scholarly journals Repurposed drugs block toxin-driven platelet clearance by the hepatic Ashwell-Morell receptor to clear Staphylococcus aureus bacteremia

2021 ◽  
Vol 13 (586) ◽  
pp. eabd6737
Author(s):  
Josh Sun ◽  
Satoshi Uchiyama ◽  
Joshua Olson ◽  
Yosuke Morodomi ◽  
Ingrid Cornax ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Critical Role ◽  
Bloodstream Infections ◽  
Therapeutic Benefit ◽  
High Morbidity ◽  
Staphylococcus Aureus Bacteremia ◽  
Sialidase Inhibitor ◽  
Repurposed Drugs ◽  
Genetic Deletion ◽  
Improve Patient

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.

scholarly journals Repurposed Drugs Block Toxin-Driven Platelet Clearance by the Hepatic Ashwell-Morell Receptor to Clear Staphylococcus aureus Bacteremia

2020 ◽  
Author(s):  
Josh Sun ◽  
Satoshi Uchiyama ◽  
Joshua Olson ◽  
Yosuke Morodomi ◽  
Ingrid Cornax ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Critical Role ◽  
Bloodstream Infections ◽  
Therapeutic Benefit ◽  
High Morbidity ◽  
Staphylococcus Aureus Bacteremia ◽  
Sialidase Inhibitor ◽  
Repurposed Drugs ◽  
Approved Drugs ◽  
Fda Approved Drugs

ABSTRACTStaphylococcus aureus (SA) bloodstream infections cause high morbidity and mortality (20-30%) despite modern supportive care. In a human bacteremia cohort, 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 post-myocardial infarction, blocked α-toxin-mediated platelet injury and resulting thrombocytopenia, thus 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 FDA-approved drugs as adjunctive therapies to improve patient outcomes.

scholarly journals Rapid Detection of Methicillin-Resistant Staphylococcus aureus Directly from Blood for the Diagnosis of Bloodstream Infections: A Mini-Review

Diagnostics ◽  
2020 ◽  
Vol 10 (10) ◽  
pp. 830
Author(s):  
Anna Rita Buonomini ◽  
Elisabetta Riva ◽  
Giovanni Di Bonaventura ◽  
Giovanni Gherardi
Keyword(s):  
Staphylococcus Aureus ◽  
Gold Standard ◽  
Methicillin Resistant Staphylococcus Aureus ◽  
Bloodstream Infections ◽  
Rapid Diagnostic Tests ◽  
Blood Cultures ◽  
High Morbidity ◽  
Human Pathogen ◽  
Gold Standard Method ◽  
Methicillin Resistant

Staphylococcus aureus represents a major human pathogen able to cause a number of infections, especially bloodstream infections (BSI). Clinical use of methicillin has led to the emergence of methicillin-resistant S. aureus (MRSA) and MRSA-BSI have been reported to be associated with high morbidity and mortality. Clinical diagnosis of BSI is based on the results from blood culture that, although considered the gold standard method, is time-consuming. For this reason, rapid diagnostic tests to identify the presence of methicillin-susceptible S. aureus (MSSA) and MRSA isolates directly in blood cultures are being used with increasing frequency to rapidly commence targeted antimicrobial therapy, also in the light of antimicrobial stewardship efforts. Here, we review and report the most common rapid non-molecular and molecular methods currently available to detect the presence of MRSA directly from blood.

scholarly journals 212. Outcomes of Adults with Uncomplicated Staphylococcus aureus Bacteremia Receiving Short-Course Vs. Prolonged-Course Antibiotic Therapy in a Multicenter, Propensity Score–Matched Cohort

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S125-S126
Author(s):  
Louise Thorlacius-Ussing ◽  
Jette Nissen ◽  
Jon J Rasmussen ◽  
Robert Skov ◽  
Magnus Arpi ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Propensity Score ◽  
Antibiotic Therapy ◽  
Antibiotic Treatment ◽  
Nearest Neighbor ◽  
Bloodstream Infections ◽  
Staphylococcus Aureus Bacteremia ◽  
Short Course ◽  
Short Courses

Abstract Background The recommended duration of antibiotic treatment for uncomplicated Staphylococcus aureus bloodstream infections is 14 days. We compared the outcomes of patients receiving short-course (6–10 days) vs. prolonged-course (11–16 days) antibiotic therapy for S. aureus bacteremia (SAB). Methods 30-day outcome of patients with penicillin (PSSAB, n = 202)) or methicillin-susceptible SAB (MSSAB, n = 203) treated with in vitro active therapy in the range of 6–16 days was analyzed using pooled data from two previously published, observational studies. Individuals were matched 1:1 by nearest neighbor propensity score matching without replacement. Regression analysis was performed to estimate the risk of all-cause mortality within 30 days after the end of antibiotic treatment. Eligible individuals had to have >1 day of follow-up after discontinuation of antimicrobials. Individuals with a diagnosis of endocarditis, bone infection, meningitis or pneumonia were excluded. Results There were 107 well-balanced matched pairs; 58 in the PSSAB and 39 in the MSSAB cohort. For PSSAB, the median duration of therapy was 8 (interquartile range [IQR], 7–10) in the short-course group and 12 days (IQR, 10–13) in the prolonged-course group. For the MSSAB cohort, these numbers were 9 days (IQR, 7–10) and 14 days (IQR, 13–16 days), respectively. No difference in mortality between short-course and prolonged-course treatment was observed (adjusted hazard ratio [aHR], 0.74; 95% confidence interval [CI], .23–2.41) and 1.14; 95% CI, 0.31–4.20), respectively for PSSAB and MSSAB. Conclusion Short courses of antibiotic therapy yielded similar clinical outcomes as prolonged courses of antibiotic therapy for S. aureus bacteremia. The findings warrant a randomized clinical trial to study the safety and efficacy of shortened antimicrobial therapy for the treatment of uncomplicated SAB. Disclosures All authors: No reported disclosures.

scholarly journals Pharmacokinetic-Pharmacodynamic Relationships Describing the Efficacy of Oritavancin in Patients with Staphylococcus aureus Bacteremia

2006 ◽  
Vol 50 (3) ◽  
pp. 994-1000 ◽  
Author(s):  
Sujata M. Bhavnani ◽  
Julie A. Passarell ◽  
Joel S. Owen ◽  
Jeffrey S. Loutit ◽  
Steven B. Porter ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Odds Ratio ◽  
Regression Tree ◽  
Bloodstream Infections ◽  
Free Drug ◽  
Classification And Regression Tree ◽  
Population Pharmacokinetic ◽  
Dose Selection ◽  
Staphylococcus Aureus Bacteremia ◽  
Drug Concentrations

ABSTRACT Bloodstream infections due to antimicrobial-resistant Staphylococcus aureus occur with increasing frequency and represent an important cause of morbidity and mortality. To date, the evaluation of pharmacokinetic-pharmacodynamic relationships for efficacy among patients with bacteremia has been limited. The objectives of these analyses were to evaluate relationships between microbiological and clinical responses for patients with S. aureus bacteremia and exposures for oritavancin, a novel bactericidal glycopeptide in development. Bayesian oritavancin exposure predictions, following treatment with 5, 6.5, 8, or 10 mg/kg of body weight/day, were derived using a validated population pharmacokinetic model for 55 patients with S. aureus bacteremia. Using classification and regression tree analysis, a breakpoint of the percentage of the dosing interval duration for which free-drug concentrations were above the MIC (free-drug % time > MIC) of 22% was identified for microbiological response; the probabilities of success greater than or equal to and less than this value were 93% and 76%, respectively. Using logistic regression, a relationship was found between microbiological response and free-drug % time > MIC (odds ratio = 4.42, P = 0.09, and odds ratio = 8.84, P = 0.05, when one patient, a medical outlier, was excluded). A similar relationship was found for clinical response. These results will be valuable in supporting dose selection of oritavancin for patients with S. aureus bacteremia.

scholarly journals 184. Staphylococcus aureus Bacteremia Management and Outcomes Following Infectious Disease Consult Over Time at a Tertiary Care Center in Canada

2021 ◽  
Vol 8 (Supplement_1) ◽  
pp. S200-S201
Author(s):  
Mark McAllister ◽  
Justin Chen ◽  
Stephanie Smith ◽  
Arienne King ◽  
Tanis C Dingle ◽  
...  
Keyword(s):  
Infectious Disease ◽  
Staphylococcus Aureus ◽  
Length Of Stay ◽  
Care Center ◽  
Tertiary Care ◽  
Retrospective Chart Review ◽  
High Morbidity ◽  
University Of Alberta ◽  
Staphylococcus Aureus Bacteremia ◽  
Over Time

Abstract Background Staphylococcus aureus bacteremia (SAB) is associated with high morbidity and mortality. Infectious disease consultation (IDC) is associated with increased adherence to guideline management and improved patient outcomes. We describe the IDC rate over time and impact of IDC on the management and outcomes of patients with SAB. Methods This retrospective chart review includes adult patients (≥ 18 years) hospitalized at the University of Alberta Hospital, Edmonton, Canada who had at least 1 blood culture growing Staphylococcus aureus during two time periods (A: Jan 2010 to Dec 2012; B: Jan to Oct 2020). Patients who died or were made palliative within 48hrs following bacteremia were excluded. Descriptive statistics were used to compare appropriateness of SAB management and outcomes in patients receiving IDC and those who did not (NIDC). Results 325 patients in period A and 129 in period B were included. Baseline demographics were similar. IDC rate increased from 63% to 88% (p< 0.001) between the study periods. IDC was associated with increased odds of receiving an echocardiogram (OR=3.56, 95% CI 2.22 – 5.57; OR=20.4, 95% 4.13 – 110.6, p< 0.001) and appropriate duration of antimicrobial therapy (OR=6.74, 95% 3.93 – 11.54; OR=43.2, 95% 5.72 – 529.5, p< 0.001) between study periods. Mean length of stay decreased in patients receiving IDC (44.8 vs 28.1 days, p=0.005) and increased in NIDC patients (19.9 vs 28.7 days, p=0.216). IDC was associated with lower 30-day mortality in period A (OR=3.53, 95% 1.95 – 6.36), however this association was not observed in period B (OR=1.43, 95% 0.40 – 5.56). There was a trend towards decreased odds of mortality in patients receiving early IDC (≤2 days from bacteremia, n=65) compared to late IDC (≥3 days from bacteremia, n=45) (OR=2.59, 95% 0.95 – 7.10, p=0.077). Conclusion Our centre’s IDC rate for SAB increased over time without specific intervention. IDC increased the odds of appropriate SAB management and was associated with decreased length of stay in period B. IDC was associated with lower 30-day mortality in period A and trended towards lower mortality in period B. Specifically, early IDC decreased odds of 30-day mortality compared to late IDC. These results suggest that routine early IDC be part of SAB management. Disclosures All Authors: No reported disclosures

scholarly journals Targeting leukocidin-mediated immune evasion protects mice from Staphylococcus aureus bacteremia

2020 ◽  
Vol 217 (9) ◽  
Author(s):  
Kayan Tam ◽  
Keenan A. Lacey ◽  
Joseph C. Devlin ◽  
Maryaline Coffre ◽  
Alexis Sommerfield ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Immune Evasion ◽  
Murine Model ◽  
Neutralizing Antibodies ◽  
Bloodstream Infections ◽  
Recurrent Infections ◽  
Host Protection ◽  
Host Pathogen Interaction ◽  
Staphylococcus Aureus Bacteremia

Staphylococcus aureus is responsible for various diseases in humans, and recurrent infections are commonly observed. S. aureus produces an array of bicomponent pore-forming toxins that target and kill leukocytes, known collectively as the leukocidins. The contribution of these leukocidins to impair the development of anti–S. aureus adaptive immunity and facilitate reinfection is unclear. Using a murine model of recurrent bacteremia, we demonstrate that infection with a leukocidin mutant results in increased levels of anti–S. aureus antibodies compared with mice infected with the WT parental strain, indicating that leukocidins negatively impact the generation of anti–S. aureus antibodies in vivo. We hypothesized that neutralizing leukocidin-mediated immune subversion by vaccination may shift this host-pathogen interaction in favor of the host. Leukocidin-immunized mice produce potent leukocidin-neutralizing antibodies and robust Th1 and Th17 responses, which collectively protect against bloodstream infections. Altogether, these results demonstrate that blocking leukocidin-mediated immune evasion can promote host protection against S. aureus bloodstream infection.

scholarly journals Antibodies against a secreted product of Staphylococcus aureus trigger phagocytic killing

2016 ◽  
Vol 213 (3) ◽  
pp. 293-301 ◽  
Author(s):  
Lena Thomer ◽  
Carla Emolo ◽  
Vilasack Thammavongsa ◽  
Hwan Keun Kim ◽  
Molly E. McAdow ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Tandem Repeats ◽  
Protective Antigen ◽  
Critical Role ◽  
Bloodstream Infections ◽  
C Terminus ◽  
D2 Domain ◽  
Opsonophagocytic Killing ◽  
Phagocytic Killing ◽  
R Domain

Host immunity against bacteria typically involves antibodies that recognize the microbial surface and promote phagocytic killing. Methicillin-resistant Staphylococcus aureus (MRSA) is a frequent cause of lethal bloodstream infection; however, vaccines and antibody therapeutics targeting staphylococcal surface molecules have thus far failed to achieve clinical efficacy. S. aureus secretes coagulase (Coa), which activates host prothrombin and generates fibrin fibrils that protect the pathogen against phagocytosis by immune cells. Because of negative selection, the coding sequence for the prothrombin-binding D1-D2 domain is highly variable and does not elicit cross-protective immune responses. The R domain, tandem repeats of a 27-residue peptide that bind fibrinogen, is conserved at the C terminus of all Coa molecules, but its functional significance is not known. We show here that the R domain enables bloodstream infections by directing fibrinogen to the staphylococcal surface, generating a protective fibrin shield that inhibits phagocytosis. The fibrin shield can be marked with R-specific antibodies, which trigger phagocytic killing of staphylococci and protect mice against lethal bloodstream infections caused by a broad spectrum of MRSA isolates. These findings emphasize the critical role of coagulase in staphylococcal escape from opsonophagocytic killing and as a protective antigen for S. aureus vaccines.

scholarly journals 1065. Evaluation of a Staphylococcus aureus Bacteremia Treatment Checklist

2018 ◽  
Vol 5 (suppl_1) ◽  
pp. S318-S319
Author(s):  
Hailey Soukup ◽  
Jessica Holt
Keyword(s):  
Staphylococcus Aureus ◽  
Primary Outcome ◽  
Blood Cultures ◽  
High Morbidity ◽  
Drug Selection ◽  
Evidence Based Treatment ◽  
Duration Of Therapy ◽  
Staphylococcus Aureus Bacteremia ◽  
Improved Outcomes ◽  
Antibiotic Duration

Abstract Background Staphylococcus aureus bacteremia (SAB) is associated with high morbidity and mortality. Appropriate management involves repeat blood cultures, echocardiography, drug selection/route, and duration of therapy. Multiple studies have demonstrated improved outcomes in patients who are managed by infectious disease (ID) physicians compared with non-ID physicians; however, not all sites have access to an ID provider. To improve management of SAB, a checklist was developed and approved for use in a large healthcare system in August 2015. Methods A retrospective review was conducted on 400 randomly selected patients with SAB, 200 pre- and 200 post-implementation of a four-part management checklist. The primary outcome was overall adherence to the checklist, which included: repeat blood cultures, echocardiography, correct antibiotic/route selection, and appropriate antibiotic duration. Secondary outcomes included adherence when an ID physician was not consulted, adherence to the four components individually, and appropriate imaging. Results Adherence to the four part bundle remained stable from 2015 to 2017, with overall adherence rates of 80% and 79%, respectively. From 2015 to 2017, patients without repeat blood cultures (7% vs. 2%, respectively) and inappropriate inpatient antibiotic selection (6% vs. 3%, respectively) improved. Outpatient prescribing (11% vs. 11%), lack of imaging (11% vs. 9%), and antibiotic duration (15% vs. 15%) were consistent from 2015 to 2017, respectively. In 2017, 13 patients were discharged on oral antibiotics and were deemed inappropriate per the study criteria, although 12 of these patients were on appropriate antibiotics while inpatient. Infectious diseases providers were consulted on 96% of cases in 2017, an increase from 90% in 2015. Conclusion Adherence to an evidence based treatment bundle remains consistent with a previous analysis, despite an increase in cases with an ID provider consulted. Repeating blood cultures and inpatient prescribing improved over the interval. Focus areas for improvement include imaging, outpatient prescribing, and duration of therapy. Disclosures All authors: No reported disclosures.

scholarly journals Epidemiology and Clinical Characteristics of Staphylococcal Bacteremia in Bahrain

2021 ◽  
Vol 33 (3) ◽  
pp. 6-15
Author(s):  
Safaa Al Khawaja ◽  
Nermin Kamal Saeed ◽  
Mahmood Al Awainati
Keyword(s):  
Staphylococcus Aureus ◽  
Health Problem ◽  
Clinical Characteristics ◽  
Electronic Record ◽  
High Morbidity ◽  
Record System ◽  
Staphylococcus Aureus Bacteremia ◽  
One Year ◽  
Community Onset ◽  
Significant Health

Background and Objectives: Staphylococcus aureus bacteremia (SAB) is a significant health problem with high morbidity & mortality. The aim of this study was to evaluate the epidemiology of SAB in Bahrain along with withs clinical characteristics and outcomes. Methods: This study was conducted at Salmaniya medical complex (SMC) microbiology laboratory including all patients with SAB for one year period (2019). Demographic, lab data & outcomes were obtained from the electronic record system of patients. Results: A total of 164 episodes of SAB were identified during the study period. About 137 were encountered among inpatients, while 27 cases among outpatients attending hemodialysis unit. Bahraini nationality & male gender were predominant (141, 85.98% & 108, 65.85% respectively). Nosocomial SAB accounts for only 29.37%, while the majority of SAB cases were of community-onset (116, 70.37%), but among such community-onset cases; 83 (50.61% of total) were of health care-associated category (56 had prior hospitalization and 27 were on regular dialysis). Among all patients with SAB, diabetes was the commonest risk factor encountered, followed by dialysis dependence and sickle cell diseases (SCD). Mortality rate was 25.6% (42 patients). Among the 122 survivors of the initial SAB episode, recurrence of bacteremia was documented among 26 cases (21.3%). Conclusion: SAB was a significant health problem among the Bahraini. Diabetes Mellitus, SCD and dialysis dependence were found to be important risk factors. Recurrence of bacteremia was a common complication among the patient’s dependant on hemodialysis Keywords: Staphylococcus aureus, Bacteremia, Nosocomial, Community onset, Hemodialysis

Sign in / Sign up

Export Citation Format

Share Document