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Introduction: SARS-CoV-2 is a novel virus that causes coronavirus disease-19 (COVID-19). Antiviral and immunomodulatory agents have been proposed as potential treatments. Azithromycin exhibits both properties and therefore may play a role. Areas covered: This article reviews the pharmacology, pharmacokinetics, clinical efficacy, and safety of azithromycin in viral infections, with emphasis on COVID-19. A literature search of PUBMED was conducted on May 30th and updated on July 28th. Expert opinion: Azithromycin presents in vitro activity against SARS-CoV-2 and could act in different points of the viral cycle. Its immunomodulatory properties include the ability to downregulate cytokine production, maintain epithelial cell integrity or prevent lung fibrosis. Azithromycin use was associated with a reduction in mortality and ventilation days in other viral infections. These properties could be beneficial throughout the COVID-19. However, the evidence of its use is scarce and of low quality. Azithromycin has been assessed in retrospective observational studies mainly in combination with hydroxychloroquine, which has shown to provide no benefit. This macrolide presents a well-known safety profile. Upcoming clinical trials will determine the role of azithromycin in the COVID-19 (including the stage of the disease where it offers the greatest benefits and the effect of its combination with other drugs).

Introduction Aspergillus may cause different types of lung infections: invasive, chronic pulmonary or allergic bronchopulmonary aspergillosis. Pharmacological management with antifungals poses as a challenge. Patients diagnosed with pulmonary aspergillosis are complex, as well as the problems associated with antifungal agents. Areas covered This article reviews the pharmacology of antifungal agents in development and currently used to treat pulmonary aspergillosis, including the mechanisms of action, pharmacokinetics, pharmacodynamics, dosing, therapeutic drug monitoring and safety. Recommendations to manage situations that arise in daily clinical practice are provided. A literature search of PubMed was conducted on November 15th, 2020 and updated on March 30th, 2021. Expert opinion Recent and relevant developments in the treatment of pulmonary aspergillosis have taken place. Novel antifungals with new mechanisms of action that extend antifungal spectrum and improve pharmacokinetic-related aspects, drug-drug interactions and safety are under current study. For those antifungals already marketed, new data related to pharmacokinetics, pharmacodynamics, dose adjustments in special situations, therapeutic drug monitoring and safety are available. To maximize efficacy and reduce the risk of associated toxicities, it is essential to choose the most appropriate antifungal; optimize its dose, interval, route of administration and length of treatment; and prevent side effects.

Biomarcadores; Disfunción endotelial; Células progenitoras Biomarcadors; Disfunció endotelial; Cèl·lules progenitores Biomarkers; Endothelial dysfunction; Progenitor cells Background: Endothelial dysfunction is central to PAH. In this study, we simultaneously analysed circulating levels of endothelial microvesicles (EMVs) and progenitor cells (PCs) in PAH and in controls, as biomarkers of pulmonary endothelial integrity and evaluated differences among PAH subtypes and as a response to treatment. Methods: Forty-seven controls and 144 patients with PAH (52 idiopathic, 9 heritable, 31 associated with systemic sclerosis, 15 associated with other connective tissue diseases, 20 associated with HIV and 17 associated with portal hypertension) were evaluated. Forty-four patients with scleroderma and 22 with HIV infection, but without PAH, were also studied. Circulating levels of EMVs, total (CD31+CD42b−) and activated (CD31+CD42b−CD62E+), as well as circulating PCs (CD34+CD133+CD45low) were measured by flow cytometry and the EMVs/PCs ratio was computed. In treatment-naïve patients, measurements were repeated after 3 months of PAH therapy. Results: Patients with PAH showed higher numbers of EMVs and a lower percentage of PCs, compared with healthy controls. The EMV/PC ratio was increased in PAH patients, and in patients with SSc or HIV without PAH. After starting PAH therapy, individual changes in EMVs and PCs were variable, without significant differences being observed as a group. Conclusion: PAH patients present disturbed vascular homeostasis, reflected in changes in circulating EMV and PC levels, which are not restored with PAH targeted therapy. Combined measurement of circulating EMVs and PCs could be foreseen as a potential biomarker of endothelial dysfunction in PAH. This research was funded by grants PI12/00510, PI15/00582 and PI18/00960 from the Institute of Health Carlos III (ISCiii), Spain, co-funded by the European Union (ERDF/ESF); the Catalan Society of Respiratory Medicine (SOCAP); and the Fundación Contra la Hipertensión Pulmonar (FCHP). OTC is the former recipient of a Marie Curie Post-Doctoral Fellowship Award BIOTRACK-IDIBAPS, and the current recipient of a Miguel Servet contract from ISCiii (CP17/00114).

Background More than 60% of patients with lung cancer are diagnosed at advanced stages. The introduction of targeted therapies requires molecular diagnosis to guide treatment. The aim of this study was to evaluate the feasibility of performing mutational analysis with brushing specimens obtained by radial-miniprobe endobronchial ultrasound (R-EBUS) plus fluoroscopy-guided bronchoscopy in patients with peripheral pulmonary adenocarcinoma. Methods Brushing specimens were deposited on cytological slides and were conserved in Roswell Park Memorial Institute (RPMI) culture medium. DNA was isolated to perform a mutational analysis with real-time quantitative polymerase chain reaction and Sanger sequencing for epidermal growth factor receptor (EGFR) and Kirsten rat sarcoma viral oncogene homolog (KRAS). Results Thirty patients with adenocarcinoma were prospectively included. In 100% of the patients, the molecular study was viable with brushing specimens. In 16 (53.3%), KRAS or EGFR mutations were detected: 10 KRAS mutations (33.3%) and 6 EGFR mutations (20%). In a comparison with histological samples, a correlation of 86.6% was detected, and only 2 patients with wild-type results from brushing specimens presented with an EGFR mutation in histological samples. Conclusions Brushing specimens conserved in RPMI medium and obtained by R-EBUS plus fluoroscopy-guided bronchoscopy are valid for molecular studies. They allow the detection of EGFR/KRAS mutations in patients with peripheral adenocarcinoma. In addition, invasive techniques are avoided, the risk of complications is reduced, and the obtained samples are optimized.

Iron deficiency affects exercise capacity because of the critical role iron plays in the optimal functioning of skeletal muscle metabolism. We hypothesized that intravenous iron may improve exercise tolerance, quality of life (QoL), and daily physical activity (DPA) in patients with chronic obstructive pulmonary disease (COPD).This was a placebo-controlled, single-blind, parallel-group, randomized clinical trial. Iron deficiency was defined as a ferritin level100ng/mL or a ferritin level between 100 and 299ng/mL with a transferrin saturation20%, with or without mild anaemia. Patients were randomized at a 2:1 ratio to receive intravenous ferric carboxymaltose or placebo. The primary objective was to investigate whether intravenous iron replacement improved endurance time from baseline by at least 33%. The secondary objectives were to evaluate impact on QoL using the COPD Assessment Test (CAT) and on DPA by accelerometry.We included 66 patients, 44 (66.7%) in the intervention group and 22 (33.3%) in the placebo group. Among patients receiving ferric carboxymaltose, 23 (52.3%) achieved the primary endpoint compared to 4 (18.2%) in the placebo group [p=0.009; relative risk 3.12, (95% CI, 1.19-8.12)]. CAT score decreased -3 (-6.0-1.3) points from baseline in the intervention group (p=0.007), in contrast to placebo group [-1 (-4.0-2.3) points, p=0.236] with no differences in DPA and adverse events in both groups.Iron replacement improved exercise capacity and QoL in stable COPD patients with iron deficiency. The treatment was well tolerated.EudraCT 2016-001238-89.

[Background] Supplemental oxygen delivered with standard oxygen therapy (SOT) improves exercise capacity in patients with idiopathic pulmonary fibrosis (IPF). Although high-flow nasal cannula oxygen therapy (HFNC) improves oxygenation in other respiratory diseases, its impact on exercise performance has never been evaluated in IPF patients. We hypothesized that HFNC may improve exercise capacity in IPF subjects compared to SOT., [Methods] This was a prospective, crossover, pilot randomized trial that compared both oxygenation methods during a constant submaximal cardiopulmonary exercise test (CPET) in IPF patients with exertional oxygen saturation (SpO2) ≤ 85% in the 6-min walking test. The primary outcome was endurance time (Tlim). Secondary outcomes were muscle oxygen saturation (StO2) and respiratory and leg symptoms., [Results] Ten IPF patients [71.7 (6) years old, 90% males] were included. FVC and DLCO were 58 ± 11% and 31 ± 13% pred. respectively. Tlim during CPET was significantly greater using HFNC compared to SOT [494 ± 173 vs. 381 ± 137 s, p = 0.01]. HFNC also associated with a higher increase in inspiratory capacity (IC) [19.4 ± 14.2 vs. 7.1 ± 8.9%, respectively; p = 0.04], and a similar trend was observed in StO2 during exercise. No differences were found in respiratory or leg symptoms between the two oxygen devices., [Conclusions] This is the first study demonstrating that HFNC oxygen therapy improves exercise tolerance better than SOT in IPF patients with exertional desaturation. This might be explained by changes in ventilatory mechanics and muscle oxygenation. Further and larger studies are needed to confirm the benefits of HFNC in IPF patients and its potential usefulness in rehabilitation programs., This study has been funded by SEPAR 2017 (Fellowship) and Rio Hortega; ISCIII (Project and fellowship).

The acquisition of driver mutations in non-tumoral cells appears to be very important during the carcinogenesis of adenocarcinoma (ADC). Recent studies suggest that cancer-related mutations may not necessarily be present only in malignant cells, but also in histologically “healthy cells”.Objective: to demonstrate the presence of EGFR or KRAS mutations in non-tumoral lung cells in subjects with ADC and negative mutational status.Results: mutations in EGFR or KRAS oncogenes were identified in the normal lung in 9.7% of the subjects. Exon 21 substitution L858R in EGFR was detected in two cases while the exon 19 deletion E746-A750 in the EGFR, the G12C and G12D substitutions in the KRAS were detected once. One patient presented three different mutations in the normal lung parenchyma (EGFR_L858R, KRAS_G12C and KRAS_G12D). The negative-mutation status of the tumor and the mutations detected in the “normal lung” were confirmed using highly sensitive and specific TaqMan PCR (CAST-PCR). No differences were found in terms of progression, progression-free survival or overall survival during the 18 months follow-up.Conclusions: These results confirm the presence of driver mutations in the histologically normal lung parenchyma cells in the absence of mutations coexisting with the primary tumor.

In COPD patients, non-anemic iron deficiency (NAID) is a common systemic manifestation. We hypothesized that in COPD patients with NAID, iron therapy may improve systemic oxidative stress. The FACE (Ferinject assessment in patients with COPD and iron deficiency to improve exercise tolerance) study was a single-blind, unicentric, parallel-group, placebo-controlled clinical trial (trial registry: 2016-001238-89). Sixty-six patients were enrolled (randomization 2:1): iron arm, n = 44 and placebo arm, n = 22, with similar clinical characteristics. Serum levels of 3-nitrotyrosine, MDA-protein adducts, and reactive carbonyls, catalase, superoxide dismutase (SOD), glutathione, Trolox equivalent antioxidant capacity (TEAC), and iron metabolism biomarkers were quantified in both groups. In the iron-treated patients compared to placebo, MDA-protein adducts and 3-nitrotyrosine serum levels significantly declined, while those of GSH increased and iron metabolism parameters significantly improved. Hepcidin was associated with iron status parameters. This randomized clinical trial evidenced that iron replacement elicited a decline in serum oxidative stress markers along with an improvement in GSH levels in patients with stable severe COPD. Hepcidin may be a surrogate biomarker of iron status and metabolism in patients with chronic respiratory diseases. These findings have potential clinical implications in the management of patients with severe COPD.

Azithromycin has shown antiviral and immunomodulatory actions that may be of interest in coronavirus disease-19 (COVID-19). The objective of this review was to summarize the potential usefulness of azithromycin in the COVID-19. Azithromycin has shown in vitro activity against SARS-CoV-2. The potential mechanisms of action include the impairment of virus binding and of membrane fusion, endocytosis, and lysosomal protease activation due to its lysosomotropic character. Among other immunomodulatory actions, azithromycin downregulates the production of proinflammatory cytokines, maintains epithelial cell integrity and may prevent lung fibrosis. These properties, which have been related to positive clinical outcomes in other settings as influenza pneumonia, may be beneficial throughout the course of COVID-19. However, scientific evidence is still scarce. Azithromycin has mostly been studied with hydroxychloroquine/chloroquine. In outpatients, this combination showed a reduction in time to clinical recovery or need for hospitalization without safety concerns. In hospitalized patients presented an increased risk of mortality and cardiovascular events. In the few studies that assessed the efficacy of azithromycin monotherapy, a reduction in the time to clinical recovery in outpatients and a trend towards a reduction in mortality in inpatients was observed. Data on critically ill patients are lacking. The quality of data was low, as most of the studies were observational and retrospective. Azithromycin may play a role in the treatment of COVID-19. Despite the paucity of data and associated limitations, azithromycin has shown promising results that deserve further study. The upcoming clinical trials will elucidate the role of this macrolide in COVID-19.

Background: Ampicillin resistant and glycopeptide susceptible Enterococcus faecium bloodstream infection (GSEF-BSI) incidence has risen. However, the treatment of choice remains unknown. Daptomycin use for the treatment of enterococcal infections has increased, despite effectiveness and safety concerns. The objective was to compare the effectiveness and safety of daptomycin and glycopeptides in the treatment of GSEF-BSI. Methods: This was a single-centre, retrospective observational cohort study performed at Hospital del Mar (Barcelona, Spain), from January 2006–May 2018. The primary outcome was clinical cure at the end of the therapy, and secondary outcomes included 14-day, 30-day, in-hospital mortality, and length of stay. Results: From a total of 192 patients with GSEF-BSI, 54 (28.1%) were treated with glycopeptides and 17 (8.9%) with daptomycin. Patients treated with daptomycin presented a lower clinical cure than patients treated with glycopeptides (58.8% vs. 83.3%, RR 0.416 (95% CI 0.189–0.915)). After controlling for confounding variables by means of multivariate analysis the significative difference was confirmed (aOR 4.313, 95% CI, 1.053–17.660). The need for treatment discontinuation due to adverse events was similar. Conclusions: Patients with GSEF-BSI treated with glycopeptides showed a higher clinical cure than those treated with daptomycin.

Background The intravenous administration of antibiotics remains the route of choice at patient admission. Although the early-oral switch once the clinical stability has been achieved, has demonstrated to be effective and safe in other settings, its implementation in the pneumology ward has not been studied. Purpose To assess the effectiveness and safety of an early-oral antimicrobial switch protocol in the pulmonology ward. Material and methods Quasi-experimental study performed in a 400-bed tertiary hospital. The protocol was implemented in March 2018 and therefore two groups were identified: intervention group (March to August 2018) and control group (March to August 2017). All patients admitted to the pneumology ward were treated with intravenous antibiotics that, in turn, were available orally: therefore, amoxicillin/clavulanate, fluoroquinolones, trimethoprim-sulfamethoxazole, clindamycin and azithromycin were included. Results A total of 200 patients were included. Main clinical outcomes are summarised in table 1. Conclusion The implementation of an early-oral antimicrobial switch protocol in the pneumology ward is effective and safe. The early-oral antibiotic switch could decrease the days of catheterisation and the potential related adverse outcomes, with a shortening in the length of stay. References and/or acknowledgements None. No conflict of interest.

Background The incidence of ampicillin-resistant Enterococcus faecium bacteraemia is increasing. Vancomycin remains the first-line treatment in areas with a high prevalence of glycopeptide-susceptible isolates, but data comparing its clinical outcomes with other treatments are lacking. The objective of this study was to compare the effectiveness and safety of linezolid and glycopeptides for the treatment of glycopeptide-susceptible E. faecium bloodstream infection (GSEF-BSI). Methods This retrospective observational cohort study was conducted from January 2006 to May 2018 at the Hospital del Mar, Barcelona, Spain, and compared the clinical outcomes and safety of linezolid and glycopeptides in adult patients with GSEF-BSI. The main outcomes included clinical cure at the end of therapy, 30-day mortality, microbiological eradication and attributable length of stay (LOS). Propensity score matching was performed to reduce potential confounders among groups. Results In total, 105 patients with GSEF-BSI were included (linezolid, n=38; glycopeptides, n=67). After propensity score matched analysis, 56 (53.3%) patients, 28 in each cohort, entered the final analysis. No differences were observed in any of the main clinical outcomes among patients treated with linezolid or glycopeptides: clinical cure [16/28 (57.1%) vs 13/28 (46.4%), P=0.593], 30-day mortality [8/28 (28.6%) vs 12/28 (42.9%), P=0.403], microbiological eradication [22/28 (78.6%) vs 20/28 (71.4%), P=0.758] and median attributable LOS (18.0 vs 17.0 days, P=0.924). Adverse events were similar in both groups. Conclusions Linezolid and glycopeptides showed similar clinical effectiveness and safety in the treatment of GSEF-BSI. Linezolid could be an alternative to glycopeptides in the treatment of GSEF-BSI.

Background The incidence of Enterococcus faecium infections has increased over the past years and is currently the third major microorganism implicated in nosocomial bacteraemia. Nevertheless, the best treatment available is yet to be established, especially in vancomycin-susceptible E. faecium . In this setting, a correct dosage is essential, as inappropriate dosage has been associated with a higher risk of treatment failure. Purpose Our objective was to describe the dosage adequacy of antibiotics used in the treatment of E. faecium bacteraemia. Material and methods Retrospective observational study performed in a 400-bed university teaching hospital from June 2011 to June 2016. Patients with E. faecium isolation from at least one positive blood culture were included. Dosage adequacy was assessed by infectious-diseases-trained pharmacists, who reviewed antimicrobial prescriptions daily and recommended an appropriate dose adjustment in the first 24 to 72 hours of treatment. Inappropriate dosage was considered if it was out of therapeutic range according to plasmatic levels when available, or if an adjustment was needed according to weight or renal function (based on John Hopkins antibiotic guide and data sheet). Categorical variables were presented as percentages and continuous variables as mean (±SD). Results Seventy patients were included Sixty (85.7%) males, 17 (24.3%) critically ill, mean age 69.8 (±13.5) years. Thirty (42.3%) patients received an inappropriate dosage, 19 (63.3%) of them were underdosed. Conclusion Almost 43% of patients were inappropriately dosed in E. faecium bacteraemia, mainly because of underdosing. These data demonstrate the large proportion of inappropriate doses, which highlights the importance of an adequate review of medication and therapeutic drug monitoring in order to assure efficacy and prevent toxicities. No conflict of interest

n the last years, the endoscopic units introduce the ultrasonic bronchofibrescope with a convex probe that allows for real-time needle aspiration of mediastinal and hilar lymph nodes guided by ultrasound images. This technique, known as real-time EBUS–TBNA, is minimally invasive and has the potential to replace mediastinoscopy, since it enables the same part of the mediastinum to be accessed.