Search

Platelets are a critical immune defense against Staphylococcus aureus bloodstream infections. Staphylococcus aureus α-toxin is a virulence factor that decreases platelet viability and accelerates platelet clearance. It has been shown that ticagrelor blocks α-toxin-mediated platelet injury and resulting thrombocytopenia, protecting mice in a lethal S. aureus sepsis model. We now present the use of ticagrelor as adjunctive therapy in a patient with a S. aureus endovascular infection and thrombocytopenia, associated with restoration of platelet count and bacteremia clearance. Ticagrelor enhanced platelet killing of the S. aureus bloodstream isolate from the treated patient in vitro., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Staphylococcus aureus expresses a panel of cell wall-anchored adhesins, including proteins belonging to the microbial surface components recognizing adhesive matrix molecule (MSCRAMM) family, exemplified by the serine-aspartate repeat protein D (SdrD), which serve key roles in colonization and infection. Deletion of sdrD from S. aureus subsp. aureus strain NCTC8325-4 attenuated bacterial survival in human whole blood ex vivo, which was associated with increased killing by human neutrophils. Remarkably, SdrD was able to inhibit innate immune-mediated bacterial killing independently of other S. aureus proteins, since addition of recombinant SdrD protein and heterologous expression of SdrD in Lactococcus lactis promoted bacterial survival in human blood. SdrD contributes to bacterial virulence in vivo, since fewer S. aureus subsp. aureus NCTC8325-4 ΔsdrD bacteria than bacteria of the parent strain were recovered from blood and several organs using a murine intravenous infection model. Collectively, our findings reveal a new property of SdrD as an important key contributor to S. aureus survival and the ability to escape the innate immune system in blood., (Copyright © 2016 Askarian et al.)

The Gram-positive human pathogen Staphylococcus aureus causes a variety of human diseases such as skin infections, pneumonia, and endocarditis. The micrococcal nuclease Nuc1 is one of the major S. aureus virulence factors and allows the bacterium to avoid neutrophil extracellular trap (NET)-mediated killing. We found that addition of the protein synthesis inhibitor clindamycin to S. aureus LAC cultures decreased nuc1 transcription and subsequently blunted nuclease activity in a molecular beacon-based fluorescence assay. We also observed reduced NET degradation through Nuc1 inhibition translating into increased NET-mediated clearance. Similarly, pooled human immunoglobulin specifically inhibited nuclease activity in a concentration-dependent manner. Inhibition of nuclease activity by clindamycin and immunoglobulin enhanced S. aureus clearance and should be considered in the treatment of S. aureus infections., (© The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America.)

Promoting platelet persistence: Blood infection by Staphylococcus aureus (SA) can be fatal. Sun et al. found that lowered platelet counts associated with mortality in a cohort of patients with bacteremia, and pinpointed SA-induced desialylation and hepatic clearance of platelets as the cause. This reduction in circulating platelets was counteracted by either of two approved drugs, the sialidase inhibitor oseltamivir or ticagrelor, an inhibitor of platelet receptor P2Y12, leading to improved outcomes in a mouse model of SA-induced bacteremia. This study supports the possibility of repurposing two clinically prescribed drugs against bloodstream infection by SA. Staphylococcus aureus (SA) bloodstream infections cause high morbidity and mortality (20 to 30%) despite modern supportive care. In a human bacteremia cohort, we found that development of thrombocytopenia was correlated to increased mortality and increased α-toxin expression by the pathogen. Platelet-derived antibacterial peptides are important in bloodstream defense against SA, but α-toxin decreased platelet viability, induced platelet sialidase to cause desialylation of platelet glycoproteins, and accelerated platelet clearance by the hepatic Ashwell-Morell receptor (AMR). Ticagrelor (Brilinta), a commonly prescribed P2Y12 receptor inhibitor used after myocardial infarction, blocked α-toxin–mediated platelet injury and resulting thrombocytopenia, thereby providing protection from lethal SA infection in a murine intravenous challenge model. Genetic deletion or pharmacological inhibition of AMR stabilized platelet counts and enhanced resistance to SA infection, and the anti-influenza sialidase inhibitor oseltamivir (Tamiflu) provided similar therapeutic benefit. Thus, a "toxin-platelet-AMR" regulatory pathway plays a critical role in the pathogenesis of SA bloodstream infection, and its elucidation provides proof of concept for repurposing two commonly prescribed drugs as adjunctive therapies to improve patient outcomes. [ABSTRACT FROM AUTHOR]

Graphical abstract Abstract Staphylococcus aureus , a leading cause of serious human infections in both healthcare and community settings, is increasingly difficult to control due to expanding resistance to multiple antibiotic classes. Methicillin-resistant S. aureus (MRSA) strains have disseminated on a global scale and are associated with adverse patient outcomes, increased hospital stays, and significant economic costs to the healthcare system. A proximal step in S. aureus infection is colonization of the nasal mucosa, and effective strategies to decolonize high risk patients to reduce the risk of invasive infection and nosocomial spread represent an important clinical priority. With rising resistance to mupirocin, the most common antibiotic utilized for nasal MRSA decontamination, we are examining the use of pure molecular iodine (I 2)-based formulations for this indication. Recently, an iodophor formulation of povidone-iodine (PVP-I) has shown significant promise for nasal MRSA decontamination by swabbing the anterior nares of patients in hospital settings, but the I 2 concentration in this treatment is less than 0.01% of total iodine species present and like all providone-iodine formulations causes skin staining. Here we determine that a novel non-staining formulation of I 2 combined with the safe organic emollient glycerin delivers high local concentrations of the active antimicrobial entity (I 2) with minimal evaporative loss, exhibits activity at ∼1 part per million against MRSA and other important Gram-positive and -negative human pathogens. This formulation for I 2 topical delivery produced similar reductions in mean bacterial burden and was associated with fewer treatment failures (<2-logfold reduction) than PVP-I in a murine model of MRSA nasal decontamination. Formulations of I 2 in glycerin emollient merit further exploration as topical disinfectants for human medical indications. [ABSTRACT FROM AUTHOR]