J M Aguado

Hospital Universitario 12 de Octubre, Madrid, Madrid, Spain

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Publications (273)1275.23 Total impact

  • Enfermedades Infecciosas y Microbiología Clínica 10/2014; · 1.48 Impact Factor
  • Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 10/2014;
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    ABSTRACT: Bacillus Calmette-Guérin (BCG) is the most effective intravesical immunotherapy for superficial bladder cancer. Although generally well tolerated, BCG-related infectious complications may occur following instillation. Much of the current knowledge about this complication comes from single case reports, with heterogeneous diagnostic and therapeutic approaches and no investigation on risk factors for its occurrence. We retrospectively analyzed 256 patients treated with intravesical BCG in our institution during a 6-year period, with a minimum follow-up of 6 months after the last instillation. We also conducted a comprehensive review and pooled analysis of additional cases reported in the literature since 1975. Eleven patients (4.3%) developed systemic BCG infection in our institution, with miliary tuberculosis as the most common form (6 cases). A 3-drug antituberculosis regimen was initiated in all but 1 patient, with a favorable outcome in 9/10 cases. There were no significant differences in the mean number of transurethral resections prior to the first instillation, the time interval between both procedures, the overall mean number of instillations, or the presence of underlying immunosuppression between patients with or without BCG infection. We included 282 patients in the pooled analysis (271 from the literature and 11 from our institution). Disseminated (34.4%), genitourinary (23.4%), and osteomuscular (19.9%) infections were the most common presentations of disease. Specimens for microbiologic diagnosis were obtained in 87.2% of cases, and the diagnostic performances for acid-fast staining, conventional culture, and polymerase chain reaction (PCR)-based assays were 25.3%, 40.9%, and 41.8%, respectively. Most patients (82.5%) received antituberculosis therapy for a median of 6.0 (interquartile range: 4.0-9.0) months. Patients with disseminated infection more commonly received antituberculosis therapy and adjuvant corticosteroids, whereas those with reactive arthritis were frequently treated only with nonsteroidal antiinflammatory drugs (p < 0.001 for all comparisons). Attributable mortality was higher for patients aged ≥65 years (7.4% vs 2.1%; p = 0.091) and those with disseminated infection (9.9% vs 3.0%; p = 0.040) and vascular involvement (16.7% vs 4.6%; p = 0.064). The scheduled BCG regimen was resumed in only 2 of 36 patients with available data (5.6%), with an uneventful outcome. In the absence of an apparent predictor of the development of disseminated BCG infection after intravesical therapy, and considering the protean variety of clinical manifestations, it is essential to keep a high index of suspicion to initiate adequate therapy promptly and to evaluate carefully the risk-benefit balance of resuming intravesical BCG immunotherapy.
    Medicine. 10/2014; 93(17):236-54.
  • Transplantation 09/2014; 98(5):e36-7. · 3.78 Impact Factor
  • Transplant Infectious Disease 06/2014; · 1.98 Impact Factor
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    ABSTRACT: Background Cytomegalovirus (CMV)-negative recipients of a graft from a CMV-positive donor (D+/R−) are at high risk of CMV disease. Current preventive strategies include universal prophylaxis (UP) and preemptive therapy (PT). However, the best strategy to prevent CMV disease and achieve better long-term outcomes remains a matter of debate.Methods We analyzed the incidence of CMV disease and long-term outcomes including graft dysfunction and patient mortality at 5 years after transplantation with both preventive strategies. High-risk (D+/R−) kidney and liver transplant recipients from the RESITRA cohort were included.ResultsOf 2410 kidney or liver transplant patients, 195 (8.3%) were D+/R−. The final cohort included 58 liver and 102 kidney recipients. UP was given in 92 patients and 68 received PT; 10.9% and 36.8% developed CMV disease, respectively (P < 0.01). The independent risk factors for CMV disease were PT strategy (hazard ratio [HR], 3.30; 95% confidence interval [CI], 1.6–6.9), kidney transplantation (HR, 3.8; 95% CI, 1.4–9.9), and cyclosporine immunosuppression (HR, 2.4; 95% CI, 1.2–4.7). PT strategy was also a risk factor for CMV disease in both liver transplantation (HR, 11.0; 95% CI, 1.2–98.7) and kidney transplantation (HR, 2.7; 95% CI, 1.3–6.0), independently. The development of CMV replication during the first 2 years after transplantation was a risk factor for graft dysfunction at 5 years after transplantation (odds ratio, 3.4; 95% CI, 1.3–9.0). Nevertheless, no significant differences were seen in either graft dysfunction or mortality between the 2 strategies.Conclusions The study supports the benefit of the UP strategy to prevent CMV disease in D+/R− liver or kidney transplant patients. The development of CMV replication during the first 2 years after transplantation was associated with graft dysfunction at 5 years after transplantation.
    Transplant Infectious Disease 05/2014; · 1.98 Impact Factor
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    ABSTRACT: Since active tuberculosis (TB) is associated with high mortality in solid organ transplant (SOT) recipients, all transplant candidates should undergo evaluation for LTBI (AI).Tuberculin skin test (TST) is currently the standard method for identifying subjects at risk. TST is considered positive if there is ≥ 5 mm of induration at 48-72 h (AI).Whenever possible, patients with either positive or negative TST results should undergo an IGRA test interpreted according to the manufacturers’ instructions (BIII).This article is protected by copyright. All rights reserved.
    Clinical Microbiology and Infection 04/2014; · 4.58 Impact Factor
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    ABSTRACT: Serial monitoring of peripheral blood lymphocyte subpopulations (PBLSs) counts might be useful in predicting post-transplant opportunistic infection (OI) after kidney transplantation (KT). PBLSs were prospectively measured in 304 KT recipients at baseline and post-transplant months 1 and 6. Areas under receiver operating characteristic curves were used to evaluate the accuracy of different subpopulations in predicting the occurrence of overall OI and, specifically, cytomegalovirus (CMV) disease. We separately analyzed patients not receiving (n = 164) or receiving (n = 140) antithymocyte globulin (ATG) as induction therapy. In the non-ATG group a CD8(+) T-cell count at month 1 <0.100 x 10(3) cells/μL had negative predictive values of 0.84 and 0.86 for the subsequent occurrence of overall OI and CMV disease, respectively. In the multivariate Cox model a CD8(+) T-cell count <0.100 x 10(3) cells/μL was an independent risk factor for OI (adjusted hazard ratio: 3.55; P-value = 0.002). In the ATG group a CD4(+) T-cell count at month 1 <0.050 x 10(3) cells/μL showed negative predictive values of 0.92 for the subsequent occurrence of overall OI and CMV disease. PBLSs monitoring effectively identifies KT recipients at low risk of OI, providing an opportunity for individualizing post-transplant prophylaxis practices. This article is protected by copyright. All rights reserved.
    Transplant International 03/2014; · 3.16 Impact Factor
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    ABSTRACT: Background. Concerns have arisen regarding the optimal antifungal regimen for Candida parapsilosis bloodstream infection (BSI) in view of its reduced susceptibility to echinocandins. Methods. The CANDIPOP Study is a prospective multicenter population-based surveillance program on Candida BSI conducted through a 12-month period in 29 Spanish hospitals. Clinical isolates were identified by DNA sequencing and antifungal susceptibility testing was performed by the EUCAST methodology. Predictors for clinical failure (all-cause mortality between days 3 to 30, or persistent candidemia for ≥72 hours after initiation of therapy) in episodes of C. parapsilosis species complex BSI were assessed by logistic regression analysis. We further analysed the impact of echinocandin-based regimen as the initial antifungal therapy (within the first 72 hours) by using a propensity score approach. Results. Out of 752 episodes of Candida BSI identified, 200 (26.6%) were due to C. parapsilosis species complex. We finally analyzed 194 episodes occurring in 190 patients. Clinical failure occurred in 58/177 (32.8%) of evaluable episodes. Orotracheal intubation (adjusted odds ratio [aOR] 2.81; P-value=0.018) and septic shock (aOR 2.91; P-value=0.081) emerged as risk factors for clinical failure, whereas early central venous catheter removal was protective (aOR 0.43; P-value=0.040). Neither univariate nor multivariate revealed that the initial use of an echinocandin-based regimen had any impact on the risk of clinical failure. Incorporation of the propensity score into the model did not change this finding. Conclusions. The initial use of an echinocandin-based regimen does not seem to negatively influence outcome in C. parapsilosis BSI.
    Clinical Infectious Diseases 03/2014; · 9.42 Impact Factor
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    ABSTRACT: We determined the characteristics of posttransplant tuberculosis and the impact of rifampin-based antituberculosis regimens on outcomes in the current era. Patients comprised 64 transplant recipients with tuberculosis, divided into 2 consecutive cohorts: an earlier cohort (cases occurring from 2003 to 2007) and a later cohort (cases from 2008 to 2011). Patients from the later versus earlier era had tuberculosis develop later after transplant (odds ratio, 1.01; 95% CI, 1.00-1.02; P= .05), were more likely to be liver transplant recipients (odds ratio, 4.52; 95% CI, 1.32-15.53; P= .02), and were more likely to receive tacrolimus-based immunosuppression (odds ratio, 3.24; 95% CI, 1.14-9.19; P= .03). Mortality rate was 10% in the later cohort and 21% in the earlier cohort (P= .20). Rifampin-based treatment was less likely to be used in patients with prior rejection (P= .04). However, neither rejection rate (P= .71) nor mortality (P= .93) after tuberculosis differed between recipients who received rifampin and recipients who did not. Thus, notable changes have occurred in the epidemiological characteristics of tuberculosis in transplant recipients. Overall mortality rate has improved, with about 90% of the patients now surviving after tuberculosis.
    Progress in transplantation (Aliso Viejo, Calif.) 03/2014; 24(1):37-43. · 0.69 Impact Factor
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    ABSTRACT: BACKGROUND: Removal of unnecessary catheters has been proposed as an important measure to reduce catheter-related morbidity. Nevertheless, there is scarce information about the potential magnitude of such intervention.
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    ABSTRACT: Removal of unnecessary catheters has been proposed as an important measure to reduce catheter-related morbidity. Nevertheless, there is scarce information about the potential magnitude of such intervention. The present study was aimed at analyzing the appropriateness of use of vascular catheters and catheter lumens in the inpatient setting. Cross-sectional survey. The entire population of adult inpatients admitted to a 1368-bed tertiary-care hospital in a single day. We used a set of preestablished criteria to evaluate the appropriateness of use of vascular catheters and catheter lumens according to the number and administration regimen of intravenous drugs. Out of 834 patients, 575 (68.9%) had ≥1 vascular catheters in place on the day of the survey. The type and distribution of the 703 surveyed catheters were peripheral venous catheter, 80.6%; central venous catheter, 15.8%; and arterial catheter, 3.6%. We found an overall mean of 2.06 ± 0.82 lumens per catheter, with significant differences between intensive care units and conventional wards (P < 0.0001). Based on our criteria, 126 out of 575 patients (21.9%) had an inappropriate number of catheters (medical wards, 20.0%; surgical wards, 23.9%; intensive care units, 26.3%), and 631 out of 14248 nonarterial catheter lumens (43.6%) were considered unnecessary. Significant room exists for improving the adequacy of the number of vascular catheters and catheter lumens as a potentially useful tool for decreasing the incidence of catheter-related bloodstream infection. Journal of Hospital Medicine 2013;. © 2013 Society of Hospital Medicine.
    Journal of Hospital Medicine 12/2013; · 2.08 Impact Factor
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    ABSTRACT: Iron is an essential factor for both the growth and virulence of most of microorganisms. As a part of the innate (or nutritional) immune system, mammals have developed different mechanisms to store and transport this element in order to limit free iron bioavailability. To survive in this hostile environment, pathogenic fungi have specific uptake systems for host iron sources, one of the most important of which is based on the synthesis of siderophores-soluble, low-molecular-mass, high-affinity iron chelators. The increase in free iron that results from iron-overload conditions is a well-established risk factor for invasive fungal infection (IFI) such as mucormycosis or aspergillosis. Therefore, iron chelation may be an appealing therapeutic option for these infections. Nevertheless, deferoxamine –the first approved iron chelator– paradoxically increases the incidence of IFI, as it serves as a xeno-siderophore to Mucorales. On the contrary, the new oral iron chelators (deferiprone and deferasirox) have shown to exert a deleterious effect on fungal growth both in vitro and in animal models. The present review focuses on the role of iron metabolism in the pathogenesis of IFI and summarises the preclinical data, as well as the limited clinical experience so far, in the use of new iron chelators as treatment for mucormycosis and invasive aspergillosis.
    Revista Iberoamericana de Micología 10/2013; 30(4):217–225. · 0.97 Impact Factor
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    ABSTRACT: The impact of iron metabolism on the risk of infectious complications has been demonstrated in various immunosuppressed populations. However, no previous studies have assessed this potential association in kidney transplant (KT) recipients. We prospectively analyzed 228 patients undergoing KT at our institution from November 2008 to February 2011. Serum iron parameters (iron level, ferritin, total iron-binding capacity, unsaturated iron-binding capacity, transferrin, and transferrin saturation) were assessed within the first 2 weeks after transplantation (median interval, 3 days; interquartile [Q1 -Q3 ] range, 1-6 days), and before the occurrence of the first infectious episode (median interval, 26 days; Q1 -Q3 range, 11-76 days). Primary outcome was the occurrence of any episode of infection during the first year. Multivariate-adjusted hazard ratios (aHRs) were estimated by Cox regression models. Patients with ferritin level ≥500 ng/mL had higher incidence rates (per 1000 transplant-days) of overall infection (P = 0.017), bacterial infection (P = 0.002), and bloodstream infection (P = 0.011) during the first post-transplant year. One-year infection-free survival rate was lower in these recipients (26% vs. 41%; P = 0.004). On multivariate analysis, after adjusting for potential confounders, ferritin emerged as an independent predictor of overall infection (aHR [per unitary increment], 1.001; P = 0.006), and bacterial infection (aHR [per unitary increment], 1.001; P = 0.020). Monitoring of serum iron parameters in the early post-transplant period may be useful in predicting the occurrence of infection in KT recipients, although further studies should be carried out to confirm this preliminary finding.
    Transplant Infectious Disease 09/2013; · 1.98 Impact Factor
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    ABSTRACT: A prospective, multicentre, population-based surveillance programme for Candida bloodstream infections was implemented in five metropolitan areas of Spain to determine its incidence and the prevalence of antifungal resistance, and to identify predictors of death. Between May 2010 and April 2011, Candida isolates were centralized to a reference laboratory for species identification by DNA sequencing and for susceptibility testing by EUCAST reference procedure. Prognostic factors associated with early (0-7 days) and late (8-30 days) death were analysed using logistic regression modelling. We detected 773 episodes: annual incidence of 8.1 cases/100 000 inhabitants, 0.89/1000 admissions and 1.36/10 000 patient-days. Highest incidence was found in infants younger than 1 year (96.4/100 000 inhabitants). Candida albicans was the predominant species (45.4%), followed by Candida parapsilosis (24.9%), Candida glabrata (13.4%) and Candida tropicalis (7.7%). Overall, 79% of Candida isolates were susceptible to fluconazole. Cumulative mortality at 7 and 30 days after the first episode of candidaemia was 12.8% and 30.6%, respectively. Multivariate analysis showed that therapeutic measures within the first 48 h may improve early mortality: antifungal treatment (OR 0.51, 95% CI 0.27-0.95) and central venous catheter removal (OR 0.43, 95% CI 0.21-0.87). Predictors of late death included host factors (e.g. patients' comorbid status and signs of organ dysfunction), primary source (OR 1.63, 95% CI 1.03-2.61), and severe sepsis or septic shock (OR 1.77, 95% CI 1.05-3.00). In Spain, the proportion of Candida isolates non-susceptible to fluconazole is higher than in previous reports. Early mortality may be improved with strict adherence to guidelines.
    Clinical Microbiology and Infection 08/2013; · 4.58 Impact Factor
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    ABSTRACT: Limited data exist regarding the role of agr dysfunction in reducing susceptibility to vancomycin in methicillin-susceptible Staphylococcus aureus (MSSA). This study investigated the clinical and molecular epidemiology of MSSA causing bacteraemia, with emphasis on the reduced susceptibility to vancomycin (RSV) phenotype (MIC ≥1.5 mg/L) and its relationship with agr dysfunction. All MSSA bloodstream isolates obtained at our hospital during 2010 were analysed. Antimicrobial susceptibility was determined and time-kill experiments were performed for oxacillin. Multilocus sequence type and agr genotype were determined and DNA microarray analysis of virulence factors was performed. agr dysfunction was assessed phenotypically and by RT-PCR quantification of RNAIII. Of 84 MSSA, 55 (65.5%) exhibited the RSV phenotype, comprising 13 clonal complexes. agr II polymorphism was more prevalent in RSV than non-RSV isolates (41.8% versus 17.2%, P = 0.023) and average levels of RNAIII gene expression were higher in RSV than non-RSV isolates (ΔCt 4.05 ± 3.29 versus 1.5 ± 2.11, P = 0.005), implying greater agr dysfunction in RSV MSSA. We demonstrated a correlation between RSV phenotype in MSSA and reduced agr expression, particularly in association with the agr II genotype. These results may help to understand the role of agr dysfunction in the increased mortality in MSSA infections.
    Journal of Antimicrobial Chemotherapy 08/2013; · 5.34 Impact Factor
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    ABSTRACT: INTRODUCTION: Severity of recurrent hepatitis C virus (HCV) infection in liver transplant recipients (LTR) is variable and the influence of different factors, including the administration of antiviral therapy in the long-term outcome is controversial. METHODS: We analyzed the outcome of a cohort of HCV-infected LTR who were transplanted in our institution. Patients were divided into 2 groups (severe and non-severe HCV disease) depending on the presence of a fibrosis score of F ≥2 in the Scheuer index and/or fibrosing cholestasic hepatitis (FCH) in a graft biopsy. Risk factors were studied using logistic regression analysis. Survival of patients was estimated using Kaplan-Meier plots. A total of 146 patients were followed for a mean of 58 months. RESULTS: Fifty-six (34%) patients developed severe HCV disease and showed shorter survival (P < 0.024). Donor age (odds ratio [OR]: 1.04; 95% confidence interval [CI]: 1.02-1.06) and pre-transplant viral load (VL) >10(6) UI/mL (OR: 3.5; 95% CI: 1.42-10.61) were the only factors associated with severe HCV infection. Over-immunosuppression (OR: 2.3; 95% CI: 1.2-4.41) was specifically associated with the development of FCH. Overall, patient survival in recipients who received a full course of anti-HCV therapy was higher than in patients who did not complete antiviral therapy (P = 0.004) or received no treatment (P = 0.007). Patients with non-severe HCV infection have a higher probability of receiving a full course of antiviral therapy (P = 0.033). CONCLUSION: In conclusion, donor age, pre-transplant VL, and over-immunosuppression were associated with the long-term development of severe HCV recurrence in liver grafts. Administration of a full course of antiviral therapy was associated with better survival.
    Transplant Infectious Disease 06/2013; · 1.98 Impact Factor
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    ABSTRACT: Objective. To elaborate practical recommendations based on scientific evidence, when available, or on expert opinions for the diagnosis, treatment and prevention of fungal respiratory infections in the critically ill patient, including solid organ transplant recipients. Methods. Twelve experts from two scientific societies (The Spanish Society for Chemotherapy and The Spanish Society of Intensive Care and Coronary Units) reviewed in a meeting held in March 2012 epidemiological issues and risk factors as basis for a document about prevention, diagnosis and treatment of respiratory fungal infections caused by Candida spp., Aspergillus spp or Zygomycetes. Results. Despite the frequent isolation of Candida spp. from respiratory tract samples, antifungal treatment is not recommended since pneumonia by this fungal species is exceptional in non-neutropenic patients. In the case of Aspergillus spp., approximately 50% isolates from the ICU represent colonization, and the remaining 50% cases are linked to invasive pulmonary aspergillosis (IPA), an infection of high mortality. Main risk factors for invasive disease in the ICU are previous treatment with steroids and chronic obstructive pulmonary disease (COPD). Collection of BAL sample is recommended for culture and galactomannan determination. Voriconazole and liposomal amphotericin B have the indication as primary therapy while caspofungin has the indication as salvage therapy. Although there is no solid data supporting scientific evidence, the group of experts recommends combination therapy in the critically ill patient with sepsis or severe respiratory failure. Zygomycetes cause respiratory infection mainly in neutropenic patients, and liposomal amphotericin B is the elective therapy. Conclusions. Presence of fungi in respiratory samples from critically ill patients drives to different diagnostic and clinical management approaches. IPA is the most frequent infection and with high mortality.
    Revista espanola de quimioterapia: publicacion oficial de la Sociedad Espanola de Quimioterapia 06/2013; 26(2):173-88. · 0.91 Impact Factor
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    ABSTRACT: BACKGROUND: Uncontrolled donations after circulatory death (DCD) present 2 well-established risk factors for infection after kidney transplantation (KT): greater rates of delayed graft function (DGF) and antithymocyte globulin (ATG)-containing sequential therapies. METHODS: We performed a prospective cohort study of our 291 KT patients between November 2008 and July 2011 to compare the incidences of infection between DCD (n = 87) and donation after brain death (DBD; n = 204) recipients. Most DCD donors were uncontrolled Maastricht categories 1 or 2. Backward stepwise Cox proportional hazards models were used to assess the impact of DCD on the primary study outcome. RESULTS: As compared to the DBD group, DCD recipients were younger, less likely to have undergone previous transplantations, exhibited lower dialysis vintage, and displayed a greater incidence of DGF and graft loss, but lower incidence of acute rejection episodes. There were no differences in the non-death-censored graft survival at 2 years (log-rank P = .835). The DCD group showed lower cumulative incidences of overall, bacterial, cytomegalovirus (CMV), and non-CMV viral infections (P < .05 for all). Multivariate analysis, associated DCD with a lower risk of overall infection (hazard ratio: 0.41; 95% confidence interval: 0.28-0.60; P = .012), an effect that remained when the analysis was restricted to patients receiving ATG induction therapy. Finally, there were no differences in the cumulative incidence of overall infection when DCD recipients were compared with age-matched DBD controls: 43.7% vs 47.1% respectively (P = .648). CONCLUSION: Despite the higher rate of DGF and the use of ATG-containing sequential therapy, uncontrolled DCD policies were safe in terms of the risk of post-transplant infection.
    Transplantation Proceedings 05/2013; 45(4):1335-1338. · 0.95 Impact Factor
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    ABSTRACT: INTRODUCTION: The prevalence and predisposing factors were determined for inappropriate urinary catheterization (UC) among inpatients in medical wards. METHODS: A cross-sectional study was conducted including all patients aged ≥18 years admitted to medical wards in a 1300-bed tertiary-care centre, and who had a urinary catheter in place on the day of the survey. RESULTS: Of 380 patients observed, 46 (12.1%) had a urinary catheter in place. Twelve of them (26.1%) were inappropriately catheterized. The most common indication for inappropriate UC was urine output monitoring in a cooperative, non-critically ill patient. Inappropriateness was associated with increased age, poor functional status, urinary incontinence, dementia, and admission from a long-term care facility. CONCLUSIONS: Further educational efforts should be focused on improving catheterization prescribing practices by physicians.
    Enfermedades Infecciosas y Microbiología Clínica 04/2013; · 1.48 Impact Factor

Publication Stats

3k Citations
1,275.23 Total Impact Points


  • 1994–2014
    • Hospital Universitario 12 de Octubre
      Madrid, Madrid, Spain
  • 1993–2013
    • Complutense University of Madrid
      • Facultad de Medicina
      Madrid, Madrid, Spain
  • 1992–2013
    • Hospital 12 de Octubre
      • • Servicio de Nefrología
      • • Servicio de Microbiología Clínica
      Madrid, Madrid, Spain
  • 2012
    • Complejo Hospitalario Universitario de Badajoz
      Ara Pacis Augustalis, Extremadura, Spain
  • 2008–2012
    • Instituto de Salud Carlos III
      Madrid, Madrid, Spain
    • Hospital Universitario Madrid Montepríncipe
      Madrid, Madrid, Spain
    • Hospital Universitario Severo Ochoa
      Madrid, Madrid, Spain
  • 2007–2010
    • University Hospital Vall d'Hebron
      • Department of Infectious Diseases
      Barcino, Catalonia, Spain
  • 1996
    • Hospital Universitario Nuestra Señora de Candelaria
      Cancelaria, Canary Islands, Spain
  • 1986–1996
    • Fundación Jiménez Díaz
      • Servicio de Microbiología
      Madrid, Madrid, Spain
  • 1987–1994
    • Universidad Autónoma de Madrid
      • Departamento de Biología
      Madrid, Madrid, Spain
  • 1990–1993
    • Universidad de Cantabria
      Santander, Cantabria, Spain
  • 1989–1992
    • Hospital Universitario Marques de Valdecilla
      Santander, Cantabria, Spain