Publications by authors named "Jesus Fortún"

100 Publications

Oral decontamination with colistin plus neomycin in solid organ transplant recipients colonized by multidrug-resistant Enterobacterales: a multicentre, randomized, controlled, open-label, parallel-group clinical trial.

Clin Microbiol Infect 2020 Dec 24. Epub 2020 Dec 24.

Quality Unit, Hospital Universitario Marqués de Valdecilla, IDIVAL, Santander, Spain.

Objectives: To evaluate the efficacy of oral colistin-neomycin in preventing multidrug-resistant Enterobacterales (MDR-E) infections in solid organ transplant (SOT) recipients.

Methods: Multicentre, open-label, parallel-group, controlled trial with balanced (1:1) randomization in five transplant units. SOT recipients were screened for MDR-E intestinal colonization (extended-spectrum β-lactamase or carbapenemase producing) before transplantation and +7 and + 14 days after transplantation and assigned 1:1 to receive treatment with colistin sulfate plus neomycin sulfate for 14 days (decolonization treatment (DT) group) or no treatment (no decolonization treatment (NDT) group). The primary outcome was diagnosis of an MDR-E infection. Safety outcomes were appearance of adverse effects, mainly diarrhoea, rash, nausea and vomiting. Patients were monitored weekly until 30 days after treatment. Intention-to-treat analysis was performed.

Results: MDR-E rectal colonization was assessed in 768 SOT recipients; 105 colonized patients were included in the clinical trial, 53 receiving DT and 52 NDT. No significant decrease in the risk of infection by MDR-E was observed in the DT group (9.4%, 5/53) compared to the NDT group (13.5%, 7/52) (relative risk 0.70; 95% confidence interval 0.24-2.08; p 0.517). Four patients (5.6%), three (5.6%) in the DT group and one (1.9%) in the NDT group, developed colistin resistance. Twelve patients (22.7%) in the DT group had diarrhoea, eight related to treatment (15.0%); one patient (1.8%) developed skin rash and another (1.8%) nausea and vomiting. Two patients (3.8%) in the NDT group developed diarrhoea.

Conclusions: DT does not reduce MDR-E infections in SOT. Colistin resistance and adverse effects such as diarrhoea are a potential issue that must be taken seriously.
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http://dx.doi.org/10.1016/j.cmi.2020.12.016DOI Listing
December 2020

Invasive Fusariosis in Nonneutropenic Patients, Spain, 2000-2015.

Emerg Infect Dis 2021 Jan;27(1)

Invasive fusariosis (IF) is associated with severe neutropenia in patients with concurrent hematologic conditions. We conducted a retrospective observational study to characterize the epidemiology of IF in 18 Spanish hospitals during 2000-2015. In that time, the frequency of IF in nonneutropenic patients increased from 0.08 cases per 100,000 admissions in 2000-2009 to 0.22 cases per 100,000 admissions in 2010-2015. Nonneutropenic IF patients often had nonhematologic conditions, such as chronic cardiac or lung disease, rheumatoid arthritis, history of solid organ transplantation, or localized fusariosis. The 90-day death rate among nonneutropenic patients (28.6%) and patients with resolved neutropenia (38.1%) was similar. However, the death rate among patients with persistent neutropenia (91.3%) was significantly higher. We used a multivariate Cox regression analysis to characterize risk factors for death: persistent neutropenia was the only risk factor for death, regardless of antifungal therapy.
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http://dx.doi.org/10.3201/eid2701.190782DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7774531PMC
January 2021

Do high MICs predict the outcome in invasive fusariosis?

J Antimicrob Chemother 2020 Dec 16. Epub 2020 Dec 16.

Istituto di Ematologia, Fondazione Policlinico Universitario A. Gemelli-IRCCS-Università Cattolica del Sacro Cuore - Largo Francesco Vito, 1, 00168 Roma RM, Italy.

Background: Invasive fusariosis (IF) affects mostly severely immunocompromised hosts and is associated with poor outcome. Since Fusarium species exhibit high MICs for most antifungal agents, this could explain the poor prognosis. However, a clear-cut correlation between MIC and outcome has not been established.

Objective: To evaluate the correlation between MIC and outcome (6 week death rate) in patients with IF.

Methods: We performed a multicentre retrospective study of patients with IF who received treatment and had MIC levels determined by EUCAST or CLSI for the drug(s) used during treatment. We compared the MIC50 and MIC distribution among survivors and patients who died within 6 weeks from the diagnosis of IF.

Results: Among 88 patients with IF, 74 had haematological diseases. Primary treatment was monotherapy in 52 patients (voriconazole in 27) and combination therapy in 36 patients (liposomal amphotericin B + voriconazole in 23). The MIC50 and range for the five most frequent agents tested were: voriconazole 8 mg/L (range 0.5-64), amphotericin B 2 mg/L (range 0.25-64), posaconazole 16 mg/L (range 0.5-64), itraconazole 32 mg/L (range 4-64), and isavuconazole 32 mg/L (range 8-64). There was no difference in MIC50 and MIC distribution among survivors and patients who died. By contrast, persistent neutropenia and receipt of corticosteroids were strong predictors of 6 week mortality.

Conclusions: Our study did not show any correlation between MIC and mortality at 6 weeks in patients with IF.
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http://dx.doi.org/10.1093/jac/dkaa516DOI Listing
December 2020

The Impact of Immunosuppression and Autoimmune Disease on Severe Outcomes in Patients Hospitalized with COVID-19.

J Clin Immunol 2021 02 24;41(2):315-323. Epub 2020 Nov 24.

Department of Immunology, Hospital Universitario Ramón y Cajal, Universidad de Alcalá, IRYCIS, Madrid, Spain.

Immunosuppression (IS) and autoimmune disease (AD) are prevalent in patients with severe coronavirus disease 2019 (COVID-19), but their impact on its clinical course is unknown. We investigated relationships between IS, AD, and outcomes in patients hospitalized with COVID-19. Data on consecutive admissions for COVID-19 were extracted retrospectively from medical records. Patients were assigned to one of four cohorts, according to whether or not they had an AD (AD and NAD) or were immunosuppressed (IS and NIS). The primary endpoint was development of severe acute respiratory distress syndrome (ARDS); secondary endpoints included death, and a composite of mechanical ventilation (MV) or death. A total of 789 patients were included: 569 (72.1%) male, 76 (9.6%) with an AD, and 63 (8.0%) with IS. Relative to the NIS-NAD cohort, patients in the IS-AD cohort had a significantly reduced risk of severe ARDS (adjusted hazard ratio [aHR] 0.42; 95% confidence interval [CI] 0.23-0.80; p = 0.008). No significant relationships between IS or AD status and either death or the composite of MV and death were identified, although a trend towards higher mortality was identified in the IS-NAD cohort (aHR vs NIS-NAD 1.71; 95% CI 0.94-3.12; p = 0.081). Patients in this cohort also had higher median serum levels of interleukin-6 compared with IS-AD patients (98.2 vs 21.6 pg/mL; p = 0.0328) and NIS-NAD patients (29.1 pg/mL; p = 0.0057). In conclusion, among patients hospitalized with COVID-19, those receiving immunosuppressive treatment for an AD may have a reduced risk of developing severe ARDS.
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http://dx.doi.org/10.1007/s10875-020-00927-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7685686PMC
February 2021

Non-severe immunosuppression might be associated with a lower risk of moderate-severe acute respiratory distress syndrome in COVID-19: A pilot study.

J Med Virol 2021 04 22;93(4):2243-2251. Epub 2020 Nov 22.

Department of Neurology, Hospital Universitario Ramón y Cajal, Universidad de Alcalá, IRYCIS, Madrid, Spain.

The role of immunosuppression among coronavirus disease 2019 (COVID-19) patients has not been elucidated and management may be challenging. This observational study included confirmed COVID-19 patients. The primary endpoint was the development of moderate-severe acute respiratory distress syndrome (ARDS). Time to moderate-severe ARDS, the need for mechanical or noninvasive ventilation (MV/NIV), death, and a composite of death or MV/NIV were secondary endpoints. Of 138 patients included, 27 (19.6%) were immunosuppressed (IS) and 95 (68.8%) were male, with a median (IQR) age of 68 (54-78) years. A significantly lower proportion of IS patients (25.9%) compared to non-IS patients (52.3%) developed moderate-severe ARDS, in both unadjusted (0.32; 95% CI, 0.13-0.83; p = .017) and adjusted (aOR, 0.25; 95% CI, 0.08-0.80; p = .019) analyses. After stratifying by pathologies, only IS patients with autoimmune diseases remained significant (aOR 0.25; 95% CI, 0.07-0.98; p = .046). Nonsignificant trends toward a longer time to moderate or severe ARDS, a lower need for MV/NIV, and a lower risk of death or MV/NIV were detected among IS. In our cohort of COVID-19 patients, nonsevere immunosuppression was associated with a lower risk of moderate-severe ARDS, especially among AD. This suggests a potential protective effect from a hypothesized hyper-inflammatory response.
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http://dx.doi.org/10.1002/jmv.26656DOI Listing
April 2021

Executive Summary of the Consensus Document on the Diagnosis and Management of Patients with Primary Immunodeficiencies.

J Allergy Clin Immunol Pract 2020 Nov - Dec;8(10):3342-3347

Paediatric Infectious Diseases, Rheumatology and Immunology Unit, University Hospital Virgen del Rocio, Institute of Biomedicine, Seville, Spain.

Primary immunodeficiencies (PIDs) are rare, undiagnosed and potentially fatal diseases. Clinical manifestations of PID can be fatal or leave sequelae that worsen the quality of life of patients. Traditionally, the treatment of PIDs has been largely supportive, with the exception of bone marrow transplantation and, more recently, gene therapy. The discovering of new affected pathways, the development of new molecules and biologics, and the increasing understanding of the molecular basis of these disorders have created opportunities in PIDs therapy. This document aims to review current knowledge and to provide recommendations about the diagnosis and clinical management of adults and children with PIDs based on the available scientific evidence taking in to account current practice and future challenges. A systematic review was conducted, and evidence levels based on the available literature are given for each recommendation where available.
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http://dx.doi.org/10.1016/j.jaip.2020.05.008DOI Listing
May 2020

Executive Summary of the Consensus Document on the Diagnosis and Management of Patients with Primary Immunodeficiencies.

Enferm Infecc Microbiol Clin 2020 11;38(9):438-443

Paediatric Infectious Diseases, Rheumatology and Immunology Unit, University Hospital Virgen del Rocio, Institute of Biomedicine, Seville, Spain.

Primary immunodeficiencies (PIDs) are rare, undiagnosed and potentially fatal diseases. Clinical manifestations of PID can be fatal or leave sequelae that worsen the quality of life of patients. Traditionally, the treatment of PIDs has been largely supportive, with the exception of bone marrow transplantation and, more recently, gene therapy. The discovering of new affected pathways, the development of new molecules and biologics, and the increasing understanding of the molecular basis of these disorders have created opportunities in PIDs therapy. This document aims to review current knowledge and to provide recommendations about the diagnosis and clinical management of adults and children with PIDs based on the available scientific evidence taking in to account current practice and future challenges. A systematic review was conducted, and evidence levels based on the available literature are given for each recommendation where available.
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http://dx.doi.org/10.1016/j.eimc.2020.07.001DOI Listing
November 2020

Malignant external otitis by Aspergillus flavus.

Enferm Infecc Microbiol Clin 2020 Nov 3. Epub 2020 Nov 3.

Infectious Diseases Department, Ramon y Cajal University Hospital, Madrid, Spain. Electronic address:

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http://dx.doi.org/10.1016/j.eimc.2020.09.010DOI Listing
November 2020

Effect of Influenza Vaccination Inducing Antibody Mediated Rejection in Solid Organ Transplant Recipients.

Front Immunol 2020 6;11:1917. Epub 2020 Oct 6.

National Centre for Microbiology, Instituto de Salud Carlos III, Madrid, Spain.

Introduction: Our goal was to study whether influenza vaccination induced antibody mediated rejection in a large cohort of solid organ transplant recipients (SOTR).

Methods: Serum anti-Human Leukocyte Antigen (HLA) antibodies were determined using class I and class II antibody-coated latex beads (FlowPRA Screening Test) by flow cytometry. Anti-HLA antibody specificity was determined using the single-antigen bead flow cytometry (SAFC) assay and assignation of donor specific antibodies (DSA) was performed by virtual-crossmatch.

Results: We studied a cohort of 490 SOTR that received an influenza vaccination from 2009 to 2013: 110 (22.4%) received the pandemic adjuvanted vaccine, 59 (12%) within the first 6 months post-transplantation, 185 (37.7%) more than 6 months after transplantation and 136 (27.7%) received two vaccination doses. Overall, no differences of anti-HLA antibodies were found after immunization in patients that received the adjuvanted vaccine, within the first 6 months post-transplantation, or based on the type of organ transplanted. However, the second immunization dose increased the percentage of patients positive for anti-HLA class I significantly compared with patients with one dose (14.6% vs. 3.8%; = 0.003). Patients with pre-existing antibodies before vaccination (15.7% for anti-HLA class I and 15.9% for class II) did not increase reactivity after immunization. A group of 75 (14.4%) patients developed anti-HLA antibodies, however, only 5 (1.02%) of them were DSA, and none experienced allograft rejection. Only two (0.4%) patients were diagnosed with graft rejection with favorable outcomes and neither of them developed DSA.

Conclusion: Our results suggest that influenza vaccination is not associated with graft rejection in this cohort of SOTR.
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http://dx.doi.org/10.3389/fimmu.2020.01917DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7574595PMC
October 2020

High versus standard doses of corticosteroids in severe COVID-19: a retrospective cohort study.

Eur J Clin Microbiol Infect Dis 2020 Oct 20. Epub 2020 Oct 20.

Department of Immunology, Hospital Universitario Ramón y Cajal, Universidad de Alcalá, IRYCIS, Madrid, Spain.

Despite the increasing evidence of the benefit of corticosteroids for the treatment of moderate-severe coronavirus disease 2019 (COVID-19) patients, no data are available about the potential role of high doses of steroids for these patients. We evaluated the mortality, the risk of need for mechanical ventilation (MV), or death and the risk of developing a severe acute respiratory distress syndrome (ARDS) between high (HD) and standard doses (SD) among patients with a severe COVID-19. All consecutive confirmed COVID-19 patients admitted to a single center were selected, including those treated with steroids and an ARDS. Patients were allocated to the HD (≥ 250 mg/day of methylprednisolone) of corticosteroids or the SD (≤ 1.5 mg/kg/day of methylprednisolone) at discretion of treating physician. Five hundred seventy-three patients were included: 428 (74.7%) men, with a median (IQR) age of 64 (54-73) years. In the HD group, a worse baseline respiratory situation was observed and male gender, older age, and comorbidities were significantly more common. After adjusting by baseline characteristics, HDs were associated with a higher mortality than SD (adjusted OR 2.46, 95% CI 1.59-3.81, p < 0.001) and with an increased risk of needing MV or death (adjusted OR 2.35, p = 0.001). Conversely, the risk of developing a severe ARDS was similar between groups. Interaction analysis showed that HD increased mortality exclusively in elderly patients. Our real-world experience advises against exceeding 1-1.5 mg/kg/day of corticosteroids for severe COVID-19 with an ARDS, especially in older subjects. This reinforces the rationale of modulating rather than suppressing immune responses in these patients.
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http://dx.doi.org/10.1007/s10096-020-04078-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7575217PMC
October 2020

Adherence to Human Colon Cells by Multidrug Resistant Strains Isolated From Solid Organ Transplant Recipients With a Focus on .

Front Cell Infect Microbiol 2020 16;10:447. Epub 2020 Sep 16.

Instituto de Investigación Valdecilla-IDIVAL, Santander, Spain.

Enterobacteria species are common causes of hospital-acquired infections, which are associated with high morbidity and mortality rates. Immunocompromised patients such as solid organ transplant (SOT) recipients are especially at risk because they are frequently exposed to antibiotics in the course of their treatments. In this work, we used a collection of 106 , 78 , 25 spp., and 24 spp. multidrug resistant strains isolated from transplant patients (hepatic, renal or renal/pancreatic) in order to examine their ability to adhere to HT-29 human colon cells, and to determine if some adhesive characteristics are associated with prevalence and persistence of these strains. A total of 33 (31%), 21 (27%), 7 spp. (28%), and 5 spp. (21%), adhered to the colon epithelial cells. Two main adherence patterns were observed in the four species analyzed, diffuse adherence, and aggregative adherence. Under transmission electronic microscopy (TEM), most bacteria lacked visible fimbria on their surface, despite their strong adherence to epithelial cells. None of the strains studied was able to induce any cytotoxic effect on HT-29 cells although some of them strongly colonizing both cells and glass coverslips at high density. Some of the strains failed to adhere to the epithelial cells but adhered strongly to the cover-slide, which shows that microscopy studies are mandatory to elucidate the adherence of bacteria to epithelial cells , and that quantitative assays using colony forming unit (CFUs) counting need to be supplemented with pictures to determine definitively if a bacterial strain adheres or not to animal cells . We report here, for the first time, the aggregative adherence pattern of two multidrug resistant (MDR) strains isolated from human patients; importantly, biofilm formation in is totally dependent on the temperature; strong biofilms were formed at room temperature (RT) but not at 37°C, which can play an important role in the colonization of hospital surfaces. In conclusion, our results show that there is a great variety of adhesion phenotypes in multidrug-resistant strains that colonize transplanted patients.
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http://dx.doi.org/10.3389/fcimb.2020.00447DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7525035PMC
September 2020

Pharmacokinetics of echinocandins in suspected candida peritonitis: A potential risk for resistance.

Int J Infect Dis 2020 Dec 13;101:24-28. Epub 2020 Sep 13.

Infectious Diseases Department, Hospital Ramón y Cajal, Madrid, Spain. Electronic address:

Introduction: A possible increase in Candida resistance, especially in Candida glabrata, has been speculated according to poor diffusion of echinocandins to peritoneal fluid.

Materials/methods: Peritoneal and serum concentrations of caspofungin, micafungin and anidulafungin were analysed in surgical patients with suspected candida peritonitis. After 4 days of starting therapy, serum and peritoneal samples (through peritoneal drainage) were obtained at baseline, 1, 6, 12 and 24 h of drug administration. Micafungin and anidulafungin concentrations were determined using high-performance liquid chromatography (HPLC/F), whereas caspofungin concentrations were established by bioassay.

Results: Twenty-three critically ill patients with suspected abdominal fungal infection who were receiving an echinocandin were prospectively recruited. No specific criteria were applied to prescribe one specific echinocandin. No special clinical differences were observed among the three groups of patients. All were receiving antibiotic therapy, 80% required inotropic drugs, and fungal peritonitis was confirmed in 74% of them. The AUC (mg × h/L) obtained in serum and peritoneal fluid were: 126.84 and 34.38, 98.52 and 18.83, and 66.9 and 8.78 for anidulafungin, micafungin and caspofungin, respectively. The median concentration in peritoneal fluid ranged from 0.66 to 1.82 μg/mL for anidulafungin, 0.68-0.88 μg/mL for micafungin and 0.21-0.46 μg/mL for caspofungin.

Conclusion: The results showed moderate penetration of echinocandins into the peritoneal fluid of these patients. These levels are below the threshold of resistance mutant selection published by other authors. This could justify a potential risk of resistance in patients with prolonged treatment with echinocandins and suboptimal control of abdominal infection.
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http://dx.doi.org/10.1016/j.ijid.2020.09.019DOI Listing
December 2020

Factors associated with the development of septic shock in patients with candidemia: a post hoc analysis from two prospective cohorts.

Crit Care 2020 03 26;24(1):117. Epub 2020 Mar 26.

Clinical Microbiology and Infectious Diseases, Hospital General Universitario Gregorio Marañón, Madrid, Spain.

Background: Almost one third of the patients with candidemia develop septic shock. The understanding why some patients do and others do not develop septic shock is very limited. The objective of this study was to identify variables associated with septic shock development in a large population of patients with candidemia.

Methods: A post hoc analysis was performed on two prospective, multicenter cohort of patients with candidemia from 12 hospitals in Spain and Italy. All episodes occurring from September 2016 to February 2018 were analyzed to assess variables associated with septic shock development defined according to The Third International Consensus Definition for Sepsis and Septic Shock (Sepsis-3).

Results: Of 317 candidemic patients, 99 (31.2%) presented septic shock attributable to candidemia. Multivariate logistic regression analysis identifies the following factors associated with septic shock development: age > 50 years (OR 2.57, 95% CI 1.03-6.41, p = 0.04), abdominal source of the infection (OR 2.18, 95% CI 1.04-4.55, p = 0.04), and admission to a general ward at the time of candidemia onset (OR 0.21, 95% CI, 0.12-0.44, p = 0.001). Septic shock development was independently associated with a greater risk of 30-day mortality (OR 2.14, 95% CI 1.08-4.24, p = 0.02).

Conclusions: Age and abdominal source of the infection are the most important factors significantly associated with the development of septic shock in patients with candidemia. Our findings suggest that host factors and source of the infection may be more important for development of septic shock than intrinsic virulence factors of organisms.
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http://dx.doi.org/10.1186/s13054-020-2793-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7099832PMC
March 2020

A New Clinical and Immunovirological Score for Predicting the Risk of Late Severe Infection in Solid Organ Transplant Recipients: The CLIV Score.

J Infect Dis 2020 07;222(3):479-487

Unit of Infectious Diseases, Hospital Universitario "12 de Octubre," Instituto de Investigación Hospital "12 de Octubre" (imas12), Madrid, Spain.

Background: We aimed at constructing a composite score based on Epstein-Barr virus DNAemia (EBVd) and simple clinical and immunological parameters to predict late severe infection (LI) beyond month 6 in solid organ transplantation (SOT) recipients.

Methods: Kidney and liver transplant recipients between May 2014 and August 2016 at 4 participating centers were included. Serum immunoglobulins and complement factors, peripheral blood lymphocyte subpopulations, and whole blood EBVd were determined at months 1, 3, and 6. Cox regression analyses were performed to generate a weighted score for the prediction of LI.

Results: Overall, 309 SOT recipients were followed-up for a median of 1000 days from transplant (interquartile range, 822-1124). Late severe infection occurred in 104 patients (33.6%). The CLIV Score consisted of the following variables at month 6: high-level EBVd (>1500 IU/mL) and recurrent infection during the previous months (6 points); recipient age ≥70 years and chronic graft dysfunction (5 points); cytomegalovirus mismatch (4 points); and CD8+ T-cell count <400 cells/μL (2 points). The area under receiver operating characteristics curve was 0.77 (95% confidence interval, 0.71-0.84). The risk of LI at day 1000 was as follows: score 0, 12.6%; score 2-5, 25.5%; score 6-9, 52.7%; score ≥10, 73.5%.

Conclusions: While waiting for further external validation, the CLIV Score based on clinical and immune-virological parameters is potentially useful to stratify the risk of LI after SOT.
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http://dx.doi.org/10.1093/infdis/jiaa090DOI Listing
July 2020

Comparison of the Safety and Tolerance Profile of Micafungin with that of Other Echinocandins and Azoles in Patients with Pre-existing Child-Pugh B or C Liver Disease: A Case-Control Retrospective Study.

Infect Dis Ther 2020 Mar 21;9(1):151-163. Epub 2020 Feb 21.

Clinical Microbiology and Infectious Diseases, Hospital General Universitario Gregorio Marañón, Madrid, Spain.

Introduction: To assess the association between exposure to micafungin, other echinocandins, or azoles and the development of short-term liver injury (STLI) or long-term liver injury (LTLI) in patients with Child-Pugh B or C liver disease.

Methods: Multicenter case-control study of patients with Child-Pugh B or C liver disease who received antifungals (AF) for ≥ 72 h (May 2009-May 2015) in six Spanish and Italian hospitals. All micafungin patients were randomly matched with one patient who received another echinocandin and with one patient who received azole treatment. Primary outcome was development of STLI or LTLI (development of any type of liver tumor during the follow-up period).

Results: Of 2335 patients with chronic liver disease admitted to the six centers, 20 (0.85%) were found to have Child-Pugh B or C liver disease and received micafungin for ≥ 72 h. During AF treatment, the frequency of STLI was 10% in each group. Most cases of STLI were asymptomatic, and AFs had to be switched to another class of AF in only two patients (one micafungin and one azole). No patients developed acute liver insufficiency, were admitted to the ICU, or had to undergo transplantation. Follow-up data (median of 1.3 years) were available for 30 patients. LTLI was observed in only one patient, who had previously received treatment with azoles.

Conclusions: Our study suggests that the administration of micafungin to patients with end-stage liver disease does not imply a higher risk of developing STLI or LTLI.
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http://dx.doi.org/10.1007/s40121-020-00282-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7054556PMC
March 2020

Selection criteria of solid organ donors in relation to infectious diseases: A Spanish consensus.

Transplant Rev (Orlando) 2020 04 13;34(2):100528. Epub 2020 Jan 13.

Organización Nacional de Trasplantes, Madrid, Spain.

The immunosuppressive treatment that recipients receive from a solid organ transplantation hinders the defensive response to infection. Its transmission from the donor can cause dysfunction or loss of the graft and even death of the recipient if proper preventive measures are not established. This potential risk should be thoroughly evaluated to minimise the risk of infection transmission from donor to recipient, especially with organ transplantation from donors with infections, without increasing graft dysfunction and morbidity and mortality in the recipient. This document aims to review current knowledge about infection screening in potential donors and offer clinical and microbiological recommendations about the use of organs from donors with infection based on available scientific evidence.
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http://dx.doi.org/10.1016/j.trre.2020.100528DOI Listing
April 2020

Executive summary of the Consensus Statement of the Transplant Infection Study Group (GESITRA) of the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC) and the National Transplant Organization (ONT) on the Selection Criteria of Donors of Solid Organs in relation to Infectious Diseases.

Enferm Infecc Microbiol Clin 2020 10 24;38(8):379-389. Epub 2019 Dec 24.

Organización Nacional de Trasplantes, Madrid, Spain.

The immunosuppressive treatment that recipients receive from a solid organ transplantation hinders the defensive response to infection. Its transmission from the donor can cause dysfunction or loss of the graft and even death of the recipient if proper preventive measures are not established. This potential risk should be thoroughly evaluated to minimise the risk of infection transmission from donor to recipient, especially with organ transplantation from donors with infections, without increasing graft dysfunction and morbidity and mortality in the recipient. This document aims to review current knowledge about infection screening in potential donors and offer clinical and microbiological recommendations about the use of organs from donors with infection based on available scientific evidence.
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http://dx.doi.org/10.1016/j.eimc.2019.10.016DOI Listing
October 2020

An evidence-based bundle improves the quality of care and outcomes of patients with candidaemia.

J Antimicrob Chemother 2020 03;75(3):730-737

Hospital Clínic, IDIBAPS (Institut d'Investigacions biomèdiques Agust Pi i Sunyer), Universitat de Barcelona, Barcelona, Spain.

Background: Candidaemia is a leading cause of bloodstream infections in hospitalized patients all over the world. It remains associated with high mortality.

Objectives: To assess the impact of implementing an evidence-based package of measures (bundle) on the quality of care and outcomes of candidaemia.

Methods: A systematic review of the literature was performed to identify measures related to better outcomes in candidaemia. Eight quality-of-care indicators (QCIs) were identified and a set of written recommendations (early treatment, echinocandins in septic shock, source control, follow-up blood culture, ophthalmoscopy, echocardiography, de-escalation, length of treatment) was prospectively implemented. The study was performed in 11 tertiary hospitals in Spain. A quasi-experimental design before and during bundle implementation (September 2016 to February 2018) was used. For the pre-intervention period, data from the prospective national surveillance were used (May 2010 to April 2011).

Results: A total of 385 and 263 episodes were included in the pre-intervention and intervention groups, respectively. Adherence to all QCIs improved in the intervention group. The intervention group had a decrease in early (OR 0.46; 95% CI 0.23-0.89; P = 0.022) and overall (OR 0.61; 95% CI 0.4-0.94; P = 0.023) mortality after controlling for potential confounders.

Conclusions: Implementing a structured, evidence-based intervention bundle significantly improved patient care and early and overall mortality in patients with candidaemia. Institutions should embrace this objective strategy and use the bundle as a means to measure high-quality medical care of patients.
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http://dx.doi.org/10.1093/jac/dkz491DOI Listing
March 2020

Biofilm formation by multidrug resistant Enterobacteriaceae strains isolated from solid organ transplant recipients.

Sci Rep 2019 06 20;9(1):8928. Epub 2019 Jun 20.

Instituto de Investigación Valdecilla-IDIVAL, Avd. Cardenal Herrera Oria, 39011, Santander, Spain.

Solid organ transplant (SOT) recipients are especially at risk of developing infections by multidrug resistant bacteria (MDR). In this study, the biofilm-forming capability of 209 MDR strains (Escherichia coli n = 106, Klebsiella pneumoniae n = 78, and Enterobacter spp. n = 25) isolated from rectal swabs in the first 48 hours before or after kidney (93 patients), liver (60 patients) or kidney/pancreas transplants (5 patients) were evaluated by using a microplate assay. Thirty-nine strains were isolated before transplant and 170 strains were isolated post-transplant. Overall, 16% of E. coli strains, 73% of K. pneumoniae strains and 4% Enterobacter strains showed moderate or strong biofilm production. Nine strains isolated from infection sites after transplantation were responsible of infections in the first month. Of these, 4 K. pneumoniae, 1 E. coli and 1 Enterobacter spp. strains isolated pre-transplant or post-transplant as colonizers caused infections in the post-transplant period. Our results suggest that in vitro biofilm formation could be an important factor for adhesion to intestine and colonization in MDR K. pneumoniae strains in SOT recipients, but this factor appears to be less important for MDR E. coli and Enterobacter spp.
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http://dx.doi.org/10.1038/s41598-019-45060-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6586660PMC
June 2019

A Case of Vanishing Pulmonary Aspergilloma.

Arch Bronconeumol 2020 06 5;56(6):394. Epub 2019 Jun 5.

Department of Infectious Diseases, Ramón y Cajal University Hospital, Madrid, Spain.

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http://dx.doi.org/10.1016/j.arbres.2019.05.004DOI Listing
June 2020

Posaconazole salvage therapy: The Posifi study.

Mycoses 2019 Jun 3;62(6):526-533. Epub 2019 Apr 3.

Infectious Diseases Department, Hospital Ramón y Cajal, IRYCIS (Instituto Ramón y Cajal de Investigación Sanitaria), Universidad de Alcalá, Madrid, Spain.

Background: Posaconazole (PCZ) is used mainly for the prevention of invasive fungal infection (IFI).

Methods: A multicentre retrospective, investigational study using a non-randomized, single-arm design carried out in six tertiary hospitals in Spain to evaluate the use of PCZ in different forms of administration in the (non-prophylactic) treatment of IFI.

Results: Over an eight-year-period, 67 patients were included in this study. PCZ was administered as salvage therapy (intolerant or refractory to a previous antifungal agent) in 65/67 (97%); of these, it was used against Aspergillosis (68.6%), Zygomycosis (13.4%), other moulds (8.9%) and yeast (10.5%). The median duration of PCZ therapy was 75 days. The oral solution was associated with low serum levels (<0.7 mg/L) in 63% of available patients. Clinical response at 3 and 12 months of PCZ therapy were for aspergillosis: 47.8% and 41.3%; for zygomycosis: 55.5% and 55.5%; and for other mycoses: 69.2% and 69.2%, respectively. Suspension by toxicity was only observed in 6% and 7.5% of patients at 3 and 12 months, respectively, mainly with grade III/IV elevations of liver function test (LFTs).

Conclusions: Posaconazole salvage therapy, especially oral tablets, can be an effective alternative option for patients with IFI who cannot tolerate or do not respond to other antifungal therapies.
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http://dx.doi.org/10.1111/myc.12911DOI Listing
June 2019

Pharmacokinetics of Micafungin in Critically Ill Patients Receiving Continuous Venovenous Hemodialysis With High Cutoff Membranes.

Ther Drug Monit 2019 06;41(3):376-382

Faculty of Medicine, School of Pharmacy, the University of Queensland.

Background: An optimal antifungal therapy for invasive candidiasis in critically ill patients is essential to reduce the high mortality rates. Acute kidney injury is common, and continuous renal replacement therapies are frequently used. Previous studies have demonstrated a lack of effect from different continuous renal replacement techniques on micafungin clearance. However, the use of high cutoff pore size membranes could potentially allow for the loss of albumin and alter micafungin pharmacokinetics. The objective was to explore the pharmacokinetics of micafungin in critically ill patients undergoing continuous venovenous high cutoff membrane hemodialysis (CVVHD-HCO).

Methods: Prospective observational study performed in critically ill patients treated with 100 mg/d of micafungin and undergoing CVVHD-HCO. CVVHD-HCO sessions were performed using Prisma-Flex monitors and dialyzers with a membrane of polyarylethersulfone of 1.1-m surface area and 45-kDa pore size. Blood samples were collected from arterial prefilter, venous postfilter, and the drainage line ports at 0 (predose), 1, 4, 12, 24 hours after dose, and micafungin concentrations were determined using HPLC-UV.

Results: Nine patients (55.6% male; age: 28-80 years) were included. Median (range) of micafungin concentrations in the effluent were <0.2 (<0.2-0.4) mg/L at low (predose) and 0.4 (<0.2-0.7) mg/L at high (1 h) concentrations. The extraction ratio was <12% at each time point. A 2-compartment model best described the time course of plasma concentrations, and body weight was the only covariate that improved the model.

Conclusions: This is the first study demonstrating that CVVHD-HCO does not alter the pharmacokinetics of micafungin, and that standard doses of this antifungal can be used.
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http://dx.doi.org/10.1097/FTD.0000000000000595DOI Listing
June 2019

Usefulness of guideline recommendations for prognosis in patients with candidemia.

Med Mycol 2019 Aug;57(6):659-667

Hospital Universitari de Bellvitge, IDIBELL (Institut D'Investigació Biomèdica de Bellvitge), Universitat de Barcelona, Barcelona, Spain.

We aimed to analyze whether the lack of inclusion of specific recommendations for the management of candidemia is an independent risk factor for early and overall mortality. Multicenter study of adult patients with candidemia in 13 hospitals. We assessed the proportion of patients on whom nine specific ESCMID and IDSA guidelines recommendations had been applied, and analyzed its impact on mortality. 455 episodes of candidemia were documented. Patients who died within the first 48 hours were excluded. Sixty-two percent of patients received an appropriate antifungal treatment. Either echinocandin or amphotericin B therapy were administered in 43% of patients presenting septic shock and in 71% of those with neutropenia. Sixty-one percent of patients with breakthrough candidemia underwent a change in antifungal drug class. Venous catheters were removed in 79% of cases. Follow-up blood cultures were performed in 72% of cases. Ophthalmoscopy and echocardiogram were performed in 48% and 50% of patients, respectively. Length of treatment was appropriate in 78% of cases. Early (2-7 days) and overall (2-30 days) mortality were 8% and 27.7%, respectively. Inclusion of less than 50% of the specific recommendations was independently associated with a higher early (HR = 7.02, 95% CI: 2.97-16.57; P < .001) and overall mortality (HR = 3.55, 95% CI: 2.24-5.64; P < .001). In conclusion, ESCMID and IDSA guideline recommendations were not performed on a significant number of patients. Lack of inclusion of these recommendations proved to be an independent risk factor for early and overall mortality.
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http://dx.doi.org/10.1093/mmy/myy118DOI Listing
August 2019

T2 magnetic resonance for the diagnosis of deep-seated invasive candidiasis in a liver recipient without candidemia.

Rev Iberoam Micol 2018 Jul - Sep;35(3):159-161. Epub 2018 Jul 4.

Infectious Diseases Department, Ramón y Cajal Hospital, Madrid, Spain.

Background: T2 magnetic resonance imaging (T2MR) is a new method for the diagnosis of invasive candidiasis, although most studies have analyzed its role in patients with candidemia or not infection.

Case Report: We present the case of a patient with arteritis and thrombosis of the hepatic graft resulted from an undocumented fungal infection in the explanted liver.T2MR in serum was a suitable diagnostic tool for the diagnosis of the deep-seated invasive candidiasis in the absence of candidemia or the isolation of the yeast in culture.

Conclusions: T2MR allowed the diagnosis of deep-seated invasive candidiasis in an immunodepressed patient without candidemia, even before the onset of symptoms.
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http://dx.doi.org/10.1016/j.riam.2018.03.002DOI Listing
May 2019

Executive summary of clinical practice guideline for the management of invasive diseases caused by Aspergillus: 2018 Update by the GEMICOMED-SEIMC/REIPI.

Enferm Infecc Microbiol Clin 2019 Oct 28;37(8):535-541. Epub 2018 Jun 28.

Laboratorio de referencia e investigación en Micología, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Spain.

Aspergillus infection is a significant cause of morbi-mortality in an at-risk population. The Study Group of Fungal Infections (GEMICOMED) from the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC) has reviewed announcements made in invasive aspergillosis management. We have organized our recommendations in such a way as to provide a guide in resolving different clinical situations concerning the entire spectrum of invasive diseases caused by Aspergillus in various populations. Diagnostic approach, treatment and preventions strategies are outlined. It is not our aim that these guidelines supplant clinical judgment with respect to specific patients; however, it is our objective to perform a comprehensive summary of quality of care evidence for invasive aspergillosis management in different settings.
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http://dx.doi.org/10.1016/j.eimc.2018.03.018DOI Listing
October 2019

Analysis of spontaneous resolution of cytomegalovirus replication after transplantation in CMV-seropositive patients with pretransplant CD8+IFNG+ response.

Antiviral Res 2018 07 18;155:97-105. Epub 2018 May 18.

Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC)/Reina Sofia University Hospital/University of Cordoba, Cordoba, Spain(1).

This prospective study evaluates whether CMV-seropositive (R+) transplant patients with pretransplant CD8+IFNG+ T-cell response to cytomegalovirus (CMV) (CD8+IFNG+ response) can spontaneously clear the CMV viral load without requiring treatment. A total of 104 transplant patients (kidney/liver) with pretransplant CD8+IFNG+ response were evaluable. This response was determined using QuantiFERON-CMV assay. The incidence of CMV replication and disease was 45.2% (47/104) and 6.7% (7/104), respectively. Of the total patients, 77.9% (81/104) did not require antiviral treatment, either because they did not have CMV replication (n = 57) or because they had asymptomatic CMV replication that could be spontaneously cleared (n = 24). Both situations are likely related to the presence of CD8+IFNG+ response to CMV, which has a key role in controlling CMV infection. However, 22.1% of the patients (23/104) received antiviral treatment, although only 7 of them did so because they had symptomatic CMV replication. These patients developed symptoms in spite of having pretransplant CD8+IFNG+ response, thus suggesting that other immunological parameters might be involved, such as a dysfunctional CD4 response or that they might have become QFNon-reactive due to the immunosuppression. In conclusion, around 80% of R+ patients with pretransplant CD8+IFNG+ response to CMV did not require antiviral treatment, although this percentage might be underestimated. Nevertheless, other strategies such as performing an additional CD8+IFNG+ response determination at posttransplant time might provide more reliable information regarding the patients who will be able to spontaneously clear the viremia.
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http://dx.doi.org/10.1016/j.antiviral.2018.05.006DOI Listing
July 2018

A 5-Year Prospective Multicenter Evaluation of Influenza Infection in Transplant Recipients.

Clin Infect Dis 2018 10;67(9):1322-1329

Transplant Infectious Diseases and Multi-Organ Transplant Program, University Health Network, Toronto, Ontario, Canada.

Background: Seasonal influenza infection may cause significant morbidity and mortality in transplant recipients. The purpose of this study was to assess the epidemiology of symptomatic influenza infection posttransplant and determine risk factors for severe disease.

Methods: Twenty centers in the United States, Canada, and Spain prospectively enrolled solid organ transplant (SOT) or hematopoietic stem cell transplant (HSCT) recipients with microbiologically confirmed influenza over 5 consecutive years (2010-2015). Demographics, microbiology data, and outcomes were collected. Serial nasopharyngeal swabs were collected at diagnosis and upto 28 days, and quantitative polymerase chain reaction for influenza A was performed.

Results: We enrolled 616 patients with confirmed influenza (477 SOT; 139 HSCT). Pneumonia at presentation was in 134 of 606 (22.1%) patients. Antiviral therapy was given to 94.1% for a median of 5 days (range, 1-42 days); 66.5% patients were hospitalized and 11.0% required intensive care unit (ICU) care. The receipt of vaccine in the same influenza season was associated with a decrease in disease severity as determined by the presence of pneumonia (odds ratio [OR], 0.34 [95% confidence interval {CI}, .21-.55], P < .001) and ICU admission (OR, 0.49 [95% CI, .26-.90], P = .023). Similarly, early antiviral treatment (within 48 hours) was associated with improved outcomes. In patients with influenza A, pneumonia, ICU admission, and not being immunized were also associated with higher viral loads at presentation (P = .018, P = .008, and P = .024, respectively).

Conclusions: Annual influenza vaccination and early antiviral therapy are associated with a significant reduction in influenza-associated morbidity, and should be emphasized as strategies to improve outcomes of transplant recipients.
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http://dx.doi.org/10.1093/cid/ciy294DOI Listing
October 2018

T2MR contributes to the very early diagnosis of complicated candidaemia. A prospective study.

J Antimicrob Chemother 2018 03;73(suppl_4):iv13-iv19

Clinical Microbiology and Infectious Diseases, Hospital General Universitario Gregorio Marañón, Madrid, Spain.

Objectives: Diagnosis of complicated candidaemia represents a challenge for clinicians since early clinical manifestations may be non-specific and difficult to identify, thus precluding an appropriate treatment.

Patients And Methods: This was a multicentre prospective study for predicting complicated episodes in patients with bloodstream infection caused by Candida species, while assessing the value of follow-up blood cultures (BCs) and the persistence of positive results for T2Candida MR (T2MR) and blood β-d-glucan (BDG) tests. Immediately after the first positive BC yielding Candida species, samples were obtained on days 0, +2, +4, +7 and +14, to simultaneously perform follow-up BC, T2MR and BDG. An episode of candidaemia was defined as 'complicated' when (i) it caused septic metastasis; and/or (ii) it was the cause of the patient's death.

Results: From January to June 2017, 30 patients were enrolled in the study. Of these, nine (30%) had complicated candidaemia. Values of persistently positive samples for the prediction of complicated episodes for BCs, T2MR and BDG, respectively, were as follows: sensitivity (44.4%, 100%, 100%); specificity (76.1%, 76.1%, 38.9%); positive predictive value (PPV) (44.4%, 64.2%, 40.9%) and negative predictive value (NPV) (76.1%, 100%, 100%). In multivariate analysis, having a positive T2MR within the first 5 days was associated with an almost 37-fold higher risk of developing complicated candidaemia.

Conclusions: The T2MR test performed in patients with proven candidaemia may be a better marker of complicated infection than follow-up BCs or BDG. It is possible that this test may change current clinical practice, influencing the length and type of antifungal therapy in this population.
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http://dx.doi.org/10.1093/jac/dky048DOI Listing
March 2018

T2Candida MR as a predictor of outcome in patients with suspected invasive candidiasis starting empirical antifungal treatment: a prospective pilot study.

J Antimicrob Chemother 2018 03;73(suppl_4):iv6-iv12

Clinical Microbiology and Infectious Diseases, Hospital General Universitario Gregorio Marañón, Madrid, Spain.

Objectives: We assessed the potential role of T2Candida MR (T2MR) and serological biomarkers [β-d-glucan (BDG) or Candida albicans germ tube antibodies (CAGTA)], alone or in combination with standard cultures, for identifying patients with suspected invasive candidiasis (IC), who may benefit from maintaining antifungal therapy.

Methods: Prospective observational multicentre study including all adult patients receiving empirical antifungal therapy for suspected IC, from January to June 2017. CAGTA, BDG and T2MR were determined at baseline and at +2 and +4 days after enrolment. Primary endpoint was the diagnostic value of CAGTA, BDG and T2MR, alone or in combination with standard culture, to predict diagnosis of IC and/or mortality in the first 7 days after starting antifungal therapy (poor outcome).

Results: Overall, 14/49 patients (28.6%) had a poor outcome (7 died within the first 7 days of antifungal therapy, whereas 7 ended with a diagnosis of IC). CAGTA [3/14 (21.4%) versus 8/35 (22.9%), P = 1] and BDG [8/14 (57.1%) versus 17/35 (48.6%), P = 0.75] results were similar in poor- and good-outcome patients. Conversely, a positive T2MR was associated with a higher risk of poor outcome [5/14 (35.7%) versus 0/35 (0.0%) P = 0.0001]. Specificity and positive predictive value of a positive T2MR for predicting poor outcome were both 100%, with a negative predictive value of 79.6%. After testing the combinations of biomarkers/standard cultures and T2MR/standard cultures, the combination of T2MR/standard cultures showed a high capacity to discriminate patients with poor outcome from those with good clinical evolution.

Conclusions: T2MR may be of significant utility to identify patients who may benefit from maintaining antifungal therapy.
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http://dx.doi.org/10.1093/jac/dky047DOI Listing
March 2018