RESUMEN
Repurposing approved drugs may rapidly establish effective interventions during a public health crisis. This has yielded immunomodulatory treatments for severe COVID-19, but repurposed antivirals have not been successful to date because of redundancy of the target in vivo or suboptimal exposures at studied doses. Nitazoxanide is an FDA approved antiparasitic medicine, that physiologically-based pharmacokinetic (PBPK) modelling has indicated may provide antiviral concentrations across the dosing interval, when repurposed at higher than approved doses. Within the AGILE trial platform (NCT04746183) an open label, adaptive, phase 1 trial in healthy adult participants was undertaken with high dose nitazoxanide. Participants received 1500mg nitazoxanide orally twice-daily with food for 7 days. Primary outcomes were safety, tolerability, optimum dose and schedule. Intensive pharmacokinetic sampling was undertaken day 1 and 5 with Cmin sampling on day 3 and 7. Fourteen healthy participants were enrolled between 18th February and 11th May 2021. All 14 doses were completed by 10/14 participants. Nitazoxanide was safe and well tolerated with no significant adverse events. Moderate gastrointestinal disturbance (loose stools) occurred in 8 participants (57.1%), with urine and sclera discolouration in 12 (85.7%) and 9 (64.3%) participants, respectively, without clinically significant bilirubin elevation. This was self-limiting and resolved upon drug discontinuation. PBPK predictions were confirmed on day 1 but with underprediction at day 5. Median Cmin was above the in vitro target concentration on first dose and maintained throughout. Nitazoxanide administered at 1500mg BID with food was safe and well tolerated and a phase 1b/2a study is now being initiated in COVID-19 patients.
RESUMEN
Congregate settings and high-density workplaces have endured a disproportionate impact from COVID-19. In order to provide further understanding of the transmission patterns of SARS-CoV-2 in these settings, whole genome sequencing (WGS) was performed on samples obtained from 8 selected outbreaks in Minnesota from March - June, 2020. WGS and phylogenetic analysis was conducted on 319 samples, constituting 14.4% of the 2,222 total SARS-CoV-2-positive individuals associated with these outbreaks. Among the sequenced specimens, three LTCFs and both correctional facilities had spread associated with a single genetic sequence. A fourth LTCF had outbreak cases associated with two distinct sequences. In contrast, cases associated with outbreaks in the two meat processing plants represented multiple SARS-CoV-2 sequences. These results suggest that a single introduction of SARS-CoV-2 into a facility can result in a widespread outbreak, and early identification and cohorting of cases, along with continued vigilance with infection prevention and control measures is imperative.
