Five years of outpatient parenteral antibiotic therapy with ceftriaxone in the paediatric emergency department: what clinical features are associated with need for admission?

BACKGROUND: More children presenting to Emergency Departments (EDs) with acute infections are now directly referred for outpatient parenteral antibiotic therapy (OPAT). Sparse data exist on what clinical features in these children are associated with OPAT failure. We hypothesised that children who were younger or presented with systemic features of infection would be more likely to need admission. METHODS: We conducted a service evaluation over a 5-year period (12 September 2015-12 September 2020) at a single UK tertiary centre paediatric ED formally known as the Royal Hospital for Sick Children Edinburgh. All children referred from the ED for OPAT with ceftriaxone were included. OPAT failure was defined as a decision by a senior clinician of need for admission. Univariate statistical testing and multivariate logistic regression modelling were performed. RESULTS: 754 children received OPAT in the ED over a 5-year period. 95 children (13%) required admission for inpatient management. Need for admission was independently associated with having a positive blood culture (adjusted OR (aOR) 8.9; 95% CI 1.49 to 47; p=0.01) or an ultrasound performed (aOR 6.8; 95% CI 3.74 to 12.7; p<0.001). We observed no significant association between age and systemic features (fever, white cell count or C reactive protein) with need for admission in our multivariate analysis. CONCLUSION: In children presenting with acute infections to our paediatric ED who were deemed suitable by senior clinicians to be managed using OPAT with ceftriaxone, younger age (above 3 months) and the presence of systemic features were not independently associated with need for admission. Overall, our service was safe and no child came to harm from early ambulation during this evaluation.

Loss of furin cleavage site attenuates SARS-CoV-2 pathogenesis.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-a new coronavirus that has led to a worldwide pandemic1-has a furin cleavage site (PRRAR) in its spike protein that is absent in other group-2B coronaviruses2. To explore whether the furin cleavage site contributes to infection and pathogenesis in this virus, we generated a mutant SARS-CoV-2 that lacks the furin cleavage site (ΔPRRA). Here we report that replicates of ΔPRRA SARS-CoV-2 had faster kinetics, improved fitness in Vero E6 cells and reduced spike protein processing, as compared to parental SARS-CoV-2. However, the ΔPRRA mutant had reduced replication in a human respiratory cell line and was attenuated in both hamster and K18-hACE2 transgenic mouse models of SARS-CoV-2 pathogenesis. Despite reduced disease, the ΔPRRA mutant conferred protection against rechallenge with the parental SARS-CoV-2. Importantly, the neutralization values of sera from patients with coronavirus disease 2019 (COVID-19) and monoclonal antibodies against the receptor-binding domain of SARS-CoV-2 were lower against the ΔPRRA mutant than against parental SARS-CoV-2, probably owing to an increased ratio of particles to plaque-forming units in infections with the former. Together, our results demonstrate a critical role for the furin cleavage site in infection with SARS-CoV-2 and highlight the importance of this site for evaluating the neutralization activities of antibodies.