Tobramycin Systemic Absorption in Lung Transplant Recipients Treated With Inhaled Tobramycin: A Cohort Study.

Inhaled tobramycin treatment has been associated with nephrotoxicity in some case reports, but limited data are available about serum levels and its possible systemic absorption in lung transplant recipients (LTR). We conducted a single-center, observational and retrospective study of all adult (>18 years old) LTR treated with inhaled tobramycin for at least 3 days between June 2019 and February 2022. Trough serum levels were collected and >2 µg/mL was considered a high drug level. The primary outcome assessed the presence of detectable trough levels, while the secondary outcome focused on the occurrence of acute kidney injury (AKI) in individuals with detectable trough levels. Thirty-four patients, with a median age of 60 years, were enrolled. The primary indications for treatment were donor bronchial aspirate bacterial isolation (18 patients) and tracheobronchitis (15 patients). In total, 28 patients (82%) exhibited detectable serum levels, with 9 (26%) presenting high levels (>2 µg/mL). Furthermore, 9 patients (26%) developed acute kidney injury during the treatment course. Median trough tobramycin levels were significantly elevated in invasively mechanically ventilated patients compared to non-ventilated individuals (2.5 µg/mL vs. 0.48 µg/mL) (p < 0.001). Inhaled tobramycin administration in LTRs, particularly in those requiring invasive mechanical ventilation, may result in substantial systemic absorption.

Characterization and real-live results of nebulized voriconazole: A single-center observational study. / [Artículo traducido] Caracterización y resultados del uso de voriconazol nebulizado en un entorno real: un estudio observacional unicéntrico.

OBJECTIVE: Pulmonary administration of voriconazole involves advantages, including optimization of lung penetration and reduction of adverse effects and interactions. However, there is scarce evidence about its use and there are no commercial presentations for nebulization. We aim to characterize a compounded voriconazole solution for nebulization and describe its use in our center. METHOD: This is a retrospective observational study including patients who received nebulized voriconazole to treat fungal lung diseases (infection or colonization). Voriconazole solution was prepared from commercial vials for intravenous administration. RESULTS: The pH and osmolarity of voriconazole solutions were adequate for nebulization. Ten patients were included, nine adults and a child. The dosage was 40 mg in adults and 10 mg in the pediatric patient, diluted to a final concentration of 10 mg/ml, administered every 12-24 hours. The median duration of treatment was 139 (range: 26-911) days. There were no reported adverse effects and the drug was not detected in plasma when nebulized only. CONCLUSION: Voriconazole nebulization is well tolerated and it is not absorbed into the systemic circulation; further research is needed to assess its efficacy.

Ertapenem blood concentration: A retrospective cohort study to analyse risk of neurotoxicity.

AIMS: Several cases of ertapenem-related neurotoxicity have been published in the current literature. However, studies evaluating the ertapenem blood concentration (EBC) as a risk of these adverse events are scarce. We aimed to evaluate the relationship between the trough EBC and the risk of neurological toxicity. METHODS: This was a retrospective study, including patients who underwent ertapenem treatment between October 2019 and February 2021. We excluded patients in the critical care unit and those whose blood samples were not properly taken in order to analyse ertapenem trough concentration. We also excluded patients whose clinical follow-up was not properly realized for the entire period of ertapenem treatment. The main outcome was the presence of any suspicious neurological side effect owing to ertapenem administration and its relationship with the plasma concentration. Secondary outcomes were to identify clinical and analytical data contributing to a higher risk of neurotoxicity. RESULTS: The initial cohort comprised 158 individuals. For the final analysis we evaluated 102 patients, reporting a neurological alteration in 13/102 (12.7%). Mean trough EBC was significantly higher in patients showing neurotoxicity in comparison with those who did not (37.8 mcg mL-1 , standard deviation [SD] ± 35.7 vs. 14.6 mcg mL-1 , SD ± 15.2; P = .002). In multivariable logistic regression analysis, EBC (odds ratio [OR] = 1.07; P = .006), a moderate renal insufficiency (OR = 9.2; P = .02) and a history of previous neurologic disease (OR = 9.9; P = .02) were identified as risk factors of neurological alteration during ertapenem treatment. CONCLUSIONS: In patients at risk, determining the ertapenem plasma concentration may help to minimize the risk of neurotoxicity.

Effect of tocilizumab versus standard of care in adults hospitalized with moderate-severe COVID-19 pneumonia.

Introduction and objectives: Tocilizumab is an interleukin-6 receptor-blocking agent proposed for the treatment of severe COVID-19; however, limited data are available on their efficacy. The aim of this study was to assess the effect of tocilizumab on the outcomes of patients with COVID-19 pneumonia by using propensity-score-matching (PSM) analysis. Methods: A retrospective observational analysis of hospitalized COVID-19 adult patients admitted to the Vall d'Hebron Hospital was performed between March and April 2020. We used the logistic regression to analyze the effect of tocilizumab on mortality, as main outcome, and PSM analysis to further validate their effect. Secondary outcomes were length-of-stay (LOS) and intensive-care-unit (ICU) stay. Same outcomes were also assessed for early tocilizumab administration, within 72 h after admission. Patients were selected by matching their individual propensity for receiving therapy with tocilizumab, conditional on their demographic and clinical variables. Results: A total of 544 COVID-19 patients were included, 197 (36.2%) were treated with tocilizumab of whom 147 were treated within the first 72 h after admission; and 347 were included in the control group. After PSM analyses, the results showed no association between tocilizumab use and overall mortality (OR = 1.03, 95%CI: 0.63-1.68). However, shorter ICU-stay in the tocilizumab group was found compared to the control group (Coefficient -4.27 95%CI: -6.63 to -1.92). Similar results were found in the early tocilizumab cohort. Conclusions: The administration of tocilizumab in patients with moderate to severe COVID-19 did not reduce the risk of mortality in our cohort of patients, regardless of the time of administration.

Introducción y objetivos: El tocilizumab es un agente bloqueador del receptor de la interleucina 6 propuesto para el tratamiento de la COVID-19 grave; sin embargo, se dispone de datos limitados sobre su eficacia. El objetivo de este estudio fue evaluar el efecto de tocilizumab en los resultados de los pacientes con neumonía por COVID-19 mediante un análisis de emparejamiento por propensity-score-matching (PSM, «puntuación de propensión¼). Métodos: Se realizó un análisis observacional retrospectivo de los pacientes adultos con COVID-19 ingresados en el Hospital Vall d'Hebron entre marzo y abril de 2020. Se utilizó la regresión logística para analizar el efecto de tocilizumab en la mortalidad, como resultado principal, y el análisis PSM para validar aún más su efecto. Los resultados secundarios fueron la duración de la estancia y la estancia en la unidad de cuidados intensivos (UCI). También se evaluaron los mismos resultados para la administración temprana de tocilizumab, dentro de las 72 h posteriores al ingreso. Los pacientes se seleccionaron mediante el emparejamiento de su propensión individual a recibir tratamiento con tocilizumab, condicionado a sus variables demográficas y clínicas. Resultados: Se incluyeron 544 pacientes de COVID-19, 197 (36,2%) fueron tratados con tocilizumab, de los cuales 147 fueron tratados dentro de las primeras 72 h tras el ingreso; y 347 fueron incluidos en el grupo control. Tras los análisis PSM, los resultados no mostraron ninguna asociación entre el uso de tocilizumab y la mortalidad global (OR = 1,03; IC del 95%: 0,63-1,68). Sin embargo, se encontró una menor estancia en la UCI en el grupo de tocilizumab en comparación con el grupo de control (coeficiente −4,27; IC del 95%: −6,63 − −1,92). Se encontraron resultados similares en la cohorte de tocilizumab temprano. Conclusiones: La administración de tocilizumab en pacientes con COVID-19 moderada a grave no redujo el riesgo de mortalidad en nuestra cohorte de pacientes, independientemente del momento de la administración.

Safety and Effectiveness of Isavuconazole Treatment for Fungal Infections in Solid Organ Transplant Recipients (ISASOT Study).

Isavuconazole (ISA) is an alternative treatment for Aspergillus spp. and other fungal infections, but evidence regarding its use in solid organ transplant recipients (SOTR) is scarce. All SOTR who received ISA for treatment of a fungal infection (FI) at our center from December 2017 to January 2021 were included. The duration of the treatment depended on the type of infection. All patients were followed up to 3 months after treatment. Fifty-three SOTR were included, and the majority (44, 83%) were lung transplant recipients. The most frequently treated FI was tracheobronchitis (25, 46.3%). Aspergillus spp. (43, 81.1%); specially A. flavus (16, 37.2%) and A. fumigatus (12, 27.9%), was the most frequent etiology. Other filamentous fungi including one mucormycosis, and four yeast infections were treated. The median duration of treatment was 81 days (IQR 15-197). Mild gamma-glutamyltransferase elevation was the most frequent adverse event (34%). ISA was prematurely discontinued in six patients (11.3%) due to mild hepatotoxicity (2), fatigue (2), gastrointestinal intolerance (1) and myopathy (1). The mean tacrolimus dose decrease was 30% after starting ISA. Seven patients received ISA with mTOR inhibitors with good tolerability. Two patients developed breakthrough FI (3.8%). Among patients who completed the treatment, 27 (50.9%) showed clinical cure and 15 (34.1%) presented fungal persistence. Three patients (6%) died while on ISA due to FI. ISA was well tolerated and appeared to be an effective treatment for FI in SOTR. IMPORTANCE We describe 53 solid organ transplant recipients treated with isavuconazole for fungal infections. Because its use in clinical practice, there is scarce data of its use in solid organ transplant recipients, where interactions with calcineurin inhibitors and mTOR and adverse drug events have limited the use of other triazoles. To the best of our knowledge, this is the first article describing the safety regarding adverse events and drug interactions of isavuconazole for the treatment of fungal infections in a cohort of solid organ transplant recipients. Also, although this is a noncomparative study, we report some real world effectivity data of these patients, including treatment of non-Aspergillus fungal infections.

Effect of tocilizumab versus standard of care in adults hospitalized with moderate-severe COVID-19 pneumonia.

INTRODUCTION AND OBJECTIVES: Tocilizumab is an interleukin-6 receptor-blocking agent proposed for the treatment of severe COVID-19; however, limited data are available on their efficacy. The aim of this study was to assess the effect of tocilizumab on the outcomes of patients with COVID-19 pneumonia by using propensity-score-matching (PSM) analysis. METHODS: A retrospective observational analysis of hospitalized COVID-19 adult patients admitted to the Vall d'Hebron Hospital was performed between March and April 2020. We used the logistic regression to analyze the effect of tocilizumab on mortality, as main outcome, and PSM analysis to further validate their effect. Secondary outcomes were length-of-stay (LOS) and intensive-care-unit (ICU) stay. Same outcomes were also assessed for early tocilizumab administration, within 72h after admission. Patients were selected by matching their individual propensity for receiving therapy with tocilizumab, conditional on their demographic and clinical variables. RESULTS: A total of 544 COVID-19 patients were included, 197 (36.2%) were treated with tocilizumab of whom 147 were treated within the first 72h after admission; and 347 were included in the control group. After PSM analyses, the results showed no association between tocilizumab use and overall mortality (OR=1.03, 95%CI: 0.63-1.68). However, shorter ICU-stay in the tocilizumab group was found compared to the control group (Coefficient -4.27 95%CI: -6.63 to -1.92). Similar results were found in the early tocilizumab cohort. CONCLUSIONS: The administration of tocilizumab in patients with moderate to severe COVID-19 did not reduce the risk of mortality in our cohort of patients, regardless of the time of administration.

Nebulized Micafungin Treatment for Scopulariopsis/Microascus Tracheobronchitis in Lung Transplant Recipients.

Scopulariopsis/Microascus isolates cause infections with high mortality in lung transplant recipients. Treatment is challenging due to antimicrobial resistance. We describe two cases of Scopulariopsis/Microascus tracheobronchitis in lung transplant recipients successfully treated with nebulized micafungin. This antifungal was well tolerated and achieved high concentrations in epithelial lining fluid up to 14 h after nebulization without significant plasma concentrations. Nebulized micafungin may be a safe and effective option for the treatment of fungal tracheobronchitis.

Tigecycline-associated hypofibrinogenemia in a real-world setting.

Background Tigecycline is a broad-spectrum antibiotic used to treat infections that do not respond to first-line treatments. High-doses and extended treatments are common; therefore, adverse events might be more frequent and severe than those observed in clinical trials. Several case-reports have referred hypofibrinogenemia in patients who received tigecycline. Objective To analyse the impact of tigecycline use on coagulation parameters, and identify which variables could be related with this. Setting The study was performed at Hospital Universitari Vall Hebron, in Barcelona, Spain. Method Observational, retrospective study. All patients older than 18, who received tigecycline for > 72 h from January 2016 to March 2018 were included. Clinical and laboratory data from before, during and at the end of tigecycline treatment were retrospectively collected. Differences between means were analyzed using the paired-sample Student's t-test. Binary logistic regression was performed to identify risk factors for hypofibrinogenemia. Main outcome measure Mean difference in fibrinogen plasma concentration and INR, before and at the end of tigecycline treatment. Results 78 patients (mean age 65; SD ± 15.5 years) were identified. The most common indications for tigecycline treatment were abdominal (66%), respiratory tract (16%) and skin&soft tissue (10%) infections. High-dose tigecycline was used in 62% of cases and the median duration of treatment was 12 days. Hypofibrinogenemia occurred in 12 patients, 5 bleeding events were observed and 4 of them required fibrinogen administration. Tigecycline caused significant alterations in fibrinogen plasma concentration (mean decrease 1.76 g/L; IC 95% 1.36 to 2.15) as well as INR (mean increase 0.11; IC 95% 0.05 to 0.17). Both were recovered after treatment cessation. We identified duration of treatment > 4 weeks (OR = 6.6), high-dose tigecycline (OR = 4.75) and high protein C levels (OR = 4.2) as independent variables associated with fibrinogen decrease, but not renal impairment. Conclusions Tigecycline administration has been related with hypofibrinogenemia, especially when high-doses of tigecycline are used. Health professionals should be aware of the potentially severe tigecycline-associated hypofibrinogenemia and monitor coagulation during treatment, especially when high-doses of tigecycline are used.

Physicochemical characterization of micafungin and anidulafungin for its nebulized administration.

OBJECTIVE: To determine by experimentation whether micafungin and  anidulafungin possess physicochemical properties suitable for  nebulization. METHOD: PH, osmolality, viscosity, density and chloride content were  determined by pH monitoring, osmometry, viscometry, densitometry  and potentiometry in two samples of different concentrations, 5 and 10  mg/mL each echinocandin. Results: The results obtained for micafungin solution were: pH 5.80 (0.14), osmolality 293.33 (1.53) mOsm/kg, chloride content  134.67 (0.58) mmol/L and density 1,009.4 (0,1) kg/m3; while for 10  mg/mL solution: osmolality 342.00 (1.00) mOsm/kg, chloride content  139.67 (0.58) mmol/L and density 1,014.5 (0.2) kg/m3. The results  obtained for 5 mg/mL anidulafungin were: pH 4.22 (0.01), osmolality  464.67 (2.52) mOsm/kg, chloride content 137.00 (0.00) mmol/L and  density 1,016.5 (0,2) kg/m3; while for 10 mg/mL solution: osmolality  656.33 (1.15) mOsm/kg, chloride content 132.00 (0.00) mmol/L and  density 1,029.8 (0.4) kg/m3. Conclusions: PH, osmolality, chloride content and density values  proved to be suitable for proper tolerability by nebulization.

Objetivo: Determinar experimentalmente si micafungina y  nidulafungina poseen propiedades fisicoquímicas adecuadas para su  nebulización.Método: Se determinó el pH, la osmolalidad, la viscosidad, la densidad y el contenido en cloruros mediante pH-metría, osmometría,  viscosimetría, densitometría y potenciometría, respectivamente, en dos  muestras de diferente concentración, 5 y 10 mg/ml, de cada  equinocandina.Resultados: Para la solución de micafungina 5 mg/ml los resultados  obtenidos fueron: pH 5,80 (0,14), osmolalidad 293,33 (1,53) mOsm/kg,  contenido en cloruros 134,67 (0,58) mmol/l y densidad  1.009,4 (0,1) kg/m3; y para la solución de 10 mg/ml: osmolalidad  342,00 (1,00) mOsm/kg, contenido en cloruros 139,67 (0,58) mmol/l y  densidad 1.014,5 (0,2) kg/m3. Para la solución de anidulafungina 5  mg/ml los resultados obtenidos fueron: pH 4,22 (0,01), osmolalidad  464,67 (2,52) mOsm/kg, contenido en cloruros 137,00 (0,00) mmol/l y  densidad 1.016,5 (0,2) kg/m3; y para la solución de 10 mg/ml:  osmolalidad 656,33 (1,15) mOsm/kg, contenido en cloruros 132,00  (0,00) mmol/l y densidad 1.029,8 (0,4) kg/m3. Conclusiones: Los valores de pH, osmolalidad, contenido en cloruros y densidad resultaron adecuados para una correcta tolerabilidad  ediante nebulización.