Clustering COVID-19 ARDS patients through the first days of ICU admission. An analysis of the CIBERESUCICOVID Cohort.

BACKGROUND: Acute respiratory distress syndrome (ARDS) can be classified into sub-phenotypes according to different inflammatory/clinical status. Prognostic enrichment was achieved by grouping patients into hypoinflammatory or hyperinflammatory sub-phenotypes, even though the time of analysis may change the classification according to treatment response or disease evolution. We aimed to evaluate when patients can be clustered in more than 1 group, and how they may change the clustering of patients using data of baseline or day 3, and the prognosis of patients according to their evolution by changing or not the cluster. METHODS: Multicenter, observational prospective, and retrospective study of patients admitted due to ARDS related to COVID-19 infection in Spain. Patients were grouped according to a clustering mixed-type data algorithm (k-prototypes) using continuous and categorical readily available variables at baseline and day 3. RESULTS: Of 6205 patients, 3743 (60%) were included in the study. According to silhouette analysis, patients were grouped in two clusters. At baseline, 1402 (37%) patients were included in cluster 1 and 2341(63%) in cluster 2. On day 3, 1557(42%) patients were included in cluster 1 and 2086 (57%) in cluster 2. The patients included in cluster 2 were older and more frequently hypertensive and had a higher prevalence of shock, organ dysfunction, inflammatory biomarkers, and worst respiratory indexes at both time points. The 90-day mortality was higher in cluster 2 at both clustering processes (43.8% [n = 1025] versus 27.3% [n = 383] at baseline, and 49% [n = 1023] versus 20.6% [n = 321] on day 3). Four hundred and fifty-eight (33%) patients clustered in the first group were clustered in the second group on day 3. In contrast, 638 (27%) patients clustered in the second group were clustered in the first group on day 3. CONCLUSIONS: During the first days, patients can be clustered into two groups and the process of clustering patients may change as they continue to evolve. This means that despite a vast majority of patients remaining in the same cluster, a minority reaching 33% of patients analyzed may be re-categorized into different clusters based on their progress. Such changes can significantly impact their prognosis.

Procalcitonin and C-reactive protein to rule out early bacterial coinfection in COVID-19 critically ill patients.

PURPOSE: Although the prevalence of community-acquired respiratory bacterial coinfection upon hospital admission in patients with coronavirus disease 2019 (COVID-19) has been reported to be < 5%, almost three-quarters of patients received antibiotics. We aim to investigate whether procalcitonin (PCT) or C-reactive protein (CRP) upon admission could be helpful biomarkers to identify bacterial coinfection among patients with COVID-19 pneumonia. METHODS: We carried out a multicentre, observational cohort study including consecutive COVID-19 patients admitted to 55 Spanish intensive care units (ICUs). The primary outcome was to explore whether PCT or CRP serum levels upon hospital admission could predict bacterial coinfection among patients with COVID-19 pneumonia. The secondary outcome was the evaluation of their association with mortality. We also conducted subgroups analyses in higher risk profile populations. RESULTS: Between 5 February 2020 and 21 December 2021, 4076 patients were included, 133 (3%) of whom presented bacterial coinfection. PCT and CRP had low area under curve (AUC) scores at the receiver operating characteristic (ROC) curve analysis [0.57 (95% confidence interval (CI) 0.51-0.61) and 0.6 (95% CI, 0.55-0.64), respectively], but high negative predictive values (NPV) [97.5% (95% CI 96.5-98.5) and 98.2% (95% CI 97.5-98.9) for PCT and CRP, respectively]. CRP alone was associated with bacterial coinfection (OR 2, 95% CI 1.25-3.19; p = 0.004). The overall 15, 30 and 90 days mortality had a higher trend in the bacterial coinfection group, but without significant difference. PCT ≥ 0.12 ng/mL was associated with higher 90 days mortality. CONCLUSION: Our study suggests that measurements of PCT and CRP, alone and at a single time point, are not useful for ruling in or out bacterial coinfection in viral pneumonia by COVID-19.

Impact of the "Zero Resistance" program on acquisition of multidrug-resistant bacteria in patients admitted to Intensive Care Units in Spain. A prospective, intervention, multimodal, multicenter study.

OBJECTIVE: To assess the impact of a multimodal interventional project ("Zero Resistance") on the acquisition of multidrug-resistant bacteria (MDR-B) during the patient's ICU stay. DESIGN: Prospective, open-label, interventional, multicenter study. SETTING: 103 ICUs. PATIENTS: Critically ill patients admitted to the ICUs over a 27-month period. INTERVENTIONS: Implementation of a bundle of 10 recommendations to prevent emergence and spread of MDR-B in the ICU. MAIN VARIABLE OF INTEREST: Rate of patients acquiring MDR-B during their ICU stay, with differentiation between colonization and infection. RESULTS: A total of 139,505 patients were included. In 5409 (3.9%) patients, 6020 MDR-B on ICU admission were identified, and in 3648 (2.6%) patients, 4269 new MDR-B during ICU stay were isolated. The rate of patients with MDR-B detected on admission increased significantly (IRR 1.43, 95% CI 1.31-1.56) (p<0.001) during the study period, with an increase of 32.2% between the initial and final monthly rates. On the contrary, the rate of patients with MDR-B during ICU stay decreased non-significantly (IRR 0.93, 95% CI 0.83-1.03) (p=0.174), with a 24.9% decrease between initial and final monthly rates. According to the classification into colonization or infection, there was a highly significant increase of MDR-B colonizations detected on admission (IRR 1.69, 95% CI 1.52-1.83; p<0.0001) and a very significant decrease of MDR-B-infections during ICU stay (IRR 0.67, 95% CI 0.57-0.80, p<0.0001). CONCLUSIONS: The implementation of ZR project-recommendations was associated with a significantly reduction an infection produced by MDR-B acquired during the patient's ICU stay.

Key Factors Associated With Pulmonary Sequelae in the Follow-Up of Critically Ill COVID-19 Patients.

INTRODUCTION: Critical COVID-19 survivors have a high risk of respiratory sequelae. Therefore, we aimed to identify key factors associated with altered lung function and CT scan abnormalities at a follow-up visit in a cohort of critical COVID-19 survivors. METHODS: Multicenter ambispective observational study in 52 Spanish intensive care units. Up to 1327 PCR-confirmed critical COVID-19 patients had sociodemographic, anthropometric, comorbidity and lifestyle characteristics collected at hospital admission; clinical and biological parameters throughout hospital stay; and, lung function and CT scan at a follow-up visit. RESULTS: The median [p25-p75] time from discharge to follow-up was 3.57 [2.77-4.92] months. Median age was 60 [53-67] years, 27.8% women. The mean (SD) percentage of predicted diffusing lung capacity for carbon monoxide (DLCO) at follow-up was 72.02 (18.33)% predicted, with 66% of patients having DLCO<80% and 24% having DLCO<60%. CT scan showed persistent pulmonary infiltrates, fibrotic lesions, and emphysema in 33%, 25% and 6% of patients, respectively. Key variables associated with DLCO<60% were chronic lung disease (CLD) (OR: 1.86 (1.18-2.92)), duration of invasive mechanical ventilation (IMV) (OR: 1.56 (1.37-1.77)), age (OR [per-1-SD] (95%CI): 1.39 (1.18-1.63)), urea (OR: 1.16 (0.97-1.39)) and estimated glomerular filtration rate at ICU admission (OR: 0.88 (0.73-1.06)). Bacterial pneumonia (1.62 (1.11-2.35)) and duration of ventilation (NIMV (1.23 (1.06-1.42), IMV (1.21 (1.01-1.45)) and prone positioning (1.17 (0.98-1.39)) were associated with fibrotic lesions. CONCLUSION: Age and CLD, reflecting patients' baseline vulnerability, and markers of COVID-19 severity, such as duration of IMV and renal failure, were key factors associated with impaired DLCO and CT abnormalities.

Prognostic implications of comorbidity patterns in critically ill COVID-19 patients: A multicenter, observational study.

Background: The clinical heterogeneity of COVID-19 suggests the existence of different phenotypes with prognostic implications. We aimed to analyze comorbidity patterns in critically ill COVID-19 patients and assess their impact on in-hospital outcomes, response to treatment and sequelae. Methods: Multicenter prospective/retrospective observational study in intensive care units of 55 Spanish hospitals. 5866 PCR-confirmed COVID-19 patients had comorbidities recorded at hospital admission; clinical and biological parameters, in-hospital procedures and complications throughout the stay; and, clinical complications, persistent symptoms and sequelae at 3 and 6 months. Findings: Latent class analysis identified 3 phenotypes using training and test subcohorts: low-morbidity (n=3385; 58%), younger and with few comorbidities; high-morbidity (n=2074; 35%), with high comorbid burden; and renal-morbidity (n=407; 7%), with chronic kidney disease (CKD), high comorbidity burden and the worst oxygenation profile. Renal-morbidity and high-morbidity had more in-hospital complications and higher mortality risk than low-morbidity (adjusted HR (95% CI): 1.57 (1.34-1.84) and 1.16 (1.05-1.28), respectively). Corticosteroids, but not tocilizumab, were associated with lower mortality risk (HR (95% CI) 0.76 (0.63-0.93)), especially in renal-morbidity and high-morbidity. Renal-morbidity and high-morbidity showed the worst lung function throughout the follow-up, with renal-morbidity having the highest risk of infectious complications (6%), emergency visits (29%) or hospital readmissions (14%) at 6 months (p<0.01). Interpretation: Comorbidity-based phenotypes were identified and associated with different expression of in-hospital complications, mortality, treatment response, and sequelae, with CKD playing a major role. This could help clinicians in day-to-day decision making including the management of post-discharge COVID-19 sequelae. Funding: ISCIII, UNESPA, CIBERES, FEDER, ESF.

Major candidate variables to guide personalised treatment with steroids in critically ill patients with COVID-19: CIBERESUCICOVID study.

PURPOSE: Although there is evidence supporting the benefits of corticosteroids in patients affected with severe coronavirus disease 2019 (COVID-19), there is little information related to their potential benefits or harm in some subgroups of patients admitted to the intensive care unit (ICU) with COVID-19. We aim to investigate to find candidate variables to guide personalized treatment with steroids in critically ill patients with COVID-19. METHODS: Multicentre, observational cohort study including consecutive COVID-19 patients admitted to 55 Spanish ICUs. The primary outcome was 90-day mortality. Subsequent analyses in clinically relevant subgroups by age, ICU baseline illness severity, organ damage, laboratory findings and mechanical ventilation were performed. High doses of corticosteroids (≥ 12 mg/day equivalent dexamethasone dose), early administration of corticosteroid treatment (< 7 days since symptom onset) and long term of corticosteroids (≥ 10 days) were also investigated. RESULTS: Between February 2020 and October 2021, 4226 patients were included. Of these, 3592 (85%) patients had received systemic corticosteroids during hospitalisation. In the propensity-adjusted multivariable analysis, the use of corticosteroids was protective for 90-day mortality in the overall population (HR 0.77 [0.65-0.92], p = 0.003) and in-hospital mortality (SHR 0.70 [0.58-0.84], p < 0.001). Significant effect modification was found after adjustment for covariates using propensity score for age (p = 0.001 interaction term), Sequential Organ Failure Assessment (SOFA) score (p = 0.014 interaction term), and mechanical ventilation (p = 0.001 interaction term). We observed a beneficial effect of corticosteroids on 90-day mortality in various patient subgroups, including those patients aged ≥ 60 years; those with higher baseline severity; and those receiving invasive mechanical ventilation at ICU admission. Early administration was associated with a higher risk of 90-day mortality in the overall population (HR 1.32 [1.14-1.53], p < 0.001). Long-term use was associated with a lower risk of 90-day mortality in the overall population (HR 0.71 [0.61-0.82], p < 0.001). No effect was found regarding the dosage of corticosteroids. Moreover, the use of corticosteroids was associated with an increased risk of nosocomial bacterial pneumonia and hyperglycaemia. CONCLUSION: Corticosteroid in ICU-admitted patients with COVID-19 may be administered based on age, severity, baseline inflammation, and invasive mechanical ventilation. Early administration since symptom onset may prove harmful.

Methodology of a Large Multicenter Observational Study of Patients with COVID-19 in Spanish Intensive Care Units.

INTRODUCTION: The COVID-19 pandemic created tremendous challenges for health-care systems. Intensive care units (ICU) were hit with a large volume of patients requiring ICU admission, mechanical ventilation, and other organ support with very high mortality. The Centro de Investigación Biomédica en Red-Enfermedades Respiratorias (CIBERES), a network of Spanish researchers to investigate in respiratory disease, commissioned the current proposal in response to the Instituto de Salud Carlos III (ISCIII) call. METHODS: CIBERESUCICOVID is a multicenter, observational, prospective/retrospective cohort study of patients with COVID-19 admitted to Spanish ICUs. Several work packages were created, including study population and ICU data collection, follow-up, biomarkers and miRNAs, data management and quality. RESULTS: This study included 6102 consecutive patients admitted to 55 ICUs homogeneously distributed throughout Spain and the collection of blood samples from more than 1000 patients. We enrolled a large population of COVID-19 ICU-admitted patients including baseline characteristics, ICU and MV data, treatments complications, and outcomes. The in-hospital mortality was 31%, and 76% of patients required invasive mechanical ventilation. A 3-6 month and 1 year follow-up was performed. Few deaths after 1 year discharge were registered. Low anti-SARS-CoV-2 S antibody levels predict mortality in critical COVID-19. These antibodies contribute to prevent systemic dissemination of SARS-CoV-2. The severity of COVID-19 impacts the circulating miRNA profile. Plasma miRNA profiling emerges as a useful tool for risk-based patient stratification in critically ill COVID-19 patients. CONCLUSIONS: We present the methodology used in a large multicenter study sponsored by ISCIII to determine the short- and long-term outcomes in patients with COVID-19 admitted to more than 50 Spanish ICUs.

Study of risk factors for healthcare-associated infections in acute cardiac patients using categorical principal component analysis (CATPCA).

Using categorical principal component analysis, we aimed to determine the relationship between health care-associated infections (HAIs) and diagnostic categories (DCs) in patients with acute heart disease using data collected in the Spanish prospective ENVIN-HELICS intensive care registry over a 10-year period (2005-2015). A total of 69,876 admissions were included, of which 5597 developed HAIs. Two 2-component CATPCA models were developed. In the first model, all cases were included; the first component was determined by the duration of the invasive devices, the ICU stay, the APACHE II score and the HAIs; the second component was determined by the type of admission (medical or surgical) and by the DCs. No clear association between DCs and HAIs was found. Cronbach's alpha was 0.899, and the variance accounted for (VAF) was 52.5%. The second model included only admissions that developed HAIs; the first component was determined by the duration of the invasive devices and the ICU stay; the second component was determined by the inflammatory response, the mortality in the ICU and the HAIs. Cronbach's alpha value was 0.855, and VAF was 46.9%. These findings highlight the role of exposure to invasive devices in the development of HAIS in patients with acute heart disease.

The evolution of the ventilatory ratio is a prognostic factor in mechanically ventilated COVID-19 ARDS patients.

BACKGROUND: Mortality due to COVID-19 is high, especially in patients requiring mechanical ventilation. The purpose of the study is to investigate associations between mortality and variables measured during the first three days of mechanical ventilation in patients with COVID-19 intubated at ICU admission. METHODS: Multicenter, observational, cohort study includes consecutive patients with COVID-19 admitted to 44 Spanish ICUs between February 25 and July 31, 2020, who required intubation at ICU admission and mechanical ventilation for more than three days. We collected demographic and clinical data prior to admission; information about clinical evolution at days 1 and 3 of mechanical ventilation; and outcomes. RESULTS: Of the 2,095 patients with COVID-19 admitted to the ICU, 1,118 (53.3%) were intubated at day 1 and remained under mechanical ventilation at day three. From days 1 to 3, PaO2/FiO2 increased from 115.6 [80.0-171.2] to 180.0 [135.4-227.9] mmHg and the ventilatory ratio from 1.73 [1.33-2.25] to 1.96 [1.61-2.40]. In-hospital mortality was 38.7%. A higher increase between ICU admission and day 3 in the ventilatory ratio (OR 1.04 [CI 1.01-1.07], p = 0.030) and creatinine levels (OR 1.05 [CI 1.01-1.09], p = 0.005) and a lower increase in platelet counts (OR 0.96 [CI 0.93-1.00], p = 0.037) were independently associated with a higher risk of death. No association between mortality and the PaO2/FiO2 variation was observed (OR 0.99 [CI 0.95 to 1.02], p = 0.47). CONCLUSIONS: Higher ventilatory ratio and its increase at day 3 is associated with mortality in patients with COVID-19 receiving mechanical ventilation at ICU admission. No association was found in the PaO2/FiO2 variation.

Tratamiento farmacológico de la covid-19: revisión narrativa de los grupo de trabajo de enfermedades infecciosas y sepsis (gteis) y del grupo de trabajo de transfusiones y hemoderivados (gtth) / Pharmacological treatment of covid-19: narrative review of the working group in infectious diseases and sepsis (gteis) and the working groups in transfusions and blood products(gtth)

La infección por el virus SARS-CoV-2, denominada COVID-19 (COronaVIrus Disease 19), fue detectada inicialmente en China en diciembre 2019, y posteriormente se ha diseminado rápidamente por todo el mundo, hasta el punto de que el 11 de marzo la OMS declaró que el brote podría definirse como pandemia. La COVID-19 presenta un cuadro que oscila desde episodios leves pseudogripales a otros graves e incluso potencialmente mortales debido, sobre todo, a insuficiencia respiratoria aguda. Es frecuente el ingreso de estos pacientes en nuestros Servicios de Medicina Intensiva en relación con un Síndrome de Distrés Respiratorio Agudo (SDRA). La falta de un tratamiento con evidencia científica ha llevado al empleo de diferentes pautas terapéuticas, en muchas ocasiones, con modificaciones rápidas de los protocolos. Recientes revisiones en revistas de prestigio han destacado la falta de terapias probadas y la necesidad de ensayo clínicos que permitan establecer pautas de tratamiento claras y objetivas. Este documento tiene por objeto ofrecer una actualización de la terapia que se está aplicando en la actualidad, y una ayuda en la asistencia diaria, sin pretender sustituir los protocolos adoptados en cada centro

Infection by the SARS-CoV-2 virus, known as COVID-19 (Corona VIrus Disease-19) was initially detected in China in December 2019, and has subsequently spread rapidly throughout the world, to the point that on March 11 the World Health Organization (WHO) reported that the outbreak could be defined as a pandemic. COVID-19 disease ranges from mild flu-like episodes to other serious and even life-threatening conditions, mainly due to acute respiratory failure. These patients are frequently admitted to our Intensive Care Units in relation to acute respiratory distress syndrome (ARDS). The lack of a treatment based on scientific evidence has led to the use of different management guidelines, in many cases with rapid changes in the applied protocols. Recent reviews in reputed journals have unders cored the lack of proven therapies and the need for clinical trials to establish clear and objective treatment guidelines. The present study provides an update on the currently applied treatment, and intends to offer help in relation to daily care, without seeking to replace the protocols adopted in each individual center

ICU-Acquired Pneumonia Is Associated with Poor Health Post-COVID-19 Syndrome.

BACKGROUND: Some patients previously presenting with COVID-19 have been reported to develop persistent COVID-19 symptoms. While this information has been adequately recognised and extensively published with respect to non-critically ill patients, less is known about the incidence and factors associated with the characteristics of persistent COVID-19. On the other hand, these patients very often have intensive care unit-acquired pneumonia (ICUAP). A second infectious hit after COVID increases the length of ICU stay and mechanical ventilation and could have an influence on poor health post-COVID 19 syndrome in ICU-discharged patients. METHODS: This prospective, multicentre, and observational study was carrid out across 40 selected ICUs in Spain. Consecutive patients with COVID-19 requiring ICU admission were recruited and evaluated three months after hospital discharge. RESULTS: A total of 1255 ICU patients were scheduled to be followed up at 3 months; however, the final cohort comprised 991 (78.9%) patients. A total of 315 patients developed ICUAP (97% of them had ventilated ICUAP). Patients requiring invasive mechanical ventilation had more persistent post-COVID-19 symptoms than those who did not require mechanical ventilation. Female sex, duration of ICU stay, development of ICUAP, and ARDS were independent factors for persistent poor health post-COVID-19. CONCLUSIONS: Persistent post-COVID-19 symptoms occurred in more than two-thirds of patients. Female sex, duration of ICU stay, development of ICUAP, and ARDS all comprised independent factors for persistent poor health post-COVID-19. Prevention of ICUAP could have beneficial effects in poor health post-COVID-19.

Nuevos sistemas de implementación del soporte nutricional en pacientes de UCI / Implementation issues for nutritional support in critically ill patients

La nutrición enteral (NE) es la vía de aporte de nutrientes preferible en los pacientes críticos. No obstante, su aplicación no es una tarea fácil dado que existen diversos problemas que limitan el empleo de NE en los pacientes críticos. Dichos problemas se encuentran en casi todas las fases del proceso: indicación de la NE, vía de acceso seleccionada para el aporte de nutrientes, método de administración de la dieta, seguimiento de la técnica y control de complicaciones y eficacia de la misma. Los condicionantes de la eficacia del soporte nutricional deben ser conocidos con vistas a poner en marcha diferentes medidas correctoras que permitan una mayor frecuencia de aplicación de la NE y una mejor eficacia de la misma. Las complicaciones gastrointestinales relacionadas con la NE representan uno de los problemas principales. La definición de las complicaciones es imprescindible para el adecuado manejo de las mismas mediante un protocolo específico en cada caso. La introducción de cambios sencillos en el proceso, como el incremento del límite del residuo gástrico desde 200 ml hasta 500 ml, pueden conseguir que la NE no sea inadecuadamente suspendida en los pacientes. El empleo de protocolos de aplicación de la NE es una herramienta de gran valor en la práctica clínica. Los sistemas automatizados de información clínica pueden ser también de gran ayuda en la valoración y seguimiento del déficit calórico de los pacientes (AU)

Enteral nutrition (EN) is the preferred route for nutrient administration in critically ill patients. Nevertheless, daily implementation of EN is not an easy issue. Several problems exists that difficult EN application in clinical practice. These problems are present in every step: indication, route of access for nutrient administration, diet infusion, complications management and nutrition efficacy of EN. It is necessary to copy with factors that limit nutritional efficacy of EN. Knowledge of these factors is the main issue for preventive and corrective measures. Gastrointestinal related complications are probably the main problem that needs attention. Adequate definitions of these complications, together with specifically directed management protocols, are of capital importance in this field. Implementation of simple changes, as the increase in gastric residual volume to 500 ml, can be followed by an increase in the nutritional efficacy of EN. Protocols and nomograms are practical tools that also can achieve a more adequate application of EN. Computerized clinical information systems are of great importance to detect, follow and manage another fundamental problem with EN in critically ill patients: the caloric debt (AU)

Artificial liver support system in acute liver failure patients waiting liver transplantation.

BACKGROUND/AIMS: To assess the efficacy of the Molecular Adsorbent Recirculating System MARS (GAMBRO LUNDIA AB, Europe) in patients with acute liver failure waiting for liver transplantation. METHODOLOGY: Case-control study in a medical-surgical ICU of a referral hospital. Patients admitted to ICU with severe acute liver failure of any etiology were included. Conventional treatment was applied in all cases according to patient's clinical condition. Patients were treated with MARS after the implementation of this therapy in the ICU. Patients without this treatment were the control group. RESULTS: Were included 45 patients (control group: 26, MARS group: 19). Comparison between groups showed only differences in plasma bilirrubin levels in the first 24 hours. ICU mortality was 52.63% in the treatment group and 42.3% in the control group (p = 0.49). In the control group 17 patients (65.4%) received a liver transplant and 11 (57.9%) in the MARS group. ICU mortality was lower for transplanted patients in the study group (27.27% vs. 87.5%) (p = 0.019). Kaplan-Meier survival curves indicate that MARS-treated patients before liver transplantation had better survival. CONCLUSIONS: Combination therapy with MARS and liver transplantation seems to be the more effective therapeutic option for patients with severe ALF.

[Pharmacodynamics and pharmacokinetics of micafungin in adults, children and neonate]. / Farmacodinamia y farmacocinética de la micafungina en adultos, niños y neonatos.

BACKGROUND: Invasive fungal infections are a significant cause of morbidity and mortality among immunocompromised patients. Although several new antifungal agents have been developed in the past few years, the management of serious fungal infections continues to be problematic. AIMS: To review the pharmacodynamics and pharmacokinetics of a new antifungal agent: micafungin. METHODS: A systematic review of biomedic databases (EBSCO Open Journals, Ovid Online, Proquest Medical Library, PubMed/Medline, Science Direct, Springer Links and Wiley Interscience) has been performed. Search was conducted from 2000 to 2008. Supplementary sources included abstracts from the Interscience Conference on Antimicrobial Agents (ICAAC) and Chemotherapy and the Infectious Diseases Society of America (IDSA) from 1998 to 2008. RESULTS: Micafungin has a potent mechanism of action: inhibits beta-1,3-D-glucan synthase interfering with fungal cell wall synthesis. This agent shares with caspofungin an identical spectrum of in vitro activity against Candida albicans, non-albicans Candida species, and Aspergillus. Due to the limited oral availability, micafungin is available for parenteral administration only. Micafungin is characterized by a linear pharmacokinetic profile and substantially fewer toxic effects. Micafungin is a poor substrate for the cytochrome P450 enzymes, and compared to azoles, fewer drug interactions have been described. No dose reduction is required in renal impairment or in mild to moderate liver failure. CONCLUSIONS: The pharmacodynamic and pharmacokinetic profiles of micafungin imply that this drug is a safe alternative for the treatment of fungal infections. Micafungin can be safely co-administered with most drugs without the need for dosage adaptation even in patients with renal o liver function impairment.

Farmacodinamia y farmacocinética de la micafungina en adultos, niños y neonatos / Pharmacodynamics and pharmacokinetcis of micafungin in adults, children and neonate

Antecedentes: Las infecciones fúngicas son una causa importante de morbilidad y mortalidad en los pacientes inmunodeficientes. A pesar que en los últimos años se han desarrollado nuevos fármacos antifúngicos, el tratamiento de estas infecciones sigue siendo problemático. Objetivos: Revisar la farmacodinamia y la farmacocinética de una nueva equinocandina: micafungina. Métodos: Se ha realizado una revisión simple utilizando una búsqueda bibliográfica en las fuentes habituales (EBSCO Open Journals, Ovid Online, Proquest Medical Library, PubMed/Medline, Science Direct, Springer Links y Wiley Interscience) desde el año 2000 hasta 2008. Adicionalmente, se han incluido los libros de resúmenes de Interscience Conference on Antimicrobial Agents and Chemotherapy and the Infectious Diseases Society of America celebradas desde 1998 hasta 2008. Resultados: La micafungina es una equinocandina con un potente mecanismo de acción: inhibe el enzima β-1,3-D-glucano sintasa e interfiere en la síntesis de la pared celular. Este fármaco comparte con la caspofungina un idéntico espectro in vitro frente a Candida albicans, especies de Candida diferentes de C. albicans y Aspergillus. Debido a la limitada biodisponibilidad oral, la micafungina se administra únicamente por vía parenteral. Se caracteriza por una farmacocinética lineal y por presentar pocos efectos adversos. La micafungina se metaboliza mínimamente por el citocromo P-450 y presenta pocas interacciones farmacológicas. No requiere reducir dosis en fracaso renal, ni en fracaso hepático leve o moderado. Conclusiones: La micafungina presenta un perfil farmacodinámico y farmacocinético que permite su administración de modo seguro, con mínimas interacciones medicamentosas y sin necesidad de ajuste de dosis en presencia de fracaso renal o hepático (AU)

Background: Invasive fungal infections are a significant cause of morbidity and mortality among immuno- compromised patients. Although several new antifungal agents have been developed in the past few years, the management of serious fungal infections continues to be problematic. Aims: To review the pharmacodynamics and pharmacokinetics of a new antifungal agent: micafungin. Methods: A systematic review of biomedic databases (EBSCO Open Journals, Ovid Online, Proquest Medical Library, PubMed/Medline,, Science Direct, Springer Links and Wiley Interscience) has been performed. Search was conducted from 2000 to 2008. Supplementary sources included abstracts from the Interscience Conference on Antimicrobial Agents (ICAAC) and Chemotherapy and the Infectious Diseases Society of America (IDSA) from 1998 to 2008. Results: Micafungin has a potent mechanism of action: inhibits β-1,3-D-glucan synthase interfering with fungal cell wall synthesis. This agent shares with caspofungin an identical spectrum of in vitro activity against Candida albicans, non-albicans Candida species, and Aspergillus. Due to the limited oral availability, micafungin is available for parenteral administration only. Micafungin is characterized by a linear pharmacokinetic profile and substantially fewer toxic effects. Micafungin is a poor substrate for the cytochrome P450 enzymes, and compared to azoles, fewer drug interactions have been described. No dose reduction is required in renal impairment or in mild to moderate liver failure. Conclusions: The pharmacodynamic and pharmacokinetic profiles of micafungin imply that this drug is a safe alternative for the treatment of fungal infections. Micafungin can be safely co-administered with most drugs without the need for dosage adaptation even in patients with renal o liver function impairment (AU)

[Anidulafungin: a new therapeutic approach in antifungal therapy. Pharmacology of anidulafungin]. / Nueva aportación en terapia antifúngica: Anidulafungina. Aspectos farmacológicos de la anidulafungina.

Anidulafungin is a new echinocandin antifungal agent which inhibits beta-1,3-D-glucan synthase and disrupts fungal cell-wall synthesis. It has marked antifungal activity against Candida spp. and Aspergillus spp., including amphotericin B and triazole resistant strains. Due to the limited oral availability, anidulafungin in clinical use is available for parenteral administration only. Elimination of anidulafungin takes place via slow non-enzymatic degradation to inactive metabolites. Less than 10% and 1% of the initially administered drug is excreted unchanged into feces and urine, respectively. It does not require dosage adjustment in subjects with hepatic or renal impairment established. Anidulafungin is generally well tolerated. Adverse events appear not to be dose or infusion related. The most common treatment related adverse events are phlebitis, headache, nausea, vomiting and pyrexia. The lack of interactions with tacrolimus, cyclosporine and corticosteroids and its limited toxicity profile places anidulafungin as an attractive new option for the treatment of invasive fungal infections especially in transplant patients.

[Therapeutic efficacy of anidulafungin for the treatment of oesophageal candidiasis, candidemia and invasive candidiasis]. / Utilidad clínica de la anidulafungina en el tratamiento de las candidiasis esofágicas, candidemias y candidiasis invasoras.

Anidulafungin is a new echinocandin that appears to have several advantages over existing antifungals. It is unique because it slowly degrades in humans, undergoing a process of biotransformation rather than being metabolized. It exhibits high in vitro and in vivo activities against Candida spp. and Aspergillus spp. In several clinical studies investigating Candida esophagitis; candidemia and invasive candidiasis, the clinical efficacy of this echinocandin was similar, or even superior, to that of established antifungals in candidemia. Antifungal activity against strains no longer susceptible to conventional antifungal agents, such as fluconazole and amphotericin B suggests that anidulafungin can be used as salvage therapy in life-threatening fungal infections. The limited toxicity profile, minimal drug-drug interactions and the fact that does not require dosage adjustment in subjects with hepatic or renal impairment, establishes this echinocandin as an attractive new option for the treatment of invasive fungal infections.

Nueva aportación en terapia antifúngica: Anidulafungina. Aspectos farmacológicos de la anidulafungina / Anidulafungin: a new therapeutic approach in antifungal therapy. Pharmacology of anidulafungin

La anidulafungina es una nueva equinocandina que inhibe la síntesis deß-1,3-D-glucano sintasa e interrumpe la síntesis de la pared célular del hongo.Presenta una marcada actividad frente a Candida spp. y Aspergillus spp.,incluyendo las especies resistentes a anfotericina B y triazoles. Debido a sulimitada biodisponibilidad oral únicamente se administra en la clínica por víaparenteral. La anidulafungina sufre un proceso de degradación espontánea enla sangre, no precisando de metabolización hepática y siendo eliminada porvía fecal en su mayoría como metabolitos inactivos. La eliminación urinaria delfármaco es inferior al 1%. No precisa ajuste de dosis en insuficiencia hepáticani renal. La anidulafungina es generalmente bien tolerada. Los efectosadversos notificados no se relacionan ni con la dosis ni con el tipo deinfusión. La mayoría de los efectos adversos son flebitis, cefalea, nauseas,vómitos y fiebre. El limitado perfil de toxicidad y las mínimas interaccionescon otros fármacos (ciclosporina, tacrólimus y corticoesteroides) hacen de laanidulafungina una nueva opción terapéutica para las infecciones fúngicasinvasoras, especialmente en pacientes receptoras de trasplantes(AU)

Anidulafungin is a new echinocandin antifungal agent which inhibitsß-1,3-D-glucan synthase and disrupts fungal cell-wall synthesis. It has markedantifungal activity against Candida spp. and Aspergillus spp., includingamphotericin B and triazole resistant strains. Due to the limited oral availability,anidulafungin in clinical use is available for parenteral administration only.Elimination of anidulafungin takes place via slow non-enzymatic degradation toinactive metabolites. Less than 10% and 1% of the initially administered drugis excreted unchanged into feces and urine, respectively. It does not requiredosage adjustment in subjects with hepatic or renal impairment established.Anidulafungin is generally well tolerated. Adverse events appear not to bedose or infusion related. The most common treatment related adverse eventsare phlebitis, headache, nausea, vomiting and pyrexia. The lack of interactionswith tacrolimus, cyclosporine and corticosteroids and its limited toxicity profileplaces anidulafungin as an attractive new option for the treatment of invasivefungal infections especially in transplant patients(AU)

Utilidad clínica de la anidulafungina en el tratamiento de las candidiasis esofágicas, candidemias y candidiasis invasoras / Therapeutic efficacy of anidulafungin for the treatment of oesophageal candidiasis, candidemia and invasive candidiasis

La anidulafungina es una nueva equinocandina que tiene ventajas respectoa otros antifúngicos. Es la única de su grupo con un metabolismoautobiodegradable. Exhibe una elevada actividad in vitro e in vivo frentea Candida spp. y Aspergillus spp. En diferentes ensayos clínicos se haapreciado que la eficacia de la anidulafungina es similar a la de otrosantifúngicos, e incluso en candidemias es el único superior al comparador alfinal del tratamiento y dos semanas después. La actividad de laanidulafungina frente a cepas resistentes a antifúngicos convencionales leconvierte en un fármaco de primera línea para el tratamiento “de rescate” enestas situaciones. El excelente perfil de seguridad, las limitadas interaccionesque presenta con otros fármacos y el hecho de no requerir ajustes dedosificación en pacientes con fracaso renal o hepático, son factores quehacen de esta equinocandina una nueva y atractiva opción terapéutica eninfecciones fúngicas invasoras(AU)

Anidulafungin is a new echinocandin that appears to have several advantagesover existing antifungals. It is unique because it slowly degrades in humans,undergoing a process of biotransformation rather than being metabolized.It exhibits high in vitro and in vivo activities against Candida spp. andAspergillus spp. In several clinical studies investigating Candida esophagitis;candidemia and invasive candidiasis, the clinical efficacy of this echinocandinwas similar, or even superior, to that of established antifungals in candidemia.Antifungal activity against strains no longer susceptible to conventionalantifungal agents, such as fluconazole and amphotericin B suggests thatanidulafungin can be used as salvage therapy in life-threatening fungalinfections. The limited toxicity profile, minimal drug–drug interactions and thefact that does not require dosage adjustment in subjects with hepatic or renalimpairment, establishes this echinocandin as an attractive new option for thetreatment of invasive fungal infections(AU)