The WHO guideline on drugs to prevent COVID-19: small numbers- big conclusions.

The World Health Organization (WHO) living guideline on drugs to prevent COVID-19 has recently advised that ongoing trials evaluating hydroxychloroquine in chemoprophylaxis should stop. The WHO guideline cites "high certainty" evidence from randomised controlled trials (RCTs) that hydroxychloroquine prophylaxis does not reduce mortality and does not reduce hospital admission, and "moderate certainty" evidence of poor tolerability because of a significantly increased rate of adverse events leading to drug discontinuation. Yet there is no such evidence. In the three pre-exposure chemoprophylaxis RCTs evaluated in the guideline there were no deaths and only two COVID-19-related hospital admissions, and there was a mistake in the analysis of the number of discontinuations (after correction there is no longer a statistically significant difference between those taking the drug and the controls). Guidelines on the prevention and treatment of COVID-19 should be based on sufficient verified evidence, understanding of the disease process, sound statistical analysis and interpretation, and an appreciation of global needs. The WHO living guideline on the prevention of COVID-19 should retract the advice to stop research on hydroxychloroquine chemoprophylaxis, should correct its errors, and should revise its guidance.

Does hydroxychloroquine still have any role in the COVID-19 pandemic?

Introduction: The 4-aminoquinolines, chloroquine, and hydroxychloroquine have been used for over 70 years for malaria and rheumatological conditions, respectively. Their broad-spectrum antiviral activity, excellent safety profile, tolerability, low cost, and ready availability made them prime repurposing therapeutic candidates at the beginning of the COVID-19 pandemic.Areas covered: Here, the authors discuss the history of hydroxychloroquine and chloroquine, the in vitro data which led to their widespread repurposing and adoption in COVID-19 and their complex pharmacokinetics. The evidence for the use of these drugs is assessed through in vivo animal experiments and the wealth of conflicting data and interpretations published during COVID-19, including the more informative results from randomized controlled trials (RCTs). The safety aspects of these drugs, in particular cardiotoxicity, are then reviewed.Expert opinion: The evidence from clinical trials in COVID-19 supports the well-established safety record of the 4-aminoquinolines at currently recommended dosage. In hospitalized patients with severe COVID-19 RCTs show clearly that the 4-aminoquinolines are not beneficial. The only treatments with proven benefit at this stage of infection are immunomodulators (dexamethasone, IL-6 receptor antagonists). No antiviral drugs have proven life-saving in late-stage COVID-19.

Blood culture negative endocarditis in the modern era of 16S rRNA sequencing.

Blood culture negative endocarditis (BCNE) accounts for up to 20% of infective endocarditis. While the most common cause of BCNE remains the initiation of antibiotics prior to culture, intracellular organisms such as Coxiella and Bartonella spp account for a significant proportion of cases. Identifying the infecting organism remains important to ensure optimal antimicrobial treatment. However, these organisms can be difficult to diagnose. We outline a systematic approach to BCNE. Over half of patients with infective endocarditis now undergo early surgery and 16S ribosomal ribonucleic acid (rRNA) polymerase chain reaction (PCR) of excised tissue can be vitally important to secure a diagnosis. Molecular testing is likely to become a key tool in improving outcomes from BCNE and contribute to an improved understanding of the aetiology. We advocate modifying the Duke criteria to incorporate organisms identified on molecular testing, including 16S rRNA PCR, in particular from explanted tissue.