Efficacy and Safety of Oral Fosfomycin for Asymptomatic Bacteriuria in Kidney Transplant Recipients: Results from a Spanish Multicenter Cohort

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

Essential topics for the regulatory consideration of phages as clinically valuable therapeutic agents: A perspective from Spain

This article belongs to the Special Issue Bacteriophages-Based Technologies for a One Health Society: Applications in Clinical, Veterinary, and Industrial Settings.Antibiotic resistance is one of the major challenges that humankind shall face in the short term. (Bacterio)phage therapy is a valuable therapeutic alternative to antibiotics and, although the concept is almost as old as the discovery of phages, its wide application was hindered in the West by the discovery and development of antibiotics in the mid-twentieth century. However, research on phage therapy is currently experiencing a renaissance due to the antimicrobial resistance problem. Some countries are already adopting new ad hoc regulations to favor the short-term implantation of phage therapy in clinical practice. In this regard, the Phage Therapy Work Group from FAGOMA (Spanish Network of Bacteriophages and Transducing Elements) recently contacted the Spanish Drugs and Medical Devices Agency (AEMPS) to promote the regulation of phage therapy in Spain. As a result, FAGOMA was asked to provide a general view on key issues regarding phage therapy legislation. This review comes as the culmination of the FAGOMA initiative and aims at appropriately informing the regulatory debate on phage therapy.This work was supported by Grant RED2018-102589-T funded by MCIN/AEI/10.13039/501100011033. R.V. and D.G. were supported by the Research Foundation–Flanders (FWO) under grant [G066919N]. Pe. G. and R.V. were supported by the Spanish Ministry of Science and Innovation (Grant number SAF2017-88664-R), with additional funding provided by the Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES), an initiative of the Instituto de Salud Carlos III. P.D.-C. was financially supported by a Ramón y Cajal contract RYC2019-028015-I and project PID2020-112835RA-I00 funded by MCIN/AEI/10.13039/501100011033, ESF Invest in your future, project SEJIGENT/2021/014, funded by Conselleria d’Innovació, Universitats, Ciència i Societat Digital (Generalitat Valenciana), and project AP2020-27 funded by VLC-Biomed (UV-La Fe 2020 Programa Acciones Preparatorias). M.M. was supported by project PID2020-113355GB-I00 of Spanish Ministry of Science and Innovation /Agencia Estatal de Investigación (AEI)/European regional fund (ERF). M.Á.T.-M. was supported by Spanish Ministry of Science and Innovation (Grant number SAF2017- 82251-R).Peer reviewe

Hemodynamic performance of different stent strategies for coronary bifurcations. Evaluation with a mathematical model

Purpose: Best percutaneous treatment strategy for lesions in coronary bifurcations is an ongoing subject of debate. There is limited data that analyses the effect of the different bifurcation strategies on coronary flow. Our aim is to evaluate the influence of different bifurcation stenting strategies on hemodynamic parameters, both in the main vessel (MV) and side branch (SB)

Efficacy and Safety of Oral Fosfomycin for Asymptomatic Bacteriuria in Kidney Transplant Recipients: Results from a Spanish Multicenter Cohort

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 ??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.ACKNOWLEDGMENTS 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. Funding sources were not involved in the study design and conduction, data analysis, or manuscript preparation

Alterations in Circulating Monocytes Predict COVID-19 Severity and Include Chromatin Modifications Still Detectable Six Months after Recovery

This study was supported by the Instituto de Salud Carlos III, Spanish Ministry of Science and Innovation (COVID-19 research call COV20/00181)—co-financed by the European Development Regional Fund “A way to achieve Europe” and by Consejería de Sanidad de la Comunidad de Madrid (CÍVICO study 2020/0082). R.L.G. and O.C.M. hold a research contract “Rio Hortega” (CM19/00120 and CM19/00092, respectively) from the Instituto de Salud Carlos III, Spanish Ministry of Science and Innovation. MCL holds a predoctoral fellowship (FPU19/06393) from the Spanish Ministry of Science and Innovation.An early analysis of circulating monocytes may be critical for predicting COVID-19 course and its sequelae. In 131 untreated, acute COVID-19 patients at emergency room arrival, monocytes showed decreased surface molecule expression, including low HLA-DR, in association with an inflammatory cytokine status and limited anti-SARS-CoV-2-specific T cell response. Most of these alterations had normalized in post-COVID-19 patients 6 months after discharge. Acute COVID-19 monocytes transcriptome showed upregulation of anti-inflammatory tissue repair genes such as BCL6, AREG and IL-10 and increased accessibility of chromatin. Some of these transcriptomic and epigenetic features still remained in post-COVID-19 monocytes. Importantly, a poorer expression of surface molecules and low IRF1 gene transcription in circulating monocytes at admission defined a COVID-19 patient group with impaired SARS-CoV-2-specific T cell response and increased risk of requiring intensive care or dying. An early analysis of monocytes may be useful for COVID-19 patient stratification and for designing innate immunity-focused therapies.Depto. de MedicinaFac. de MedicinaTRUEUnión EuropeaMinisterio de Ciencia e Innovación (España)Comunidad de MadridInstituto de Salud Carlos IIIpu

Real-world experience with bezlotoxumab for prevention of recurrence of Clostridioides difficile infection

Bezlotoxumab is marketed for the prevention of recurrent Clostridioides difficile infection (rCDI). Its high cost could be determining its prescription to a different population than that represented in clinical trials. The objective of the study was to verify the effectiveness and safety of bezlotoxumab in preventing rCDI and to investigate factors related to bezlotoxumab failure in the real world. A retrospective, multicentre cohort study of patients treated with bezlotoxumab in Spain was conducted. We compared the characteristics of cohort patients with those of patients treated with bezlotoxumab in the pivotal MODIFY trials. We assessed recurrence rates 12 weeks after completion of treatment against C. difficile, and we analysed the factors associated with bezlotoxumab failure. Ninety-one patients were included in the study. The cohort presented with more risk factors for rCDI than the patients included in the MODIFY trials. Thirteen (14.2%) developed rCDI at 12 weeks of follow-up, and rCDI rates were numerically higher in patients with two or more previous episodes (25%) than in those who had fewer than two previous episodes of C. difficile infection (CDI) (10.4%); p = 0.09. There were no adverse effects attributable to bezlotoxumab. Despite being used in a more compromised population than that represented in clinical trials, we confirm the effectiveness of bezlotoxumab for the prevention of rCDI

Longitudinal dynamics of SARS-CoV-2-specific cellular and humoral immunity after natural infection or BNT162b2 vaccination

The timing of the development of specific adaptive immunity after natural SARS-CoV-2 infection, and its relevance in clinical outcome, has not been characterized in depth. Description of the long-term maintenance of both cellular and humoral responses elicited by real-world anti-SARS-CoV-2 vaccination is still scarce. Here we aimed to understand the development of optimal protective responses after SARS-CoV-2 infection and vaccination. We performed an early, longitudinal study of S1-, M- and N-specific IFN-γ and IL-2 T cell immunity and anti-S total and neutralizing antibodies in 88 mild, moderate or severe acute COVID-19 patients. Moreover, SARS-CoV-2-specific adaptive immunity was also analysed in 234 COVID-19 recovered subjects, 28 uninfected BNT162b2-vaccinees and 30 uninfected healthy controls. Upon natural infection, cellular and humoral responses were early and coordinated in mild patients, while weak and inconsistent in severe patients. The S1-specific cellular response measured at hospital arrival was an independent predictive factor against severity. In COVID-19 recovered patients, four to seven months post-infection, cellular immunity was maintained but antibodies and neutralization capacity declined. Finally, a robust Th1-driven immune response was developed in uninfected BNT162b2-vaccinees. Three months post-vaccination, the cellular response was comparable, while the humoral response was consistently stronger, to that measured in COVID-19 recovered patients. Thus, measurement of both humoral and cellular responses provides information on prognosis and protection from infection, which may add value for individual and public health recommendations

Isavuconazole for the Treatment of Invasive Mold Disease in Solid Organ Transplant Recipients: A Multicenter Study on Efficacy and Safety in Real-life Clinical Practice

[Background] 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.[Methods] 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.[Results] 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.[Conclusions] Isavuconazole is a safe therapeutic option for IMD in SOT recipients, with efficacy comparable to other patient groups.Peer reviewe

Efficacy and Safety of Oral Fosfomycin for Asymptomatic Bacteriuria in Kidney Transplant Recipients: Results from a Spanish Multicenter Cohort

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.Peer reviewe

Long-Term Follow-Up of Patients Diagnosed with COVID-19-Associated Pulmonary Aspergillosis (CAPA)

COVID-19-associated pulmonary aspergillosis (CAPA) have been documented during the COVID-19 pandemic. The vast majority of these patients do not meet the classic EORTC/MSGERC criteria for invasive pulmonary aspergillosis. The question arises as to whether there may have been an over-diagnosis of this disease. Here we review our experience and analyze the evolution of 27 patients who were diagnosed with CAPA during hospital admission. Surviving patients were followed-up for a mean time of 15 months (SD 3.78) by a group of experts and clinical records of diseased patients were reviewed. After expert evaluation and follow-up, 10 patients were finally assumed as CAPA according to expert opinion. These cases represent 40% of the initially CAPA assumed cases. Our data suggest the need to reconsider actual diagnosis criteria for CAPA what could drive to better identification of these patients