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 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 Combination therapy with amphotericin B and fluconazole against invasive candidiasis in neutropenic-mouse and infective-endocarditis rabbit models.

1997 ◽  
Vol 41 (6) ◽  
pp. 1345-1348 ◽  
Author(s):  
H Sanati ◽  
C F Ramos ◽  
A S Bayer ◽  
M A Ghannoum
Keyword(s):  
Infective Endocarditis ◽  
Combination Therapy ◽  
Mouse Model ◽  
Amphotericin B ◽  
Antifungal Agents ◽  
Combined Therapy ◽  
Rabbit Model ◽  
Model Treatment ◽  
The Brain

Although there are an increasing number of new antifungal agents available, the morbidity and mortality due to invasive mycoses remain high. The high rates of polyene toxicities and the development of azole resistance have raised the issue of using antifungal agents of these classes in combination, despite theoretical concerns regarding antagonism between such agents. This study was designed to evaluate the in vivo efficacy of combined therapy with amphotericin B and fluconazole against Candida albicans. Two distinct animal models were used in this study: a neutropenic-mouse model of hematogenously disseminated candidiasis and the infective-endocarditis rabbit model. Treatment efficacy was assessed by determining reductions in mortality as well as decreases in tissue fungal densities. In the neutropenic-mouse model, amphotericin B, as well as combination therapy, significantly prolonged survival compared to untreated controls (P < 10(-5) and P = 0.001, respectively). The fungal densities in the kidneys of neutropenic mice were significantly reduced with either amphotericin B monotherapy or amphotericin B-fluconazole combined therapy compared to those of controls (P < 10(-6)). Fluconazole monotherapy also reduced fungal densities in the kidneys; however, this decrease was not statistically significant (P = 0.17). In contrast, treatment with either fluconazole alone or combined with amphotericin B (but not amphotericin B monotherapy) significantly decreased fungal densities in the brain (P = 0.025). In the rabbit endocarditis model, amphotericin B monotherapy or combined therapy significantly decreased fungal densities in cardiac vegetations (P < 0.01 versus the controls). Although no significant antagonism was seen when fluconazole was given in combination with amphotericin B, combination therapy did not augment the antifungal activity of amphotericin B.

scholarly journals Antibodies to a Surface-Exposed, N-terminal Domain of Aggregation Substance Are Not Protective in the Rabbit Model of Enterococcus faecalis Infective Endocarditis

2001 ◽  
Vol 69 (5) ◽  
pp. 3305-3314 ◽  
Author(s):  
John K. McCormick ◽  
Helmut Hirt ◽  
Christopher M. Waters ◽  
Timothy J. Tripp ◽  
Gary M. Dunny ◽  
...  
Keyword(s):  
Infective Endocarditis ◽  
Enterococcus Faecalis ◽  
Rabbit Model ◽  
Surface Protein ◽  
Conjugative Plasmid ◽  
Aggregation Substance ◽  
Exposed Region ◽  
Correct Sequence

ABSTRACT The aggregation substance (AS) surface protein fromEnterococcus faecalis has been implicated as an important virulence factor for the development of infective endocarditis. To evaluate the role of antibodies specific for Asc10 (the AS protein from the conjugative plasmid pCF10) in protective immunity to infective endocarditis, an N-terminal region of Asc10 lacking the signal peptide and predicted to be surface exposed (amino acids 44 to 331; AS44–331) was cloned with a C-terminal histidine tag translational fusion and expressed fromEscherichia coli. N-terminal amino acid sequencing of the purified protein revealed the correct sequence, and rabbit polyclonal antisera raised against AS44–331 reacted specifically to Asc10 expressed from E. faecalis OG1SSp, but not to other proteins as judged by Western blot analysis. Using these antisera, flow cytometry analysis demonstrated that antibodies to AS44–331 bound to a surface-exposed region of Asc10. Furthermore, antibodies specific for AS44–331were opsonic for E. faecalis expressing Asc10 in vitro but not for cells that did not express Asc10. New Zealand White rabbits immunized with AS44–331 were challenged intravenously withE. faecalis cells constitutively expressing Asc10 in the rabbit model of experimental endocarditis. Highly immune animals did not show significant differences in clearance of organisms from the blood or spleen or in formation of vegetations on the aortic valve, in comparison with nonimmune animals. Although in vivo expression of Asc10 was demonstrated by immunohistochemistry, these experiments provide evidence that immunity to Asc10 does not play a role in protection from experimental infective endocarditis due toE. faecalis and may have important implications for the development of immunological approaches to combat enterococcal endocarditis.

In vivo oral efficacy of levofloxacin for treatment of systemic Pseudomonas aeruginosa infections in a murine model of septicemia.

1996 ◽  
Vol 40 (12) ◽  
pp. 2894-2897 ◽  
Author(s):  
S K Yagel ◽  
J F Barrett ◽  
D J Amaratunga ◽  
M B Frosco
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Body Weight ◽  
Single Dose ◽  
Divided Dose ◽  
Murine Model ◽  
Total Daily Dose ◽  
Dosing Regimen ◽  
Daily Dose ◽  
Effective Doses

The in vivo efficacies of levofloxacin and ciprofloxacin in lethal, systemic Pseudomonas aeruginosa infections in mice were compared. MICs of levofloxacin and ciprofloxacin ranged from 0.5 to 2.0 micrograms/ml and from 0.12 to 1.0 microgram/ml respectively. Infecting doses ranged from 5.0 x 10(1) to 3.2 x 10(3) CFU per mouse, depending on the isolate. Test fluoroquinolones were administered orally at 1 h (single dose) or at 1 and 3 h (divided dose) postinfection, with 10 infected mice used for each of six concentrations of each fluoroquinolone tested (1 to 40 mg/kg of body weight) in each dosing regimen. Whether given in a single or a divided dose, the total daily dose was the same for each fluoroquinolone. For mice treated 1 h postinfection with levofloxacin and ciprofloxacin, the effective doses for 50% of the infected mice ranged from 2.09 to 13.80 mg/kg and from 2.34 to 11.22 mg/kg, respectively, and for those treated 1 and 3 h postinfection, the effective doses for 50% of the infected mice ranged from 3.71 to 16.98 mg/kg and from 2.95 to 13.18 mg/kg, respectively. Although the potency varied for both levofloxacin and ciprofloxacin among all strains of P. aeruginosa tested, there were small differences within the same strain for levofloxacin and ciprofloxacin when given in the same dosing regimen. Levofloxacin proved nearly as effective as ciprofloxacin against a systemic P. aeruginosa infection in mice.

scholarly journals 1065. Efficacy of Cefiderocol in Experimental Stenotrophomonas maltophilia Pneumonia in Persistently Neutropenic Rabbits

2021 ◽  
Vol 8 (Supplement_1) ◽  
pp. S625-S625
Author(s):  
Vidmantas Petraitis ◽  
Ruta Petraitiene ◽  
Povilas Kavaliauskas ◽  
Ethan Naing ◽  
Andrew Garcia ◽  
...  
Keyword(s):  
Stenotrophomonas Maltophilia ◽  
Rabbit Model ◽  
Standard Of Care ◽  
Outer Cell ◽  
Research Support ◽  
First Line Therapy ◽  
Highly Active ◽  
Immunocompromised Hosts

Abstract Background Stenotrophomonas maltophilia causes lethal pneumonia, bacteremia, and sepsis in immunocompromised patients. As a standard of care, trimethoprim-sulfamethoxazole (T/S) is considered to be the first-line therapy for Stenotrophomonas pneumonia. Cefiderocol (CFDC) is a new parenteral siderophore cephalosporin that is transported through the outer cell membrane as a siderophore mimic that then inhibits Gram-negative cell wall biosynthesis. CFDC has potent activity in vitro against S. maltophilia; however, little is known about its in vivo activity against Stenotrophomonas pneumonia in immunocompromised hosts. We therefore studied CFDC in comparison to TS in the persistently neutropenic rabbit model of Stenotrophomonas pneumonia. This rabbit model, in contrast to conventional murine models, reflects the human pattern of infection more accurately over time. Methods We initially studied the plasma pharmacokinetics of CFDC in non-infected and infected animals. Stenotrophomonas pneumonia was established by direct endotracheal inoculation of S. maltophilia 1×1010 CFUs for tracheobronchial colonization that evolved into bronchopneumonia. Experimental groups consisted of CFDC, T/S, and untreated controls (UC). Rabbits received CFDC at 120 mg/kg IV Q8h and T/S at 5 mg/kg IV Q12h. Profound persistent neutropenia was maintained with cytosine arabinoside. Treatment was continued for 10 days. Results There were no significant differences between non-infected and infected rabbits in CFDC pharmacokinetics. Rabbits treated with CFDC and T/S demonstrated significant decreases of residual pulmonary and BAL bacterial burden vs UC (p≤0.001). CFDC achieved full clearance of S. maltophilia from lung tissue and BAL. This antibacterial activity coincided with significant reduction of lung weights (marker of organism-mediated pulmonary injury) in the CFDC group vs T/S and UC (p&lt; 0.01). Survival was prolonged in the CFDC treatment group with 87% survival in comparison to that of T/S (25%) and UC (0%) (p&lt; 0.01). Table 1. Efficacy of Cefiderocol in Experimental Stenotrophomonas maltophilia Pneumonia in Persistency Neutropenic Rabbits Conclusion Cefiderocol is highly active in treatment of experimental S. maltophilia pneumonia in persistently neutropenic rabbits, thus laying the foundation for future clinical investigations against this lethal infection. Disclosures Naoki Ishibashi, MD, Shionogi, Inc. (Employee) Benjamin Georgiades, n/a, Shionogi, Inc. (Consultant) Roger Echols, MD, Shionogi (Consultant) Robert A. Bonomo, MD, entasis (Research Grant or Support)Merck (Grant/Research Support)NIH (Grant/Research Support)VA Merit Award (Grant/Research Support)VenatoRx (Grant/Research Support) Yoshinori Yamano, PhD, Shionogi (Employee) Thomas J. Walsh, MD, PhD (hon), Scynexis (Consultant, Grant/Research Support)Shionogi (Consultant, 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 Daptomycin–β-Lactam Combinations in a Rabbit Model of Daptomycin-Nonsusceptible Methicillin-Resistant Staphylococcus aureus Endocarditis

2016 ◽  
Vol 60 (7) ◽  
pp. 3976-3979 ◽  
Author(s):  
Henry F. Chambers ◽  
Li Basuino ◽  
Stephanie M. Hamilton ◽  
Eun Ju Choo ◽  
Pamela Moise
Keyword(s):  
Staphylococcus Aureus ◽  
Rabbit Model ◽  
Beta Lactams ◽  
Once Daily ◽  
Methicillin Resistant ◽  
Content Type ◽  
Daily Dose ◽  
Resistant Strains

ABSTRACTBeta-lactams enhance thein vitroactivity of daptomycin against methicillin-resistant strains ofStaphylococcus aureus. Experiments were performed in a rabbit model of aortic valve endocarditis caused by methicillin-resistant daptomycin-nonsusceptibleS. aureusstrain CB5054 to determine if a cephalosporin, ceftriaxone, administered as a once-daily dose of 100 mg/kg of body weight, or a carbapenem, ertapenem, administered as a once-daily dose of 40 mg/kg, improved the efficacy of daptomycin, administered as a once-daily dose of 12 mg/kg. Daptomycin was ineffective alone in reducing organism densities compared to untreated controls in vegetations and spleen, but densities were 1.4 log10CFU/g lower in kidney. The combination of daptomycin plus ceftriaxone or daptomycin plus ertapenem reduced bacterial densities in all tissues compared to single agents, with 0.6 to 1.0 log10CFU/g fewer organisms in vegetations, 1.5 to 2.5 log10CFU/g fewer organisms in spleen, and 1.8 to 2.5 log10CFU/g fewer organisms in kidney, although differences were statistically significant only in spleen for daptomycin plus ceftriaxone and in kidney for daptomycin plus ertapenem. Drug exposures in rabbits were less than those achievable in humans, which may have limited thein vivoactivity, particularly in vegetations.

Acyl-Enzymes as Thrombolytic Agents in a Rabbit Model of Venous Thrombosis

1982 ◽  
Vol 47 (03) ◽  
pp. 269-274 ◽  
Author(s):  
R A G Smith ◽  
R J Dupe ◽  
P D English ◽  
J Green
Keyword(s):  
Venous Thrombosis ◽  
Active Site ◽  
Fibrinolytic Activity ◽  
Rabbit Model ◽  
Fibrinolytic Agent ◽  
Essential Nature ◽  
Thrombolytic Agents

SummaryA derivative of human lys-plasmin in which the active site has been reversibly acylated (BRL 26920; p-anisoyl human lys-plasmin) has been examined as a fibrinolytic agent in a previously described rabbit model of venous thrombosis and shown to be significantly more active and less fibrinogenolytic than free plasmin. A p-anisoylated derivative of a streptokinase (SK)-activated plasmin preparation was significantly less fibrinogenolytic in vivo than the non-acylated enzyme. Acylation increased the fibrinolytic activity of preparations of SK-plasmin activator complexes. BRL 26921, the active site anisoylated derivative of the primary 2-chain SK-plasminogen complex was the most potent fibrinolytic agent studied. SK-Val442-plasminogen complexes, free or acylated, were biologically inactive in this model and confirm the essential nature of fibrin binding processes for effective thrombolysis in vivo.

Opiophobia in Cancer Biology- Justified? - The Role of Perioperative Use of Opioids in Cancer Recurrence

2019 ◽  
Vol 25 (28) ◽  
pp. 3020-3027 ◽  
Author(s):  
Mir W. Sekandarzad ◽  
Chris Doornebal ◽  
Markus W. Hollmann
Keyword(s):  
Pain Management ◽  
Cancer Biology ◽  
Tumor Biology ◽  
Cancer Recurrence ◽  
Standard Of Care ◽  
Cancer Surgery ◽  
Perioperative Pain Management ◽  
Tumor Growth And Metastasis

: Opioids remain the standard of care in the provision of analgesia in the patient undergoing cancer surgery preoperatively. : The effects of opioids on tumor growth and metastasis have been discussed for many years. In recent years their use as part of the perioperative pain management bundle in the patients undergoing cancer surgery has been thought to promote cancer recurrence and metastasis. : This narrative review highlights earlier and more recent in vitro, in vivo and human retrospective studies that yield conflicting results as to the immune-modulatory effects of morphine on tumor biology. The article examines and explains the discrepancies with regards to the seemingly opposite results of morphine in the tumor milieu. The results of both, earlier studies that demonstrated procarcinogenic effects versus the data of more recent refined rodent studies that yielded neutral or even anti-carcinogenic effects are presented here. : Until the results of prospective randomized controlled trials are available to clarify this important question, it is currently not warranted to support opiophobia and opioids continue to constitute a pivotal role in the pain management of cancer patients.

scholarly journals Unraveling the molecular pathobiology of vocal fold systemic dehydration using an in vivo rabbit model

PLoS ONE ◽  
2020 ◽  
Vol 15 (7) ◽  
pp. e0236348
Author(s):  
Naila Cannes do Nascimento ◽  
Andrea P. dos Santos ◽  
M. Preeti Sivasankar ◽  
Abigail Cox
Keyword(s):  
Vocal Fold ◽  
Rabbit Model
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