We aimed to compare the efficacy of ceftazidime-avibactam (CAZ-AVI) versus the best available therapy (BAT) in solid organ transplant (SOT) recipients with bloodstream infection caused by ...carbapenemase-producing Klebsiella pneumoniae (CPKP-BSI). A retrospective (2016-2021) observational cohort study was performed in 14 INCREMENT-SOT centers (ClinicalTrials.gov identifier: NCT02852902; Impact of Specific Antimicrobials and MIC Values on the Outcome of Bloodstream Infections Due to ESBL- or Carbapenemase-producing Enterobacterales in Solid Organ Transplantation: an Observational Multinational Study). Outcomes were 14-day and 30-day clinical success (complete resolution of attributable manifestations, adequate source control, and negative follow-up blood cultures) and 30-day all-cause mortality. Multivariable logistic and Cox regression analyses adjusted for the propensity score to receive CAZ-AVI were constructed. Among 210 SOT recipients with CPKP-BSI, 149 received active primary therapy with CAZ-AVI (66/149) or BAT (83/149). Patients treated with CAZ-AVI had higher 14-day (80.7% vs 60.6%, P = .011) and 30-day (83.1% vs 60.6%, P = .004) clinical success and lower 30-day mortality (13.25% vs 27.3%, P = .053) than those receiving BAT. In the adjusted analysis, CAZ-AVI increased the probability of 14-day (adjusted odds ratio aOR, 2.65; 95% confidence interval CI, 1.03-6.84; P = .044) and 30-day clinical success (aOR, 3.14; 95% CI, 1.17-8.40; P = .023). In contrast, CAZ-AVI therapy was not independently associated with 30-day mortality. In the CAZ-AVI group, combination therapy was not associated with better outcomes. In conclusion, CAZ-AVI may be considered a first-line treatment in SOT recipients with CPKP-BSI.
Background
Whether active therapy with β‐lactam/β‐lactamase inhibitors (BLBLI) is as affective as carbapenems for extended‐spectrum β‐lactamase‐producing Enterobacterales (ESBL‐E) bloodstream ...infection (BSI) secondary to urinary tract infection (UTI) in kidney transplant recipients (KTRs) remains unclear.
Methods
We retrospectively evaluated 306 KTR admitted to 30 centers from January 2014 to October 2016. Therapeutic failure (lack of cure or clinical improvement and/or death from any cause) at days 7 and 30 from ESBL‐E BSI onset was the primary and secondary study outcomes, respectively.
Results
Therapeutic failure at days 7 and 30 occurred in 8.2% (25/306) and 13.4% (41/306) of patients. Hospital‐acquired BSI (adjusted OR aOR: 4.10; 95% confidence interval CI: 1.50‐11.20) and Pitt score (aOR: 1.47; 95% CI: 1.21‐1.77) were independently associated with therapeutic failure at day 7. Age‐adjusted Charlson Index (aOR: 1.25; 95% CI: 1.05‐1.48), Pitt score (aOR: 1.72; 95% CI: 1.35‐2.17), and lymphocyte count ≤500 cells/μL at presentation (aOR: 3.16; 95% CI: 1.42‐7.06) predicted therapeutic failure at day 30. Carbapenem monotherapy (68.6%, primarily meropenem) was the most frequent active therapy, followed by BLBLI monotherapy (10.8%, mostly piperacillin‐tazobactam). Propensity score (PS)‐adjusted models revealed no significant impact of the choice of active therapy (carbapenem‐containing vs any other regimen, BLBLI‐ vs carbapenem‐based monotherapy) within the first 72 hours on any of the study outcomes.
Conclusions
Our data suggest that active therapy based on BLBLI may be as effective as carbapenem‐containing regimens for ESBL‐E BSI secondary to UTI in the specific population of KTR. Potential residual confounding and unpowered sample size cannot be excluded (ClinicalTrials.gov identifier: NCT02852902).
Treatment of carbapenemase‐producing Enterobacterales bloodstream infections in solid organ transplant recipients is challenging. The objective of this study was to develop a specific score to ...predict mortality in solid organ transplant recipients with carbapenemase‐producing Enterobacterales bloodstream infections. A multinational, retrospective (2004‐2016) cohort study (INCREMENT‐SOT, ClinicalTrials.gov NCT02852902) was performed. The main outcome variable was 30‐day all‐cause mortality. The INCREMENT‐SOT‐CPE score was developed using logistic regression. The global cohort included 216 patients. The final logistic regression model included the following variables: INCREMENT‐CPE mortality score ≥8 (8 points), no source control (3 points), inappropriate empirical therapy (2 points), cytomegalovirus disease (7 points), lymphopenia (4 points), and the interaction between INCREMENT‐CPE score ≥8 and CMV disease (minus 7 points). This score showed an area under the receiver operating characteristic curve of 0.82 (95% confidence interval CI 0.76‐0.88) and classified patients into 3 strata: 0‐7 (low mortality), 8‐11 (high mortality), and 12‐17 (very‐high mortality). We performed a stratified analysis of the effect of monotherapy vs combination therapy among 165 patients who received appropriate therapy. Monotherapy was associated with higher mortality only in the very‐high (adjusted hazard ratio HR 2.82, 95% CI 1.13‐7.06, P = .03) and high (HR 9.93, 95% CI 2.08‐47.40, P = .004) mortality risk strata. A score‐based algorithm is provided for therapy guidance.
The authors develop a predictive risk score for a solid organ transplant recipient's for mortality in patients with bloodstream infections due to carbapenemase‐producing Enterobacterales, which is useful to differentiate patients who can be treated with antimicrobial monotherapy from those who should receive combination therapy.
The actin cytoskeleton coordinates the organization of signaling microclusters at the immune synapse (IS); however, the mechanisms involved remain poorly understood. We show here that nitric oxide ...(NO) generated by endothelial nitric oxide synthase (eNOS) controls the coalescence of protein kinase C-θ (PKC-θ) at the central supramolecular activation cluster (c-SMAC) of the IS. eNOS translocated with the Golgi to the IS and partially colocalized with F-actin around the c-SMAC. This resulted in reduced actin polymerization and centripetal retrograde flow of β-actin and PKC-θ from the lamellipodium-like distal (d)-SMAC, promoting PKC-θ activation. Furthermore, eNOS-derived NO S-nitrosylated β-actin on Cys374 and impaired actin binding to profilin-1 (PFN1), as confirmed with the transnitrosylating agent S-nitroso-L-cysteine (Cys-NO). The importance of NO and the formation of PFN1-actin complexes on the regulation of PKC-θ was corroborated by overexpression of PFN1- and actin-binding defective mutants of β-actin (C374S) and PFN1 (H119E), respectively, which reduced the coalescence of PKC-θ at the c-SMAC. These findings unveil a novel NO-dependent mechanism by which the actin cytoskeleton controls the organization and activation of signaling microclusters at the IS.
There are scarce data on the efficacy of ertapenem in the treatment of bacteremia due to extended-spectrum-beta-lactamase (ESBL)-producing
(ESBL-E) in kidney transplant (KT) recipients. We evaluated ...the association between treatment with ertapenem or meropenem and clinical cure in KT recipients with nonsevere bacteremic urinary tract infections (B-UTI) caused by ESBL-E. We performed a registered, retrospective, international (29 centers in 14 countries) cohort study (INCREMENT-SOT, NCT02852902). The association between targeted therapy with ertapenem versus meropenem and clinical cure at day 14 (the principal outcome) was studied by logistic regression. Propensity score matching and desirability of outcome ranking (DOOR) analyses were also performed. A total of 201 patients were included; only 1 patient (treated with meropenem) in the cohort died. Clinical cure at day 14 was reached in 45/100 (45%) and 51/101 (50.5%) of patients treated with ertapenem and meropenem, respectively (adjusted OR 1.29; 95% CI 0.51 to 3.22;
= 0.76); the propensity score-matched cohort included 55 pairs (adjusted OR for clinical cure at day 14, 1.18; 95% CI 0.43 to 3.29;
= 0.74). In this cohort, the proportion of cases treated with ertapenem with better DOOR than with meropenem was 49.7% (95% CI, 40.4 to 59.1%) when hospital stay was considered. It ranged from 59 to 67% in different scenarios of a modified (weights-based) DOOR sensitivity analysis when potential ecological advantage or cost was considered in addition to outcome. In conclusion, targeted therapy with ertapenem appears as effective as meropenem to treat nonsevere B-UTI due to ESBL-E in KT recipients and may have some advantages.
The new and unique possibilities that nanomaterials offer have greatly impacted biomedicine, from the treatment and diagnosis of diseases, to the specific and optimized delivery of therapeutic ...agents. Technological advances in the synthesis, characterization, standardization, and therapeutic performance of nanoparticles have enabled the approval of several nanomedicines and novel applications. Discoveries continue to rise exponentially in all disease areas, from cancer to neurodegenerative diseases. In Spain, there is a substantial net of researchers involved in the development of nanodiagnostics and nanomedicines. In this review, we summarize the state of the art of nanotechnology, focusing on nanoparticles, for the treatment of diseases in Spain (2017-2022), and give a perspective on the future trends and direction that nanomedicine research is taking.
The actin cytoskeleton coordinates the organization of signaling microclusters at the immune synapse (IS); however, the mechanisms involved remain poorly understood. We show here that nitric oxide ...(NO) generated by endothelial nitric oxide synthase (eNOS) controls the coalescence of protein kinase C-theta (PKC-theta ) at the central supramolecular activation cluster (c-SMAC) of the IS. eNOS translocated with the Golgi to the IS and partially colocalized with F-actin around the c-SMAC. This resulted in reduced actin polymerization and centripetal retrograde flow of Beta-actin and PKC-theta from the lamellipodium-like distal (d)-SMAC, promoting PKC-theta activation. Furthermore, eNOS-derived NO S-nitrosylated Beta-actin on Cys374 and impaired actin binding to profilin-1 (PFN1), as confirmed with the transnitrosylating agent S-nitroso-L-cysteine (Cys-NO). The importance of NO and the formation of PFN1-actin complexes on the regulation of PKC-theta was corroborated by overexpression of PFN1- and actin-binding defective mutants of Beta-actin (C374S) and PFN1 (H119E), respectively, which reduced the coalescence of PKC-theta at the c-SMAC. These findings unveil a novel NO-dependent mechanism by which the actin cytoskeleton controls the organization and activation of signaling microclusters at the IS.
Realizamos el estudio con el propósito de conocer, a través de un cuestionario específico, el impacto de la enfermedad pulmonar obstructiva crónica (EPOC) sobre las actividades de la vida diaria en ...un grupo amplio de pacientes en España. Asimismo estudiamos su relación con parámetros clínicos, funcionales y socioeconómicos, y con escalas validadas de calidad de vida, para evaluar su utilidad en la práctica habitual y determinar qué variables pueden definir a los pacientes “frágiles” o que requieren una mayor atención.
Se ha realizado un estudio observacional, descriptivo, multicéntrico y transversal, con la participación de 227 neumólogos de toda España, que incluyó a pacientes con el diagnóstico de EPOC. A todos éstos se les pasó un cuestionario específico con 7 preguntas que medían el impacto de la enfermedad sobre aspectos de la vida diaria Las respuestas se valoraron de 0 a 2, según el grado de afectación, lo que supone un intervalo entre 0 y 14 unidades. Definimos al paciente como “frágil” si presentaba valores iguales o mayores de 9 en el cuestionario de impacto. Se evaluó la relación entre la escala de impacto y variables clínicas, situación socioeconómica, espirometría y calidad de vida medida con el cuestionario específico St. George's Respiratory Questionnaire (SGRQ).
Estudiamos a 1.057 pacientes (un 95,2% varones), con una edad media (± desviación estándar) de 67 ± 9 años y volumen espiratorio forzado en el primer segundo (FEV
1), expresado en porcentaje, del 41,8 ± 13,3%. La puntuación media del cuestionario de impacto fue de 6,3 ± 3,1. Las actividades con mayor afectación fueron deporte y ocio, actividad física habitual y vida sexual (mucha afectación en el 52,5, el 30,3 y el 20,2% de los pacientes, respectivamente). Encontramos relación entre la puntuación del cuestionario y parámetros conocidos de gravedad (SGRQ, disnea, número de agudizaciones y FEV
1 expresado en litros). Los pacientes definidos como frágiles tenían mayor edad y menor nivel tanto cultural como económico.
El cuestionario de impacto de la EPOC se correlaciona bien con los clásicos parámetros clínicos y funcionales de valoración de la gravedad de la enfermedad (disnea, FEV
1 y exacerbaciones) y con el cuestionario de calidad de vida relacionada con la salud SGRQ. Así pues, podría ser un instrumento útil para identificar un perfil de paciente frágil, que presenta, además de una peor situación clínica y funcional, una situación socioeconómica más desfavorecida.
The aim of this study was to determine the impact of chronic obstructive pulmonary disease (COPD) on activities of daily living in a large group of patients in Spain who responded to a specific questionnaire. A second aim was to explore the practical utility of the questionnaire and determine which variables could be used to identify “fragile” patients or patients in greater need of attention. To do this, we examined the relationship between questionnaire results and clinical variables, lung function measurements, socioeconomic status, and validated quality of life questionnaires.
We conducted an observational, descriptive, multicenter, cross-sectional study in which 227 respiratory specialists from all over Spain collected data from 1057 patients with COPD. Each patient was given a specific questionnaire containing 7 items that measured the extent to which COPD affected different aspects of their lives. The patients rated each item on a scale of 0 to 2, depending on the level of impact. Total possible scores, thus, ranged from 0 to 14, and patients with a score of 9 or higher were classified as fragile. We then explored the relationship between questionnaire results and clinical variables, socioeconomic status, spirometric values, and quality of life as measured by the St George's Respiratory Questionnaire (SGRQ).
We studied 1057 patients (95.2% male) with a mean (SD) age of 67 (9) years and a mean predicted forced expiratory volume in 1 second (FEV
1) of 41.8% (13.3%). The mean questionnaire score was 6.3 (3.1). The activities that were affected most were sport and leisure, habitual physical activity, and sex life (major impact reported by 52.5%, 30.3%, and 20.2% of patients, respectively). We found a correlation between questionnaire scores and known disease severity markers such as SGRQ scores, dyspnea, number of exacerbations, and FEV
1 in liters. Patients included in the fragile category were older and had a lower socioeconomic status.
COPD impact questionnaire scores correlated well with SGRQ scores and the usual clinical variables and lung function measurements for evaluating disease severity (dyspnea, FEV
1, and exacerbations). The questionnaire could, therefore, be a useful tool for identifying fragile patients who, in addition to having poorer clinical status and lung function measurements, have a lower socioeconomic status.
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