ABSTRACT
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.
ABSTRACT
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.