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1.
J Antimicrob Chemother ; 76(5): 1332-1338, 2021 Apr 13.
Artículo en Inglés | MEDLINE | ID: mdl-33585908

RESUMEN

BACKGROUND: The emergence of antibiotic-resistant species calls for fast and reliable phenotypic susceptibility testing to adapt clinical management as fast as possible. OBJECTIVES: We assessed the real-life performance of EUCAST rapid antimicrobial susceptibility testing (RAST) and analysed its impact on patient management. METHODS: RAST was performed on clinical blood cultures containing Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa or Acinetobacter baumannii complex. Categorical agreement with VITEK2 was analysed. A pre-post quasi-experimental observational study was designed to compare antibiotic treatment in sepsis patients in the RAST patient group (n = 51) and a historical control cohort (n = 54). RESULTS: In total, 436 isolates, corresponding to 2314 disc diameters, were measured; 18.4% of these measurements were in the area of technical uncertainty. For the 81.6% categorical results, which could be compared, 94.7% were in agreement, whereas 5.3% of the results were not. In the RAST group, optimal therapy was initiated on the same day as blood culture positivity, while this was the case in the historical group after 24 h. In six cases, RAST allowed for rapid antibiotic escalation. The 30 day mortality rate was lower in the RAST group, although this was not statistically significant. CONCLUSIONS: RAST provides a reliable tool to improve clinical management of sepsis patients by providing rapid phenotypic susceptibility data. While not necessarily being an instrument for de-escalation, especially in areas of low prevalence, early detection allows for timely coverage of resistant isolates. Thus, RAST significantly adds to successful antibiotic stewardship programmes.

2.
Int J Med Microbiol ; 311(2): 151477, 2021 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-33524636

RESUMEN

OBJECTIVE: We aim to describe the epidemiological, clinical and microbiological characteristics of the linezolid- and vancomycin- resistant Enterococcus faecium (LVRE) in a tertiary care hospital in Germany. METHODS: We conducted a retrospective analysis of 196 LVRE cases observed from 1st January 2012 to 31th December 2018. Patients' medical charts were reviewed and available LVRE (n = 102) were subjected to whole-genome-sequencing. Antibiotic consumption was measured in defined daily dose (DDD)/100 bed-days (BD). RESULTS: The prevalence of LVRE isolates among VRE was 6.3 % in 2018. Most patients had an onco-hematological disease (134/196, 68.4 %). From 2012-2018 an increase of +356.7 % of linezolid defined daily dose/100 bed-days was observed. In 71.4 % (90/126, 70 missing values) of the patients, linezolid was prescribed in the previous 6 months. The median exposure to linezolid was 15 days (Interquartile, IQR 9-23). 42/196 (21.4 %) patients had an LVRE-related infection with an overall 30-day mortality rate of 33 %. In 121/196 (61.7 %) patients, linezolid-susceptible VREfm were isolated before LVRE, suggesting secondary acquisition of linezolid resistance. Genetic analysis revealed that most isolates belonged to ST117 (64/102 available isolates, 62.7 %). The G2576T 23S rDNA mutation was identified as the most common resistance mechanism (96/102, 94.1 %). poxtA was identified in two isolates, while cfr, and optrA were not detected. CONCLUSIONS: Incidence of LVRE related to 23S rDNA mutations is rising and probably associated with antibiotic consumption. Restrictions in the use of linezolid may be needed in order to retain therapeutic options in VRE.


Asunto(s)
Farmacorresistencia Bacteriana , Enterococcus faecium/efectos de los fármacos , Infecciones por Bacterias Grampositivas , Linezolid/farmacología , Resistencia a la Vancomicina , Antibacterianos/farmacología , Enterococcus faecium/genética , Alemania/epidemiología , Infecciones por Bacterias Grampositivas/tratamiento farmacológico , Infecciones por Bacterias Grampositivas/epidemiología , Humanos , Pruebas de Sensibilidad Microbiana , ARN Ribosómico 23S/genética , Estudios Retrospectivos , Vancomicina
3.
PLoS Pathog ; 17(2): e1009304, 2021 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-33544760

RESUMEN

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.

4.
Artículo en Inglés | MEDLINE | ID: mdl-33245470

RESUMEN

Increasing worldwide, prevalence of carbapenem-resistant gram-negative bacteria demands urgent a need for rapid detection and accurate identification of carbapenemases. The BD Phoenix CPO detect (PCD) assay possesses an in-built capacity for parallel susceptibility testing and detection of carbapenemases. Here, the ability of the assay to detect and classify carbapenemase production was tested in a collection of carbapenem-resistant Enterobacterales and non-fermentative gram-negative rods. The ability of the PCD assay to detect and classify carbapenemases was investigated in a collection of 194 clinical, carbapenem-resistant isolates (Enterobacterales [n = 65]; non-fermentative gram-negative rods [n = 129]). AST results were compared to MICS determined by gradient diffusion to determine accuracy of the PCD assay. The accuracy of the PCD assay to detect carbapenemases was compared to the results of molecular isolate characterization using a LDT multiplex carbapenemase PCR assay. All 194 isolates classified as carbapenem-resistant by reference susceptibility testing were also classified correctly as CRO by the PCD assay. Performance analysis of the PCD assay to detect carbapenemase production revealed an overall sensitivity of 98.29% and specificity of 17.95% for the detection of carbapenemase production. For the classification of carbapenemases classes A, B, and D, the PCD correctly classified 79.17% Enterobacterales and 67.16% non-fermentative gram-negative rods. The PCD assay is a reliable tool for the detection of carbapenem resistance and allows for parallel analysis of carbapenemase production. However, while sensitivity is high, low specificity in carbapenemase detection and erroneous classification demands mandatory confirmation by alternative methods, especially in non-fermentative gram-negative bacteria.

5.
mBio ; 11(5)2020 10 20.
Artículo en Inglés | MEDLINE | ID: mdl-33082256

RESUMEN

Although it is normally an innocuous part of the human skin microbiota, Staphylococcus epidermidis has emerged as a major nosocomial pathogen, and implanted foreign materials are an essential risk factor for the development of an infection. The extraordinary efficiency of S. epidermidis to colonize artificial surfaces is particularly related to the ability to form biofilms. Biofilm formation itself critically depends on stable pathogen binding to extracellular host matrix components, e.g. fibronectin (Fn), covering inserted devices in vast amounts. Extracellular matrix binding protein (Embp) and its subdomains referred to as the F-repeat and the FG-repeat are critical for adherence of S. epidermidis to surface-immobilized Fn. Embp-Fn interactions preferentially occur with surface-bound, but not folded, globular Fn via binding to the F3 domain. High-resolution structure analysis of F- and FG-repeats revealed that both repeats are composed of two tightly connected triple α-helix bundles, exhibiting an elongated but rather rigid structural organization in solution. Both F- and FG-repeat possess Fn-binding capacity via interactions with type III subdomain FN12, involving residues within the C and F ß-sheet. FN12 essentially supports stability of the globular Fn state, and thus these findings reasonably explain why Embp-mediated interaction of S. epidermidis necessitates Fn surface immobilization. Thus, Embp employs an uncharacterized bacterial Fn-binding mechanism to promote staphylococcal adherence.IMPORTANCE Staphylococcus epidermidis is a leading pathogen in implant-associated hospital infections. The pathogenesis critically depends on bacterial binding to ECM components, specifically fibronectin (Fn). The cell surface-localized, 1-MDa extracellular matrix binding protein (Embp) is essentially characterized by 10 F- and 40 FG-repeats. These repetitive units, each characterized by two α-helical bundles, organize themselves in a rigid, elongated form. Embp binds preferentially to surface-localized but not soluble Fn, with both F- and FG-repeats being sufficient for Fn binding and resulting bacterial adherence. Binding preferentially involves Fn type III domain, specifically residues of FN12 ß-sheets C and F. Both play key role in stabilizing the globular Fn conformation, explaining the necessity of Fn surface immobilization for a subsequent interaction with Embp. In comparison to many other bacterial Fn-binding proteins using the Fn N terminus, Embp employs a previously undescribed mechanism supporting the adhesion of S. epidermidis to surface-immobilized Fn.

6.
Eur J Haematol ; 105(6): 722-730, 2020 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-32658347

RESUMEN

OBJECTIVES: Major complications affecting the central nervous system (CNS) present a challenge after allogeneic stem cell transplantation (allo-SCT). METHODS: Incidence, risk factors, and outcome were retrospectively analyzed in 888 patients in a monocentric study. RESULTS: Cumulative incidence (CI) of major CNS complications at 1 year was 14.8% (95%CI 12.3%-17.2%). Median follow-up is 11 months. CNS complications were documented in 132 patients: in 36 cases, classified metabolic; 26, drug-related neurotoxicity (14 attributed to cyclosporine A, 4 to antilymphocyte globulin); 11, cerebrovascular (ischemic n = 8, bleeding n = 3); 9, infections; 9, psychiatric; and 9, malignant. The cause of CNS symptoms remained unclear for 37 patients (28%). Multivariate analysis demonstrated an association of CNS complication with patient age (P < .001). The estimated OS of patients with any CNS complication was significantly lower than in patients without neurological complications (P < .001), and the CI of non-relapse mortality (NRM) was higher for patients with CNS complication (P < .001). A significant negative impact on survival can only be demonstrated for metabolic CNS complications and CNS infections (NRM, P < .0001 and P = .0003, respectively), and relapse (P < .0001). CONCLUSION: CNS complications after allo-SCT are frequent events with a major contribution to morbidity and mortality. In particular, the situations of unclear neurological complications need to be clarified by intensive research.

7.
BMC Infect Dis ; 20(1): 366, 2020 May 24.
Artículo en Inglés | MEDLINE | ID: mdl-32448208

RESUMEN

BACKGROUND: Kosakonia cowanii, formerly known as Enterobacter cowanii, is a Gram-negative bacillus belonging to the order Enterobacterales. The species is usually recognized as a plant pathogen and has only anecdotally been encountered as a human pathogen. Here we describe the rare case of a K. cowanii infection presenting as an acute cholecystitis and provide a review of available literature. Evident difficulties in species identification by biochemical profiling suggests that potentially, K. cowanii might represent an underestimated human pathogen. CASE PRESENTATION: A 61-year old immunocompromised man presented to the hospital with fever and pain in the upper right abdomen. Sonography revealed an inflamed gall bladder and several gall stones. A cholecystectomy proved diagnosis of an acute cholecystitis with a partial necrosis of the gall bladder. Surgical specimen grew pure cultures of Gram-negative rods unambiguously identified as K. cowanii by MALDI-TOF, 16S-rRNA analysis and whole genome sequencing. CONCLUSIONS: Reporting cases of Kosakonia species can shed light on the prevalence and clinical importance of this rare cause of human infection. Our case is the first to describe an infection without prior traumatic inoculation of the pathogen from its usual habitat, a plant, to the patient. This raises the question of the route of infections as well as the pathogen's ability to colonize the human gut.


Asunto(s)
Colecistitis Aguda/diagnóstico , Colecistitis Aguda/microbiología , Infecciones por Enterobacteriaceae/diagnóstico , Enterobacteriaceae/genética , Enfermedades Raras/diagnóstico , Enfermedades Raras/microbiología , Colecistectomía , Infecciones por Enterobacteriaceae/microbiología , Vesícula Biliar/patología , Cálculos Biliares/cirugía , Humanos , Huésped Inmunocomprometido , Masculino , Persona de Mediana Edad , Necrosis , ARN Bacteriano/genética , ARN Ribosómico 16S/genética , Resultado del Tratamiento , Secuenciación Completa del Genoma
8.
Expert Rev Anti Infect Ther ; 18(4): 349-366, 2020 04.
Artículo en Inglés | MEDLINE | ID: mdl-32056452

RESUMEN

Introduction: Compared to Staphylococcus aureus, coagulase-negative staphylococci (CoNS) are characterized by a lower capacity to cause acute, live-threatened infections. CoNS are, however, of ever increasing importance as pathogens causing infections in immunocompromised patients and after foreign-material implantation. Typically, antibiotics fail to cure foreign body-related infections and removal of the implanted device is inevitable.Areas covered: This review focuses on the emergence of CoNS species, their pathogenic potential in particular due to their ability to form therapy-refractory biofilms on biotic and abiotic surfaces and evasion strategies to resist host response and antibiotic treatment. Their medical significance and proven and novel therapy strategies are discussed.Expert opinion: CoNS contribute significantly to morbidity and socio-economic costs. The anticipated developments in modern medicine, in particular the increasing use of foreign materials and the rising numbers of immunocompromised patients, as well as the changing demographic and hospital-related factors will inevitably contribute to further emergence of CoNS infections. Increasing rates of (multi-)resistant CoNS strains will limit the therapeutic armamentarium and aggravate treatment strategies. Increased research is necessary to understand their role as resistance and virulence gene reservoir and to reduce CoNS infections by the development of innovative colonization-preventing materials and other CoNS-tailored treatment strategies.

9.
Acta Orthop ; 89(5): 580-584, 2018 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-29947288

RESUMEN

Background and purpose - Cutibacterium acnes, formerly known as Propionibacterium acnes, is often isolated from deep tissues of the shoulder. It is recognized as an important causative agent of foreign-material associated infections. However, the incidence and significance of its detection in tissues from patients without clinical evidence for infection is unclear. We assessed the incidence of C. acnes colonization of osteosynthesis material in asymptomatic patients, and evaluated the short-term outcome in relation to the microbiological findings. Patients and methods - We microbiologically analyzed osteosynthesis material of 34 asymptomatic patients after surgery on the clavicle. Material obtained from 19 asymptomatic patients after osteosynthesis of the fibula served as a control group. Patients were clinically followed up for 3-24 months after removal of the osteosynthesis material. Results - Bacteria were recovered from devices in 29 of 34 patients from the clavicle group. 27 of 29 positive samples grew C. acnes. Isolation of C. acnes was more common in male than in female patients. No bacterial growth was observed on foreign material from patients in the fibula group. All patients remained asymptomatic at follow-up. Interpretation - Growth of C. acnes is common on osteosynthesis material of the shoulder, especially in males. Samples were positive irrespective of clinical signs of infection. Therefore, detection of C. acnes in this clinical setting is of questionable clinical significance. The high positivity rate in asymptomatic patients discourages routine sampling of material in cases without clinical evidence for infection.


Asunto(s)
Placas Óseas/microbiología , Fijación Interna de Fracturas/instrumentación , Propionibacterium acnes/aislamiento & purificación , Fracturas del Hombro/cirugía , Articulación del Hombro/microbiología , Adulto , Anciano , Tornillos Óseos/microbiología , Clavícula/lesiones , Clavícula/cirugía , Remoción de Dispositivos , Contaminación de Equipos , Femenino , Peroné/lesiones , Peroné/cirugía , Estudios de Seguimiento , Fijación Interna de Fracturas/métodos , Humanos , Masculino , Persona de Mediana Edad , Propionibacterium acnes/crecimiento & desarrollo , Articulación del Hombro/cirugía , Adulto Joven
10.
PLoS One ; 13(4): e0195757, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-29649276

RESUMEN

OBJECTIVES: To determine the spectrum of infections with multidrug-resistant Gram-negative bacteria (MDR-GNB) and the clinical impact of the newly available betalactam/betalactamase inhibitor combinations ceftolozane/tazobactam and ceftazidime/avibactam in a German academic tertiary care center. METHODS: Retrospective analysis. RESULTS: Between September 1, 2015 and August 31, 2016, 119 individual patients (0.22% of all hospital admissions) were colonized or infected with carbapenem-resistant MDR-GNB. The species distribution was Pseudomonas aeruginosa, n = 66; Enterobacteriaceae spp., n = 44; and Acinetobacter baumannii, n = 18. In 9 patients, carbapenem-resistant isolates belonging to more than one species were detected. Infection was diagnosed in 50 patients (total: 42.0%; nosocomial pneumonia: n = 23, 19.3%; bloodstream infection: n = 11, 9.2%). Antimicrobial treatment with broad-spectrum antibiotics prior to detection of a carbapenem-resistant isolate was documented in 105 patients (88.2%, prior administration of carbapenems: 62.2%). Nosocomial transmission was documented in 29 patients (24.4%). In 26 patients (21.8%), at least one carbapenem-susceptible, third-generation cephalosporin non-susceptible isolate was documented prior to detection of a carbapenem-resistant isolate belonging to the same species (median 38 days, IQR 23-78). 12 patients (10.1%) had documented previous contact to the healthcare system in a country with high burden of carbapenemase-producing strains. Genes encoding carbapenemases were detected in 60/102 patient isolates (58.8%; VIM-2, n = 25; OXA-48, n = 21; OXA-23-like, n = 10). Susceptibility to colistin was 94.3%. Ceftolozane/tazobactam and ceftazidime/avibactam were administered to 3 and 5 patients, respectively (in-hospital mortality: 66% and 100%). Development of drug-resistance under therapy was observed for both antimicrobials. CONCLUSIONS: i) The major predisposing factors for acquisition of carbapenem-resistant MDR-GNB were selective pressure due to preceding antimicrobial therapy and nosocomial transmission. ii) Colistin remains the backbone of antimicrobial chemotherapy for infections caused by carbapenem-resistant MDR-GNB. iii) Novel ß-lactam/ß-lactamase inhibitor combinations are of limited usefulness in our setting because of the high prevalence of Ambler class B carbapenemases and the emergence of nonsusceptibility under therapy.


Asunto(s)
Carbapenémicos/farmacología , Infección Hospitalaria , Bacterias Gramnegativas/efectos de los fármacos , Infecciones por Bacterias Gramnegativas/epidemiología , Infecciones por Bacterias Gramnegativas/microbiología , Resistencia betalactámica , Inhibidores de beta-Lactamasas/farmacología , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Femenino , Alemania/epidemiología , Bacterias Gramnegativas/clasificación , Bacterias Gramnegativas/genética , Infecciones por Bacterias Gramnegativas/tratamiento farmacológico , Infecciones por Bacterias Gramnegativas/transmisión , Hospitales Universitarios , Humanos , Masculino , Pruebas de Sensibilidad Microbiana , Prevalencia , Estudios Retrospectivos , Resultado del Tratamiento , Inhibidores de beta-Lactamasas/uso terapéutico
11.
Diagn Microbiol Infect Dis ; 89(4): 253-257, 2017 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-28974396

RESUMEN

Given constantly high or even rising incidences of both colonization and infection with vancomycin-resistant enterococci (VRE), timely and accurate identification of carriers in high-risk patient populations is of evident clinical importance. In this study, a two-tier approach consisting of PCR-based screening and cultural confirmation of positive results is compared to the conventional approach solely based on culture on selective media. The 2-tier strategy was highly consistent with the conventional approach, and was found to possess high sensitivity and specificity (93.1% and 100%, respectively). The introduction of the PCR-based combined VRE screening approach significantly (P<0.0001) reduced median overall time to result by 44.3hours. The effect was found to be most pronounced in VRE negative samples. Positive vanA PCR was highly consistent with culture (PPV: 92.0%, 95% CI: 72.5-98.6%, NPV: 99.6%, 95% CI: 98.9-99.6%), thus allowing for preliminary reporting of VRE detection. In contrast, a vanB positive PCR does not allow for preliminary reporting (PPV: 58.5%, 95% CI: 44.2-71.6%, NPV: 99.8%, 95% CI: 99.2-100%). The introduction of a molecular assay for rapid detection of VRE from rectal swabs combined with cultural confirmation proved to be reliable and time saving, especially in a setting of low VRE prevalence and predominance of vanA positive strains.


Asunto(s)
Técnicas de Tipificación Bacteriana , Infecciones por Bacterias Grampositivas/diagnóstico , Enterococos Resistentes a la Vancomicina/aislamiento & purificación , Proteínas Bacterianas/genética , Ligasas de Carbono-Oxígeno/genética , Medios de Cultivo/química , Humanos , Reacción en Cadena de la Polimerasa , Recto/microbiología , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Enterococos Resistentes a la Vancomicina/clasificación
12.
J Antimicrob Chemother ; 72(9): 2483-2488, 2017 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-28637339

RESUMEN

Background: Avibactam is a novel broad-range ß-lactamase inhibitor active against Ambler class A (including ESBL and KPC) and some Ambler class C and D (e.g. OXA-48) enzymes. We here report on the emergence of ceftazidime/avibactam resistance in clinical, multiresistant, OXA-48 and CTX-M-14-producing Klebsiella pneumoniae isolate DT12 during ceftazidime/avibactam treatment. Methods and results: Comparative whole-genome sequence analysis identified two SNPs in the CTX-M-14-encoding gene leading to two amino acid changes (P170S and T264I). Compared with WT CTX-M-14, expression of the CTX-M-14Δ170Δ264 isoform in Escherichia coli led to a >64- and 16-fold increase in ceftazidime and ceftazidime/avibactam MICs, respectively, functionally linking the observed SNPs and elevated MICs. The mutated CTX-M-14 isoform exhibited augmented ceftazidime hydrolytic activity, which was a reasonable cause for impaired susceptibility to avibactam inhibition. The P170S exchange in CTX-M-14 was found in association with elevated ceftazidime/avibactam MICs for independent K. pneumoniae isolates, but was not sufficient for full resistance. Apparently, additional CTX-M-independent mechanisms contribute to ceftazidime/avibactam resistance in K. pneumoniae DT12. Conclusions: This study on the molecular basis of ceftazidime/avibactam resistance in clinical K. pneumoniae emerging in vivo underscores the need for continuous monitoring of ceftazidime/avibactam susceptibility during therapy. Despite sustained inhibition of OXA-48, rapid development of CTX-M-14 isoforms exhibiting augmented ceftazidime hydrolytic activity may limit the usefulness of ceftazidime/avibactam monotherapies in infections caused by isolates carrying blaCTX-M-14 and blaOXA-48.


Asunto(s)
Antibacterianos/farmacología , Compuestos de Azabiciclo/farmacología , Ceftazidima/farmacología , Klebsiella pneumoniae/efectos de los fármacos , Klebsiella pneumoniae/genética , Compuestos de Azabiciclo/administración & dosificación , Compuestos de Azabiciclo/uso terapéutico , Ceftazidima/administración & dosificación , Ceftazidima/uso terapéutico , Combinación de Medicamentos , Farmacorresistencia Bacteriana Múltiple , Genoma Bacteriano , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Infecciones por Klebsiella/tratamiento farmacológico , Infecciones por Klebsiella/microbiología , Klebsiella pneumoniae/aislamiento & purificación , Masculino , Pruebas de Sensibilidad Microbiana , Persona de Mediana Edad , Inhibidores de beta-Lactamasas/farmacología
13.
Ann Hematol ; 96(6): 895-904, 2017 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-28331964

RESUMEN

Hypomorphic germline variants in TERT, the gene encoding the reverse transcriptase component of the human telomerase complex, occur with a frequency of 3-5% in acute myeloid leukemia. We analyzed the clinical and prognostic impact of the most common TERT A1062T variant in younger patients with acute myeloid leukemia intensively treated within two prospective multicenter trials. Four hundred and twenty patients (age 17-60 years) were analyzed for the TERT A1062T variant by direct sequencing. Fifteen patients (3.6%) carried the TERT A1062T variant. Patients with the TERT A1062T variant had a trend towards less favorable and more intermediate 2/adverse karyotypes/genotypes according to the European Leukemia Net classification. In univariate and multivariate analysis, patients with the TERT A1062T variant had a significantly inferior overall survival compared to wild-type patients (6-year overall survival 20 vs. 41%, p = 0.005). Patients with the TERT A1062T variant showed a high rate of treatment-related mortality: 5/15 (33%) died during induction therapy or in complete remission as compared to 62/405 (15%) of the wild-type patients. In patients with the TERT variant, 14/15 (93%) suffered from non-hematological/non-infectious grade 3/4 adverse events (mostly hepatic and/or mucosal) as compared to 216/405 (53%) wild-type patients (p = 0.006). In multivariate analysis, the TERT A1062T variant was an independent risk factor predicting for adverse events during induction chemotherapy. In conclusion, the TERT A1062T variant is an independent negative prognostic factor in younger patients with acute myeloid leukemia and seems to predispose those patients to treatment-related toxicity.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Leucemia Mieloide/terapia , Mutación Puntual , Polimorfismo de Nucleótido Simple , Trasplante de Células Madre/métodos , Telomerasa/genética , Enfermedad Aguda , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Ensayos Clínicos como Asunto , Terapia Combinada , Diarrea/etiología , Femenino , Humanos , Leucemia Mieloide/enzimología , Leucemia Mieloide/genética , Masculino , Persona de Mediana Edad , Mucositis/etiología , Estudios Multicéntricos como Asunto , Análisis Multivariante , Pronóstico , Estudios Prospectivos , Trasplante de Células Madre/efectos adversos , Análisis de Supervivencia , Resultado del Tratamiento , Adulto Joven
14.
Mol Microbiol ; 103(5): 860-874, 2017 03.
Artículo en Inglés | MEDLINE | ID: mdl-27997732

RESUMEN

The otherwise harmless skin inhabitant Staphylococcus epidermidis is a major cause of healthcare-associated medical device infections. The species' selective pathogenic potential depends on its production of surface adherent biofilms. The Cell wall-anchored protein Aap promotes biofilm formation in S. epidermidis, independently from the polysaccharide intercellular adhesin PIA. Aap requires proteolytic cleavage to act as an intercellular adhesin. Whether and which staphylococcal proteases account for Aap processing is yet unknown. Here, evidence is provided that in PIA-negative S. epidermidis 1457Δica, the metalloprotease SepA is required for Aap-dependent S. epidermidis biofilm formation in static and dynamic biofilm models. qRT-PCR and protease activity assays demonstrated that under standard growth conditions, sepA is repressed by the global regulator SarA. Inactivation of sarA increased SepA production, and in turn augmented biofilm formation. Genetic and biochemical analyses demonstrated that SepA-related induction of biofilm accumulation resulted from enhanced Aap processing. Studies using recombinant proteins demonstrated that SepA is able to cleave the A domain of Aap at residue 335 and between the A and B domains at residue 601. This study identifies the mechanism behind Aap-mediated biofilm maturation, and also demonstrates a novel role for a secreted staphylococcal protease as a requirement for the development of a biofilm.


Asunto(s)
Proteínas Bacterianas/metabolismo , Biopelículas/crecimiento & desarrollo , Metaloendopeptidasas/metabolismo , Procesamiento Proteico-Postraduccional , Staphylococcus epidermidis/enzimología , Staphylococcus epidermidis/fisiología , Adhesinas Bacterianas/metabolismo , Adhesión Bacteriana , Polisacáridos Bacterianos/metabolismo , Unión Proteica , Staphylococcus epidermidis/química , Staphylococcus epidermidis/genética
16.
Int J Med Microbiol ; 306(6): 471-8, 2016 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-27292911

RESUMEN

Biofilm-associated Staphylococcus epidermidis implant infections are notoriously reluctant to antibiotic treatment. Here we studied the effect of sub-inhibitory concentrations of penicillin, oxacillin, vancomycin, daptomycin, linezolid and tigecycline on S. epidermidis 1585 biofilm formation, expression of extracellular matrix binding protein (Embp) and potential implications for S. epidermidis - macrophage interactions. Penicillin, vancomycin, daptomycin, and linezolid had no biofilm augmenting effect at any of the concentrations tested. In contrast, at sub-inhibitory concentrations tigecycline and oxacillin exhibited significant biofilm inducing activity. In S. epidermidis 1585, SarA is a negative regulator of giant 1 MDa Embp, and down regulation of sarA induces Embp-dependent assembly of a multi-layered biofilm architecture. Dot blot immune assays, confocal laser scanning microscopy, and qPCR showed that under biofilm inducing conditions, tigecycline augmented embp expression compared to the control grown without antibiotics. Conversely, expression of regulator sarA was suppressed, suggesting that tigecycline exerts its effects on embp expression through SarA. Tigecycline failed to induce biofilm formation in embp transposon mutant 1585-M135, proving that under these conditions Embp up-regulation is necessary for biofilm accumulation. As a functional consequence, tigecycline induced biofilm formation significantly impaired the up-take of S. epidermidis by mouse macrophage-like cell line J774A.1. Our data provide novel evidence for the molecular basis of antibiotic induced biofilm formation, a phenotype associated with inherently increased antimicrobial tolerance. While this could explain failure of antimicrobial therapies, persistence of S. epidermidis infections in the presence of sub-inhibitory antimicrobials is additionally propelled by biofilm-related impairment of macrophage-mediated pathogen eradication.


Asunto(s)
Antibacterianos/metabolismo , Proteínas Bacterianas/biosíntesis , Biopelículas/crecimiento & desarrollo , Proteínas Portadoras/biosíntesis , Evasión Inmune , Minociclina/análogos & derivados , Staphylococcus epidermidis/efectos de los fármacos , Staphylococcus epidermidis/fisiología , Animales , Proteínas Bacterianas/genética , Proteínas Portadoras/genética , Línea Celular , Perfilación de la Expresión Génica , Humanos , Immunoblotting , Macrófagos/microbiología , Ratones , Microscopía Confocal , Minociclina/metabolismo , Fagocitosis , Reacción en Cadena en Tiempo Real de la Polimerasa , Staphylococcus epidermidis/inmunología , Staphylococcus epidermidis/metabolismo , Tigeciclina , Transactivadores/biosíntesis , Transactivadores/genética
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