Atovaquone for treatment of COVID-19: A prospective randomized, double-blind, placebo-controlled clinical trial.

Background: An in silico screen was performed to identify FDA approved drugs that inhibit SARS-CoV-2 main protease (Mpro), followed by in vitro viral replication assays, and in vivo pharmacokinetic studies in mice. These studies identified atovaquone as a promising candidate for inhibiting viral replication. Methods: A 2-center, randomized, double-blind, placebo-controlled trial was performed among patients hospitalized with COVID-19 infection. Enrolled patients were randomized 2:1 to atovaquone 1500 mg BID versus matched placebo. Patients received standard of care treatment including remdesivir, dexamethasone, or convalescent plasma as deemed necessary by the treating team. Saliva was collected at baseline and twice per day for up to 10 days for RNA extraction for SARS-CoV-2 viral load measurement by quantitative reverse-transcriptase PCR. The primary outcome was the between group difference in log-transformed viral load (copies/mL) using a generalized linear mixed-effect models of repeated measures from all samples. Results: Of the 61 patients enrolled; 41 received atovaquone and 19 received placebo. Overall, the population was predominately male (63%) and Hispanic (70%), with a mean age of 51 years, enrolled a mean of 5 days from symptom onset. The log10 viral load was 5.25 copies/mL vs. 4.79 copies/mL at baseline in the atovaquone vs. placebo group. Change in viral load did not differ over time between the atovaquone plus standard of care arm versus the placebo plus standard of care arm. Pharmacokinetic (PK) studies of atovaquone plasma concentration demonstrated a wide variation in atovaquone levels, with an inverse correlation between BMI and atovaquone levels, (Rho -0.45, p = 0.02). In post hoc analysis, an inverse correlation was observed between atovaquone levels and viral load (Rho -0.54, p = 0.005). Conclusion: In this prospective, randomized, placebo-controlled trial, atovaquone did not demonstrate evidence of enhanced SARS-CoV-2 viral clearance compared with placebo. However, based on the observed inverse correlation between atovaquone levels and viral load, additional PK-guided studies may be warranted to examine the antiviral effect of atovaquone in COVID-19 patients.

Changes in Infective Endocarditis Admissions in Pennsylvania During the Opioid Epidemic.

BACKGROUND: With the current opioid crisis in the United States, infectious complications related to injection drug use are increasingly reported. Pennsylvania is at the epicenter of the opioid crisis, with the third highest rate of drug overdose deaths in the United States. METHODS: A retrospective cohort study was performed using the Pennsylvania Health Care Cost Containment Council database of all residents hospitalized for infective endocarditis (IE) in an acute care hospital from 1 January 2013 through 31 March 2017. Patients were separated into those with and those without substance use via diagnosis codes. The primary outcome was length of stay. Secondarily, we evaluated demographics, infection history, hospital charges, and insurance status. RESULTS: Of the 17 224 hospitalizations, 1921 (11.1%) were in patients with drug use-associated IE (DU-IE). Total quarterly IE admissions increased 20%, with a 6.5% increase in non-drug use-associated IE (non-DU-IE) admissions and a 238% increase in DU-IE admissions. In adjusted models, DU-IE was not associated with significant changes in length of stay (incidence rate ratio, 1.02; 95% confidence interval, .975-1.072; P = .36). Patients with DU-IE were predominantly insured by Medicaid (68.3% vs 13.4% for non-DU-IE), they had higher hospital charges ($86 622 vs $66 802), and they were more likely to leave against medical advice (15.7% vs 1.1%) (all P < .001). CONCLUSIONS: Our study demonstrates an increase in IE admissions, driven by an increase in admissions for DU-IE. The higher charges, proportion of patients on Medicaid, and rates of leaving against medical advice among the DU-IE group shows the downstream effects of the opioid crisis.

Ibogaine-associated cardiac arrest and death: case report and review of the literature.

A naturally occurring hallucinogenic plant alkaloid, ibogaine has been used as an adjuvant for opiate withdrawal for the past 50 years. In the setting of an escalating nationwide opiate epidemic, use of substances such as ibogaine may also increase. Therefore, familiarity with the mechanisms and potential adverse effects of ibogaine is important for clinicians. We present the case report of a man whose use of ibogaine resulted in cardiac arrest and death, complemented by a review of the literature regarding ibogaine's clinical effects. A 40-year-old man who used ibogaine for symptoms of heroin withdrawal suffered acute cardiac arrest leading to cerebral edema and brain death. His presentation was consistent with ibogaine-induced cardiotoxicity and ibogaine-induced cardiac arrest, and a review of the literature regarding the history, mechanisms, risks and clinical outcomes associated with ibogaine is presented. The case presented underscores the significant potential clinical risks of ibogaine. It is important the healthcare community be aware of the possible effects of ibogaine such that clinicians can provide informed counseling to their patients regarding the risks of attempting detoxification with ibogaine.