SummaryBackgroundStaphylococcus aureus bacteraemia is a common cause of severe community-acquired and hospital-acquired infection worldwide. We tested the hypothesis that adjunctive rifampicin would reduce bacteriologically confirmed treatment failure or disease recurrence, or death, by enhancing early S aureus killing, sterilising infected foci and blood faster, and reducing risks of dissemination and metastatic infection.MethodsIn this multicentre, randomised, double-blind, placebo-controlled trial, adults (≥18 years) with S aureus bacteraemia who had received ≤96 h of active antibiotic therapy were recruited from 29 UK hospitals. Patients were randomly assigned (1:1) via a computer-generated sequential randomisation list to receive 2 weeks of adjunctive rifampicin (600 mg or 900 mg per day according to weight, oral or intravenous) versus identical placebo, together with standard antibiotic therapy. Randomisation was stratified by centre. Patients, investigators, and those caring for the patients were masked to group allocation. The primary outcome was time to bacteriologically confirmed treatment failure or disease recurrence, or death (all-cause), from randomisation to 12 weeks, adjudicated by an independent review committee masked to the treatment. Analysis was intention to treat. This trial was registered, number ISRCTN37666216, and is closed to new participants.FindingsBetween Dec 10, 2012, and Oct 25, 2016, 758 eligible participants were randomly assigned: 370 to rifampicin and 388 to placebo. 485 (64%) participants had community-acquired S aureus infections, and 132 (17%) had nosocomial S aureus infections. 47 (6%) had meticillin-resistant infections. 301 (40%) participants had an initial deep infection focus. Standard antibiotics were given for 29 (IQR 18–45) days; 619 (82%) participants received flucloxacillin. By week 12, 62 (17%) of participants who received rifampicin versus 71 (18%) who received placebo experienced treatment failure or disease recurrence, or died (absolute risk difference −1·4%, 95% CI −7·0 to 4·3; hazard ratio 0·96, 0·68–1·35, p=0·81). From randomisation to 12 weeks, no evidence of differences in serious (p=0·17) or grade 3–4 (p=0·36) adverse events were observed; however, 63 (17%) participants in the rifampicin group versus 39 (10%) in the placebo group had antibiotic or trial drug-modifying adverse events (p=0·004), and 24 (6%) versus six (2%) had drug interactions (p=0·0005).InterpretationAdjunctive rifampicin provided no overall benefit over standard antibiotic therapy in adults with S aureus bacteraemia.FundingUK National Institute for Health Research Health Technology Assessment.

Background: Patients with some types of immunodeficiency can experience chronic or relapsing infection with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). This leads to morbidity and mortality, infection control challenges, and the risk of evolution of novel viral variants. The optimal treatment for chronic coronavirus disease 2019 (COVID-19) is unknown. Objective: Our aim was to characterize a cohort of patients with chronic or relapsing COVID-19 disease and record treatment response. Methods: We conducted a UK physician survey to collect data on underlying diagnosis and demographics, clinical features, and treatment response of immunodeficient patients with chronic (lasting > _21 days) or relapsing (> _2 episodes) of COVID-19. Results: We identified 31 patients (median age 49 years). Their underlying immunodeficiency was most commonly characterized by antibody deficiency with absent or profoundly reduced peripheral B-cell levels; prior anti-CD20 therapy, and X-linked agammaglobulinemia. Their clinical features of COVID-19 were similar to those of the general population, but their median duration of symptomatic disease was 64 days (maximum 300 days) and individual patients experienced up to 5 episodes of illness. Remdesivir monotherapy (including when given for prolonged courses of < _20 days) was associated with sustained viral clearance in 7 of 23 clinical episodes (30.4%), whereas the combination of remdesivir with convalescent plasma or anti-SARS-CoV-2 mAbs resulted in viral clearance in 13 of 14 episodes (92.8%). Patients receiving no therapy did not clear SARS-CoV-2. Conclusions: COVID-19 can present as a chronic or relapsing disease in patients with antibody deficiency. Remdesivir monotherapy is frequently associated with treatment failure, but the combination of remdesivir with antibody-based therapeutics holds promise. (J Allergy Clin Immunol 2021;nnn:nnn-nnn.)

Some changes to the conditions for approval were decided in the course of the deliberation. The revised conditions for approval are as follows:[Conditions for approval] 1. The applicant is required to conduct a pharmacokinetic study in accordance with the approved dosage and administration in Japan, and submit the study data and analysis results immediately after the completion of the study and within 1 year after the date of the marketing approval.2. The applicant is required to conduct a clinical study of the product in patients with seasonal influenza virus infection to verify the efficacy and confirm the safety, and to submit the study data and analysis results immediately after the completion of the study.3. The applicant must not manufacture the product without the request of the Minister of Health, Labour and Welfare, unless the study data and analysis results specified in the above 1 and 2 are submitted and necessary actions are taken accordingly.4. The applicant is required to establish a strict distribution management system, and take thorough safety measures in order to ensure that the product is not used in patients with seasonal influenza virus infection, even when the product is to be marketed.5. The applicant is required to take strict and proper measures in order to ensure that the product is not administered to patients unless each individual patient, who is judged to be eligible for its use, or his/her family member is informed of the efficacy and risk of the product in writing and their written informed consent is obtained prior to the start of treatment. *Japanese Accepted Name (modified INN)This English version of the Japanese review report is intended to be a reference material to provide convenience for users. In the event of inconsistency between the Japanese original and this English translation, the former shall prevail. The PMDA will not be responsible for any consequence resulting from the use of this English version. 2.A.(1) Drug substance 2.A.(1).1) Characterization (a) General propertiesThe determined physicochemical properties of the drug substance include description, X-ray powder diffraction, solubility, hygroscopicity, melting point and thermal analysis, dissociation constant, partition coefficient, and crystalline polymorphism.The drug substance is a white to light yellow powder. It is sparingly soluble in acetonitrile and in methanol, and slightly soluble in water and in ethanol (99.5). It is slightly soluble at pH 2.0 to 5.5 and sparingly soluble at pH 5.5 to 6.1.The drug substance is not hygroscopic at 25°C/51% to 93%RH. The melting point is 187°C to 193°C, and the dissociation constant (pKa) is 5.1 due to the hydroxyl group of favipiravir. Measurement results on the partition ratio of favipiravir in water/octanol at 25°C indicate that favipiravir tends to be distributed in the 1-octanol phase at pH 2 to 4 and in the water phase at pH 5 to 13. (b) Structure determinationThe structure of the drug substance is supported by elemental analysis, ultraviolet-visible spectrophotome...

Norovirus is acknowledged to be a leading cause of acute gastroenteritis worldwide, and its importance as a cause of chronic infection in immune deficient hosts is increasingly recognised. Current evidence suggests that a coordinated response of innate immune mechanisms, CD8+ cytotoxicity and a humoral response, with CD4+ orchestration, is necessary for norovirus clearance. We explain how primary immune deficiency impairs these host defences and predisposes to chronic infection, associated with protracted diarrhoea, weight loss, and requirement for parenteral nutrition. The mucosal villous atrophy frequently seen in norovirus infection appears to be immune mediated, suggesting that some functional immune response is required in order for chronic norovirus infection to become symptomatic in primary immune deficiency. We provide a comprehensive summary of published cases of norovirus infection in patients with primary immune deficiency. Spontaneous viral clearance has been described; however, the majority of reported cases have had prolonged and severe illness. Treatment strategies are discussed in detail. Approaches that have been tried in patients with primary immune deficiency include exclusion diets, enteral and intravenous immunoglobulins, breast milk, immunosuppressants, ribavirin, and nitazoxanide. To date, only ribavirin has been used with apparent success to achieve clearance of chronic norovirus in primary immune deficiency, and randomised controlled trials are needed to evaluate a number of promising therapies that are discussed.