Polymyxin B remains the last-line treatment option for multidrug-resistant Gram-negative bacterial infections. Current U.S. Food and Drug Administration-approved prescribing information recommends that polymyxin B dosing should be adjusted according to the patient's renal function, despite studies that have shown poor correlation between creatinine and polymyxin B clearance. The objective of the present study was to determine whether steady-state polymyxin B exposures in patients with normal renal function were different from those in patients with renal insufficiency. Nineteen adult patients who received intravenous polymyxin B (1.5 to 2.5 mg/kg [actual body weight] daily) were included. To measure polymyxin B concentrations, serial blood samples were obtained from each patient after receiving polymyxin B for at least 48 h. The primary outcome was polymyxin B exposure at steady state, as reflected by the area under the concentration-time curve (AUC) over 24 h. Five patients had normal renal function (estimated creatinine clearance [CL CR ] Ն 80 ml/min) at baseline, whereas 14 had renal insufficiency (CL CR Ͻ 80 ml/min). The mean AUC of polymyxin B Ϯ the standard deviation in the normal renal function cohort was 63.5 Ϯ 16.6 mg·h/liter compared to 56.0 Ϯ 17.5 mg·h/liter in the renal insufficiency cohort (P ϭ 0.42). Adjusting the AUC for the daily dose (in mg/kg of actual body weight) did not result in a significant difference (28.6 Ϯ 7.0 mg·h/liter versus 29.7 Ϯ 11.2 mg·h/liter, P ϭ 0.80). Polymyxin B exposures in patients with normal and impaired renal function after receiving standard dosing of polymyxin B were comparable. Polymyxin B dosing adjustment in patients with renal insufficiency should be reexamined.KEYWORDS polymyxins, dosing adjustment, drug exposure P arenteral polymyxins (polymyxin B and polymyxin E [colistin]) have become one of the most important antibiotics for therapy of extensively drug-resistant Gramnegative bacterial infections over the past decade, including infections caused by carbapenem-resistant nonfermenters and carbapenem-resistant Enterobacteriaceae. The similarities and differences between polymyxin B and colistin have been reviewed elsewhere (1). Polymyxin B has been increasingly used due to the active drug form used, more straight-forward dosing, more favorable pharmacokinetics, and potentially lower incidence of nephrotoxicity than colistin (2, 3). Current U.S. Food and Drug Administration-approved prescribing information recommends polymyxin B dosing adjustment in patients with renal insufficiency (package inserts from Bedford Laboratories,

Background: There is no generally accepted methodology for in vivo assessment of antiviral activity in SARS-CoV-2 infections. Ivermectin has been recommended widely as a treatment of COVID-19, but whether it has clinically significant antiviral activity in vivo is uncertain.Methods: In a multicentre open label, randomized, controlled adaptive platform trial, adult patients with early symptomatic COVID-19 were randomized to one of six treatment arms including high dose oral ivermectin (600µg/kg daily for seven days), the monoclonal antibodies casirivimab and imdevimab (600mg/600mg), and no study drug. The primary outcome was the comparison of viral clearance rates in the modified intention-to-treat population (mITT). This was derived from daily log10 viral densities in standardized duplicate oropharyngeal swab eluates. This ongoing trial is registered at ClinicalTrials.gov (NCT05041907).Results: Randomization to the ivermectin arm was stopped after enrolling 205 patients into all arms, as the prespecified futility threshold was reached. Following ivermectin the mean estimated rate of SARS-CoV-2 viral clearance was 9.1% slower [95%CI -27.2% to +11.8%; n=45] than in the no drug arm [n=41], whereas in a preliminary analysis of the casirivimab/imdevimab arm it was 52.3% faster [95%CI +7.0% to +115.1%; n=10 (Delta variant) versus n=41].Conclusions: High dose ivermectin did not have measurable antiviral activity in early symptomatic COVID-19. Pharmacometric evaluation of viral clearance rate from frequent serial oropharyngeal qPCR viral density estimates is a highly efficient and well tolerated method of assessing SARS CoV-2 antiviral therapeutics in vivo.Funding: 'Finding treatments for COVID-19: A phase 2 multi-centre adaptive platform trial to assess antiviral pharmacodynamics in early symptomatic COVID-19 (PLAT-COV)' is supported by the Wellcome Trust Grant ref: 223195/Z/21/Z through the COVID-19 Therapeutics Accelerator.Clinical trial number: ClinicalTrials.gov (NCT05041907).

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