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Isavuconazole has theoretical advantages over other mold-active triazoles for the treatment of invasive aspergillosis and mucormycosis after solid organ transplantation (SOT). The available clinical experience, nevertheless, is scarce.We performed a retrospective study including all adult SOT recipients with proven or probable invasive mold disease (IMD) that received isavuconazole for ≥24 h as first-line or salvage therapy at 10 Spanish centers between September 2017 and November 2021. The primary efficacy outcome was clinical response (complete or partial resolution of attributable symptoms and findings) by weeks 6 and 12. Safety outcomes included the rates of treatment-emergent adverse events and premature isavuconazole discontinuation.We included 81 SOT recipients that received isavuconazole for a median of 58.0 days because of invasive aspergillosis (n = 71) or mucormycosis (n = 10). Isavuconazole was used as first-line (72.8%) or salvage therapy due because of previous treatment-emergent toxicity (11.1%) or refractory IMD (7.4%). Combination therapy was common (37.0%), mainly with an echinocandin or liposomal amphotericin B. Clinical response by weeks 6 and 12 was achieved in 53.1% and 54.3% of patients, respectively, and was more likely when isavuconazole was administered as first-line single-agent therapy. At least 1 treatment-emergent adverse event occurred in 17.3% of patients, and 6.2% required premature discontinuation. Daily tacrolimus dose was reduced in two-thirds of patients by a median of 50.0%, although tacrolimus levels remained stable throughout the first month of therapy.Isavuconazole is a safe therapeutic option for IMD in SOT recipients, with efficacy comparable to other patient groups.

Background Infections caused by carbapenemase-producing Enterobacterales (CPE) are not well represented in pivotal trials with ceftazidime/avibactam. The best strategy for the treatment of these infections is unknown. Methods We conducted a multicentre retrospective observational study of patients who received ≥48 h of ceftazidime/avibactam or best available therapy (BAT) for documented CPE infections. The primary outcome was 30 day crude mortality. Secondary outcomes were 21 day clinical response and microbiological response. A multivariate logistic regression model was used to identify factors predictive of 30 day crude mortality. A propensity score to receive treatment with ceftazidime/avibactam was used as a covariate in the analysis. Results The cohort included 339 patients with CPE infections. Ceftazidime/avibactam treatment was used in 189 (55.8%) patients and 150 (44.2%) received BAT at a median of 2 days after diagnosis of infection. In multivariate analysis, ceftazidime/avibactam treatment was associated with survival (OR 0.41, 95% CI 0.20–0.80; P = 0.01), whereas INCREMENT-CPE scores of >7 points (OR 2.57, 95% CI 1.18–1.5.58; P = 0.01) and SOFA score (OR 1.20, 95% CI 1.08–1.34; P = 0.001) were associated with higher mortality. In patients with INCREMENT-CPE scores of >7 points, ceftazidime/avibactam treatment was associated with lower mortality compared with BAT (16/73, 21.9% versus 23/49, 46.9%; P = 0.004). Ceftazidime/avibactam was also an independent factor of 21 day clinical response (OR 2.43, 95% CI 1.16–5.12; P = 0.02) and microbiological eradication (OR 0.40, 95% CI 0.18–0.85; P = 0.02). Conclusions Ceftazidime/avibactam is an effective alternative for the treatment of CPE infections, especially in patients with INCREMENT-CPE scores of >7 points. A randomized controlled trial should confirm these findings.

Background Risk factors for nontuberculous mycobacteria (NTM) infections after solid organ transplant (SOT) are not well characterized. Here we aimed to describe these factors. Methods Retrospective, multinational, 1:2 matched case-control study that included SOT recipients ≥12 years old diagnosed with NTM infection from 1 January 2008 to 31 December 2018. Controls were matched on transplanted organ, NTM treatment center, and post-transplant survival greater than or equal to the time to NTM diagnosis. Logistic regression on matched pairs was used to assess associations between risk factors and NTM infections. Results Analyses included 85 cases and 169 controls (59% male, 88% White, median age at time of SOT of 54 years [interquartile range {IQR} 40–62]). NTM infection occurred in kidney (42%), lung (35%), heart and liver (11% each), and pancreas transplant recipients (1%). Median time from transplant to infection was 21.6 months (IQR 5.3–55.2). Most underlying comorbidities were evenly distributed between groups; however, cases were older at the time of NTM diagnosis, more frequently on systemic corticosteroids and had a lower lymphocyte count (all P < .05). In the multivariable model, older age at transplant (adjusted odds ratio [aOR] 1.04; 95 confidence interval [CI], 1.01–1.07), hospital admission within 90 days (aOR, 3.14; 95% CI, 1.41–6.98), receipt of antifungals (aOR, 5.35; 95% CI, 1.7–16.91), and lymphocyte-specific antibodies (aOR, 7.73; 95% CI, 1.07–56.14), were associated with NTM infection. Conclusions Risk of NTM infection in SOT recipients was associated with older age at SOT, prior hospital admission, receipt of antifungals or lymphocyte-specific antibodies. NTM infection should be considered in SOT patients with these risk factors.

[Background] This study describes the genotypic and phenotypic characterization of novel human cytomegalovirus (HCMV) genetic variants of a cohort of 94 clinically resistant HCMV patients., [Methods and results] Antiviral-resistant mutations were detected in the UL97, UL54, and UL56 target genes of 25 of 94 (26.6%) patients. The genotype-phenotype correlation study resolved the status of 5 uncharacterized UL54 deoxyribonucleic acid polymerase (G441S, A543V, F460S, R512C, A928T) and 2 UL56 terminase (F345L, P800L) mutations found in clinical isolates. A928T conferred high, triple resistance to ganciclovir, foscarnet, and cidofovir, and A543V had 10-fold reduced susceptibility to cidofovir. Viral growth assays showed G441S, A543V, F345L, and P800L impaired viral growth capacities compared with wild-type AD169 HCMV. Three-dimensional modeling predicted A543V and A928T phenotypes but not R512C, reinforcing the need for individual characterization of mutations by recombinant phenotyping., [Conclusions] Extending mutation databases is crucial to optimize treatments and to improve the assessment of patients with resistant/refractory HCMV infection., The research was carried out in the Hospital Clinic of Barcelona, Spain and was funded by “Fondo de Investigación en Salud (FIS) PI 17/0150 of the Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación del Gobierno de España”, the Agency for Health Technology Assessment, and “Ministerio de Economía y Competitividad”, by “Fundació La Marató” 201824 (21/267), by “Centro de Investigación Biomédica en Red” (CIBER) CB21/13/0081 and “Agencia de Gestión de Ayudas Universitarias y de Investigación” (AGAUR).

International audience; Spatial changes of fatty acids in the retina in response to different dietary n-3 formulations have never been explored, although a diet rich in EPA and DHA is recommended to protect the retina against the effects of aging. In this study, Wistar rats were fed for 8 weeks with balanced diet including either EPA-containing phospholipids, EPA-containing triglycerides, DHA-containing phospholipids, or DHA-containing triglycerides. Qualitative changes in fatty acid composition of plasma, erythrocytes and retina were evaluated by gas chromatography-flame ionization detector. Following the different dietary intakes, changes to the quantity and spatial organization of phosphatidylcholine (PC) and phosphatidylethanolamine (PE) species in retina were determined by liquid chromatography coupled to tandem mass spectrometry and MALDI (Matrix Assisted Laser Desorption Ionization) coupled to mass spectrometry imaging. The omega-3 content in the lipids of plasma and erythrocytes suggests that phospholipids as well as triglycerides are good omega-3 carriers for retina. However, a significant increase in DHA content in retina was observed, especially molecular species as di-DHA-containing PC and PE, as well as an increase in very long chain polyunsaturated fatty acids (VLC-PUFAs, more than 28 carbons) following phospholipid-EPA and triglyceride-DHA diets only. All supplemented diets triggered spatial organization changes of DHA in the photoreceptor layer around the optic nerve. Taken together, these findings suggest that dietary omega-3 supplementation can modify the content of fatty acids in the rat retina.

[Background] Antiviral prophylaxis is recommended in cytomegalovirus (CMV)-seropositive kidney transplant (KT) recipients receiving antithymocyte globulin (ATG) as induction. An alternative strategy of premature discontinuation of prophylaxis after CMV-specific cell-mediated immunity (CMV-CMI) recovery (immunoguided prevention) has not been studied. Our aim was to determine whether it is effective and safe to discontinue prophylaxis when CMV-CMI is detected and to continue with preemptive therapy., [Methods] In this open-label, noninferiority clinical trial, patients were randomized 1:1 to follow an immunoguided strategy, receiving prophylaxis until CMV-CMI recovery or to receive fixed-duration prophylaxis until day 90. After prophylaxis, preemptive therapy (valganciclovir 900 mg twice daily) was indicated in both arms until month 6. The primary and secondary outcomes were incidence of CMV disease and replication, respectively, within the first 12 months. Desirability of outcome ranking (DOOR) assessed 2 deleterious events (CMV disease/replication and neutropenia)., [Results] A total of 150 CMV-seropositive KT recipients were randomly assigned. There was no difference in the incidence of CMV disease (0% vs 2.7%; P = .149) and replication (17.1% vs 13.5%; log-rank test, P = .422) between both arms. Incidence of neutropenia was lower in the immunoguided arm (9.2% vs 37.8%; odds ratio, 6.0; P < .001). A total of 66.1% of patients in the immunoguided arm showed a better DOOR, indicating a greater likelihood of a better outcome., [Conclusions] Prophylaxis can be prematurely discontinued in CMV-seropositive KT patients receiving ATG when CMV-CMI is recovered since no significant increase in the incidence of CMV replication or disease is observed., This work was supported by the 2013–2016 National R&D&I Plan and the Carlos III Health Institute (grantPI15/00402 to J.T.C.). It also had the support of The Spanish Society of Nephrology (grant S.E.N. to C.F.), as well as support from the National R&D&I Plan 2013–2016 and the Carlos III Health Institute, General Sub-Directorate of Networks and Cooperative Research Centres, Ministry of Science and Innovation, Spanish Network for Research in Infectious Diseases (REIPI RD16/0016/000, RD16/0016/0003, RD16/0016/0007, RD16/0016/0008, RD16/0016/0009 and RD16/0016/0012), co-financed by the European Regional Development Fund “A way to achieve Europe,” Operational Programme Intelligent Growth 2014–2020; Spanish Network for Renal Disease Research (RedInRen, RD16/0009/0006, RD16/0009/0008, RD16/0009/0013, RD16/0009/0014, RD16/0009/0019, RD16/0009/0027, RD16/0009/0034); CIBERES (CB06/06/0058); the Spanish Group for the Study of Infection in Transplantation and the Immunosuppressed Host of the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC) and Spanish Clinical Research Network funded by the ISCIII-Subdirectorate General for the Evaluation and Promotion of Research through projects PT13/0002/0010-PT17/0017/0012 and PT13/0002/0014-PT17/0017/0032 integrated in the 2013–2016 National R&D&I Plan and by the National Plan for Scientific and Technical Research and Innovation (2017–2020) and co-financed by the European Regional Development Fund.

Objectives: (1) To describe the epidemiology of patient safety (PS) incidents registered in an electronic notification system in primary care (PC) health centres, (2) to define a risk map, and (3) to identify the critical areas where intervention is needed. Design: Descriptive analytical study of incidents reported from 1 January to 31 December 2018, on the TPSC Cloud™ platform (The Patient Safety Company) accessible from the corporate website (Intranet) of the regional public health service. Setting: 24 Catalan Institute of Health PC health centres of the Tarragona region (Spain). Participants: Professionals from the PC health centres and a Patient Safety Functional Unit. Measurements: Data obtained from records voluntarily submitted to an electronic, standardised and anonymised form. Data recorded: healthcare unit, notifier, type of incident, risk matrix, causal and contributing factors, preventability, level of resolution and improvement actions. Results: A total of 1544 reports were reviewed and 1129 PS incidents were analysed: 25.0% of incidents did not reach the patient, 66.5% reached the patient without causing harm, and 8.5% caused adverse events. Nurses provided half of the reports (48.5%), while doctors reported more adverse events (70.8%, p &lt, 0.01). Of the 96 adverse events, 46.9% only required observation, 34.4% caused temporary damage that required treatment, 13.5% required (or prolonged) hospitalization, and 5.2% caused severe permanent damage and/or a situation close to death. Notably, 99.2% were considered preventable. The main critical areas were: communication (27.8%), clinical-administrative management (25.1%), care delivery (23.5%) and medicines (18.4%), few incidents were related to diagnosis (3.6%). Conclusions: PS incident notification applications are adequate for reporting incidents and adverse events associated with healthcare. Approximately 75% and 10% of incidents reach the patient and cause some damage, respectively, and most cases are considered preventable. Adequate and strengthened risk management of critical areas is required to improve PS.

[Objective] To prove that 7-day courses of antibiotics for bloodstream infections caused by members of the Enterobacterales (eBSIs) allow a reduction in patients' exposure to antibiotics while achieving clinical outcomes similar to those of 14-day schemes., [Methods] A randomized trial was performed. Adult patients developing eBSI with appropriate source control were assigned to 7 or 14 days of treatment, and followed 28 days after treatment cessation; treatments could be resumed whenever necessary. The primary endpoint was days of treatment at the end of follow-up. Clinical outcomes included clinical cure, relapse of eBSI and relapse of fever. A superiority margin of 3 days was set for the primary endpoint, and a non-inferiority margin of 10% was set for clinical outcomes. Efficacy and safety were assessed together with a DOOR/RADAR (desirability of outcome ranking and response adjusted for duration of antibiotic risk) analysis., [Results] 248 patients were assigned to 7 (n = 119) or 14 (n = 129) days of treatment. In the intention-to-treat analysis, median days of treatment at the end of follow-up were 7 and 14 days (difference 7, 95%CI 7–7). The non-inferiority margin was also met for clinical outcomes, except for relapse of fever (–0.2%, 95%CI –10.4 to 10.1). The DOOR/RADAR showed that 7-day schemes had a 77.7% probability of achieving better results than 14-day treatments., [Conclusions] 7-day schemes allowed a reduction in antibiotic exposure of patients with eBSI while achieving outcomes similar to those of 14-day schemes. The possibility of relapsing fever in a limited number of patients, without relevance to final outcomes, may not be excluded, but was overcome by the benefits of shortening treatments., This work received technical support from the Spanish Network of Research in Infectious Diseases (REIPI) and the Spanish Clinical Research Network (SCReN) of the Instituto de Salud Carlos III, Ministerio de Economía y Competitividad, Spanish Government (PT13/0002/0010).

BACKGROUND The diagnosis of invasive aspergillosis (IA) can be problematic in solid organ transplantation (SOT). The prognosis greatly varies according to the type of transplant, and the impact of prophylaxis is not well defined. PATIENTS AND METHODS The Diaspersot cohort analyses the impact of IA in SOT in Spain during the last 10 years. Proven and probable/putative IA was included. RESULTS We analysed 126 cases of IA. The incidences of IA were as follows: 6.5%, 2.9%, 1.8% and 0.6% for lung, heart, liver and kidney transplantation, respectively. EORTC/MSG criteria confirmed only 49.7% of episodes. Tree-in-bud sign or ground-glass infiltrates were present in 56.3% of patients, while serum galactomannan (optical density index >0.5) was positive in 50.6%. A total of 41.3% received combined antifungal therapy. Overall mortality at 3 months was significantly lower (p

Current guidelines recommend against systematic screening for or treating asymptomatic bacteriuria (AB) among kidney transplant (KT) recipients, although the evidence regarding episodes occurring early after transplantation or in the presence of anatomical abnormalities is inconclusive. Oral fosfomycin may constitute a good option for the treatment of posttransplant AB, particularly due to the emergence of multidrug-resistant (MDR) uropathogens. Available clinical evidence supporting its use in this specific setting, however, remains scarce. We performed a retrospective study in 14 Spanish institutions from January 2005 to December 2017. Overall, 137 episodes of AB diagnosed in 133 KT recipients treated with oral fosfomycin (calcium and trometamol salts) with a test-of-cure urine culture within the first 30 days were included. Median time from transplantation to diagnosis was 3.1 months (interquartile range [IQR], 1.1 to 10.5). Most episodes (96.4% [132/137]) were caused by Gram-negative bacteria (GNB), and 56.9% (78/137) were categorized as MDR (extended‐spectrum β‐lactamase‐producing Enterobacterales [20.4%] and carbapenem‐resistant GNB [2.9%]). Rate of microbiological failure at month 1 was 40.1% (95% confidence interval [CI], 31.9% to 48.9%) for the whole cohort and 42.3% (95% CI, 31.2% to 54.0%) for episodes due to MDR pathogens. Previous urinary tract infection (odds ratio [OR], 2.42; 95% CI, 1.11 to 5.29; P value = 0.027) and use of fosfomycin as salvage therapy (OR, 8.31; 95% CI, 1.67 to 41.35; P value = 0.010) were predictors of microbiological failure. No severe treatment-related adverse events were detected. Oral fosfomycin appears to be a suitable and safe alternative for the treatment (if indicated) of AB after KT, including those episodes due to MDR uropathogens., This study was supported by Plan Nacional de I+D+i 2013‐2016 and Instituto de Salud Carlos III (ISCIII), Subdirección General de Redes y Centros de Investigación Cooperativa, Ministry of Science and Innovation, Spanish Network for Research in Infectious Diseases (REIPI RD16/0016), and Spanish Network for Research in Renal Diseases (REDInREN RD16/0009) and cofinanced by the European Development Regional Fund entitled A way to achieve Europe. M.F.-R. holds a research contract (Miguel Servet, CP18/00073), from the Spanish Ministry of Science and Innovation, ISCIII.

IntroductionInfections caused by carbapenemase-producing Enterobacterales are frequent and associated with high rates of mortality. Intestinal carriers are at increased risk of infection by these microorganisms. Decolonisation strategies with antibiotics have not obtained conclusive results. Faecal microbiota transplantation (FMT) could be an effective and safe strategy to decolonise intestinal carriers of KPC-producing Klebsiella pneumoniae (KPC-Kp) but this hypothesis needs evaluation in appropriate clinical trials.Methods and analysisThe KAPEDIS trial is a single-centre, randomised, double-blind, placebo-controlled, phase 2, superiority clinical trial of FMT for eradication of intestinal colonisation by KPC-Kp. One hundred and twenty patients with rectal colonisation by KPC-Kp will be randomised 1:1 to receive encapsulated lyophilised FMT or placebo. The primary outcome is KPC-Kp eradication at 30 days. Secondary outcomes are: (1) frequency of adverse events; (2) changes in KPC-Kp relative load within the intestinal microbiota at 7, 30 and 90 days, estimated by real-time quantitative PCR analysis of rectal swab samples and (3) rates of persistent eradication, KPC-Kp infection and crude mortality at 90 days. Participants will be monitored for adverse effects throughout the intervention.Ethics and disseminationEthical approval was obtained from Reina Sofía University Hospital Institutional Review Board (approval reference number: 2019-003808-13). Trial results will be published in peer-reviewed journals and disseminated at national and international conferences.Trial registration numberNCT04760665.

Resumen La tuberculosis (TB) es una de las infecciones mas importantes en pacientes inmunodeprimidos debido a su elevada frecuencia y alta morbimortalidad. La TB es la principal causa de muerte entre pacientes infectados por VIH. El diagnostico y tratamiento precoz de la infeccion tuberculosa latente es clave para evitar su progresion a enfermedad. Del mismo modo, el diagnostico precoz de la TB es clave para mejorar el pronostico de los pacientes y evitar su transmision. La expresion clinica de la TB en pacientes inmunodeprimidos esta condicionada por el grado de inmunodepresion de los pacientes. Es importante tener presente esta peculiaridad para no retrasar el diagnostico de sospecha de TB. Las bases del tratamiento de la TB en inmunodeprimidos son las mismas que en la poblacion general. Sus peculiaridades derivan principalmente de las interacciones farmacologicas. Examinamos las bases de diagnostico y tratamiento de la TB y la infeccion tuberculosa latente en pacientes inmunodeprimidos.

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. This work was supported by GESITRA/SEIMC, ONT and‘Plan Nacional de I+D+I’ and Instituto de Salud Carlos III(Fondo de Investigaciones Sanitarias 12/02269 and ProyectoIntegrado de Excelencia 13/00045), Subdirección General de Redesy Centros de Investigacion Cooperativa, Spanish Ministry of Econ-omy and Competitiveness, Spanish Network for Research inInfectious Diseases (REIPI RD16/0016), co-financed by the Euro-pean Development Regional Fund A way to achieve Europe.

Way of life changes such as high consumption of processed foods rich in fat and sugar and sedentary lifestyle are associated with the increasing prevalence of metabolic syndrome (MetS) that affects about 35% in the American population. MetS is the main risk factor for diabetes mellitus, which is associated with vascular changes in the retina. However, the early consequences of MetS in the retina are not well described. We therefore aimed at characterizing the early effects of a high fructose and high fat diet (HFHF) on the function and structure of the rat retina, and evaluate the associations with metabolic changes. Brown Norway rats of 6 weeks of age were fed for 8 days, 5 weeks or 13 weeks with HFHF diet, or a standard chow. After only 4 weeks of this diet, rats exhibited a reduction in cone photoreceptor sensitivity to light. Moreover, we observed that MetS significantly exacerbated laser-induced choroidal neovascularization by 72% and 67% 2 weeks and 3 weeks post laser treatment, respectively. These retinal abnormalities were associated with deregulation of glucose metabolism but not lipid metabolism. These data showed retinal modifications in HFHF-induced MetS in the rat, at very early stage of the disease.

Cytomegalovirus; Immuno-guided prophylaxis; Lung transplantation Citomegalovirus; Profilaxis inmunoguiada; Trasplante de pulmón Citomegalovirus; Profilaxi immuno-guiada; Trasplantament de pulmó INTRODUCTION: Prolonged use of antivirals to prevent the development of cytomegalovirus (CMV) disease in lung transplant patients has been shown to have significant side effects, for which alternatives are being sought to reduce their use. The monitoring of cell immunity against CMV could be an alternative as it has shown to be useful in identifying transplant patients at low risk of infection, who could benefit from shorter prophylaxis. The aim of the CYTOCOR study is to demonstrate that the combination of a reduced prophylaxis strategy with subsequent CMV-specific immunological monitoring would allow CMV infection to be controlled in lung transplant patients as effectively as the usual strategy (prophylaxis followed by pre-emptive therapy), while reducing the side effects of antivirals due to the shorter duration of prophylaxis. METHODS AND ANALYSIS: Phase III randomised, open, multicentre, parallel, non-inferiority clinical trial to study the efficacy and safety of the combination of a prophylaxis strategy up to month +3 post-transplant followed by immuno-guided prophylaxis using the QuantiFERON-CMV technique up to month +12 post-transplant to prevent CMV disease in CMV-seropositive lung transplant recipients. This strategy will be compared with a combination of a usual prophylaxis strategy up to month +6 post-transplant followed by pre-emptive therapy up to month +12. To study the incidence of CMV disease, patients will be followed up to 18 months post-transplantation. A total of 150 patients are expected to be recruited for the study. ETHICS AND PUBLIC DISSEMINATION: The clinical trial has been approved by the Research Ethics Committees and authorised by the Spanish Agency of Medicines and Medical Devices (AEMPS).If the hypothesis of this clinical trial is verified, the dissemination of the results could change clinical practice by increasing knowledge about the safety and efficacy of discontinuing valganciclovir prophylaxis in lung transplant recipients. We would like to acknowledge the support of the Spanish Network for Research in Infectious Disease (REIPI, RD16/0016), the Group for the Study of Infections in Transplant Recipients (GESITRA) of the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC) and SCReN (Spanish Clinical Research Network) funded by the ISCIII-Sub-Directorate General for Research Assessment and Promotion through project PT13/0002/0010-PT17/0017/0012 and PT17/0017/0032.

BACKGROUND There is little evidence of the impact of antimicrobial stewardship programmes on antimicrobial resistance. OBJECTIVES To study the efficacy and safety of a package of educational and interventional measures to optimize linezolid use and its impact on bacterial resistance. METHODS A quasi-experimental study was designed and carried out before and after implementation of a stewardship programme in hospitalized patients with Gram-positive infections treated with linezolid. RESULTS The intervention reduced linezolid consumption by 76%. The risk of linezolid-resistant CoNS isolates (OR = 0.37; 95% CI = 0.27-0.49; P

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.

Urinary tract infections (UTI) are one of the most common infections in solid organ transplant (SOT) recipients. A systematic review was performed to assess the management of UTI in SOT recipients. Recommendations are provided on the management of asymptomatic bacteriuria, and prophylaxis and treatment of UTI in SOT recipients. The diagnostic-therapeutic management of recurrent UTI and the role of infection in kidney graft rejection or dysfunction are reviewed. Finally, recommendations on antimicrobials and immunosuppressant interactions are also included.

The orbitofrontal cortex (OFC) is known to play a crucial role in learning the consequences of specific events. However, the contribution of OFC thalamic inputs to these processes is largely unknown. Using a tract-tracing approach, we first demonstrated that the submedius nucleus (Sub) shares extensive reciprocal connections with the OFC. We then compared the effects of excitotoxic lesions of the Sub or the OFC on the ability of rats to use outcome identity to direct responding. We found that neither OFC nor Sub lesions interfered with the basic differential outcomes effect. However, more specific tests revealed that OFC rats, but not Sub rats, were disproportionally relying on the outcome, rather than on the discriminative stimulus, to guide behavior, which is consistent with the view that the OFC integrates information about predictive cues. In subsequent experiments using a Pavlovian contingency degradation procedure, we found that both OFC and Sub lesions produced a severe deficit in the ability to update Pavlovian associations. Altogether, the submedius therefore appears as a functionally relevant thalamic component in a circuit dedicated to the integration of predictive cues to guide behavior, previously conceived as essentially dependent on orbitofrontal functions.SIGNIFICANCE STATEMENTIn the present study, we identify a largely unknown thalamic region, the submedius nucleus, as a new functionally relevant component in a circuit supporting the flexible use of predictive cues. Such abilities were previously conceived as largely dependent on the orbitofrontal cortex. Interestingly, this echoes recent findings in the field showing, in research involving an instrumental setup, an additional involvement of another thalamic nuclei, the parafascicular nucleus, when correct responding requires an element of flexibility (Bradfield et al., 2013a). Therefore, the present contribution supports the emerging view that limbic thalamic nuclei may contribute critically to adaptive responding when an element of flexibility is required after the establishment of initial learning.

Tuberculosis (TB) is one of the most significant infections in immunosuppressed patients due to its high frequency and high morbidity and mortality. TB is the leading cause of death among HIV-infected patients. The diagnosis and early treatment of latent tuberculosis infection is vital to preventing it progression to disease. Similarly, the early diagnosis of TB is key to improving the prognosis of patients and preventing its transmission. The clinical expression of TB in immunosuppressed patients is conditioned by the patient's degree of immunosuppression. It is important to keep this peculiarity in mind so as not to delay the diagnosis of suspected TB. TB treatment is basically the same in immunosuppressed patients as in the general population and any differences mainly derive from pharmacological interactions. We examined the diagnosis and treatment of TB and latent tuberculosis infection in immunosuppressed patients.

Solid organ transplant (SOT) recipients are especially at risk of developing infections by multidrug resistant (MDR) Gram-negative bacilli (GNB), as they are frequently exposed to antibiotics and the healthcare setting, and are regulary subject to invasive procedures. Nevertheless, no recommendations concerning prevention and treatment are available. A panel of experts revised the available evidence; this document summarizes their recommendations: (1) it is important to characterize the isolate´s phenotypic and genotypic resistance profile; (2) overall, donor colonization should not constitute a contraindication to transplantation, although active infected kidney and lung grafts should be avoided; (3) recipient colonization is associated with an increased risk of infection, but is not a contraindication to transplantation; (4) different surgical prophylaxis regimens are not recommended for patients colonized with carbapenem-resistant GNB; (5) timely detection of carriers, contact isolation precautions, hand hygiene compliance and antibiotic control policies are important preventive measures; (6) there is not sufficient data to recommend intestinal decolonization; (7) colonized lung transplant recipients could benefit from prophylactic inhaled antibiotics, specially for Pseudomonas aeruginosa; (8) colonized SOT recipients should receive an empirical treatment which includes active antibiotics, and directed therapy should be adjusted according to susceptibility study results and the severity of the infection. J.T.S. holds a research contract from the Fundación para la Formación e Investigación de los Profesionales de la Salud de Extremadura (FundeSalud), Instituto de Salud Carlos III. M.F.R. holds a clinical research contract “Juan Rodés” (JR14/00036) from the Spanish Ministry of Economy and Competitiveness, Instituto de Salud Carlos III.

Objective Previous studies on monitoring of post-transplant cytomegalovirus (CMV)-specific cell-mediated immunity (CMI) are limited by single-centre designs and disparate risk categories. We aimed to assess the clinical value of a regular monitoring strategy in a large multicentre cohort of intermediate-risk kidney transplant (KT) recipients. Methods We recruited 124 CMV-seropositive KT recipients with no T-cell-depleting induction pre-emptively managed at four Spanish institutions. CMV-specific interferon-γ-producing CD4+ and CD8+ T cells were counted through the first post-transplant year by intracellular cytokine staining after stimulation with pp65 and immediate early-1 peptides (mean of six measurements per patient). The primary outcome was the occurrence of any CMV event (asymptomatic infection and/or disease). Optimal cut-off values for CMV-specific T cells were calculated at baseline and day 15. Results Twelve-month cumulative incidence of CMV infection and/or disease was 47.6%. Patients with pre-transplant CMV-specific CD8+ T-cell count Conclusions Monitoring for CMV-specific CMI in intermediate-risk KT recipients must be regular to reflect dynamic changes in overall immunosuppression and individual susceptibility. The early assessment at post-transplant day 15 remains particularly informative.

The control of Plum pox virus (PPV), the most important viral disease that affects stone fruit trees, requires the use of reliable detection methods. The effectiveness of spot real-time reverse transcriptase polymerase chain reaction (RT-PCR) for the detection of PPV in samples collected from nursery blocks was compared with a validated PPV detection technique, the double antibody sandwich indirect enzyme-linked immunosorbent assay (DASI-ELISA) using the PPV-specific monoclonal antibody 5B-IVIA/AMR. In total, 5047 nursery plants were analysed by both techniques. The agreement between the techniques was almost perfect (Cohen’s kappa index of 0·88 ± 0·01). The diagnostic parameters (sensitivity, specificity and likelihood ratios) of both techniques were simultaneously evaluated in 2473 nursery plants by latent class models using maximum likelihood functions and a Bayesian approach. The sensitivity and specificity of both techniques did not vary according to the latent model applied. Spot real-time RT-PCR was more sensitive while DASI-ELISA was more specific for PPV detection. In addition, the findings demonstrate that latent class models are a flexible and potent statistical method to estimate the accuracy of diagnostic tests for plant pathology.

Resumen Introduccion La candidemia es una infeccion nosocomial con elevada mortalidad. Los cambios clinicos y microbiologicos descritos en otras areas y las novedades terapeuticas de los ultimos anos hacen preciso conocer si la epidemiologia clinica de las candidemias en nuestro medio ha cambiado. Material y metodos Estudio prospectivo, multicentrico y observacional de todos los episodios de candidemia en pacientes adultos atendidos entre el 1 octubre 2005 y el 30 septiembre 2006 en 17 hospitales de Andalucia. Resultados El numero total de episodios fue de 220, la incidencia de 0,58 episodios/por cada 1.000 altas. Candida albicans fue la etiologia mas frecuente (53%). El 89% de las cepas fueron sensibles a fluconazol. La sepsis fue la presentacion clinica mas frecuente (65,7%). El tratamiento empirico fue inapropiado en el 38,7%. La mortalidad global fue del 40%. Se analizaron los factores pronosticos a los 30 dias. En el analisis univariante la mortalidad se asocio con: edad > 60 anos, candidemia de foco desconocido, indice de Pitt ≥ 2, APACHE elevado, shock septico al diagnostico, persistencia del segundo hemocultivo positivo, tratamiento empirico inapropiado, no retirada del cateter venoso central y aislamiento de una especie diferente a C. parapsilosis entre otros. El analisis multivariante identifico como variables independientes de mal pronostico, la edad > 60 anos, un indice de Pitt ≥ 2, y el tratamiento empirico inapropiado y como factor protector la etiologia C. parapsilosis. Conclusiones La epidemiologia clinica de las candidemias en nuestra region es similar a la descrita en otras areas y el tratamiento empirico inapropiado es el unico factor independiente de mal pronostico que se puede mejorar.

Background It is necessary to determine the incidence and risk factors for tuberculosis (TB), as well as strategies to assess and treat latent tuberculosis infection (LTBI) in lung transplant recipients. Methods A retrospective cohort study of 398 lung transplant recipients was performed. Episodes of TB were studied and the incidence rate was calculated. Logistic regression analysis was used to analyze specific variables as potential risk factors for TB. Results Median follow-up was 558 days (range 1-6636). Six cases (1.5%) of TB were documented in 398 transplant patients. The incidence density of TB was 406.3 cases/10(5) patient-years (95% confidence interval [CI] 164.7-845), which is higher than in the general population (13.10 cases/10(5) person-years). All cases occurred in the period 1993-2006, when the tuberculin skin test (TST) and treatment of LTBI in positive TST patients were not part of the protocol. Pretransplant computed tomography (CT) showed residual lesions in 50% of patients who developed TB, although the TST was negative and the chest radiograph was inconclusive. Multivariate analysis identified the presence of residual lesions in the pretransplant chest CT (odds ratio [OR] 11.5, 95% CI 1.9-69.1, P = 0.008), use of azathioprine (OR 10.6, 95% CI 1.1-99.1, P = 0.038), and use of everolimus (OR 6.7, 95% CI 1.1-39.8, P = 0.036) as independent risk factors for TB. Conclusions Residual lesions in the pretransplant chest CTs and the use of azathioprine and mTOR inhibitors are associated with the risk of TB.

Preventing influenza infection early after transplantation is essential, given the disease's high mortality. A multicentre prospective cohort study in adult solid organ transplant recipients (SOTR) receiving the influenza vaccine during four consecutive influenza seasons (2009–2013) was performed to assess the immunogenicity and safety of influenza vaccination in SOTR before and 6 months after transplantation. A total of 798 SOTR, 130 of them vaccinated within 6 months of transplantation and 668 of them vaccinated more than 6 months since transplantation. Seroprotection was similar in both groups: 73.1% vs. 76.5% for A/(H1N1)pdm (p 0.49), 67.5% vs. 74.1% for A/H3N2 (p 0.17) and 84.2% vs. 85.2% for influenza B (p 0.80), respectively. Geometric mean titres after vaccination did not differ among groups: 117.32 (95% confidence interval (CI) 81.52, 168.83) vs. 87.43 (95% CI 72.87, 104.91) for A/(H1N1)pdm, 120.45 (95% CI 82.17, 176.57) vs. 97.86 (95% CI 81.34, 117.44) for A/H3N2 and 143.32 (95% CI 103.46, 198.53) vs. 145.54 (95% CI 122.35, 174.24) for influenza B, respectively. After adjusting for confounding factors, time since transplantation was not associated with response to vaccination. No cases of rejection or severe adverse events were detected in patients vaccinated within the first 6 months after transplantation. In conclusion, influenza vaccination within the first 6 months after transplantation is as safe and immunogenic as vaccination thereafter. Thus, administration of the influenza vaccine can be recommended as soon as 1 month after transplantation.

Solid organ transplant may be the only therapeutic alternative in some HIV-infected patients. Experience in North America and Europe during the last five years shows that survival at three years after an organ transplant is similar to that observed in HIV-negative patients. The criteria agreed upon to select HIV patients for transplant are: no opportunistic infections (except tuberculosis, oesophageal candidiasis or P. jiroveci -previously carinii- pneumonia), CD4 lymphocyte count above 200 cells/.L (100 cells/.L in the case of liver transplant) and an HIV viral load which is undetectable or suppressible with antiretroviral therapy. Another criterion is a two-year abstinence from heroin and cocaine, although the patient may be in a methadone programme. The main problems in the post-transplant period are pharmacokinetic and pharmacodynamic interactions between antiretorivirals and immunosuppressors, rejection and the management of relapse of HCV infection, which is one of the main causes of post-liver transplant mortality. Up to now, experience with pegylated interferon and ribavirin is scarce in this population. The English version of the manuscript is available at http://www.gesidaseimc.com.

A multicenter, comparative study was performed to determine the epidemiological, clinical, and prognostic differences between the diseases caused by Mycobacterium tuberculosis and Mycobacterium kansasii in human immunodeficiency virus (HIV)-infected patients. From 1 January 1995 through 31 December 1999, 25 HIV-infected patients received diagnoses of M. kansasii infection, and another 75 were selected as control subjects from among patients who had M. tuberculosis infection. Variables associated with M. tuberculosis disease in the multivariate analysis were previous intravenous drug use (odds ratio [OR], 8; 95% confidence interval [CI], 1.5-41.4) and interstitial radiologic pattern (OR, 12.7; 95% CI, 1.7-94.3). Variables associated with M. kansasii were previous diagnosis of acquired immunodeficiency syndrome (OR, 15.8; 95% CI, 4.2-59.6) and concomitant opportunistic infections (OR, 14.2; 95% CI, 2-105.7). Clinical and radiologic features were similar for both groups, but epidemiological characteristics and prognosis were different. M. kansasii disease was associated more closely with level of immunosuppression and progression of HIV infection than was disease caused by M. tuberculosis.

Background. It is necessary to develop a safe alternative to isoniazid for tuberculosis prophylaxis in liver trans-plant recipients. This study was designed to investigate the efficacy and safety of levofloxacin.Methods. An open-label, prospective, multicenter, randomized study was conducted to compare the efficacyand safety of levofloxacin (500 mg q24h for 9 months) initiated in patients awaiting liver transplantation and iso-niazid (300 mg q24h for 9 months) initiated post-transplant when liver function was stabilized. Efficacy was mea-sured by tuberculosis incidence at 18 months after transplantation. All adverse events related to the medication wererecorded.Results. CONSORT guidelines were followed in order to present the results. The safety committee suspendedthe study through a safety analysis when 64 patients had been included (31 in the isoniazid arm and 33 in the levo-floxacinarm).Thereasonforsuspensionwasanunexpectedincidenceofseveretenosynovitisinthelevofloxacinarm(18.2%). Although the clinical coursewas favorable in all cases, tenosynovitis persisted for 7 weeks in some patients.No patients treated with isoniazid, developed tenosynovitis. Only 32.2% of patients randomized to isoniazid (10/31)and 54.5% of patients randomized to levofloxacin (18/33, P=.094) completed prophylaxis. No patient developedtuberculosis during the study follow-up (median 270 days).Conclusions. Levofloxacin prophylaxis of tuberculosis in liver transplant candidates is associated with a highincidence of tenosynovitis that limits its potential utility.Keywords. tuberculosis; levofloxacin; tenosynovitis; investigator-driven clinical trial.Less than 30% of liver transplant recipients with a pos-itivetuberculinpurifiedproteinderivate(PPD)skintestcurrently receive prophylaxis with isoniazid because ofits potential hepatotoxicity [1–3],which can destabilizechronic liver diseasewhen used in the pretransplant pe-riod. For this reason some experts recommend that iso-niazid prophylaxis should not be initiated until aftertransplantation when liver function is stable [1–3].However, the prophylaxis with isoniazid is frequentlynever initiated or discontinued due to the elevation oftransaminase levels. In fact, some experts believe that,in this scenario, the risks of using isoniazid outweighits potential benefits [4]. Other alternatives [5, 6]arenot free of hepatotoxicity [2,7–11].