Favipiravir in early symptomatic COVID-19, a randomised placebo-controlled trial.

Background: Well tolerated antivirals administered early in the course of COVID-19 infection when the viremia is highest could prevent progression to severe disease. Favipiravir inhibits SARS-CoV-2 viral replication in vitro with evidence of clinical benefit in open label trials. Placebo controlled studies of people with early symptomatic COVID-19 with regular assessments of SARS-CoV-2 viral load can determine if it has an antiviral effect and improves clinical outcomes. Methods: People with PCR-confirmed COVID-19 and 5 days or less of symptoms were randomised 1:1 to favipiravir 1800 mg on day 1, then 800 mg twice daily or matched placebo for 14 days. SARS-CoV-2 viral load was quantitated from second daily self-collected nose-throat swabs while receiving study drug. The primary endpoint was time to virological cure defined as 2 successive swabs negative for SARS-CoV-2 by PCR and secondary outcomes were progression of disease severity, symptom resolution and safety. Findings: Between 31 July 2020 and 19 September 2021, 200 people were enrolled (199 in the community, 1 in hospital) with 190 receiving one or more doses of drug (modified intention to treat [mITT] population). There was no difference in time to virological cure (Log-rank p=0.6 comparing Kaplan Meier curves), progression to hospitalisation (14 favipiravir, 9 placebo; p=0.38), time to symptom resolution (cough, fever, sore throat) and there were no deaths. 51 people related an adverse event that was possibly drug related, but these were evenly distributed (n=24 favipiravir, n=27 placebo). Sensitivity analyses where the definition of virological cure was changed to: a single negative PCR, exclude datapoints based on the presence or absence of human DNA in the swab, a SARS-CoV-2 viral load < 300 copies/mL being considered negative all demonstrated no difference between arms. Interpretation: Favipiravir does not improve the time to virological cure or clinical outcomes and shows no evidence of an antiviral effect when treating early symptomatic COVID-19 infection. Funding: The study was supported in part by grants from the Commonwealth Bank Australia, the Lord Mayor's Charitable Foundation, Melbourne Australia and the Orloff Family Charitable Trust, Melbourne, Australia. JHM is supported by the Medical Research Future Fund, AYP, JT are supported by the Australian National Health and Medical Research Council.

Attributable mortality and excess length of stay associated with third-generation cephalosporin-resistant Enterobacterales bloodstream infections: a prospective cohort study in Suva, Fiji.

OBJECTIVES: There are scant primary clinical data on antimicrobial resistance (AMR) burden from low- and middle-income countries (LMICs). We adapted recent World Health Organization methodology to measure the effect of third-generation cephalosporin resistance (3GC-R) on mortality and excess length of hospital stay in Fiji. METHODS: We conducted a prospective cohort study of inpatients with Enterobacterales bloodstream infections (BSIs) at Colonial War Memorial Hospital, Suva. We used cause-specific Cox proportional hazards models to estimate the effect of 3GC-R on the daily risk (hazard) of in-hospital mortality and being discharged alive (competing risks), and we used multistate modelling to estimate the excess length of hospital stay. RESULTS: From July 2020 to February 2021 we identified 162 consecutive Enterobacterales BSIs; 3GC-R was present in 66 (40.7%). Crude mortality for patients with 3GC-susceptible and 3GC-R BSIs was 16.7% (16/96) and 30.3% (20/66), respectively. 3GC-R was not associated with the in-hospital mortality hazard rate (adjusted hazard ratio [aHR] 1.13, 95% confidence interval [CI] 0.51-2.53) or being discharged alive (aHR 0.99, 95% CI 0.65-1.50), whereas Charlson comorbidity index score (aHR 1.62, 95% CI 1.36-1.93) and Pitt bacteraemia score (aHR 3.57, 95% CI 1.31-9.71) were both associated with an increased hazard rate of in-hospital mortality. 3GC-R was associated with an increased length of stay of 2.6 days (95% CI 2.5-2.8). 3GC-R was more common among hospital-associated infections, but genomics did not identify clonal transmission. CONCLUSION: Patients with Enterobacterales BSIs in Fiji had high mortality. There were high rates of 3GC-R, which was associated with increased hospital length of stay but not with in-hospital mortality.

Epidemiology, antimicrobial resistance and outcomes of Staphylococcus aureus bacteraemia in a tertiary hospital in Fiji: A prospective cohort study.

Background: Staphylococcus aureus bacteraemia (SAB) is one of the commonest bloodstream infections globally and is associated with a high mortality rate. Most published data comes from temperate, high-income countries. We describe the clinical epidemiology, microbiology, management and outcomes of patients with SAB treated in a tropical, middle-income setting at Fiji's largest hospital. Methods: A prospective, observational study was performed of consecutive SAB cases admitted to Colonial War Memorial Hospital (CWMH) in Suva, between July 2020 and February 2021. Detailed demographic, clinical and microbiological data were collected, including the key outcome of in-patient mortality. To estimate the population incidence, all SAB cases diagnosed at the CWMH laboratory were included - even if not admitted to CWMH - with the population of Fiji's Central Division used as the denominator. Findings: A total of 176 cases of SAB were detected over eight-months, which equated to an incidence of 68.8 cases per 100,000 population per year. Of these, 95 cases were admitted to CWMH within 48 h of index culture. Approximately 8.4% (8/95) of admitted cases were caused by methicillin-resistant Staphylococcus aureus (MRSA). All cause in-patient mortality was 25.3%, increasing to 55% among patients aged 60 or older. Interpretation: This reported incidence of SAB in central Fiji is one of the highest in the world. SAB was associated with significant mortality, especially in those over 60 years of age, despite a relatively low frequency of methicillin resistance. Funding: Supported by the National Health and Medical Research Council (Australia) and the GRAM (Global Research on Antimicrobial Resistance) Project, Oxford University (United Kingdom).