Impact of the use of antibiotics on the clinical response to immune checkpoint inhibitors in patients with non-small cell lung cancer / Impacto del uso de antibióticos en la respuesta clínica de los inhibidores del punto de control en pacientes con carcinoma de pulmón no microcítico

Objectives. Recent research suggests that the use of antibiotics could reduce the efficacy of checkpoint inhibitors, in addition to other well-known factors. It could be due to gut microbiota modification, which impact over the immune system response. However, the information available so far is contradictory. The objective of this research was to clarify whether antibiotic use influences efficacy of checkpoint inhibitors treatments in non-small cell lung cancer patients in clinical practice. Methods. Therefore, a retrospective observational study was designed. Use of antibiotics among patients treated with atezolizumab, pembrolizumab or nivolumab was assessed within 2 months of checkpoint inhibitors treatments initiation. Results. A total of 140 patients were included, mostly men, with good performance status (ECOG 0-1), all of them previously treated with chemotherapy. An antibiotic prescription was identified in 31% of these patients, mainly fluoroquinolones or beta-lactams. The most frequent indication was respiratory infection. Both progression-free survival and overall survival were lower for patients treated with anti-infective drugs, although this difference was not statistically significant. Conclusion. More studies are needed to draw conclusions about the impact of antibiotics on the efficacy of immunotherapy. (AU)

Objetivos. Investigaciones recientes sugieren que el uso de antibióticos podría reducir la eficacia de los inhibidores del punto de control inmunológico, además de otros factores ya conocidos. Podría deberse a la modificación de la microbiota, por su impacto en la respuesta del sistema inmune. En cualquier caso, la información disponible hasta el momento es contradictoria. El objetivo de esta investigación es esclarecer si el uso de antibióticos influye en la eficacia de los inhibidores del punto de control para el tratamiento de pacientes con carcinoma de pulmón no microcítico en la práctica clínica. Métodos. Se diseñó un estudio observacional, retrospectivo. Se investigó el uso de antibióticos entre aquellos pacientes a tratamiento con atezolizumab, pembrolizumab o nivolumab en los 2 meses previos o posteriores a su inicio. Resultados. Se incluyeron 140 pacientes, principalmente hombres con aceptable estado general (ECOG 0-1), todos previamente tratados con quimioterapia. Se identificó una prescripción antibiótica en el 31% de la población, principalmente fluoroquinolonas o betalactámicos. La indicación más frecuente para dicha prescripción era la infección respiratoria. Tanto la supervivencia libre de progresión con la supervivencia global fue inferior en el grupo tratado con antiinfecciosos, aunque no se alcanzó significación estadística. Conclusiones. Son necesario más estudios para concluir acerca del impacto de los antibióticos en la eficacia de la inmunoterapia. (AU)

Health-related quality of life in men with localized prostate cancer treated with radiotherapy: validation of an abbreviated version of the Expanded Prostate Cancer Index Composite for Clinical Practice in Spain.

BACKGROUND: Health-related quality of life (HRQoL) is greatly affected by prostate cancer (PCa) and associated treatments. This study aimed to measure the impact of radiotherapy on HRQoL and to further validate the Spanish version of the 16-item Expanded Prostate Cancer Index Composite (EPIC-16) in routine clinical practice. METHODS: An observational, non-interventional, multicenter study was conducted in Spain with localized PCa patients initiating treatment with external beam radiotherapy (EBRT) or brachytherapy (BQT). Changes from baseline in EPIC-16, University of California-Los Angeles Prostate Cancer Index (UCLA-PCI), and patient-perceived health status were longitudinally assessed at end of radiotherapy (V2) and 90 days thereafter (V3). Psychometric evaluations of the Spanish EPIC-16 were conducted. RESULTS: Of 516 patients enrolled, 495 were included in the analysis (EBRT, n = 361; BQT, n = 134). At baseline, mean (standard deviation [SD]) EPIC-16 global scores were 11.9 (7.5) and 10.3 (7.7) for EBRT and BQT patients, respectively; scores increased, i.e., HRQoL worsened, from baseline, by mean (SD) of 6.8 (7.6) at V2 and 2.4 (7.4) at V3 for EBRT and 4.2 (7.6) and 3.9 (8.2) for BQT patients. Changes in Spanish EPIC-16 domains correlated well with urinary, bowel, and sexual UCLA-PCI domains. EPIC-16 showed good internal consistency (Cronbach's alpha = .84), reliability, and construct validity. CONCLUSION: The Spanish EPIC-16 questionnaire demonstrated sensitivity, strong discriminative properties and reliability, and validity for use in clinical practice. EPIC-16 scores worsened after radiotherapy in different HRQoL domains; however, a strong tendency towards recovery was seen at the 3-month follow-up visit.

Patient satisfaction survey: substitution of reference etanercept with a biosimilar product.

OBJECTIVES: To assess patient satisfaction after pharmacy-mediated replacement of the originator etanercept prefilled syringe with its biosimilar prefilled pen. METHODS: Prospective observational study from March to May 2018, to assess satisfaction with the new drug dispensed. Patients were asked to answer a paper questionnaire with three questions: pain at injection site, ease of administration, and overall patient satisfaction with the change, rated on a scale from 1 (not satisfied) to 5 (extremely satisfied). RESULTS: The questionnaire was given to 134 patients (74 men, 60 women), with an average age of 55 years. 118 patients (88%) were from the Rheumatology Service and 16 patients (12%) from Dermatology. The median treatment duration with etanercept was 61 months. 87 (65%) completed questionnaires were collected. The mean pain score was 3.4. Most patients found administration easy with the biosimilar pen, with an average score of 3.7. Mean overall satisfaction was rated at 3.3, being higher among men, younger patients, and those with shorter duration of treatment. CONCLUSIONS: The change of the original product from etanercept to a biosimilar product was acceptable for most of the patients who responded to the survey. Surveys allow us to determine the opinion and preferences of patients, thus achieving higher satisfaction with their treatment. Further research is needed to evaluate the effect of automatic replacement. A collaborative multidisciplinary switching programme should be implemented based on the feedback provided by patients.

Epidemiology and risk factors for Clostridium difficile infection in critically ill patients in Spain: The PROCRID study / Epidemiología y factores de riesgo para la infección por Clostridium difficile en pacientes críticos en España: Estudio PROCRID

INTRODUCTION: Our objectives were to describe the incidence, clinical characteristics, and risk factors for Clostridium difficile infection (CDI) in critically ill patients and to determine C. difficile PCR-ribotypes. METHODS: Prospective, observational study in 26 Spanish ICUs. Patients with diarrhea meeting ESCMID criteria for CDI were included. Molecular characterization of isolates was performed using PCR ribotyping. RESULTS: Of 4258 patients admitted to the ICUs, 190 (4.5%) developed diarrhea. Only 16 patients (8.4%) were diagnosed with CDI. Ribotype 078/126 (25.0%) was the most frequently identified. The mortality rate was similar in patients with ICD compared to patients with diarrhea not caused by C. difficile (p = 0.115). Chronic renal insufficiency was identified as the only factor independently associated with the development of CDI (OR 5.87, 95% CI 1.24-27.83; p = 0.026). CONCLUSIONS: The incidence of CDI in Spanish ICUs is low. Only chronic renal insufficiency was observed to be a risk factor for CDI development

INTRODUCCIÓN: Pretendemos describir la incidencia, las características clínicas y los factores de riesgo de la infección por Clostridium difficile (ICD) en pacientes ingresados en unidades de cuidados intensivos, así como los ribotipos identificados. MÉTODOS: Estudio observacional, prospectivo, realizado en 26 unidades de cuidados intensivos de España. Se incluyeron pacientes con diarrea y criterios clínicos de la ESCMID por sospecha de ICD. La caracterización molecular se realizó mediante PCR. RESULTADOS: De 4.258 pacientes ingresados, 190 (4,5%) presentaron diarrea; en 16 causada por ICD. El ribotipo más frecuentemente aislado fue 078/126 (25%). La tasa de mortalidad cruda fue similar en pacientes con ICD y en pacientes con diarrea no causada por Clostridium difficile (p = 0,115). La insuficiencia renal crónica fue identificada como factor independientemente asociado a desarrollo de ICD (OR: 5,87; IC 95%: 1,24-27,83; p = 0,026). CONCLUSIONES: La incidencia de ICD en las unidades de cuidados intensivos españolas es baja. La insuficiencia renal crónica es el único factor identificado para desarrollo de ICD

Epidemiology and risk factors for Clostridium difficile infection in critically ill patients in Spain: The PROCRID study.

INTRODUCTION: Our objectives were to describe the incidence, clinical characteristics, and risk factors for Clostridium difficile infection (CDI) in critically ill patients and to determine C. difficile PCR-ribotypes. METHODS: Prospective, observational study in 26 Spanish ICUs. Patients with diarrhea meeting ESCMID criteria for CDI were included. Molecular characterization of isolates was performed using PCR ribotyping. RESULTS: Of 4258 patients admitted to the ICUs, 190 (4.5%) developed diarrhea. Only 16 patients (8.4%) were diagnosed with CDI. Ribotype 078/126 (25.0%) was the most frequently identified. The mortality rate was similar in patients with ICD compared to patients with diarrhea not caused by C. difficile (p=0.115). Chronic renal insufficiency was identified as the only factor independently associated with the development of CDI (OR 5.87, 95% CI 1.24-27.83; p=0.026). CONCLUSIONS: The incidence of CDI in Spanish ICUs is low. Only chronic renal insufficiency was observed to be a risk factor for CDI development.

Performance of a Quantitative PCR-Based Assay and Beta-d-Glucan Detection for Diagnosis of Invasive Candidiasis in Very-Low-Birth-Weight Preterm Neonatal Patients (CANDINEO Study).

An epidemiological, multicenter, noninterventional, observational case-control study was conducted to describe the performance of serum beta-d-glucan (BDG) and Candida PCR in blood, serum, and sterile samples for the diagnosis of invasive candidiasis (IC) in very-low-birth-weight (VLBW) preterm neonates and to compare these techniques with culture of samples from blood and other sterile sites. Seventeen centers participated in the study, and the number of episodes analyzed was 159. A total of 9 episodes of IC from 9 patients (7 confirmed and 2 probable) and 150 episodes of suspected sepsis from 117 controls were identified. The prevalence of IC was 5.7% (95% confidence interval [95% CI], 2.1 to 9.3). The mortality was significantly higher in episodes of IC (44.4%) than in the non-IC episodes (11.1%, P < 0.01). The sensitivity and specificity of the PCR performed on blood/serum samples were 87.5% and 81.6%, respectively. The sensitivity and specificity of the BDG results were lower (75.0% and 64.6%). For cases with negative culture results, the PCR and the BDG results were positive in 27 (17.4%) and 52 (33.5%) episodes, respectively. The presence of multiorgan failure, improvement with empirical antifungal therapy, thrombocytopenia, and Candida colonization were significantly associated (P < 0.01) with PCR or BDG positivity regardless of the results of the cultures. Serum BDG analysis and Candida PCR could be used as complementary diagnostic techniques to detect IC in VLBW neonates.

Phase IV prospective clinical study to evaluate the effect of taurine on liver function in postsurgical adult patients requiring parenteral nutrition.

BACKGROUND: Taurine's role in bile acid metabolism and anti-inflammatory activity could exert a protective effect on hepatobiliary complications associated with parenteral nutrition (PN). In this study, the effects of 2 amino acid solutions, with and without taurine, on liver function administered to nonacutely ill postsurgical patients as part of a short-term PN regimen were prospectively compared. METHODS: Adult patients randomly received (double-blind) Tauramin 10% or a standard PN solution without taurine as the control (1.5 g amino acid/kg body weight [bw]/d; infusion rate of ≤4 mg glucose/kg bw/d) for a period of 5-30 days. γ-Glutamyl transpeptidase (GGT) and other indicators of liver function, glucose metabolism, lipid profile, inflammation markers, and treatment safety data were collected. RESULTS: Thirty-five patients receiving taurine PN and 39 receiving control PN were enrolled (intention-to-treat [ITT] population). Most patients (n = 62) discontinued after day 7 of follow-up (per-protocol [PP] population: n = 24 and n = 27, respectively). ITT patients with high GGT values after 5 days of PN comprised 68.6% and 64.1%, respectively. The mean change in GGT values with respect to the baseline values was 167 ± 192 and 157 ± 185 IU/L, respectively. Low-density lipoprotein (LDL) cholesterol levels after 7 days of PN were significantly decreased in the taurine PN group of PP patients (-2.83 ± 30.9 vs 23.9 ± 27.0 mg/dL for control PN; P < .05). None of the adverse events reported (taurine PN: n = 6; control PN: n = 7) were treatment related. CONCLUSION: PN solutions with and without taurine had similar effects on liver function parameters, except for an LDL reduction in PN with taurine, when administered to nonacutely ill postsurgical patients in the short term (5-7 days).

RNAIII-inhibiting-peptide-loaded polymethylmethacrylate prevents in vivo Staphylococcus aureus biofilm formation.

Staphylococci, common orthopedic pathogens, form antibiotic-resistant biofilms. Polymethylmethacrylate (PMMA) beads loaded with the quorum-sensing inhibitor RNAIII-inhibiting peptide (RIP) were implanted in rats and shown to prevent methicillin-resistant Staphylococcus aureus infection. RIP release was bimodal, typical of previously-tested antibiotics. These results suggest that RIP-PMMA warrants further evaluation for management of orthopedic infections caused by staphylococci.

Ceftobiprole medocaril (BAL5788) treatment of experimental Haemophilus influenzae, Enterobacter cloacae, and Klebsiella pneumoniae murine pneumonia.

Ceftobiprole (BAL9141) is an investigational cephalosporin active against methicillin- and vancomycin-resistant staphylococci administered as a water-soluble prodrug, ceftobiprole medocaril (BAL5788). Using an immunocompetent murine pneumonia model of Haemophilus influenzae, Enterobacter cloacae, or extended-spectrum beta-lactamase (ESBL) nonproducing or producing Klebsiella pneumoniae pneumonia, we compared results of treatment with ceftobiprole medocaril (71 mg/kg, sc, qid), ceftriaxone (50 mg/kg, im, bid), or cefepime (50 mg/kg, ip, q.i.d.). Results were expressed as median and 25th to 75th percentile log10 colony forming units per gram of lung tissue. Ceftobiprole, ceftriaxone, and cefepime were each more active than was no treatment and were equally active for treatment of experimental H. influenzae, E. cloacae, or ESBL-nonproducing K. pneumoniae pneumonia. For ESBL-producing K. pneumoniae, no differences were detected between no treatment and treatment with ceftobiprole, ceftriaxone, or cefepime. Ceftobiprole is active against H. influenzae, E. cloacae, and ESBL-nonproducing K. pneumoniae in an immunocompetent experimental murine pneumonia model.

Garenoxacin treatment of experimental endocarditis caused by viridans group streptococci.

The activity of garenoxacin was compared to that of levofloxacin or penicillin in a rabbit model of Streptococcus mitis group (penicillin MIC, 0.125 microg/ml) and Streptococcus sanguinis group (penicillin MIC, 0.25 microg/ml) endocarditis. Garenoxacin and levofloxacin had MICs of 0.125 and 0.5 microg/ml, respectively, for both study isolates. Rabbits with catheter-induced aortic valve endocarditis were given no treatment, penicillin at 1.2x10(6) IU/8 h intramuscularly, garenoxacin at 20 mg/kg of body weight/12 h intravenously, or levofloxacin at 40 mg/kg/12 h intravenously. For both isolates tested, garenoxacin area under the curve (AUC)/MIC and maximum concentration of drug in serum (Cmax)/MIC ratios were 368 and 91, respectively. Rabbits were sacrificed after 3 days of treatment; cardiac valve vegetations were aseptically removed and quantitatively cultured. For S. mitis group experimental endocarditis, all studied antimicrobial agents were more active than no treatment (P<0.001), whereas for S. sanguinis group endocarditis, no studied antimicrobial agents were more active than no treatment. We conclude that AUC/MIC and Cmax/MIC ratios may not predict activity of some quinolones in experimental viridans group endocarditis and that garenoxacin and levofloxacin may not be ideal choices for serious infections caused by some quinolone-susceptible viridans group streptococci.

Comparative study of antimicrobial release kinetics from polymethylmethacrylate.

Polymethylmethacrylate loaded with antimicrobial agents (most commonly vancomycin and/or aminoglycosides) is used for treatment and prevention of orthopaedic infections. Emergence of organisms resistant to vancomycin or aminoglycosides or both has been reported. Therefore, we studied in vitro release from polymethylmethacrylate beads of antimicrobials with suitable spectra for orthopaedic infections, including cefazolin, ciprofloxacin, gatifloxacin, levofloxacin, linezolid, and rifampin (2.5%, 7.5%, and 15%). Beads were placed in a continuous flow chamber, and antimicrobial concentrations in chamber outflow were determined by bioassay at timed intervals thereafter. Release profiles were bimodal with initial rapid release of high concentrations followed by sustained, slow release. Antimicrobial agents studied showed varied release profiles, indicating that elution from polymethylmethacrylate is unique to individual antimicrobial agents. Increasing antimicrobial concentration in polymethylmethacrylate increased peak concentrations and area under the curve. Cefazolin, ciprofloxacin, gatifloxacin, levofloxacin, linezolid, and rifampin may be suitable for incorporation into polymethylmethacrylate for management of orthopaedic infections.

Prosthetic joint infection.

Infection is the second most common cause of prosthetic joint failure. Signs and symptoms associated with prosthetic joint infection may develop weeks or even years following arthroplasty. While some patients with prosthetic joint infection present with findings consistent with acute septic arthritis, many present with pain alone. Morbidity and cost associated with repeat surgery, prolonged medical treatment and joint immobilization render importance to the accurate and timely diagnosis, and appropriate treatment of prosthetic joint infection. No consensus exists, however, in terms of the most cost-effective diagnostic methods or the ideal medical and/or surgical interventions. This review describes diagnostic tests and available treatment for prosthetic joint infection and gives a practical approach to this challenging clinical entity.

High rate of aminoglycoside resistance among staphylococci causing prosthetic joint infection.

Gentamicin and tobramycin are two aminoglycosides commonly impregnated into polymethylmethacrylate for treatment and prevention of prosthetic joint infection. Susceptibilities of staphylococci to aminoglycosides are not reported routinely in the United States. The gentamicin and tobramycin minimum inhibitory value of 93 staphylococci from patients with PJI were determined. Forty-one and 66% of the isolates were resistant to gentamicin and tobramycin, respectively. Methicillin-resistant Staphylococcus aureus isolates were more likely to be resistant to gentamicin or tobramycin than were their methicillin susceptible counterparts. The findings suggest that consideration should be given to the further study of agents other than aminoglycosides for incorporation into polymethylmethacrylate for the treatment and prevention of prosthetic joint infection.

Molecular Methods in the Diagnosis of Endocarditis.

Advances in molecular microbiologic diagnostics have yielded new tools to diagnose infective endocarditis. These tools can detect microorganisms that are difficult to grow or are uncultivable, because of prior antimicrobial therapy or because of innate characteristics of the microorganisms. This paper reviews molecular microbiologic diagnostic techniques and their role in the diagnosis of infective endocarditis.

Association between inflammation and hemostatic markers in atherothrombotic stroke.

INTRODUCTION: It has been reported that the influence of fibrinogen on the incidence of ischemic events is related to inflammation processes and reflects an association with advance atherosclerosis. The aim of this study was to evaluate the association of thrombogenic and inflammatory profiles in patients who have suffered a stroke. MATERIALS AND METHODS: The study involved 17 patients with atherothrombotic stroke and 34 healthy subjects as control group. The patients were examined 48 h, 3 and 6 months after the stroke occurred. To determine the inflammatory and thrombogenic profiles, plasma levels of fibrinogen, total sialic acid (TSA), C-reactive protein (CRP), tissue factor (TF) and fibrin D-dimer (D-dimer) were measured. RESULTS: The study showed that at 48 h and 3 months the levels of fibrinogen, TF, D-dimer, TSA and CRP were significantly higher than control group. TF, D-dimer and TSA remains significantly elevated throughout the entire study period. TF and D-dimer decreased over time without reaching the normal values. The multiple regression analysis showed that, at 48 h, 68% of the variance of fibrinogen and 22% of the variance of TF could be explained by the influence of CRP. At 3 and 6 months, 78% of the variance of fibrinogen could be explained by the influence of TSA. CONCLUSIONS: The results suggest a relation among inflammation markers, fibrinogen and TF in the acute phase of stroke. As TF and D-dimer are still elevated at 6 months, an increased thrombogenicity for a longer period following the acute event is present.

Análisis de la variabilidad en el uso de diálisis en el territorio insalud / Analisys of the variability in the use of dialysis in the Insalud zone

Introducción: El objetivo de este trabajo es examinar la magnitud de la variación en el uso de diálisis en los hospitales dependientes del Instituto Nacional de la Salud (INSALUD) y la influencia que ejerce la estructura, la morbi-mortalidad y el nivel socioeconómico en esta variación. Material y métodos: Se trata de un estudio epidemiológico de tipo ecológico en el que las unidades de análisis son el hospital y/o la provincia y el ámbito del estudio el territorio INSALUD. Los recursos, la utilización y la población asignada se obtuvieron de los datos del Sistema de Información de Atención Especializada (SIAE) del territorio INSALUD en 1996. La frecuencia de hospitalización se obtuvo del Conjunto Mínimo Básico de Datos (CMBD) y la mortalidad del INE. Las unidades de análisis fueron cada uno de los hospitales y las provincias del territorio gestionado por el INSALUD. Para el análisis estadístico se utilizó la comparación con el estándar del Ministerio de Sanidad y Consumo (MSC), la razón de variación, la comparación entre extremos de utilización, y la regresión múltiple. Resultados: Sólo el 17,5 por ciento de los hospitales y el 22,2 por ciento de las provincias cumplen el 90 por ciento del estándar de utilización de diálisis recomendado por el Ministerio de Sanidad y Consumo. El 75 por ciento de los hospitales y el 57 por ciento de las provincias no cumplen el estándar por infrautilización. La razón de variación en el uso de diálisis es de 41,7 por hospitales y de 2,9 por provincias. Los hospitales del INSALUD más utilizadores realizan más diálisis tanto en el propio hospital como en centros concertados y peritoneal, disponen de más nefrólogos, de mayor número de equipos de diálisis, y presentan una mayor frecuencia de ingresos por insuficiencia renal, todo ello ajustado por habitante. Por provincias, donde se practica más diálisis por habitante, se llevan a cabo un mayor número de tratamientos de diálisis en centros concertados, y la mortalidad por enfermedad renal es más alta. La disponibilidad de equipos de diálisis, la frecuencia de ingresos por insuficiencia renal y el nivel económico explican el 34 por ciento de la variabilidad en el uso de diálisis entre hospitales. El resto de las variables examinadas no están asociadas. Conclusiones: El número de pacientes en diálisis en el ámbito del INSALUD es menor que el estándar recogido en los Criterios de Ordenación de Recursos del Ministerio de Sanidad y Consumo, para el año 1996 y se detecta entre los hospitales una variabilidad muy alta que se atenúa al examinarla por provincias. El que la disponibilidad de recursos, junto con la renta y la frecuencia de ingresos por insuficiencia renal, explique un porcentaje moderado de variabilidad en el uso de diálisis indica que posiblemente otros factores, como el estilo de práctica clínica y o la variabilidad en la prevalencia de insuficiencia renal, puedan ser contribuidores a la variabilidad en el uso de diálisis. Deben hacerse más estudios examinando estos extremos para evaluar las causas de la variabilidad en el uso de diálisis (AU)