Zanamivir aqueous solution in severe influenza: A global Compassionate Use Program, 2009-2019.

BACKGROUND: Zanamivir is a neuraminidase inhibitor effective against influenza A and B viruses. In 2009, GlaxoSmithKline (GSK) began clinical development of intravenous (IV) zanamivir and initiated a global Compassionate Use Program (CUP) in response to the evolving H1N1 global pandemic. The goal of the CUP was to provide zanamivir to critically ill patients with limited treatment options. METHODS: Zanamivir was administered to patients with suspected or confirmed influenza infection who were not suitable for other approved antiviral treatments. Reporting of serious adverse events (SAEs) was mandatory and recorded in the GSK safety database. A master summary tracking sheet captured requests and patient characteristics. A case report form was available for detailing medical conditions, dosing, treatment duration, and clinical outcomes. RESULTS: In total, 4,033 requests were made for zanamivir treatment of hospitalized patients from 38 countries between 2009 and 2019; ≥95% patients received zanamivir via the IV route. Europe had the highest number of requests (n = 3,051) followed by North America (n = 713). At least 20 patients were aged ≤6 months, of whom 12 were born prematurely. The GSK safety database included 466 patients with ≥1 SAE, of whom 374 (80%) had a fatal outcome. Drug-related SAEs were reported in 41 (11%) patients, including hepatic failure (n = 6 [2%]) and acute kidney injury (n = 5 [1%)]. CONCLUSIONS: The CUP facilitated global access to zanamivir prior to product approval. No new safety concerns were identified in the CUP compared with IV zanamivir clinical studies.

Streptococcus sanguis secretes CD14-binding proteins that stimulate cytokine synthesis: a clue to the pathogenesis of infective (bacterial) endocarditis?

Streptococcus sanguis is the major causative organism of infective (bacterial) endocarditis but, surprisingly, almost nothing is known about how it induces endocardial inflammation. In earlier studies we have shown that many bacteria secrete potent cytokine-inducing or -inhibiting proteins. We have therefore isolated the material secreted by S. sanguis grown on blood agar or in broth culture and have tested its ability to induce human peripheral blood monocytes to synthesize pro-inflammatory cytokines. The activation of monocytes by the secreted components of S. sanguis was almost totally blocked by heat and trypsin treatment but not by the lipopolysaccharide-inactivating antibiotic, polymyxin B, suggesting that activity is due to secreted proteins. The activity of the secreted material was significantly reduced by anti-CD14 monoclonal antibodies suggesting that the active protein (or proteins) was binding to the CD14/Toll-like receptor (TLR)4 complex. Fractionation of the secreted proteins by high performance liquid chromatography (HPLC) identified two proteins as being responsible for the majority of the cytokine induction: a manganese-dependent superoxide dismutase and a 190 kDa protein, which could not be sequenced, but which was neither CshA nor the PI/II proteins. These proteins, or the receptors to which they bind, may be therapeutic targets and may allow the development of adjunctive therapies to prevent endocardial damage during the often prolonged treatment of infective endocarditis with antibiotics. In addition, blocking of CD14 may have some therapeutic benefit.