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.

Is the Success of Cefazolin plus Ertapenem in Methicillin-Susceptible Staphylococcus aureus Bacteremia Based on Release of Interleukin 1-beta?

2022 ◽  
Author(s):  
Dan Smelter ◽  
Mary Hayney ◽  
George Sakoulas ◽  
Warren Rose
Keyword(s):  
Staphylococcus Aureus ◽  
Peripheral Blood ◽  
Interleukin 1 ◽  
Interleukin 1 Beta ◽  
Blood Monocytes ◽  
Salvage Regimen ◽  
Peripheral Blood Monocytes ◽  
Staphylococcus Aureus Bacteremia

Cefazolin and ertapenem has been shown to be an effective salvage regimen for refractory methicillin-susceptible Staphylococcus aureus bacteremia. Our findings suggest cefazolin plus ertapenem in vitro stimulates interleukin-1β release from peripheral blood monocytes both with and without S. aureus presence. This IL-1β augmentation was primarily driven by ertapenem. These findings support further exploration of cefazolin plus ertapenem in MSSA bacteremia and may partially explain its marked potency in vivo despite modest synergy in vitro .

scholarly journals Efficacy of Bacteriophages in a Staphylococcus aureus Nondiabetic or Diabetic Foot Infection Murine Model

2019 ◽  
Vol 64 (2) ◽  
Author(s):  
S. Albac ◽  
M. Medina ◽  
D. Labrousse ◽  
D. Hayez ◽  
D. Bonnot ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Mouse Models ◽  
Murine Model ◽  
Phage Therapy ◽  
Single Injection ◽  
Antibacterial Efficacy ◽  
Content Type ◽  
Diabetic Foot Infection ◽  
Preclinical And Clinical Studies

ABSTRACT This study investigated the in vivo efficacy of three bacteriophages combined compared with linezolid in two mouse models (nondiabetic and diabetic) of Staphylococcus aureus foot infection. In both models, a single injection of bacteriophages in the hindpaw showed significant antibacterial efficacy. Linezolid was as effective as bacteriophages in nondiabetic animals but ineffective in diabetic animals. These findings further support preclinical and clinical studies for the development of phage therapy.

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 Recurrent infections and immune evasion strategies of Staphylococcus aureus

2012 ◽  
Vol 15 (1) ◽  
pp. 92-99 ◽  
Author(s):  
Hwan Keun Kim ◽  
Vilasack Thammavongsa ◽  
Olaf Schneewind ◽  
Dominique Missiakas
Keyword(s):  
Staphylococcus Aureus ◽  
Immune Evasion ◽  
Recurrent Infections

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 The Lantibiotic Lacticin 3147 Prevents Systemic Spread ofStaphylococcus aureusin a Murine Infection Model

2012 ◽  
Vol 2012 ◽  
pp. 1-6 ◽  
Author(s):  
Clare Piper ◽  
Pat G. Casey ◽  
Colin Hill ◽  
Paul D. Cotter ◽  
R. Paul Ross
Keyword(s):  
Staphylococcus Aureus ◽  
Murine Model ◽  
Chemotherapeutic Agent ◽  
Negative Control ◽  
Infection Model ◽  
Intraperitoneal Route ◽  
Systemic Spread ◽  
Lacticin 3147 ◽  
Phosphate Buffered Saline

The objective of this study was to investigate thein vivoactivity of the lantibiotic lacticin 3147 against the luminescentStaphylococcus aureusstrain Xen 29 using a murine model. Female BALB/c mice (7 weeks old, 17 g) were divided into groups (n=5) and infected with the Xen 29 strain via the intraperitoneal route at a dose of1×106 cfu/animal. After 1.5 hr, the animals were treated subcutaneously with doses of phosphate-buffered saline (PBS; negative control) or lacticin 3147. Luminescent imaging was carried 3 and 5 hours postinfection. Mice were then sacrificed, and the levels ofS. aureusXen 29 in the liver, spleen, and kidneys were quantified. Notably, photoluminescence and culture-based analysis both revealed that lacticin 3147 successfully controlled the systemic spread ofS. aureusin mice thus indicating that lacticin 3147 has potential as a chemotherapeutic agent forin vivoapplications.

scholarly journals Internalization ofStaphylococcus aureusin Lymphocytes Induces Oxidative Stress and DNA Fragmentation: Possible Ameliorative Role of Nanoconjugated Vancomycin

2011 ◽  
Vol 2011 ◽  
pp. 1-15 ◽  
Author(s):  
Subhankari Prasad Chakraborty ◽  
Santanu Kar Mahapatra ◽  
Sumanta Kumar Sahu ◽  
Sabyasachi Das ◽  
Satyajit Tripathy ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Staphylococcus Aureus ◽  
Immune Cell ◽  
Bloodstream Infections ◽  
Treated Group ◽  
Control Group ◽  
Similar Dose ◽  
Effective Doses

Staphylococcus aureusis the most frequently isolated pathogen causing bloodstream infections, skin and soft tissue infections and pneumonia. Lymphocyte is an important immune cell. The aim of the present paper was to test the ameliorative role of nanoconjugated vancomycin against Vancomycin-sensitiveStaphylococcus aureus(VSSA) and vancomycin-resistantStaphylococcus aureus(VRSA) infection-induced oxidative stress in lymphocytes. VSSA and VRSA infections were developed in Swiss mice by intraperitoneal injection of  CFU/mL bacterial solutions. Nanoconjugated vancomycin was adminstrated to VSSA- and VRSA-infected mice at its effective dose for 10 days. Vancomycin was adminstrated to VSSA- and VRSA-infected mice at a similar dose, respectively, for 10 days. Vancomycin and nanoconjugated vancomycin were adminstrated to normal mice at their effective doses for 10 days. The result of this study reveals that in vivo VSSA and VRSA infection significantly increases the level of lipid peroxidation, protein oxidation, oxidized glutathione level, nitrite generation, nitrite release, and DNA damage and decreases the level of reduced glutathione, antioxidant enzyme status, and glutathione-dependent enzymes as compared to control group, which were increased or decreased significantly near to normal in nanoconjugated vancomycin-treated group. These findings suggest the potential use and beneficial role of nanoconjugated vancomycin against VSSA and VRSA infection-induced oxidative stress in lymphocytes.

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 Impact of sarA on Daptomycin Susceptibility of Staphylococcus aureus Biofilms In Vivo

2009 ◽  
Vol 53 (10) ◽  
pp. 4096-4102 ◽  
Author(s):  
Elizabeth C. Weiss ◽  
Agnieszka Zielinska ◽  
Karen E. Beenken ◽  
Horace J. Spencer ◽  
Sonja J. Daily ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Murine Model ◽  
Biofilm Formation ◽  
Parent Strain ◽  
Skin Lesions ◽  
The Other ◽  
Clonal Lineage ◽  
Experimental Group ◽  
Increased Susceptibility

ABSTRACT We used a murine model of catheter-associated biofilm formation to determine whether the mutation of the staphylococcal accessory regulator (sarA) has an impact on the susceptibility of established Staphylococcus aureus biofilms to treatment with daptomycin in vivo. The experiments were done with two clinical isolates, one of which (UAMS-1) was obtained from the bone of a patient suffering from osteomyelitis, while the other (UAMS-1625) is an isolate of the USA300 clonal lineage of community-acquired methicillin (meticillin)-resistant S. aureus. UAMS-1625 had a reduced capacity to form a biofilm in vivo compared to that of UAMS-1 (P = 0.0015), but in both cases the mutation of sarA limited biofilm formation compared to that of the corresponding parent strain (P ≤ 0.001). The mutation of sarA did not affect the daptomycin MIC for either strain, but it did result in increased susceptibility in vivo in the context of an established biofilm. Specifically, daptomycin treatment resulted in the clearance of detectable bacteria from <10% of the catheters colonized with the parent strains, while treatment with an equivalent daptomycin concentration resulted in the clearance of 46.4% of the catheters colonized with the UAMS-1 sarA mutant and 69.1% of the catheters colonized with the UAMS-1625 sarA mutant. In the absence of daptomycin treatment, mice with catheters colonized with the UAMS-1625 parent strain also developed skin lesions in the region adjacent to the implanted catheter. No such lesions were observed in any other experimental group, including untreated mice containing catheters colonized with the UAMS-1625 sarA mutant.

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