RESUMEN
BackgroundWhile human-to-human transmission of Clostridioides difficile occurs often, other infection sources, including food, animals and environment, are under investigation.AimWe present a large study on C. difficile in a food item in Europe, encompassing 12 European countries (Austria, France, Greece, Ireland, Italy, the Netherlands, Poland, Slovakia, Spain, Sweden, Romania and the United Kingdom).MethodsPotato was selected because of availability, ease of sampling and high C. difficile positivity rates. Identical protocols for sampling and isolation were used, enabling a direct comparison of the C. difficile positivity rate.ResultsFrom C. difficile-positive potato samples (33/147; 22.4%), we obtained 504 isolates, grouped into 38 PCR ribotypes. Positivity rates per country varied (0-100%) and were at least 10% in 9/12 countries. No geographical clustering of samples with high positivity rates or in PCR ribotype distribution was observed. The most frequently detected PCR ribotypes (014/020, 078/126, 010 and 023) are also commonly reported in Europe among human clinically relevant isolates, in animal isolates and in the environment. Whole genome sequencing revealed several genetically related strain pairs (Spain/RT126, France/RT010, Austria and Sweden/RT276) and a cluster of very similar strains in RT078/126.ConclusionOur results suggest, the high potato contamination rates could have public health relevance. They indicate potatoes can serve as a vector for introducing C. difficile spores in the household environment, where the bacterium can then multiply in sensitive hosts with disrupted or unmature microbiota. Potato contamination with PCR ribotypes shared between humans, animals and soil is supportive of this view.
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Clostridioides difficile , Infecciones por Clostridium , Solanum tuberosum , Animales , Clostridioides , Clostridioides difficile/genética , Infecciones por Clostridium/diagnóstico , Infecciones por Clostridium/epidemiología , Infecciones por Clostridium/microbiología , Europa (Continente)/epidemiología , Humanos , Reacción en Cadena de la Polimerasa , Ribotipificación , Solanum tuberosum/genéticaRESUMEN
Methicillin-resistant Staphylococcus aureus (MRSA) remains an important cause of serious infection, for which vancomycin is often recommended as the first-choice antibiotic treatment. Appropriate vancomycin prescribing requires accurate measurement of minimum inhibitory concentrations (MICs) to avoid treatment failure, and yet determination can be challenging due to methodological difficulties associated with susceptibility testing. An International Working Group of infectious disease specialists and clinical/medical microbiologists reached a consensus that empirical MRSA infection therapies should be chosen regardless of the suspected origin of the infecting strain (e.g., community or hospital) due to the complex intermingling epidemiology of MRSA clones in these settings. Also, if an elevated vancomycin MIC in the susceptible range is obtained in routine testing, an alternative second method should be used for confirmation and to aid antibiotic therapy recommendations. There is no absolutely dependable method for the accurate determination of vancomycin MIC, but broth microdilution appears to be the most reliable.
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Antibacterianos/farmacología , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Infecciones Estafilocócicas/tratamiento farmacológico , Vancomicina/uso terapéutico , Consenso , Humanos , Staphylococcus aureus Resistente a Meticilina/fisiología , Pruebas de Sensibilidad Microbiana , Infecciones Estafilocócicas/microbiologíaRESUMEN
This post-hoc analysis compared the pharmacokinetics and clinical outcomes of ceftaroline fosamil 600 mg every 12 (q12h) versus every 8 hours (q8h) in patients with acute bacterial skin and skin-structure infection (ABSSSI) and signs of sepsis. Clinical outcomes at test-of-cure in patients with ABSSSI and systemic inflammatory signs/systemic inflammatory response syndrome (SIRS) as well as ceftaroline minimum inhibitory concentrations (MICs) against baseline pathogens were compared between the COVERS trial (ceftaroline fosamil 600 mg q8h, 2-h infusion) and the CANVAS 1 and 2 trials (ceftaroline fosamil 600 mg q12h, 1-h infusion). Ceftaroline exposure among patients in COVERS with or without markers of sepsis was compared using population pharmacokinetic modelling. In COVERS, 62% (312/506) and 41% (208/506) of ceftaroline fosamil-treated patients had ≥1 systemic inflammatory sign or SIRS, respectively, compared with 55% (378/693) and 22% (155/693), respectively, in the CANVAS trials. Clinical cure rates for the modified intent-to-treat population in COVERS and CANVAS were similar for ceftaroline fosamil-treated patients with ≥1 sign of sepsis [82% (255/312) and 85% (335/394)] and for those with SIRS [84% (168/199) and 85% (131/155)]. Ceftaroline MIC distributions were similar across trials. Sepsis did not affect predicted individual steady-state ceftaroline exposure. Clinical cure rates in patients with ≥1 systemic inflammatory sign or SIRS were comparable for both ceftaroline fosamil dosage regimens. Pathogen susceptibilities to ceftaroline were similar across trials. Ceftaroline exposure was not affected by disease severity. Ceftaroline fosamil 600 mg q12h is a robust dosage regimen for most ABSSSI patients with sepsis [ClinicalTrials.gov ID: NCT01499277, NCT00424190, NCT00423657].
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Antibacterianos/administración & dosificación , Cefalosporinas/administración & dosificación , Enfermedades Cutáneas Bacterianas/complicaciones , Enfermedades Cutáneas Bacterianas/tratamiento farmacológico , Síndrome de Respuesta Inflamatoria Sistémica/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Antibacterianos/farmacocinética , Bacterias/efectos de los fármacos , Bacterias/aislamiento & purificación , Cefalosporinas/farmacocinética , Ensayos Clínicos Fase III como Asunto , Femenino , Humanos , Masculino , Pruebas de Sensibilidad Microbiana , Persona de Mediana Edad , Ensayos Clínicos Controlados Aleatorios como Asunto , Estudios Retrospectivos , Enfermedades Cutáneas Bacterianas/patología , Síndrome de Respuesta Inflamatoria Sistémica/patología , Resultado del Tratamiento , CeftarolinaRESUMEN
Iclaprim, a diaminopyrimidine antimicrobial, was compared with vancomycin for treatment of patients with acute bacterial skin and skin-structure infections (ABSSSIs) in two studies (REVIVE-1 and REVIVE-2). Here, the efficacy and tolerability of iclaprim in a pooled analysis of results from both studies was explored. REVIVE-1 and REVIVE-2 were phase 3, double-blind, randomised, multicentre, active-controlled, non-inferiority (margin of 10%) trials, each designed to enrol 600 patients with ABSSSI using identical study protocols. Iclaprim 80 mg and vancomycin 15 mg/kg were administered intravenously every 12 h for 5-14 days. The primary endpoint was a ≥20% reduction from baseline in lesion size [early clinical response (ECR)] at the early time point (ETP) (48-72 h after starting study drug) in the intent-to-treat population. In REVIVE-1, ECR at the ETP was 80.9% with iclaprim versus 81.0% with vancomycin (treatment difference -0.13%, 95% CI -6.42% to 6.17%). In REVIVE-2, ECR was 78.3% with iclaprim versus 76.7% with vancomycin (treatment difference 1.58%, 95% CI -5.10% to 8.26%). The pooled ECR was 79.6% with iclaprim versus 78.8% with vancomycin (treatment difference 0.75%, 95% CI -3.84 to 5.35%). Iclaprim and vancomycin were comparable for the incidence of mostly mild adverse events, except for a higher incidence of elevated serum creatinine with vancomycin (nâ¯=â¯7) compared with iclaprim (nâ¯=â¯0). Iclaprim achieved non-inferiority compared with vancomycin for ECR at the ETP and secondary endpoints with a similar safety profile in two phase 3 studies for treatment of ABSSSI suspected or confirmed as caused by Gram-positive pathogens. [Clinical Trials Registration. NCT02600611 and NCT02607618.].
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Antibacterianos/uso terapéutico , Pirimidinas/uso terapéutico , Enfermedades Cutáneas Bacterianas/tratamiento farmacológico , Infecciones Estafilocócicas/tratamiento farmacológico , Infecciones Estreptocócicas/tratamiento farmacológico , Vancomicina/uso terapéutico , Enfermedad Aguda , Adulto , Creatinina/sangre , Método Doble Ciego , Esquema de Medicación , Femenino , Humanos , Masculino , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Staphylococcus aureus Resistente a Meticilina/crecimiento & desarrollo , Pruebas de Sensibilidad Microbiana , Persona de Mediana Edad , Seguridad del Paciente , Enfermedades Cutáneas Bacterianas/microbiología , Infecciones Estafilocócicas/microbiología , Staphylococcus aureus/efectos de los fármacos , Staphylococcus aureus/crecimiento & desarrollo , Infecciones Estreptocócicas/microbiología , Streptococcus pyogenes/efectos de los fármacos , Streptococcus pyogenes/crecimiento & desarrollo , Resultado del TratamientoRESUMEN
BACKGROUND: Less than 6% of U.S. medical school applicants are African-American. The lack of diversity among physicians, by race as well as other measures, confers a negative impact on the American healthcare system because underrepresented minority (URM) physicians are more likely to practice in underserved communities and deliver more equitable, culturally competent care. METHODS: MERIT (Medical Education Resources Initiative for Teens) is a nonprofit organization based in Baltimore, Maryland, USA. MERIT prepares URM high school students for health careers by providing a holistic support system for seven consecutive years. The program model, which utilizes weekly Saturday sessions, summer internships, and longitudinal mentoring, is built on four foundational pillars: (1) Ignite the Fire, (2) Illuminate the Path, (3) Create the Toolkit, and (4) Sustain the Desire. RESULTS: Since 2011, MERIT has supported 51 students in the Baltimore City Public School System. For the past two years, 100% (n = 14) of MERIT seniors enrolled in universities, compared to only 20.2% of Baltimore City students overall. While it is too early to know whether MERIT alumni will realize their goals of becoming healthcare professionals, they are currently excelling in universities and over 75% (n = 17) are still planning to pursue graduate degrees in health-related fields. DISCUSSION: After piloting an effective program model, MERIT now has three key priorities moving forward: (1) Creating a sustainable and thriving organization, (2) increasing the number of scholars the program supports in Baltimore, and (3) expanding MERIT to other cities.
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Diversidad Cultural , Educación Médica/normas , Grupos Minoritarios/educación , Criterios de Admisión Escolar , Apoyo Social , Estudiantes de Medicina/estadística & datos numéricos , Adolescente , Baltimore , Selección de Profesión , Educación Médica/economía , Educación Médica/estadística & datos numéricos , Femenino , Humanos , Masculino , Mentores , Grupos Minoritarios/estadística & datos numéricosRESUMEN
PURPOSE OF REVIEW: Biological therapies for Clostridium difficile infection (CDI) include probiotics and faecal microbiota transplant (FMT). There is significant interest in their use in treating refractory/recurrent CDI. This review summarizes the latest evidence for these approaches. RECENT FINDINGS: The small number of randomized controlled trials (RCTs) using probiotics in CDI have produced variable results; the most recent showed no benefit in preventing disease. However, several meta-analyses published in the last year have suggested benefit in their use, but these conclusions are limited by the poor quality of many of the primary studies, and lack of standardization of the probiotic administered. In contrast, FMT appears highly effective for the treatment of CDI. In the only published RCT, the cure rate was 81%, which is close to the rate shown by meta-analyses of previous case series. The use of artificially produced bacterial mixtures in place of faecal samples is now under investigation. SUMMARY: Biological therapies for CDI, especially FMT, will continue to attract attention. Further, large-scale RCTs are required to identify which patients are most likely to benefit from these therapies in the future.
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Terapia Biológica/métodos , Clostridioides difficile , Enterocolitis Seudomembranosa/terapia , Heces/microbiología , Humanos , Prebióticos , Probióticos/uso terapéuticoRESUMEN
OBJECTIVES: In November 2008, a study was performed with support from the European Centre for Disease Prevention and Control (ECDC) to obtain an overview of Clostridium difficile infections (CDIs) in European hospitals. A collection of 398 C. difficile isolates obtained from this hospital-based survey was utilized to identify antimicrobial susceptibility patterns of common C. difficile PCR ribotypes across Europe. METHODS: The MICs of three approved therapeutic agents (vancomycin, metronidazole and fidaxomicin) and LFF571 (a novel semi-synthetic thiopeptide antibiotic) were determined by the agar dilution method. RESULTS: MICs of fidaxomicin and LFF571 were in general 2-4-fold lower than those of vancomycin and metronidazole. Isolates belonging to clade 2, including the hypervirulent ribotype 027, had one-dilution higher MIC50 and MIC90 values for fidaxomicin and metronidazole, whereas similar MIC values were observed for vancomycin and LFF571. Isolates belonging to C. difficile PCR ribotype 001 were more susceptible to fidaxomicin than other frequently found PCR ribotypes 014/020 and 078. Six isolates from three different countries had a metronidazole MIC of 2 mg/L. Four of the six isolates were characterized as PCR ribotype 001. CONCLUSIONS: There was no evidence of in vitro resistance of C. difficile to any of the four agents tested. However, the results suggest type-specific differences in susceptibility for the treatment agents we investigated. Continuous surveillance of C. difficile isolates in Europe is needed to determine the possible clinical implications of ribotype-specific changes in susceptibility to therapeutic agents.
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Antibacterianos/farmacología , Clostridioides difficile/efectos de los fármacos , Tiazoles/farmacología , Aminoglicósidos/farmacología , Aminoglicósidos/uso terapéutico , Antibacterianos/uso terapéutico , Infecciones por Clostridium/tratamiento farmacológico , Infecciones por Clostridium/microbiología , Infección Hospitalaria/tratamiento farmacológico , Infección Hospitalaria/microbiología , Enterocolitis Seudomembranosa/tratamiento farmacológico , Enterocolitis Seudomembranosa/microbiología , Europa (Continente) , Fidaxomicina , Humanos , Metronidazol/uso terapéutico , Pruebas de Sensibilidad Microbiana , Tipificación de Secuencias Multilocus , Reacción en Cadena de la Polimerasa , Ribotipificación , Tiazoles/uso terapéutico , Resultado del Tratamiento , Vancomicina/farmacología , Vancomicina/uso terapéuticoRESUMEN
OBJECTIVES: First-line treatment options for Clostridium difficile infection (CDI) are limited. NVB302 is a novel type B lantibiotic under evaluation for the treatment of CDI. We compared the responses to NVB302 and vancomycin when used to treat simulated CDI in an in vitro gut model. METHODS: We used ceftriaxone to elicit simulated CDI in an in vitro gut model primed with human faeces. Vancomycin and NVB302 were instilled into separate gut models and the indigenous gut microbiota and C. difficile total viable counts, spores and toxin levels were monitored throughout. RESULTS: Ceftriaxone instillation promoted C. difficile germination and high-level toxin production. Commencement of NVB302 and vancomycin instillation reduced C. difficile total viable counts rapidly with only C. difficile spores remaining within 3 and 4 days, respectively. Cytotoxin was reduced to undetectable levels 5 and 7 days after vancomycin and NVB302 instillation commenced in vessel 2 and 3, respectively, and remained undetectable for the remainder of the experiments. C. difficile spores were unaffected by the presence of vancomycin or NVB302. NVB302 treatment was associated with faster resolution of Bacteroides fragilis group. CONCLUSIONS: Both NVB302 and vancomycin were effective in treating simulated CDI in an in vitro gut model. C. difficile spore recrudescence was not observed following successful treatment with either NVB302 or vancomycin. NVB302 displayed non-inferiority to vancomycin in the treatment of simulated CDI, and had less deleterious effects against B. fragilis group. NVB302 warrants further clinical investigation as a potentially novel antimicrobial agent for the treatment of CDI.
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Antibacterianos/farmacología , Bacteriocinas/farmacología , Clostridioides difficile/efectos de los fármacos , Infecciones por Clostridium/tratamiento farmacológico , Tracto Gastrointestinal/efectos de los fármacos , Vancomicina/farmacología , Anciano , Antibacterianos/uso terapéutico , Bacteriocinas/uso terapéutico , Infecciones por Clostridium/fisiopatología , Evaluación Preclínica de Medicamentos , Heces/microbiología , Tracto Gastrointestinal/microbiología , Humanos , Pruebas de Sensibilidad Microbiana/métodos , Vancomicina/uso terapéuticoRESUMEN
Fatty acid amide hydrolase (FAAH) is an integral membrane serine hydrolase responsible for the degradation of fatty acid amide signaling molecules such as endocannabinoid anandamide (AEA), which has been shown to possess cannabinoid-like analgesic properties. Herein we report the optimization of spirocyclic 7-azaspiro[3.5]nonane and 1-oxa-8-azaspiro[4.5]decane urea covalent inhibitors of FAAH. Using an iterative design and optimization strategy, lead compounds were identified with a remarkable reduction in molecular weight and favorable CNS drug like properties. 3,4-Dimethylisoxazole and 1-methyltetrazole were identified as superior urea moieties for this inhibitor class. A dual purpose in vivo efficacy and pharmacokinetic screen was designed to be the key decision enabling experiment affording the ability to move quickly from compound synthesis to selection of preclinical candidates. On the basis of the remarkable potency, selectivity, pharmacokinetic properties and in vivo efficacy, PF-04862853 (15p) was advanced as a clinical candidate.
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Amidohidrolasas/antagonistas & inhibidores , Analgésicos/farmacología , Descubrimiento de Drogas , Inhibidores Enzimáticos/farmacología , Dolor/tratamiento farmacológico , Compuestos de Espiro/farmacología , Administración Oral , Analgésicos/administración & dosificación , Analgésicos/química , Analgésicos/uso terapéutico , Animales , Compuestos Aza/administración & dosificación , Compuestos Aza/química , Compuestos Aza/farmacología , Compuestos Aza/uso terapéutico , Disponibilidad Biológica , Cromatografía Líquida de Alta Presión , Evaluación Preclínica de Medicamentos , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/uso terapéutico , Ratas , Compuestos de Espiro/administración & dosificación , Compuestos de Espiro/química , Compuestos de Espiro/uso terapéuticoRESUMEN
OBJECTIVES: Therapeutic options in Clostridium difficile infection (CDI) are limited. We examined linezolid activity in vitro and potential therapeutic efficacy using a gut model of CDI. METHODS: MICs were determined by agar incorporation for 118 diverse C. difficile faecal isolates, including epidemic strains and strains with reduced susceptibility to metronidazole. CDI was established in two gut model experiments using C. difficile epidemic strains (ribotypes 027 and 106) and linezolid was dosed to achieve human gut concentrations. RESULTS: Linezolid demonstrated good in vitro activity against 98% of the isolates. Two isolates (PCR ribotypes 023 and 067) demonstrated resistance to linezolid, although supplementary susceptibility testing of ribotype 023 isolates did not detect further resistance. In a gut model that simulates CDI, linezolid reduced the duration of cytotoxin production by C. difficile PCR ribotype 027 without influencing viable counts of vegetative forms of the organism. C. difficile PCR ribotype 106 viable counts declined at a faster rate than those of PCR ribotype 027 following dosing with linezolid, but cytotoxin titres declined at a similar rate to an untreated control. Gut flora perturbation occurring on linezolid exposure reversed after drug cessation. Recrudescence of spore germination with subsequent cytotoxin was seen with the C. difficile ribotype 106 strain. Resistance to linezolid was not detected either during linezolid instillation or post-dosing. CONCLUSIONS: Linezolid may reduce toxin levels, as reported in staphylococci and streptococci. Further evaluation is warranted of the effect of linezolid on expression of C. difficile toxin, and to investigate potential recurrence of CDI following cessation of linezolid.
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Acetamidas/administración & dosificación , Antibacterianos/administración & dosificación , Clostridioides difficile/efectos de los fármacos , Infecciones por Clostridium/tratamiento farmacológico , Tracto Gastrointestinal/microbiología , Oxazolidinonas/administración & dosificación , Acetamidas/farmacología , Antibacterianos/farmacología , Clostridioides difficile/aislamiento & purificación , Infecciones por Clostridium/microbiología , Heces/microbiología , Humanos , Técnicas In Vitro , Linezolid , Metronidazol/farmacología , Pruebas de Sensibilidad Microbiana , Oxazolidinonas/farmacologíaRESUMEN
The efficacy of tolevamer, a nonantimicrobial styrene derivative toxin-binding agent, in treating simulated Clostridium difficile infection in an in vitro human gut model was investigated. Tolevamer reduced neither the duration nor magnitude of cytotoxin activity by C. difficile, reflecting poor efficacy observed in recent phase III clinical trials.