Purpose: Community transmission of SARS-CoV-2 was detected in Spain in February 2020, with 216% intensive care unit (ICU) capacity expanded in Vitoria by March 18 th , 2020. Methods:We identified patients from the two public hospitals in Vitoria who were admitted to ICU with confirmed infection by SARS-CoV-2. Data reported here were available in March 31th, 2020. Mortality was assessed in those who completed 7-days of ICU stay. Results: We identified 48 patients (27 males) with confirmed SARS-CoV-2. Median [interquartile range (IQR)] age of patients was 63 [51-75] years. Symptoms began a median of 7 [5-12] days before ICU admission. The most common comorbidities identified were obesity (n = 48%), arterial hypertension (n = 44%) and chronic lung disease (n = 37%). All patients were admitted by hypoxemic respiratory failure and none received non-invasive mechanical ventilation. Forty-five (94%) underwent intubation, 3 HFNT, 1 (2%) extracorporeal membrane oxygenation (ECMO) and 22 (49%) required prone position. After 15 days, 14/45 (31%) intubated patients died (13% within one week), 10 (22%) were extubated, and 21/45 (47%) underwent mechanical ventilation. Six patients had documented co-infection. Procalcitonin plasma above 0.5 µg/L was associated with 16% vs. 19% (p = 0.78) risk of death after 7 days. Conclusion: This early experience with SARS-CoV-2 in Spain suggests that a strategy of right oxygenation avoiding non-invasive mechanical ventilation was life-saving. Seven-day mortality in SARS-CoV-2 requiring intubation was lower than 15%, with 80% of patients still requiring mechanical ventilation. After 15 days of ICU admission, half of patients remained intubated, whereas one third died. Page 4 of 25 J o u r n a l P r e -p r o o f third were non-survivors. Our clinical observations provide useful insights that can help to improve management and outcomes.

ARC is a prevalent condition in critically ill patients, especially in young people, with urinary CrCl being the best diagnostic method because mathematical estimates tend to underestimate CrCl. ARC increases renal drug elimination and has a clear influence on certain antimicrobial plasma levels, but is yet to define its impact on clinical outcomes and on pharmacokinetics of other types of drugs. Research on the need to stage ARC and establish specific dosing guidelines is warranted.

The aim of this study was to assess the influence of renal function, in particular the presence of augmented renal clearance (ARC), on the pharmacokinetics of linezolid in critically ill patients. The effect of continuous infusion on the probability of therapeutic success from a pharmacokinetic/pharmacodynamic (PK/PD) perspective was also evaluated. Methods: Seventeen patients received linezolid (600 mg every 12 h) as a 30-min infusion and 26 as a continuous infusion (50 mg/h). The PK parameters were calculated and the probability of PK/PD target attainment (PTA) was estimated by Monte Carlo simulation (MCS) for different doses administered by intermittent (600 mg every 12 h or 600 mg every 8 h) or continuous infusion (50 mg/h or 75 mg/h). Results: In patients without ARC, the standard dose was adequate to attain the PK/PD target. However, linezolid clearance was significantly higher in ARC patients, leading to sub-therapeutic concentrations. Continuous infusion (50 mg/h) provided concentrations !2 mg/l in 70% of the ARC patients. MCS revealed that concentrations !2 mg/l would be reached in >90% of patients receiving 75 mg/h. Conclusions: ARC increases linezolid clearance and leads to a high risk of underexposure with the standard dose. Continuous infusion increases the PTA, but an infusion rate of 75 mg/h should be considered to ensure concentrations !2 mg/ml.

Antimicrobial treatment in critically ill patients remains challenging. The aim of this study was to develop a population pharmacokinetic model for linezolid in critically ill patients and to evaluate the adequacy of current dosing recommendation (600 mg/12 h). Forty inpatients were included, 23 of whom were subjected to continuous renal replacement therapies (CRRT). Blood and effluent samples were drawn after linezolid administration at defined time points, and linezolid levels were measured. A population pharmacokinetic model was developed, using NONMEM 7.3. The percentage of patients that achieved the pharmacokinetic/pharmacodynamic (PK/PD) targets was calculated (AUC24/MIC > 80 and 100% T>MIC). A two-compartment model best described the pharmacokinetics of linezolid. Elimination was conditioned by the creatinine clearance and by the extra-corporeal clearance if the patient was subjected to CRRT. For most patients, the standard dose of linezolid did not cover infections caused by pathogens with MIC ≥ 2 mg/L. Continuous infusion may be an alternative, especially when renal function is preserved.

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