RESUMEN
Post stroke infection occurs in 15-20% of acute stroke patients and is associated with a poor longterm outcome. In a prospective study on 113 acute ischemic stroke patients with diabetes mellitus 15.9% suffered nosocomial infection. We found chronic hyperglycemia measured by skin autofluorescence in arbitrary units to be an independent predictor of a nosocomial infection post stroke (ORâ¯=â¯3.24 [CI 95%: 1.13; 9.26], pâ¯=â¯0.029). Skin autofluorescence represents the glycemic memory beyond HbA1c. Potential mechanisms leading from increased skin autofluorescence to vulnerability for infectious complications include more severe strokes due to preexisting vasculopathy and exacerbated post stroke immunosuppression.
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Glucemia/metabolismo , Infección Hospitalaria/etiología , Diabetes Mellitus Tipo 2/metabolismo , Productos Finales de Glicación Avanzada/metabolismo , Piel/metabolismo , Accidente Cerebrovascular/complicaciones , Anciano , Anciano de 80 o más Años , Infección Hospitalaria/diagnóstico , Infección Hospitalaria/metabolismo , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/diagnóstico , Femenino , Hemoglobina Glucada/metabolismo , Humanos , Mediciones Luminiscentes , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Estudios Prospectivos , Medición de Riesgo , Factores de Riesgo , Accidente Cerebrovascular/diagnóstico , Accidente Cerebrovascular/metabolismoRESUMEN
Secondary infections typically worsen outcomes of patients recovering from septic shock. Neutrophil [polymorphonuclear leukocytes (PMNs)] migration to secondarily inoculated sites may play a key role in inhibiting progression from local bacterial inoculation to secondary infection. Mitochondrial N-formyl peptide (mtFP) occupancy of formyl peptide receptor-1 (FPR1) has been shown to suppress PMN chemotaxis. Therefore, we studied the association between circulating mtFPs and the development of secondary infection in patients with septic shock. We collected clinical data and plasma samples from patients with septic shock admitted to the intensive care unit for longer than 72 h. Impacts of circulating nicotinamide adenine dinucleotide dehydrogenase subunit-6 (ND6) upon clinical outcomes were analyzed. Next, the role of ND6 in PMN chemotaxis was investigated using isolated human PMNs. Studying plasma samples from 97 patients with septic shock, we found that circulating ND6 levels at admission were independently and highly associated with the development of secondary infection (odds ratio = 30.317, 95% CI: 2.904 to 316.407, P = 0.004) and increased 90-d mortality (odds ratio = 1.572, 95% CI: 1.002 to 2.465, P = 0.049). In ex vivo experiments, ND6 pretreatment suppressed FPR1-mediated PMN chemotactic responses to bacterial peptides in the presence of multiple cytokines and chemokines, despite increased nondirectional PMN movements. Circulating mtFPs appear to contribute to the development of secondary infection and increased mortality in patients with septic shock who survive their early hyperinflammatory phase. The increased susceptibility to secondary infection is probably partly mediated by the suppression of FPR1-mediated PMN chemotaxis to secondary infected sites.
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Infección Hospitalaria/etiología , NADH Deshidrogenasa/metabolismo , Choque Séptico/complicaciones , Anciano , Anciano de 80 o más Años , Factores Quimiotácticos/metabolismo , Quimiotaxis , Infección Hospitalaria/metabolismo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mitocondrias/metabolismo , NADH Deshidrogenasa/fisiología , Activación Neutrófila , Neutrófilos/metabolismo , Péptidos/metabolismo , Receptores de Formil Péptido/metabolismo , Choque Séptico/metabolismo , Choque Séptico/fisiopatologíaRESUMEN
Novel therapeutics are needed to treat pathologies associated with the Clostridioides difficile binary toxin (CDT), particularly when C. difficile infection (CDI) occurs in the elderly or in hospitalized patients having illnesses, in addition to CDI, such as cancer. While therapies are available to block toxicities associated with the large clostridial toxins (TcdA and TcdB) in this nosocomial disease, nothing is available yet to treat toxicities arising from strains of CDI having the binary toxin. Like other binary toxins, the active CDTa catalytic subunit of CDT is delivered into host cells together with an oligomeric assembly of CDTb subunits via host cell receptor-mediated endocytosis. Once CDT arrives in the host cell's cytoplasm, CDTa catalyzes the ADP-ribosylation of G-actin leading to degradation of the cytoskeleton and rapid cell death. Although a detailed molecular mechanism for CDT entry and host cell toxicity is not yet fully established, structural and functional resemblances to other binary toxins are described. Additionally, unique conformational assemblies of individual CDT components are highlighted herein to refine our mechanistic understanding of this deadly toxin as is needed to develop effective new therapeutic strategies for treating some of the most hypervirulent and lethal strains of CDT-containing strains of CDI.
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Proteínas Bacterianas/antagonistas & inhibidores , Toxinas Bacterianas/antagonistas & inhibidores , Clostridioides difficile/patogenicidad , Infección Hospitalaria/tratamiento farmacológico , Enterocolitis Seudomembranosa/tratamiento farmacológico , Enterotoxinas/antagonistas & inhibidores , ADP-Ribosilación/efectos de los fármacos , Citoesqueleto de Actina/efectos de los fármacos , Citoesqueleto de Actina/metabolismo , Citoesqueleto de Actina/ultraestructura , Actinas/deficiencia , Actinas/genética , Antibacterianos/uso terapéutico , Proteínas Bacterianas/química , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Toxinas Bacterianas/química , Toxinas Bacterianas/genética , Toxinas Bacterianas/metabolismo , Sitios de Unión , Clostridioides difficile/efectos de los fármacos , Clostridioides difficile/genética , Clostridioides difficile/metabolismo , Infección Hospitalaria/metabolismo , Infección Hospitalaria/microbiología , Infección Hospitalaria/patología , Endocitosis/efectos de los fármacos , Enterocolitis Seudomembranosa/metabolismo , Enterocolitis Seudomembranosa/microbiología , Enterocolitis Seudomembranosa/patología , Enterotoxinas/química , Enterotoxinas/genética , Enterotoxinas/metabolismo , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Células Epiteliales/microbiología , Células Epiteliales/ultraestructura , Humanos , Modelos Moleculares , Unión Proteica , Dominios Proteicos , Dominios y Motivos de Interacción de Proteínas , Estructura Secundaria de ProteínaRESUMEN
S. epidermidis is a substantial component of the human skin microbiota, but also one of the major causes of nosocomial infection in the context of implanted medical devices. We here aimed to advance the understanding of S. epidermidis genotypes and phenotypes conducive to infection establishment. Furthermore, we investigate the adaptation of individual clonal lines to the infection lifestyle based on the detailed analysis of individual S. epidermidis populations of 23 patients suffering from prosthetic joint infection. Analysis of invasive and colonizing S. epidermidis provided evidence that invasive S. epidermidis are characterized by infection-supporting phenotypes (e.g. increased biofilm formation, growth in nutrient poor media and antibiotic resistance), as well as specific genetic traits. The discriminating gene loci were almost exclusively assigned to the mobilome. Here, in addition to IS256 and SCCmec, chromosomally integrated phages was identified for the first time. These phenotypic and genotypic features were more likely present in isolates belonging to sequence type (ST) 2. By comparing seven patient-matched nasal and invasive S. epidermidis isolates belonging to identical genetic lineages, infection-associated phenotypic and genotypic changes were documented. Besides increased biofilm production, the invasive isolates were characterized by better growth in nutrient-poor media and reduced hemolysis. By examining several colonies grown in parallel from each infection, evidence for genetic within-host population heterogeneity was obtained. Importantly, subpopulations carrying IS insertions in agrC, mutations in the acetate kinase (AckA) and deletions in the SCCmec element emerged in several infections. In summary, these results shed light on the multifactorial processes of infection adaptation and demonstrate how S. epidermidis is able to flexibly repurpose and edit factors important for colonization to facilitate survival in hostile infection environments.
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Proteínas Bacterianas/genética , Biopelículas/crecimiento & desarrollo , Infección Hospitalaria/microbiología , Mutación , Mucosa Nasal/microbiología , Infecciones Estafilocócicas/microbiología , Staphylococcus epidermidis/genética , Anciano , Anciano de 80 o más Años , Proteínas Bacterianas/metabolismo , Infección Hospitalaria/genética , Infección Hospitalaria/metabolismo , Femenino , Genotipo , Hemólisis , Humanos , Secuencias Repetitivas Esparcidas , Masculino , Persona de Mediana Edad , Mucosa Nasal/metabolismo , Fenotipo , Infecciones Estafilocócicas/genética , Infecciones Estafilocócicas/metabolismo , Staphylococcus epidermidis/clasificación , Staphylococcus epidermidis/crecimiento & desarrollo , Staphylococcus epidermidis/aislamiento & purificaciónRESUMEN
BACKGROUND AND PURPOSE: The aim of this study was to evaluate and independently validate SAA (serum amyloid A)-a recently discovered blood biomarker-to predict poststroke infections. METHODS: The derivation cohort (A) was composed of 283 acute ischemic stroke patients and the independent validation cohort (B), of 367 patients. The primary outcome measure was any stroke-associated infection, defined by the criteria of the US Centers for Disease Control and Prevention, occurring during hospitalization. To determine the association of SAA levels on admission with the development of infections, logistic regression models were calculated. The discriminatory ability of SAA was assessed, by calculating the area under the receiver operating characteristic curve. RESULTS: After adjusting for all predictors that were significantly associated with any infection in the univariate analysis, SAA remained an independent predictor in study A (adjusted odds ratio, 1.44 [95% CI, 1.16-1.79]; P=0.001) and in study B (adjusted odds ratio, 1.52 [1.05-2.22]; P=0.028). Adding SAA to the best regression model without the biomarker, the discriminatory accuracy improved from 0.76 (0.69-0.83) to 0.79 (0.72-0.86; P<0.001; likelihood ratio test) in study A. These results were externally validated in study B with an improvement in the area under the receiver operating characteristic curve, from 0.75 (0.70-0.81) to 0.76 (0.71-0.82; P<0.038). CONCLUSIONS: Among patients with ischemic stroke, blood SAA measured on admission is a novel independent predictor of infection after stroke. SAA improved the discrimination between patients who developed an infection compared with those who did not in both derivation and validation cohorts. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00390962.
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Reglas de Decisión Clínica , Infección Hospitalaria/metabolismo , Accidente Cerebrovascular Isquémico/metabolismo , Proteína Amiloide A Sérica/metabolismo , Anciano , Anciano de 80 o más Años , Área Bajo la Curva , Biomarcadores , Proteína C-Reactiva/metabolismo , Infección Hospitalaria/epidemiología , Trastornos de Deglución/fisiopatología , Femenino , Neumonía Asociada a la Atención Médica/epidemiología , Neumonía Asociada a la Atención Médica/metabolismo , Humanos , Accidente Cerebrovascular Isquémico/fisiopatología , Accidente Cerebrovascular Isquémico/terapia , Recuento de Leucocitos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Polipéptido alfa Relacionado con Calcitonina/metabolismo , Curva ROC , Reproducibilidad de los Resultados , Sepsis/metabolismo , Sepsis/fisiopatología , Sepsis/terapia , Infecciones Urinarias/metabolismo , Infecciones Urinarias/fisiopatología , Infecciones Urinarias/terapiaRESUMEN
BACKGROUND: Systemic inflammation induced by sterile or infectious insults is associated with an enhanced susceptibility to life-threatening opportunistic, mostly bacterial, infections due to unknown pathogenesis. Natural killer (NK) cells contribute to the defence against bacterial infections through the release of Interferon (IFN) γ in response to Interleukin (IL) 12. Considering the relevance of NK cells in the immune defence we investigated whether the function of NK cells is disturbed in patients suffering from serious systemic inflammation. METHODS: NK cells from severely injured patients were analysed from the first day after the initial inflammatory insult until the day of discharge in terms of IL-12 receptor signalling and IFN-γ synthesis. FINDINGS: During systemic inflammation, the expression of the IL-12 receptor ß2 chain, phosphorylation of signal transducer and activation 4, and IFN-γ production on/in NK cells was impaired upon exposure to Staphylococcus aureus. The profound suppression of NK cells developed within 24â¯h after the initial insult and persisted for several weeks. NK cells displayed signs of exhaustion. Extrinsic changes were mediated by the early and long-lasting presence of growth/differentiation factor (GDF) 15 in the circulation that signalled through the transforming growth factor ß receptor I and activated Smad1/5. Moreover, the concentration of GDF-15 in the serum inversely correlated with the IL-12 receptor ß2 expression on NK cells and was enhanced in patients who later acquired septic complications. INTERPRETATION: GDF-15 is associated with the development of NK cell dysfunction during systemic inflammation and might represent a novel target to prevent nosocomial infections. FUND: The study was supported by the Department of Orthopaedics and Trauma Surgery, University Hospital Essen.
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Antígeno CD56/metabolismo , Infección Hospitalaria/etiología , Infección Hospitalaria/metabolismo , Factor 15 de Diferenciación de Crecimiento/sangre , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/metabolismo , Adulto , Biomarcadores , Comorbilidad , Infección Hospitalaria/sangre , Infección Hospitalaria/diagnóstico , Femenino , Humanos , Inmunofenotipificación , Mediadores de Inflamación/metabolismo , Interferón gamma/metabolismo , Interleucina-12/metabolismo , Masculino , Persona de Mediana Edad , Fosforilación , Receptores de Interleucina-12/metabolismo , Factor de Transcripción STAT4/metabolismo , Índice de Severidad de la Enfermedad , Transducción de Señal , Síndrome de Respuesta Inflamatoria Sistémica/sangre , Síndrome de Respuesta Inflamatoria Sistémica/etiología , Síndrome de Respuesta Inflamatoria Sistémica/metabolismoRESUMEN
Methicillin-resistant Staphylococcus aureus (MRSA) originally emerged in nosocomial settings and has subsequently spread into the community. In turn, community-associated (CA) MRSA lineages are nowadays introduced from the community into hospitals where they can cause hospital-associated (HA) infections. This raises the question of how the CA-MRSA lineages adapt to the hospital environment. Previous studies implicated particular virulence factors in the CA-behaviour of MRSA. However, we hypothesized that physiological changes may also impact staphylococcal epidemiology. With the aim to identify potential metabolic adaptations, we comparatively profiled the cytosolic proteomes of CA- and HA-isolates from the USA300 lineage that was originally identified as CA-MRSA. Interestingly, enzymes for gluconeogenesis, the tricarboxylic acid cycle and biosynthesis of amino acids are up-regulated in the investigated CA-MRSA isolates, while enzymes for glycolysis and the pentose phosphate pathway are up-regulated in the HA-MRSA isolates. Of note, these data apparently match with the clinical presentation of each group. These observations spark interest in central carbon metabolism as a key driver for adaptations that streamline MRSA for propagation in the community or the hospital.
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Adaptación Fisiológica , Metaboloma , Staphylococcus aureus Resistente a Meticilina/metabolismo , Factores de Virulencia/metabolismo , Infección Hospitalaria/metabolismo , Infección Hospitalaria/microbiología , Humanos , Staphylococcus aureus Resistente a Meticilina/aislamiento & purificación , Infecciones Estafilocócicas/metabolismoRESUMEN
Background With the Ministry of Health's projected increase in nursing home beds and optimization of antimicrobial use in health care settings, it is therefore timely to consider baseline prevalence and patterns of antimicrobial use at nursing homes in Singapore as well as to evaluate the prevalence of potential clinically significant drug-drug interactions involving antimicrobials. Objective The primary objective was to determine the prevalence and patterns of antimicrobial use at nursing homes in Singapore. The secondary objective was to evaluate the prevalence of potential clinically significant drug-drug interactions involving antimicrobials. Setting Four nursing homes in Singapore. Method A retrospective cross-sectional study was conducted among nursing home residents. The antimicrobial prevalence, defined daily doses, days of therapy, and potential drug-drug interactions were determined using data from archived resident medication prescribing and administration records. Main outcome measure Prevalence and patterns of antimicrobial use, drug-drug interactions involving antimicrobials. Results Among 707 residents (mean age: 80.7 ± 8.8 years, female: 57.1%), 10% used antimicrobials during the study month, with a 1-day point prevalence of 3%. The utilization rates of antimicrobials were 28.9 defined daily doses/1000 resident-days and 24.8 days of therapy/1000 resident-days. Potential drug-drug interactions involving antimicrobials were identified among 32 of the 70 (46%) residents who were prescribed antimicrobials. Of these, 26 (81%) residents had 43 potential clinically significant drug-drug interactions. Conclusions The prevalence and utilization rates of antimicrobial use in Singapore nursing homes appear to be low. Yet, potential clinically significant drug-drug interactions are prevalent.
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Antiinfecciosos/metabolismo , Antiinfecciosos/uso terapéutico , Infección Hospitalaria/epidemiología , Infección Hospitalaria/metabolismo , Interacciones Farmacológicas/fisiología , Casas de Salud/tendencias , Anciano , Anciano de 80 o más Años , Infección Hospitalaria/tratamiento farmacológico , Estudios Transversales , Femenino , Humanos , Masculino , Prevalencia , Estudios Retrospectivos , Singapur/epidemiologíaRESUMEN
Virulence profiles and innate immune responses were studied in Acinetobacter baumannii from nosocomial infections collected over one year in a tertiary care hospital in Mexico. A. baumannii were identified by VITEK 2 System followed by susceptibility tests. Carbapenemase genes, active efflux mechanism to imipenem and meropenem and outer membrane proteins profile were analyzed to evaluate their role on the activity of carbapenem resistance. All isolates were genotyped by pulsed field gel electrophoresis. The ability to form biofilm was determined on a polystyrene surface. The resistance to complement was determined with a pooled human normal serum and TNFα release by infected macrophages was determined by ELISA. The 112 isolates from this study were associated with a 52% of mortality. All were resistance to ß-lactams, fluoroquinolones, and trimethroprim-sulfamethoxal, 96 and 90% were resistant to meropenem and imipenem, respectively, but with high susceptibility to polymyxin B, colistin and tigecyclin. Isolates were classified in 11 different clones. Most isolates, 88% (99/112), were metallo-ß-lactamases and carbapenemases producers, associated in 95% with the presence of blaOXA-72 gene. Only 4/99 and 1/99 of the carbapenem-resistant isolates were related to efflux mechanism to meropenem or imipenem resistance, respectively. The loss of expression of 22, 29, and/or 33-36-kDa proteins was detected in 8/11 of the clinical isolates with resistance to carbapenem. More than 96% (108/112) of the isolates were high producers of biofilms on biotic surfaces. Finally, all isolates showed variable resistance to normal human serum activity and were high inductors of TNFα release by macrophages. In summary, these results suggest that multidrug-resistant A. baumannii can persist in the hospital environment through its ability to form biofilms. The high mortality observed was due to their ability to survive normal human serum activity and capability to induce potent inflammatory immune response making this nosocomial pathogen a serious threat to hospitalized patients.
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Infecciones por Acinetobacter/tratamiento farmacológico , Acinetobacter baumannii/aislamiento & purificación , Infección Hospitalaria/tratamiento farmacológico , Inmunidad Innata , Infecciones por Acinetobacter/metabolismo , Acinetobacter baumannii/efectos de los fármacos , Acinetobacter baumannii/patogenicidad , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Carbapenémicos/metabolismo , Infección Hospitalaria/metabolismo , Farmacorresistencia Bacteriana Múltiple/efectos de los fármacos , Farmacorresistencia Bacteriana Múltiple/genética , Humanos , México , Pruebas de Sensibilidad Microbiana , Centros de Atención Terciaria , Factor de Necrosis Tumoral alfa/metabolismo , Virulencia , beta-Lactamasas/metabolismoRESUMEN
Pseudomonas aeruginosa is an opportunistic pathogen that regularly causes nosocomial infections in hospitalized patients. The type VI secretion system (T6SS) is responsible for the secretion of numerous virulence effector proteins that can both interfere with competing microbes and manipulate host cells. Here, we report a detailed investigation of a P. aeruginosa H2-T6SS-dependent phospholipase effector, TplE, which acts as a trans-kingdom toxin. Delivery of TplE to the periplasmic space of rival bacteria leads to growth inhibition. Importantly, TplE, also contains a eukaryotic PGAP1-like domain, which targets the host ER apparatus, ultimately leading to disruption of the ER. TplE activity leads to the activation of the unfolded protein response (UPR) through the IRE1α-XBP1 pathway, enhancing autophagic flux. These findings indicate that this T6SS-delivered phospholipase effector is active against both prokaryotic and eukaryotic cellular targets, highlighting the T6SS as a versatile weapon in the Pseudomonas arsenal.
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Autofagia/fisiología , Estrés del Retículo Endoplásmico/fisiología , Proteínas de la Membrana/metabolismo , Monoéster Fosfórico Hidrolasas/metabolismo , Pseudomonas aeruginosa/metabolismo , Sistemas de Secreción Tipo VI/metabolismo , Animales , Proteínas Bacterianas/metabolismo , Sistemas de Secreción Bacterianos/metabolismo , Infección Hospitalaria/metabolismo , Humanos , Virulencia/fisiologíaRESUMEN
The implementation of antimicrobial stewardship programs (ASPs) is a promising strategy to help address the problem of antimicrobial resistance. We sought to determine the efficacy of ASPs and their effect on clinical and economic parameters. We searched PubMed, EMBASE, and Google Scholar looking for studies on the efficacy of ASPs in hospitals. Based on 26 studies (extracted from 24,917 citations) with pre- and postimplementation periods from 6 months to 3 years, the pooled percentage change of total antimicrobial consumption after the implementation of ASPs was -19.1% (95% confidence interval [CI] = -30.1 to -7.5), and the use of restricted antimicrobial agents decreased by -26.6% (95% CI = -52.3 to -0.8). Interestingly, in intensive care units, the decrease in antimicrobial consumption was -39.5% (95% CI = -72.5 to -6.4). The use of broad-spectrum antibiotics (-18.5% [95% CI = -32 to -5.0] for carbapenems and -14.7% [95% CI = -27.7 to -1.7] for glycopeptides), the overall antimicrobial cost (-33.9% [95% CI = -42.0 to -25.9]), and the hospital length of stay (-8.9% [95% CI = -12.8 to -5]) decreased. Among hospital pathogens, the implementation of ASPs was associated with a decrease in infections due to methicillin-resistant Staphylococcus aureus (risk difference [RD] = -0.017 [95% CI = -0.029 to -0.005]), imipenem-resistant Pseudomonas aeruginosa (RD = -0.079 [95% CI = -0.114 to -0.040]), and extended-spectrum beta-lactamase Klebsiella spp. (RD = -0.104 [95% CI = -0.153 to -0.055]). Notably, these improvements were not associated with adverse outcomes, since the all-cause, infection-related 30-day mortality and infection rates were not significantly different after implementation of an ASP (RD = -0.001 [95% CI = -0.009 to 0.006], RD = -0.005 [95% CI = -0.016 to 0.007], and RD = -0.045% [95% CI = -0.241 to 0.150], respectively). Hospital ASPs result in significant decreases in antimicrobial consumption and cost, and the benefit is higher in the critical care setting. Infections due to specific antimicrobial-resistant pathogens and the overall hospital length of stay are improved as well. Future studies should focus on the sustainability of these outcomes and evaluate potential beneficial long-term effects of ASPs in mortality and infection rates.
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Antibacterianos/uso terapéutico , Infección Hospitalaria/tratamiento farmacológico , Infecciones por Klebsiella/tratamiento farmacológico , Infecciones por Pseudomonas/tratamiento farmacológico , Infecciones Estafilocócicas/tratamiento farmacológico , Carbapenémicos/uso terapéutico , Infección Hospitalaria/metabolismo , Hospitales , Humanos , Unidades de Cuidados Intensivos , Klebsiella/efectos de los fármacos , Klebsiella/metabolismo , Tiempo de Internación , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Staphylococcus aureus Resistente a Meticilina/metabolismo , Pseudomonas aeruginosa/efectos de los fármacos , Pseudomonas aeruginosa/metabolismo , beta-Lactamasas/metabolismoRESUMEN
The ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) are the leading cause of nosocomial infections throughout the world. Most of them are multidrug resistant isolates, which is one of the greatest challenges in clinical practice. Multidrug resistance is amongst the top three threats to global public health and is usually caused by excessive drug usage or prescription, inappropriate use of antimicrobials, and substandard pharmaceuticals. Understanding the resistance mechanisms of these bacteria is crucial for the development of novel antimicrobial agents or other alternative tools to combat these public health challenges. Greater mechanistic understanding would also aid in the prediction of underlying or even unknown mechanisms of resistance, which could be applied to other emerging multidrug resistant pathogens. In this review, we summarize the known antimicrobial resistance mechanisms of ESKAPE pathogens.
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Bacterias , Infección Hospitalaria , Farmacorresistencia Bacteriana Múltiple/fisiología , Bacterias/genética , Bacterias/metabolismo , Infección Hospitalaria/tratamiento farmacológico , Infección Hospitalaria/genética , Infección Hospitalaria/metabolismoRESUMEN
PURPOSE: Patients admitted to intensive care unit (ICU) with Klebsiella pneumoniae infections are characterized by high mortality. The aims of the present study were to investigate the population pharmacokinetics parameters and to assess the probability of target attainment of meropenem in critically ill patients to provide information for more effective regimens. METHODS: Twenty-seven consecutive patients were included in the study. Meropenem was administered as 3-h intravenous (i.v.) infusions at doses of 1-2 g every 8 or 12 h. Meropenem plasma concentrations were measured by a high-performance liquid chromatography (HPLC) method, and a population pharmacokinetics analysis was performed using NONMEM software. Meropenem plasma disposition was simulated for extended (3 h; 5 h) or continuous i.v. infusions, and the following parameters were calculated: time during which free drug concentrations were above minimum inhibitory concentration (MIC) (fT > MIC), free minimum plasma concentrations above 4× MIC (fCmin > 4× MIC), probability of target attainment (PTA), and cumulative fraction of response (CFR). RESULTS: Gender and severity of sepsis affected meropenem clearance, whose typical population values ranged from 6.22 up to 12.04 L/h (mean ± standard deviation (SD) value, 9.38 ± 4.47 L/h). Mean C min value was 7.90 ± 7.91 mg/L, suggesting a high interindividual variability. The simulation confirmed that 88 and 97.5 % of patients achieved effective C min > 4× MIC values after 3- and 5-h i.v. infusions of meropenem 2 g × 3/day, respectively. On the contrary, the same total daily doses reached the target C min > 4× MIC values in 100 % of patients when administered as continuous i.v. infusions. CONCLUSIONS: Several factors may influence meropenem pharmacokinetics in ICU patients. Continuous i.v. infusions of meropenem seem to be more effective than standard regimens to achieve optimal therapeutic targets.
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Antibacterianos/farmacocinética , Infección Hospitalaria/metabolismo , Infecciones por Klebsiella/metabolismo , Sepsis/metabolismo , Tienamicinas/farmacocinética , Adulto , Anciano , Antibacterianos/sangre , Antibacterianos/uso terapéutico , Enfermedad Crítica , Infección Hospitalaria/tratamiento farmacológico , Femenino , Humanos , Infusiones Intravenosas , Infecciones por Klebsiella/tratamiento farmacológico , Klebsiella pneumoniae , Masculino , Meropenem , Persona de Mediana Edad , Modelos Biológicos , Sepsis/tratamiento farmacológico , Tienamicinas/sangre , Tienamicinas/uso terapéuticoRESUMEN
BACKGROUND: Previous studies have demonstrated that the administration of antibiotics to patients before performing diagnostic testing for periprosthetic joint infection (PJI) can interfere with the accuracy of test results. Although a single-institution study has suggested that alpha-defensin maintains its concentration and sensitivity even after antibiotic treatment, this has not yet been demonstrated in a larger multiinstitutional study. QUESTIONS/PURPOSES: (1) For the evaluation of PJI, is prior antibiotic administration associated with decreased alpha-defensin levels? (2) When prior antibiotics are given, is alpha-defensin a better screening test for PJI than the traditional tests (erythrocyte sedimentation rate [ESR], C-reactive protein [CRP], fluid white blood cells, fluid polymorphonuclear cells [PMNs], and fluid culture)? METHODS: This retrospective study included data from 106 hip and knee arthroplasties with Musculoskeletal Infection Society-defined PJI from four centers. Of the 106 patients in this study, 30 (28%) were treated with antibiotics for PJI before diagnostic workup (ABX group), and 76 (72%) were not treated before the diagnostic workup (NO-ABX group). There were no differences in age, sex, joint, culture-negative rate, or bacteriology between groups. The patients in the ABX group had antibiotics initiated by physicians who commenced care before assessment for PJI by the treating surgeon's service. We compared the alpha-defensin levels and sensitivity between the ABX and NO-ABX groups. Additionally, the sensitivity of the alpha-defensin test was compared to that of traditional tests for PJI among patients on antibiotics. RESULTS: The administration of antibiotics before performing the alpha-defensin test for PJI was not associated with a decreased median alpha-defensin level (ABX group, median 4.2 [range, 1.79-12.8 S/CO] versus NO-ABX, median 4.9 [range, 0.5-16.8 S/CO], difference of medians: 0.68 S/CO [95% confidence interval {CI}, -0.98 to 1.26], p = 0.451). Furthermore, the alpha-defensin test had a higher sensitivity (100%; 95% CI, 88.4%-100.0%) in diagnosing PJI among patients on antibiotics when compared with the ESR (69.0% [95% CI, 49.17%-84.72%], p = 0.001), the CRP (79.3% [95% CI, 60.3%-92.0%], p = 0.009), the fluid PMN% (79.3% [95% CI, 60.3%-92.0%), p = 0.009), and fluid culture (70.0% [95% CI, 50.6%-85.3%], p = 0.001). CONCLUSIONS: The alpha-defensin test maintains its concentration and sensitivity for PJI even in the setting of antibiotic administration. Furthermore, among patients with PJI on antibiotics, the alpha-defensin tests demonstrated a higher sensitivity in detecting PJI when compared with the ESR, CRP, fluid PMN%, and fluid culture. The high sensitivity of the alpha-defensin test, even in the setting of prior antibiotic treatment, provides excellent utility as a screening test for PJI. LEVEL OF EVIDENCE: Level III, diagnostic study.
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Antibacterianos/administración & dosificación , Profilaxis Antibiótica , Artroplastia de Reemplazo de Cadera/efectos adversos , Artroplastia de Reemplazo de Rodilla/efectos adversos , Infección Hospitalaria/diagnóstico , Prótesis de Cadera/efectos adversos , Prótesis de la Rodilla/efectos adversos , Infecciones Relacionadas con Prótesis/diagnóstico , alfa-Defensinas/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Artroplastia de Reemplazo de Cadera/instrumentación , Artroplastia de Reemplazo de Rodilla/instrumentación , Biomarcadores/metabolismo , Infección Hospitalaria/metabolismo , Infección Hospitalaria/microbiología , Infección Hospitalaria/prevención & control , Esquema de Medicación , Femenino , Humanos , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Infecciones Relacionadas con Prótesis/metabolismo , Infecciones Relacionadas con Prótesis/microbiología , Infecciones Relacionadas con Prótesis/prevención & control , Reproducibilidad de los Resultados , Estudios Retrospectivos , Líquido Sinovial/metabolismo , Líquido Sinovial/microbiología , Resultado del Tratamiento , Estados UnidosAsunto(s)
Antibacterianos/administración & dosificación , Infección Hospitalaria/tratamiento farmacológico , Fosfomicina/administración & dosificación , Péptido Natriurético Encefálico/metabolismo , Fragmentos de Péptidos/metabolismo , Antibacterianos/efectos adversos , Infección Hospitalaria/metabolismo , Monitoreo de Drogas/métodos , Farmacorresistencia Bacteriana Múltiple , Diagnóstico Precoz , Fosfomicina/efectos adversos , Insuficiencia Cardíaca/metabolismo , HumanosRESUMEN
Ceftolozane/tazobactam is an antipseudomonal antibacterial approved for the treatment of complicated urinary tract infections (cUTIs) and complicated intra-abdominal infections (cIAIs) and in phase 3 clinical development for treatment of nosocomial pneumonia. A population pharmacokinetic (PK) model with the plasma-to-epithelial lining fluid (ELF) kinetics of ceftolozane/tazobactam was used to justify dosing regimens for patients with nosocomial pneumonia in phase 3 studies. Monte Carlo simulations were performed to determine ceftolozane/tazobactam dosing regimens with a > 90% probability of target attainment (PTA) for a range of pharmacokinetic/pharmacodynamic targets at relevant minimum inhibitory concentrations (MICs) for key pathogens in nosocomial pneumonia. With a plasma-to-ELF penetration ratio of approximately 50%, as observed from an ELF PK study, a doubling of the current dose regimens for different renal functions that are approved for cUTIs and cIAIs is needed to achieve > 90% PTA for nosocomial pneumonia. For example, a 3-g dose of ceftolozane/tazobactam for nosocomial pneumonia patients with normal renal function is needed to achieve a > 90% PTA (actual 98%) for the 1-log kill target against pathogens with an MIC of ≤ 8 mg/L in ELF, compared with the 1.5-g dose approved for cIAIs and cUTIs.
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Antibacterianos/farmacología , Antibacterianos/farmacocinética , Cefalosporinas/farmacología , Cefalosporinas/farmacocinética , Ácido Penicilánico/análogos & derivados , Adulto , Antibacterianos/sangre , Líquido del Lavado Bronquioalveolar/química , Cefalosporinas/sangre , Infección Hospitalaria/tratamiento farmacológico , Infección Hospitalaria/metabolismo , Combinación de Medicamentos , Femenino , Humanos , Masculino , Pruebas de Sensibilidad Microbiana , Persona de Mediana Edad , Modelos Biológicos , Método de Montecarlo , Ácido Penicilánico/sangre , Ácido Penicilánico/farmacocinética , Ácido Penicilánico/farmacología , Neumonía/tratamiento farmacológico , Neumonía/metabolismo , Tazobactam , Adulto JovenRESUMEN
Elizabethkingia meningoseptica is an infrequent colonizer of the respiratory tract; its pathogenicity is uncertain. In the context of a 22-month outbreak of E. meningoseptica acquisition affecting 30 patients in a London, UK, critical care unit (3% attack rate) we derived a measure of attributable morbidity and determined whether E. meningoseptica is an emerging nosocomial pathogen. We found monomicrobial E. meningoseptica acquisition (n = 13) to have an attributable morbidity rate of 54% (systemic inflammatory response syndrome ≥2, rising C-reactive protein, new radiographic changes), suggesting that E. meningoseptica is a pathogen. Epidemiologic and molecular evidence showed acquisition was water-source-associated in critical care but identified numerous other E. meningoseptica strains, indicating more widespread distribution than previously considered. Analysis of changes in gram-negative speciation rates across a wider London hospital network suggests this outbreak, and possibly other recently reported outbreaks, might reflect improved diagnostics and that E. meningoseptica thus is a pseudo-emerging pathogen.
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Infección Hospitalaria/epidemiología , Infección Hospitalaria/microbiología , Infecciones por Flavobacteriaceae/epidemiología , Flavobacteriaceae/aislamiento & purificación , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Antibacterianos/uso terapéutico , Proteína C-Reactiva/metabolismo , Cuidados Críticos , Infección Hospitalaria/tratamiento farmacológico , Infección Hospitalaria/metabolismo , Brotes de Enfermedades , Femenino , Flavobacteriaceae/efectos de los fármacos , Infecciones por Flavobacteriaceae/tratamiento farmacológico , Infecciones por Flavobacteriaceae/metabolismo , Infecciones por Flavobacteriaceae/microbiología , Humanos , Incidencia , Unidades de Cuidados Intensivos , Londres/epidemiología , Masculino , Pruebas de Sensibilidad Microbiana/métodos , Persona de Mediana Edad , Adulto JovenRESUMEN
Production of metallo-beta-lactamase (MBL) is one of the main mechanisms for resistance in carbapenem antibiotics. Detection of MBL-producer Pseudomonas aeruginosa is crucial in preventing its spread to other gram-negative bacteria. The aim of this study was to evaluate combination disc (CD) for identification of MBL-producer P. aeruginosa by polymerase chain reaction (PCR). A total of 255 imipenem resistant P. aeruginosa were collected from burn patients. Antibiotic susceptibility testing was conducted after purification and identification. Double-disc synergy test (DDST) with EDTA and combination disc test (CDT) with dipicolinic acid were performed for phenotypic detection of MBL and the PCR was carried out for blaVIM, blaIMP, blaNDM-1, blaSPM-1 genes. DDST with EDTA was negative in all cases, but 161 isolates were positive in CDT with dipicolinic acid. Further, blaVIM and blaIMP were detected in five and four strains, respectively. None of the isolates were positive for BlaNDM-1 and blaSPM-1 . The results of this study showed that the prevalence of MBL is low in imipenem resistance P. aeruginosa and that other mechanisms could be involved in resistance to imipenem in this bacterium.
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Quemaduras/microbiología , Pseudomonas aeruginosa/aislamiento & purificación , Pseudomonas aeruginosa/metabolismo , beta-Lactamasas/metabolismo , Antibacterianos/farmacología , Proteínas Bacterianas/metabolismo , Quemaduras/metabolismo , Carbapenémicos/farmacología , Infección Hospitalaria/tratamiento farmacológico , Infección Hospitalaria/metabolismo , Infección Hospitalaria/microbiología , Humanos , Irán , Pruebas de Sensibilidad Microbiana/métodos , Reacción en Cadena de la Polimerasa , Prevalencia , Infecciones por Pseudomonas/tratamiento farmacológico , Infecciones por Pseudomonas/microbiología , Centros de Atención TerciariaRESUMEN
OBJECTIVE: To analyze the impact of inflammation and negative nitrogen balance (NBAL) on nutritional status and outcomes after subarachnoid hemorrhage (SAH). METHODS: This was a prospective observational study of SAH patients admitted between May 2008 and June 2012. Measurements of C-reactive protein (CRP), transthyretin (TTR), resting energy expenditure (REE), and NBAL (g/day) were performed over 4 preset time periods during the first 14 postbleed days (PBD) in addition to daily caloric intake. Factors associated with REE and NBAL were analyzed with multivariable linear regression. Hospital-acquired infections (HAI) were tracked daily for time-to-event analyses. Poor outcome at 3 months was defined as a modified Rankin Scale score ≥ 4 and assessed by multivariable logistic regression. RESULTS: There were 229 patients with an average age of 55 ± 15 years. Higher REE was associated with younger age (p = 0.02), male sex (p < 0.001), higher Hunt Hess grade (p = 0.001), and higher modified Fisher score (p = 0.01). Negative NBAL was associated with lower caloric intake (p < 0.001), higher body mass index (p < 0.001), aneurysm clipping (p = 0.03), and higher CRP:TTR ratio (p = 0.03). HAIs developed in 53 (23%) patients on mean PBD 8 ± 3. Older age (p = 0.002), higher Hunt Hess (p < 0.001), lower caloric intake (p = 0.001), and negative NBAL (p = 0.04) predicted time to first HAI. Poor outcome at 3 months was associated with higher Hunt Hess grade (p < 0.001), older age (p < 0.001), negative NBAL (p = 0.01), HAI (p = 0.03), higher CRP:TTR ratio (p = 0.04), higher body mass index (p = 0.03), and delayed cerebral ischemia (p = 0.04). CONCLUSIONS: Negative NBAL after SAH is influenced by inflammation and associated with an increased risk of HAI and poor outcome. Underfeeding and systemic inflammation are potential modifiable risk factors for negative NBAL and poor outcome after SAH.