicología , Disfunción Cognitiva/mortalidad , Disfunción Cognitiva/psicología , Hospitalización/tendencias , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Infecciones por Clostridium/diagnóstico , Cognición/fisiología , Disfunción Cognitiva/diagnóstico , Femenino , Humanos , Masculino , Estudios RetrospectivosRESUMEN
Toxin A (TcdA) and toxin B (TcdB) of Clostridium difficile cause gross pathological changes (e.g., inflammation, secretion, and diarrhea) in the infected host, yet the molecular and cellular pathways leading to observed host responses are poorly understood. To address this gap, we evaluated the effects of single doses of TcdA and/or TcdB injected into the ceca of mice, and several endpoints were analyzed, including tissue pathology, neutrophil infiltration, epithelial-layer gene expression, chemokine levels, and blood cell counts, 2, 6, and 16 h after injection. In addition to confirming TcdA's gross pathological effects, we found that both TcdA and TcdB resulted in neutrophil infiltration. Bioinformatics analyses identified altered expression of genes associated with the metabolism of lipids, fatty acids, and detoxification; small GTPase activity; and immune function and inflammation. Further analysis revealed transient expression of several chemokines (e.g., Cxcl1 and Cxcl2). Antibody neutralization of CXCL1 and CXCL2 did not affect TcdA-induced local pathology or neutrophil infiltration, but it did decrease the peripheral blood neutrophil count. Additionally, low serum levels of CXCL1 and CXCL2 corresponded with greater survival. Although TcdA induced more pronounced transcriptional changes than TcdB and the upregulated chemokine expression was unique to TcdA, the overall transcriptional responses to TcdA and TcdB were strongly correlated, supporting differences primarily in timing and potency rather than differences in the type of intracellular host response. In addition, the transcriptional data revealed novel toxin effects (e.g., altered expression of GTPase-associated and metabolic genes) underlying observed physiological responses to C. difficile toxins.
Asunto(s)
Proteínas Bacterianas/toxicidad , Toxinas Bacterianas/toxicidad , Ciego/metabolismo , Enterotoxinas/toxicidad , Regulación de la Expresión Génica/efectos de los fármacos , Transcriptoma , Animales , Ciego/efectos de los fármacos , Regulación de la Expresión Génica/inmunología , Ratones , Ratones Endogámicos C57BLRESUMEN
Antibiotic treatment, including vancomycin, for Clostridium difficile infection (CDI) has been associated with recurrence of disease in up to 25% of infected persons. This study investigated the effects of vancomycin on the clinical outcomes, intestinal histopathology, and anaerobic community during and after treatment in a murine model of CDI. C57BL/6 mice were challenged with C. difficile strain VPI 10463 after pretreatment with an antibiotic cocktail. Twenty-four hours after infection, mice were treated daily with vancomycin, nitazoxanide, fidaxomicin, or metronidazaole for 5 days. Mice were monitored for either 6 or 12 days postinfection. Clinical, diarrhea, and histopathology scores were measured. Cecal contents or stool samples were assayed for clostridial or Bacteroides DNA and C. difficile toxins A and B. Vancomycin treatment of infected mice was associated with improved clinical, diarrhea, and histopathology scores and survival during treatment. However, after discontinuation of the drug, clinical scores and histopathology were worse in treated mice than in untreated infected controls. At the end of the study, 62% of the vancomycin-treated mice succumbed to recurrence, with an overall mortality rate equivalent to that of the untreated infected control group. Fidaxomicin-treated mice had outcomes similar to those of vancomycin-treated mice. C. difficile predominated over Bacteroides in cecal contents of vancomycin-treated mice, similar to findings for untreated infected mice. Decreasing the duration of vancomycin treatment from 5 days to 1 day decreased recurrence and deaths. In conclusion, vancomycin improved clinical scores and histopathology acutely but was associated with poor outcome posttreatment in C. difficile-infected mice. Decreasing vancomycin exposure may decrease relapse and improve survival in CDI.
Asunto(s)
Antibacterianos/uso terapéutico , Clostridioides difficile/patogenicidad , Enterocolitis Seudomembranosa/tratamiento farmacológico , Enterocolitis Seudomembranosa/mortalidad , Vancomicina/uso terapéutico , Aminoglicósidos/uso terapéutico , Animales , Bacteroides/genética , Ciego/microbiología , Clostridioides difficile/efectos de los fármacos , Clostridioides difficile/genética , Infecciones por Clostridium/tratamiento farmacológico , ADN Bacteriano/aislamiento & purificación , Heces/microbiología , Fidaxomicina , Intestinos/efectos de los fármacos , Intestinos/lesiones , Intestinos/microbiología , Masculino , Metronidazol/uso terapéutico , Ratones , Ratones Endogámicos C57BL , Nitrocompuestos , Recurrencia , Tiazoles/uso terapéutico , Resultado del TratamientoRESUMEN
BACKGROUND: Although several animal models of cryptosporidiosis have been reported, most involve genetically or pharmacologically immune-suppressed hosts. METHODS: We report challenge with excysted (in vitro and in vivo) and unexcysted (in vivo) Cryptosporidium parvum oocysts in human colonic adenocarcinoma (HCT-8) cells and weaned nourished and malnourished C57BL/6 mice, following outcomes of growth rate, stool shedding, and tissue burden. We tested treatment with an oligodeoxynucleotide containing unmethylated CpG motif (CpG-ODN) and alanyl-glutamine in vivo and in vitro. RESULTS: C. parvum-challenged mice showed prolonged weight loss (>10% over 4 days), robust stool shedding (>3 logs/d over 7 days), and epithelial infection in the ileum, cecum, and colon. Of 2 potential therapeutic compounds evaluated in the model, CpG-ODN reduced body weight loss (to <6% on days 3-7 after challenge), reduced shedding of organisms (by 25% on days 1 and 3 after challenge), and decreased the burden of parasites in the ileum. Alanyl-glutamine showed similar benefits. In vitro findings suggested that effects on the epithelial component of the mucosa probably likely responsible for beneficial effects seen in vivo. CONCLUSIONS: Weaned mice provide a convenient and reproducible model of cryptosporidial disease, including its vicious cycle with body weight loss and heavier infection with malnutrition, and this model may be useful in exploring innovative therapeutic solutions for this challenging infectious disease.
Asunto(s)
Criptosporidiosis/terapia , Cryptosporidium parvum/patogenicidad , Desnutrición/parasitología , Desnutrición/terapia , Animales , Línea Celular Tumoral , Colon/efectos de los fármacos , Colon/parasitología , Colon/patología , Criptosporidiosis/complicaciones , Criptosporidiosis/patología , Cryptosporidium parvum/aislamiento & purificación , ADN Protozoario/genética , ADN Protozoario/aislamiento & purificación , Dipéptidos/uso terapéutico , Heces/parasitología , Femenino , Humanos , Íleon/efectos de los fármacos , Íleon/parasitología , Íleon/patología , Desnutrición/complicaciones , Desnutrición/patología , Ratones , Ratones Endogámicos C57BL , Oligodesoxirribonucleótidos/uso terapéuticoRESUMEN
Clostridioides (formerly Clostridium) difficile is the most important infectious cause of antibiotic-associated diarrhea worldwide and a leading cause of healthcare-associated infection in the United States. The incidence of C. difficile infection (CDI) in children has increased, with 20 000 cases now reported annually, also posing indirect educational and economic consequences. In contrast to infection in adults, CDI in children is more commonly community-associated, accounting for three-quarters of all cases. A wide spectrum of disease severity ranging from asymptomatic carriage to severe diarrhea can occur, varying by age. Fulminant disease, although rare in children, is associated with high morbidity and even fatality. Diagnosis of CDI can be challenging as currently available tests detect either the presence of organism or disease-causing toxin but cannot distinguish colonization from infection. Since colonization can be high in specific pediatric groups, such as infants and young children, biomarkers to aid in accurate diagnosis are urgently needed. Similar to disease in adults, recurrence of CDI in children is common, affecting 20% to 30% of incident cases. Metronidazole has long been considered the mainstay therapy for CDI in children. However, new evidence supports the safety and efficacy of oral vancomycin and fidaxomicin as additional treatment options, whereas fecal microbiota transplantation is gaining popularity for recurrent infection. Recent advancements in our understanding of emerging epidemiologic trends and management of CDI unique to children are highlighted in this review. Despite encouraging therapeutic advancements, there remains a pressing need to optimize CDI therapy in children, particularly as it pertains to severe and recurrent disease.
Asunto(s)
Clostridioides difficile , Infecciones por Clostridium , Adulto , Niño , Humanos , Preescolar , Antibacterianos/efectos adversos , Vancomicina/efectos adversos , Infecciones por Clostridium/diagnóstico , Infecciones por Clostridium/tratamiento farmacológico , Infecciones por Clostridium/epidemiología , Diarrea/tratamiento farmacológicoRESUMEN
PURPOSE: Clostridioides difficile infection (CDI) is the leading cause of antibiotic-related diarrhea and healthcare-associated infections, affecting in particular elderly patients and their global health. This review updates the understanding of this infection, with focus on cognitive impairment and frailty as both risk factors and consequence of CDI, summarizing recent knowledge and potential mechanisms to this interplay. METHODS: A literature search was conducted including terms that would incorporate cognitive and functional impairment, aging, quality of life, morbidity and mortality with CDI, microbiome and the gut-brain axis. RESULTS: Advanced age remains a critical risk for severe disease, recurrence, and mortality in CDI. Observational and quality of life studies show evidence of functional loss in older people after acute CDI. In turn, frailty and cognitive impairment are independent predictors of death following CDI. CDI has long-term impact in the elderly, leading to increased risk of readmissions and mortality even months after the acute event. Immune senescence and the aging microbiota are key in susceptibility to CDI, with factors including inflammation and exposure to luminal microbial products playing a role in the gut-brain axis. CONCLUSIONS: Frailty and poor health status are risk factors for CDI in the elderly. CDI affects quality of life, cognition and functionality, contributing to a decline in patient health over time and leading to early and late mortality. Narrative synthesis of the evidence suggests a framework for viewing the cycle of functional and cognitive decline in the elderly with CDI, impacting the gut-brain and gut-muscle axes.
Asunto(s)
Infecciones por Clostridium , Fragilidad , Humanos , Anciano , Calidad de Vida , Infecciones por Clostridium/epidemiología , Factores de Riesgo , CogniciónRESUMEN
Antibiotic-induced microbiota disruption and its persistence create conditions for dysbiosis and colonization by opportunistic pathogens, such as those causing Clostridioides difficile (C. difficile) infection (CDI), which is the most severe hospital-acquired intestinal infection. Given the wide differences in microbiota across hosts and in their recovery after antibiotic treatments, there is a need for assays to assess the influence of dysbiosis and its recovery dynamics on the susceptibility of the host to CDI. Germination of C. difficile spores is a key virulence trait for the onset of CDI, which is influenced by the level of primary vs secondary bile acids in the intestinal milieu that is regulated by the microbiota composition. Herein, the germination of C. difficile spores in fecal supernatant from mice that are subject to varying degrees of antibiotic treatment is utilized as an ex vivo assay to predict intestinal dysbiosis in the host based on their susceptibility to CDI, as determined by in vivo CDI metrics in the same mouse model. Quantification of spore germination down to lower detection limits than the colony-forming assay is achieved by using impedance cytometry to count single vegetative bacteria that are identified based on their characteristic electrical physiology for distinction vs aggregated spores and cell debris in the media. As a result, germination can be quantified at earlier time points and with fewer spores for correlation to CDI outcomes. This sets the groundwork for a point-of-care tool to gauge the susceptibility of human microbiota to CDI after antibiotic treatments.
Asunto(s)
Clostridioides difficile , Infecciones por Clostridium , Humanos , Animales , Ratones , Antibacterianos/efectos adversos , Clostridioides , Disbiosis/inducido químicamente , Esporas Bacterianas/fisiología , Infecciones por Clostridium/microbiologíaRESUMEN
INTRODUCTION: Clostridioides difficile is the leading cause of healthcare-associated infections in the USA, with an estimated 1 billion dollars in excess cost to the healthcare system annually. C. difficile infection (CDI) has high recurrence rate, up to 25% after first episode and up to 60% for succeeding episodes. Preliminary in vitro and in vivo studies indicate that alanyl-glutamine (AQ) may be beneficial in treating CDI by its effect on restoring intestinal integrity in the epithelial barrier, ameliorating inflammation and decreasing relapse. METHODS AND ANALYSIS: This study is a randomised, placebo-controlled, double-blind, phase II clinical trial. The trial is designed to determine optimal dose and safety of oral AQ at 4, 24 and 44 g doses administered daily for 10 days concurrent with standard treatment of non-severe or severe uncomplicated CDI in persons age 18 and older. The primary outcome of interest is CDI recurrence during 60 days post-treatment follow-up, with the secondary outcome of mortality during 60 days post-treatment follow-up. Exploratory analysis will be done to determine the impact of AQ supplementation on intestinal and systemic inflammation, as well as intestinal microbial and metabolic profiles. ETHICS AND DISSEMINATION: The study has received University of Virginia Institutional Review Board approval (HSR200046, Protocol v9, April 2023). Findings will be disseminated via conference presentations, lectures and peer-reviewed publications. TRIAL REGISTRATION NUMBER: NCT04305769.