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OBJECTIVE: One year after the declaration of the SARS-CoV-2 pandemic, only dexamethasone has clearly shown a reduction in mortality for COVID-19 hospitalized patients. For interleukin-6 inhibitors, results are variable and nclear. The objective was to review and analyze the effect of tocilizumab and sarilumab on survival in this setting. METHOD: The PRISMA statements were fulfilled for the systematic review. A systematic search in Medline, Embase and medRxiv was conducted to identify randomized controlled trials with tocilizumab or sarilumab in hospitalized patients with COVID-19. Mortality data from non-critical and critical patients were extracted. A random-effects (DerSimonian-Laird) meta-analysis was performed for both subgroups and the whole population using MAVIS software v. 1.1.3. Similarity and homogeneity among trials were assessed. RESULTS: Twenty-five and 23 articles were identified in Medline and Embase, respectively, five were trials with tocilizumab and/or sarilumab; two more were identified at medRxiv. Seven randomized clinical trials fulfilled the inclusion criteria. Another trial was pre-published and included post-hoc. The meta-analysis, with eight randomized clinical trials and 6,340 patients, showed a benefit on mortality for interleukin-6 heterogeneity (I2 = 7%), but a low similarity among studies. The results showed no differences among critical and non-critical patients. A sensitivity analysis excluding non-similar or heterogeneous studies showed different results, without benefit and with low precision of the result in non-critical patients. CONCLUSIONS: A benefit in mortality for interleukine-6 inhibitors was found, but with important differences among the scenarios analyzed in the clinical trials. Positive results are mainly caused by two randomized clinical trials which are similar in concomitant use of steroids and veryhigh mortality in critical patents. Sarilumab was poorly represented in the meta-analysis. Nevertheless, an association between the benefit and the critical/non-critical condition was not found. More randomized clinical trials, mainly focused in atients at high mortality risk, are needed to confirm the benefit of interleukine- 6 inhibitors for COVID-19. Sarilumab was underrepresented in the meta- analysis. Copyright AULA MEDICA EDICIONES 2014. Published by AULA MEDICA. All rights reserved. OBJETIVO: Un año después de la declaración de la pandemia por SARS‑CoV-2, solo dexametasona había mostrado claramente una reducción de la mortalidad en pacientes hospitalizados por COVID-19. Los resultados de los inhibidores de interleucina 6 son diversos y poco claros. El objetivo de este trabajo es revisar y analizar el efecto de tocilizumab y sarilumab sobre la supervivencia de los pacientes en este escenario.Método: La revisión sistemática siguió las recomendaciones de PRISMA. Se realizó una búsqueda sistemática en Medline, Embase y medRxiv para identificar ensayos controlados aleatorizados con tocilizumab o sarilumab en pacientes hospitalizados con COVID-19. Se recopilaron los datos de mortalidad de pacientes críticos y no críticos y se llevó a cabo un metaanálisis de efectos aleatorios (Der Simonian-Laird) para ambos subgrupos y para toda la población, usando el software MAVIS v. 1.1.3. La similitud y homogeneidad entre los ensayos fue evaluada. RESULTADOS: Se identificaron 25 y 23 artículos en Medline y Embase, respectivamente;cinco eran ensayos con tocilizumab y/o sarilumab; se identificaron dos más en medRxiv. En total, siete ensayos clínicos aleatorizados cumplieron los criterios de inclusión. Posteriormente, se prepublicó otro ensayo que cumplía los criterios de inclusión y se incorporó al análisis. El metaanálisis, con ocho ensayos clínicos aleatorizados y 6.340 pacientes, mostró un beneficio sobre la mortalidad para los inhibidores de interleucina-6 (hazard ratio 0,85;intervalo de confianza al 95% 0,74-0,99), con baja h terogeneidad (I2 = 7%), pero reducida similitud entre los estudios. Los resultados no mostraron diferencias entre pacientes críticos y no críticos. Un análisis de sensibilidad excluyendo estudios heterogéneos o no similares mostró resultados diferentes, sin beneficio y con baja precisión del resultado en pacientes no críticos. CONCLUSIONES: Se encontró un beneficio en la mortalidad de los inhibidores de la interleucina 6, pero con importantes diferencias entre los escenarios analizados en los ensayos clínicos. Los resultados positivos se eben principalmente a dos ensayos que son similares en el uso concomitante de esteroides y una mortalidad muy alta en pacientes críticos. Sarilumab estuvo escasamente representado en el metaanálisis. Sin embargo, el metaanálisis por subescenarios no encontró una relación entre el beneficio y la condición de pacientes críticos/no críticos. Se necesitan más ensayos clínicos aleatorizados, principalmente enfocados en pacientes con alto riesgo de mortalidad, para confirmar el beneficio de los inhibidores de interleucina-6 en COVID-19.
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Background and importance Isavuconazole is a new antifungal triazole authorised for invasive aspergillosis and mucormycosis. It is a therapeutic alternative to voriconazole and liposomal amphotericin B for invasive aspergillosis, and to liposomal amphotericin B in mucormycosis. Aim and objectives To analyse prescription characteristics of isavuconazole in patients with COVID-19 in an intensive care unit (ICU) as well as its effectiveness and safety. Material and methods A cross-sectional, observational study was conducted (June 2020-April 2021). Patients with COVID-19 in an ICU on treatment with isavuconazole were included. Electronic prescription program and clinical history were used to collect the following data: sex, age, comorbidities, coinfection with other pathogens in addition to SARS-CoV-2, type of therapy (empirical/targeted), duration and previous azole treatment (yes/no). Effectiveness was evaluated by symptoms resolution, reasons for treatment suspension and status (alive/death) 30 days after completion of treatment. Safety was assessed according to adverse events (AE). Results Thirty-three patients (54.5% men) with mean age of 61 (35-77) years were evaluated. Twenty-nine patients (87.9%) had comorbidities, the most frequent were: hypertension (19.1%), dyslipidaemia (12.8%), obesity (11.7%) and diabetes (8.5%). Thirty-two (96.9%) had coinfections, with a mean of 1.8 (SD 1.2) infections/patient. The most implicated pathogens were: Acinetobacter baumanii (18.8%), Candida albicans (11.6%) and Aspergillus fumigatus (8.7%). Twentythree patients (69.7%) received isavuconazole as empirical therapy and 10 (30.3%) as targeted. Mean duration of treatment was 12.3 (SD 7.5) days. Twenty-five (75.6%) patients had not previously received azole treatment, 7 (21.3%) had received voriconazole and 1 (3%) fluconazole. Symptoms resolution was observed in 12 (36.4%) cases. Seven patients (21.2%) discontinued treatment due to negative culture, 12 (36.4%) due to symptoms resolution and 14 (42.4%) due to death. At 30 days completion of treatment, 15 patients (45.5%) remained alive and 18 (54.5%) had died. AE were recorded in 6 cases (18.2%): liver disorders (n=4) and electrolytic alterations (n=2). Conclusion and relevance Most patients presented comorbidities and coinfections in addition to COVID-19. Effectiveness of isavuconazol was adequate in approximately one-third of patients, despite the high severity and clinical complexity. Approximately half the patients remained alive at 30 days following completion of treatment. Isavuconazol was well tolerated in most cases.
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Background and importanceThe SARS-CoV-2 pandemic has generated new needs in outpatient care of the hospital pharmacy. Despite the current improvement in the pandemic situation, many of the implemented progress have been maintained. Telepharmacy and home delivery programmes avoid hospital visits for vulnerable patients (elderly, pluripathology, mobility problems).Aim and objectivesTo analyse the degree of satisfaction of patients included in a telepharmacy and home delivery programme.Material and methodsDescriptive retrospective study of patients included in a telepharmacy and home delivery programme between November 2020 and September 2021 was conducted. Electronic clinical history and prescription software Farmatools were used to record data: sex, age, pathology, locality, transport conditions of the medication and number of shipments per patient. A telephone survey was conducted, consisting of four questions about: satisfaction with telepharmacy programme (yes/no), adequate pharmaceutical telephone support (yes/no), medication delivery conditions (correct/incorrect) and global assessment (ranged 1–10). Comments and suggestions were also requested.ResultsFifty-six patients were included, 35 (63%) were women and 21 (37%) men. Mean age was 65 (37–90) years. The pathologies involved were: 11 (20%) infectious diseases, 10 (18%) respiratory, 9 (16%) rheumatic, 8 (14%) neurological, 7 (12%) renal, 5 (9%) haematological, 3 (5%) ophthalmological, 2 (4%) digestive and 1 (2%) allergic. A total of 456 medication shipments were delivered during the study period, with a mean of 8 (2–24) per patient. The shipments were distributed among 31 different localities in the same health area. The medication for 27 (48%) patients required refrigerated transport, and 29 (52%) required ambient temperature. All (100%) patients were satisfied with telepharmacy programme and reported an adequate pharmaceutical telephone support. Medication delivery conditions were considered correct to 54 (96%) patients and incorrect to 2 (4%). Mean global assessment score was 9.6 (8–10). Four (7%) patients suggested an improvement in delivery conditions.Conclusion and relevanceThe survey results indicated a high degree of satisfaction of the patients included in the telepharmacy and home delivery programme. Although this system of pharmaceutical care and distribution of medicines was implemented because of the pandemic, its subsequent maintenance has allowed vulnerable patients to benefit. Further measures could be implemented to improve delivery conditions.References and/or acknowledgementsConflict of interestNo conflict of interest
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Background and importanceCefiderocol is a new siderophore cephalosporin for the treatment of multidrug-resistant Gram-negative pathogens such as Acinetobacter baumannii (AB).Aim and objectivesTo describe our clinical experience with cefiderocol use in two SARS-CoV-2 patients with ventilator-associated pneumonia (VAP) due to multidrug-resistant AB (MRAB).Material and methodsA descriptive retrospective study on cefiderocol therapy in two patients with MRAB was conducted until 31 Augsut 2021. The electronic medical record was used to collect data: comorbidities, baseline clinical context, treatment, and clinical evolution of patients.ResultsA 49-year-old man with hypertension, obesity and chronic renal insufficiency was diagnosed with SARS-CoV-2. He required orotracheal intubation (OI) and mechanical ventilation (MV). The patient presented VAP after 4 weeks in the intensive care unit (ICU). Panresistant AB was isolated from bronchoalveolar lavage (BAL) and was treated with cefepime, imipenem, tigecycline and nebulised colistin. Given his poor clinical improvement, cefiderocol 2 g/8 hours (14 days) was initiated. No renal dose adjustment was performed for cefiderocol. Clinical evolution was favourable. The patient remained afebrile and acute phase reactants (APR) decreased. Unfavourable evolution and increased APR were observed on the third day after treatment with cefiderocol, with presence of AB in BAL. The patient died of multiorgan dysfunction syndrome 8 days later.A 65-year-old man with hypertension, dyslipidaemia and diabetes was diagnosed with SARS-CoV-2. He required OI and MV. After 4 weeks in ICU, the patient presented VAP due to MRAB and coinfection with Mycoplasma pneumoniae. Tigecycline, nebulised colistin and ceftazidime/avibactam were used. A clinical worsening was observed and cefiderocol 2 g/8 hours (14 days) and amikacin (5 days) were started. The patient remained afebrile and APR slightly decreased after initiation of cefiderocol and amikacin treatments. BAL culture was negative, although AB colonisation persisted in pharynx. Tigecycline, piperacillin/tazobactam and nebulised colistin were administered. After 71 days in ICU, the patient was transferred to a hospital ward, where he remained for 98 days before discharge.Conclusion and relevanceThe use of cefiderocol led to a slight improvement in two patients with VAP caused by MRAB. One patient died due to multiorgan dysfunction syndrome after cefiderocol therapy, and the other case required subsequent antibiotherapy due to persistence of MRAB.References and/or acknowledgementsConflict of interestNo conflict of interest
ABSTRACT
OBJECTIVE: A possible benefit has been suggested for early treatment of severe coronavirus disease 2019 (COVID-19) with remdesivir. The efficacy of this drug is controversial and could significantly influence the efficiency in healthcare systems. The objective is the methodological interpretation of subgroup analyzes according to starting of remdesivir treatment with respect to symptom onset of COVID-19. METHODS: A search in Pubmed® database was performed. Randomized clinical trials (RCTs) with subgroup analysis regarding early and late use of remdesivir were selected. All endpoints were assessed using two methodologies. First methodology considered statistical interaction, pre-specification, biological plausibility, and consistency of results. Second methodology was a validated tool with preliminary questions to discard subset analysis without relevant minimum conditions, and a checklist with recommendations for applicability. RESULTS: A total of 54 results were found and five RCTs were selected. According first methodology, consistent heterogeneity was only found in time to clinical improvement and better clinical status score at day 15 for patients with severe COVID-19 and <7 days of symptoms. About second methodology, these results about early use of remdesivir may be applied to clinical practice with caution. CONCLUSIONS: We developed a systematic search and application of an established methodology for interpretation of subgroup analysis about early use of remdesivir. Results in severe COVID-19 suggested that early use of remdesivir provides a greater benefit in <7 days of symptoms for time to clinical improvement and better clinical status score at day 15. Future studies could use 7-day cut-off of symptoms to evaluate remdesivir.
Subject(s)
COVID-19 Drug Treatment , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/therapeutic use , Alanine/analogs & derivatives , Alanine/therapeutic use , Antiviral Agents/therapeutic use , HumansABSTRACT
Background and importance A greater benefit was suggested with early treatment with remdesivir against COVID-19. Aim and objectives To develop a systematic review and methodological interpretation of subgroup analyses according to timing of use of remdesivir in COVID-19. Material and methods A bibliographic review in MEDLINE was conducted up to 10 October 2020. The 'Clinical Queries/ Narrow' tool was used with the search strategy: ((Therapy/ Narrow[filter]) AND (remdesivir AND COVID)). Randomised clinical trials (RCTs) with subset analysis about early and late use of remdesivir (≤10 vs >10 days from symptom onset, or ≤9 vs >9 days) were selected. The rest of the studies were excluded. All endpoints with subgroup analysis regarding timing of remdesivir use were assessed. Two methodologies were applied. The first considered statistical interaction among subsets, prespecification, biological plausibility and consistency of the subgroup analyses of similar RCTs.1 The second methodology was a validated tool with preliminary questions to discard subset analysis without minimal relevance, and a checklist.2 This checklist assigned a score related to a recommendation for applicability of subgroup analysis in clinical practice. Results 20 results were found after review;16 studies were excluded because they were not RCTs and 1 study had no efficacy evaluation of remdesivir. Therefore, three RCTs were selected. Endpoints considered were: time to clinical improvement, mortality, viral load, and clinical status at days 11 and 15. According to the first methodology, no statistical interaction was observed in the outcomes of the RCTs. Prespecification was established in time to clinical improvement, and clinical status at day 15 of an RCT. Biological plausibility was described in the subset analysis of each endpoint of the RCTs. No consistency of subgroup analyses were found. The second methodology discarded the applicability of the subset analysis through preliminary questions in two RCTs because of the absence of minimal relevance. For the third RCT, 'null' recommendation (score -3 points) of clinical applicability was reached for clinical status at day 11. Conclusion and relevance No differences were found between early and late use of remdesivir in COVID-19. We developed the first study with a systematic review and methodology about subgroup analysis of timing of use of remdesivir.