scholarly journals Efficacy of Anti-Staphylococcal Lysin, LSVT-1701, in Combination with Daptomycin in Experimental Left-Sided Infective Endocarditis Due to Methicillin-Resistant Staphylococcus aureus (MRSA)

2021 ◽  
Author(s):  
David Huang ◽  
Eric Gaukel ◽  
Nancy Kerzee ◽  
Katyna Borroto-Esoda ◽  
Simon Lowry ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Single Dose ◽  
Infective Endocarditis ◽  
Aortic Valve ◽  
Methicillin Resistant Staphylococcus Aureus ◽  
Rabbit Model ◽  
Standard Of Care ◽  
Target Tissue ◽  
Daily Dose ◽  
Phage Lysins

MRSA endovascular infections are frequently recalcitrant to treatment with standard-of-care antibiotics. Anti-staphylococcal phage lysins represent important candidate adjunctive agents against invasive MRSA infections because of both their microbicidal and anti-biofilm properties. We utilized the rabbit model of aortic valve infective endocarditis (using the prototype MRSA strain, MW2) to examine the combined efficacy of the lysin, LSVT-1701, plus daptomycin. LSVT-1701 was given at two dose-regimens (32.5 mg/kg and 50 mg/kg) with different dose-durations (single dose vs daily dose for 2 d vs daily dose for 4 d); daptomycin was given at a sub-lethal daily dose of 4 mg/kg for 4 d to maximize potential synergistic interaction outcomes. The combination of LSVT-1701 plus daptomycin was highly effective at reducing target tissue MRSA counts (cardiac vegetations, kidneys, and spleen), especially when the lysin was given for multiple days and/or at higher daily doses. Of importance, when given for four daily doses, both lysin dose-regimens in combination with daptomycin sterilized all target tissues. These findings suggest that LSVT-1701 warrants further clinical evaluation as adjunctive therapy for the treatment of invasive MRSA infections.

scholarly journals 1071. Efficacy of Anti-Staphylococcal Lysin, LSVT-1701, in Combination with Daptomycin in Experimental Left-Sided Infective Endocarditis (IE) Due to Methicillin-Resistant Staphylococcus aureus (MRSA)

2021 ◽  
Vol 8 (Supplement_1) ◽  
pp. S628-S628
Author(s):  
David Huang ◽  
Eric Gaukel ◽  
Katyna Borroto-Esoda ◽  
Yan Xiong ◽  
Wessam Abdelhady ◽  
...  
Keyword(s):  
Single Dose ◽  
Infective Endocarditis ◽  
Limit Of Detection ◽  
Rabbit Model ◽  
Standard Of Care ◽  
Target Tissue ◽  
Daily Dose ◽  
Proven Efficacy ◽  
Daily Dose Regimen

Abstract Background Anti-staphylococcal phage lysins, such as LSVT-1701, represent important candidate adjunctive agents against invasive MRSA infections because of both their microbicidal and anti-biofilm properties. We, thus, sought to examine the in vivo efficacy of LSVT-1701 combination with daptomycin, a standard-of-care anti-MRSA agent with proven efficacy against bacteremia and IE in humans. Methods We utilized the rabbit model of aortic valve infective endocarditis (using the prototype MRSA strain, MW2) to examine the combined efficacy of LSVT-1701 plus daptomycin. We examined microbiologic outcomes in distinct target tissues (cardiac vegetations, spleen and kidney) in this model, as well as the pharmacokinetic and pharmacodynamic drivers and target attainment values most predictive of treatment outcomes. LSVT-1701 was given at two dose-regimens (32.5 mg/kg and 50 mg/kg) with different dose-durations (single dose vs daily dose for 2 d vs daily dose for 4 d); daptomycin was administered in combination with daptomycin at a sub-lethal daily dose of 4 mg/kg for 4 d to maximize potential synergistic interaction outcomes. Results The Table below shows all LSVT-1701 regimens in combination with daptomycin significantly reduced MRSA burdens in all target tissue as compared to untreated controls. The reduction in MRSA counts was statistically significant in instances of both increasing LSVT-1701 dose level (i.e., single doses of 50 mg/kg vs 32.5 mg/kg iv), as well as increased numbers of lysin doses (i.e., four daily doses vs a single-dose or two daily-doses) in combination with daptomycin. Of note, both the LSVT-1701 50 mg/kg and 32.5 mg/kg daily dose-strategies given for four days in combination with daptomycin sterilized all target tissues (i.e., quantitative cultures ≤ the lower limit of detection of 1 log10 CFU/g. tissue). MRSA bio-burdens in blood, vegetations, kidneys and spleen in rabbit IE model Conclusion LSVT-1701 administered at 32.5 or 50 mg/kg in a 4 d daily-dose regimen in combination with daptomycin resulted in microbiologic sterilization of all target organs in this MRSA IE model. These data support further clinical development of LSVT-1701 for the treatment of MRSA endovascular infections including IE. Disclosures David Huang, MD, PhD, Lysovant (Consultant) Eric Gaukel, BS, Lysovant (Employee) Katyna Borroto-Esoda, PhD, Lysovant (Consultant) Arnold Bayer, MD, PhD, Lysovant (Grant/Research Support)

scholarly journals Efficacy of Anti-Staphylococcal Lysin, LSVT-1701, in Combination with Daptomycin in Experimental Left-Sided Infective Endocarditis Due to Methicillin-Resistant Staphylococcus aureus (MRSA)

2021 ◽  
Author(s):  
David B. Huang ◽  
Eric Gaukel ◽  
Nancy Kerzee ◽  
Katyna Borroto-Esoda ◽  
Simon Lowry ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Infective Endocarditis ◽  
Aortic Valve ◽  
Clinical Evaluation ◽  
Adjunctive Therapy ◽  
Methicillin Resistant Staphylococcus Aureus ◽  
Rabbit Model ◽  
Target Tissue ◽  
Methicillin Resistant ◽  
Highly Effective

We utilized the rabbit model of aortic valve infective endocarditis to examine the combined efficacy of the lysin, LSVT-1701, plus daptomycin. The combination of LSVT-1701 plus daptomycin was highly effective at reducing target tissue MRSA counts. When given for four daily doses, both lysin dose-regimens in combination with daptomycin sterilized all target tissues. These findings suggest that LSVT-1701 warrants further clinical evaluation as adjunctive therapy for the treatment of invasive MRSA infections.

scholarly journals Efficacy of Telavancin in a Rabbit Model of Aortic Valve Endocarditis Due to Methicillin-Resistant Staphylococcus aureus or Vancomycin-Intermediate Staphylococcus aureus

2005 ◽  
Vol 49 (8) ◽  
pp. 3163-3165 ◽  
Author(s):  
Andres G. Madrigal ◽  
Li Basuino ◽  
Henry F. Chambers
Keyword(s):  
Staphylococcus Aureus ◽  
Aortic Valve ◽  
Methicillin Resistant Staphylococcus Aureus ◽  
No Reduction ◽  
Rabbit Model ◽  
Daily Regimen ◽  
Methicillin Resistant ◽  
Days Of Therapy ◽  
Time Kill

ABSTRACT The activities of telavancin and vancomycin were compared in vitro and in the rabbit model of aortic valve endocarditis against a methicillin-resistant Staphylococcus aureus strain, COL, and a vancomycin-intermediate S. aureus (VISA) strain, HIP 5836. Telavancin was bactericidal in time-kill studies at a concentration of 5 μg/ml against both COL and HIP5836. Vancomycin was bacteriostatic at 5 μg/ml and bactericidal at 10 μg/ml against COL and was bacteriostatic at 10 μg/ml against VISA strain HIP 5836. Compared to untreated controls, a twice-daily regimen of 30 mg/kg of telavancin reduced mean aortic valve vegetation titers of the COL strain by 4.7 log10 CFU/g after 4 days of therapy and sterilized 6/11 vegetations compared to 3.4 log10 CFU/g with 3/10 vegetations sterilized for a regimen of twice-daily vancomycin, 30 mg/kg; these differences were not statistically significant. Telavancin was significantly more effective than vancomycin in the VISA model, producing a 5.5 log10 CFU/g reduction versus no reduction in CFU with vancomycin. In experiments comparing 2-day regimens of telavancin at 30 mg/kg and 50 mg/kg twice daily, organisms were rapidly eliminated from vegetations, but the effect was not different between the two doses. These results suggest that telavancin may be an effective treatment for endocarditis and other serious staphylococcal infections accompanied by bacteremia, including infections caused by staphylococci not susceptible to vancomycin.

scholarly journals Lysostaphin Treatment of Experimental Aortic Valve Endocarditis Caused by a Staphylococcus aureus Isolate with Reduced Susceptibility to Vancomycin

1999 ◽  
Vol 43 (7) ◽  
pp. 1754-1755 ◽  
Author(s):  
Roberto L. Patron ◽  
Michael W. Climo ◽  
Beth P. Goldstein ◽  
Gordon L. Archer
Keyword(s):  
Staphylococcus Aureus ◽  
Single Dose ◽  
Aortic Valve ◽  
Untreated Control ◽  
Rabbit Model ◽  
Treated Group ◽  
Effective Alternative ◽  
Aureus Isolate ◽  
Dosing Regimens ◽  
Drug Free

ABSTRACT The rabbit model of endocarditis was used to test the effectiveness of vancomycin and two different lysostaphin dosing regimens for the treatment of infections caused by a Staphylococcus aureusstrain with reduced susceptibility to vancomycin (glycopeptide-intermediate susceptible S. aureus [GISA]). Vancomycin was ineffective, with no evidence of sterilization of aortic valve vegetations. However, rates of sterilization of aortic valve vegetations were significantly better for animals treated with either a single dose of lysostaphin (43%) or lysostaphin given twice daily for 3 days (83%) than for animals treated with vancomycin. Rabbits given a single dose of lysostaphin followed by a 3-day drug-free period had mean reductions in aortic valve vegetation bacterial counts of 7.27 and 6.63 log10 CFU/g compared with those for untreated control rabbits and the vancomycin-treated group, respectively. We conclude that lysostaphin is an effective alternative for the treatment of experimental aortic valve endocarditis caused by a clinical VISA strain.

scholarly journals Ceftobiprole Is Superior to Vancomycin, Daptomycin, and Linezolid for Treatment of Experimental Endocarditis in Rabbits Caused by Methicillin-Resistant Staphylococcus aureus

2009 ◽  
Vol 54 (2) ◽  
pp. 610-613 ◽  
Author(s):  
P. Tattevin ◽  
L. Basuino ◽  
D. Bauer ◽  
B. A. Diep ◽  
H. F. Chambers
Keyword(s):  
Staphylococcus Aureus ◽  
Treatment Group ◽  
Methicillin Resistant Staphylococcus Aureus ◽  
Methicillin Resistance ◽  
Rabbit Model ◽  
Laboratory Strain ◽  
Penicillin Binding Protein ◽  
Beta Lactam ◽  
Methicillin Resistant ◽  
High Affinity

ABSTRACT Beta lactam agents are the most active drugs for the treatment of streptococci and methicillin-susceptible Staphylococcus aureus endocarditis. However, methicillin-resistant S. aureus (MRSA) is resistant to all beta lactam agents licensed to date, and alternative treatments are limited. Ceftobiprole is a novel broad-spectrum cephalosporin that binds with high affinity to PBP 2a, the penicillin binding protein that mediates the methicillin resistance of staphylococci and is active against MRSA. Ceftobiprole was compared to vancomycin, daptomycin, and linezolid in a rabbit model of MRSA aortic valve endocarditis caused by the homogeneously methicillin-resistant laboratory strain COL. Residual organisms in vegetations were significantly fewer in ceftobiprole-treated rabbits than in any other treatment group (P < 0.05 for each comparison). In addition, the numbers of organisms in spleens and in kidneys were significantly lower in ceftobiprole-treated rabbits than in linezolid- and vancomycin-treated animals (P < 0.05 for each comparison). Anti-MRSA beta lactam agents such as ceftobiprole may represent a significant therapeutic advance over currently available agents for the treatment of MRSA endocarditis.

scholarly journals Successful single-dose teicoplanin prophylaxis against experimental streptococcal, enterococcal, and staphylococcal aortic valve endocarditis.

1997 ◽  
Vol 41 (9) ◽  
pp. 1916-1921 ◽  
Author(s):  
G S Perdikaris ◽  
A Pefanis ◽  
H Giamarellou ◽  
A Nikolopoulos ◽  
E P Margaris ◽  
...  
Keyword(s):  
Single Dose ◽  
Methicillin Resistant Staphylococcus Aureus ◽  
Rabbit Model ◽  
Outpatient Setting ◽  
Attractive Alternative ◽  
Beta Lactams ◽  
Streptococcus Oralis ◽  
Vancomycin Group ◽  
Alternative Antibiotic ◽  
Comparative Agent

Teicoplanin is a glycopeptide antibiotic that is administered both intramuscularly and intravenously. It has a prolonged half-life and a less toxic profile in comparison to those of vancomycin. The efficacy of a single dose of teicoplanin (18 mg/kg of body weight given intramuscularly) for the prevention of endocarditis due to Streptococcus oralis, Enterococcus faecium, and methicillin-resistant Staphylococcus aureus (MRSA) was evaluated after applying the rabbit model. Vancomycin at a single dose of 30 mg/kg given intravenously was used as the comparative agent for the prevention of endocarditis due to MRSA and E. faecium, while ampicillin at a single dose of 40 mg/kg given intravenously was used as the comparative agent for the prevention of endocarditis due to S. oralis. Rabbits in the teicoplanin group were infected at 1 h postdosing with approximately 10(7) CFU of each strain. Rabbits in the other groups were infected at 0.5 h postdosing with approximately 10(7) CFU of S. oralis (ampicillin group) or E. faecium and MRSA (vancomycin group). All rabbits were sacrificed 5 days later. Teicoplanin and vancomycin protected the animals challenged with E. faecium by 87.5 and 50%, respectively, and protected the animals challenged with MRSA by 100 and 92%, respectively. Teicoplanin and ampicillin protected the animals challenged with S. oralis by 100 and 77%, respectively. Prevention of endocarditis by teicoplanin was likely to be due to a prolonged inhibition of bacterial growth by the sustained supra-MICs. It is concluded that teicoplanin is very effective in preventing experimental streptococcal, enterococcal, and staphylococcal endocarditis and may be an attractive alternative antibiotic in patients allergic to beta-lactams, especially in the outpatient setting.

scholarly journals Multimicrobial Pneumonia during the Early Stages of a Global Pandemic

2021 ◽  
Vol 8 (6) ◽  
Author(s):  
Jalal H ◽  
◽  
Henriksen G ◽  
Keyword(s):  
Staphylococcus Aureus ◽  
Pseudomonas Aeruginosa ◽  
Methicillin Resistant Staphylococcus Aureus ◽  
Acute Infection ◽  
Standard Of Care ◽  
Antibiotic Use ◽  
Lung Parenchyma ◽  
Community Acquired Pneumonia ◽  
Methicillin Resistant ◽  
Global Pandemic

Community-acquired pneumonia is an acute infection of lung parenchyma which causes local and systemic inflammatory changes via cytokines. Several bacteria and viruses are responsible for this type of pneumonia, and the most common bacterial cause is Streptococcus pneumoniae. The classic symptoms are cough, fever, and pleuritic chest pain. In the Winter of 2020, a new strain of coronavirus known as SARS-CoV-2 spread throughout the world and was responsible for a global pandemic that transformed the way we live our lives. A 93-year old female presented to the hospital with respiratory distress and was found to have not only COVID-19 pneumonia but also superimposed Methicillin-resistant Staphylococcus aureus and Pseudomonas aeruginosa pneumonia. Following the most up-to-date guidelines, she was determined to have community-acquired pneumonia. Methicillin-resistant Staphylococcus aureus and Pseudomonas aeruginosa are uncommon causes of communityacquired pneumonia. She was treated with the standard of care at the time, which included vancomycin, piperacillin-tazobactam, and hydroxychloroquine. This case highlights the rarity of this specific presentation of community acquired pneumonia in regards to microbial etiology. It showcases that patients may develop certain diseases despite not having any risk factors. A major takeaway point is that apt decision making is a critical and time sensitive matter when determining whether a bacterial co-infection is present since it can affect patient outcomes. Since co-infections are relatively infrequent, antibiotic use in COVID-19 positive patients needs to be tailored accordingly. At the same time, it is crucial to keep in mind that co-infections are associated with increased severity of COVID-19 as well as poorer outcomes.

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