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 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 1563. Population Pharmacokinetics and Pharmacodynamics of Daily and Extended Interval Dalbavancin Dosing Regimens for Salvage Therapy of Staphylococcus aureus Endocarditis: Mechanistic Modeling of Rabbit Infection Data to Support Human Dosing Regimens

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S570-S570
Author(s):  
Andras Farkas ◽  
Arsheena Yassin ◽  
Bruno Fantin ◽  
Agnes Lefort
Keyword(s):  
Staphylococcus Aureus ◽  
Salvage Therapy ◽  
Rabbit Model ◽  
Inoculum Size ◽  
Mechanistic Modeling ◽  
Weekly Dose ◽  
Treatment Regimens ◽  
Days Of Therapy ◽  
Attractive Option ◽  
Dosing Regimens

Abstract Background Dalbavancins’ (DAL) long half-life and favorable susceptibility profile makes it an attractive option for salvage therapy for endocarditis caused by Staphylococcus aureus (SA), including those with elevated vancomycin (VAN) MIC. The aim of our study was to establish the PKPD of DAL based on a rabbit model of infection and extrapolate those results to the design of human treatment regimens. Methods Data from a rabbit endocarditis model of SA with VAN MICs of 2 and 8 mg/L were fitted using an inoculum-size dependent model and the Pmetrics software. Then, the results were linked to a human PK model to simulate regimens with or without a loading dose. Probability of target attainment (PTAs) for achieving bacterial density of <2 log CFU per gram of vegetation was compared with outcomes based on standard antibiotic therapy (SAT) at 3, 10, 21, 31, and 42 days. Results Mean (SD) PTAs of 34.3% (10.5%), 61.3% (7.0%), 73.5% (5.4%), 79.5% (4.3%), and 83.1% (3.4%) were estimated for all regimens combined with maximum PTAs of 41.8%, 63.6%, 77.8%, 86.6%, and 88.9% for the highest weekly dose at 3, 10, 21, 31 and 42 days of therapy, respectively. While all approaches should achieve an adequate probability of clearing of the colonies by day 21, only doses near 2,000 mg/week are likely to approximate sterilization rates similar to that expected by the SAT at day 42. We observed no meaningful differences in PTAs for weekly vs. daily dosing given with a load. Also, increasing the total weekly dose over 2,000 mg seems to offer minimal additional benefit (Figure 1A–D). Trough-level accumulation is expected as total weekly doses increase, showing a median (IQR) of 62.6 (73.1,85.2) [101.8 (89.9,117.4)] mg/L and 106.5 (91.63,123.6) [135.3 (118.3,156.0)] mg/L at 42 days for the 1,000 mg and 1,500 mg weekly [in equal daily fractions] doses, respectively. Conclusion Our design suggests that these DAL dosing regimens in humans are likely to provide reasonable rates of sterilization when treating endocarditis caused by SA isolates, and administration of near 2,000 mg weekly doses may be considered to improve upon sterilizing effect, but at the cost of accumulating DAL levels. Efficacy and safety of new regimens should be confirmed in well-controlled clinical trials. Disclosures All authors: No reported disclosures.

scholarly journals Combinations of Lysostaphin with β-Lactams Are Synergistic against Oxacillin-Resistant Staphylococcus epidermidis

2002 ◽  
Vol 46 (6) ◽  
pp. 2017-2020 ◽  
Author(s):  
Nandini Kiri ◽  
Gordon Archer ◽  
Michael W. Climo
Keyword(s):  
Staphylococcus Aureus ◽  
Aortic Valve ◽  
Staphylococcus Epidermidis ◽  
Concentration Index ◽  
Inhibitory Concentration ◽  
Rabbit Model ◽  
Fractional Inhibitory Concentration ◽  
Fractional Inhibitory Concentration Index ◽  
Synergy Testing ◽  
Better Than

ABSTRACT Oxacillin-resistant Staphylococcus aureus is rapidly killed by the endopeptidase lysostaphin, and the addition of β-lactam antibiotics provides synergistic killing. We investigated the possibility that β-lactams given in combination with lysostaphin would improve the activity of lysostaphin against oxacillin-resistant Staphylococcus epidermidis (ORSE), which is normally less susceptible to lysostaphin. Checkerboard synergy testing was performed for lysostaphin given in combination with oxacillin against 10 ORSE isolates for which the lysostaphin MICs were ≥ 8 μg/ml. The fractional inhibitory concentration index ranged from 0.0234 to 0.2656, indicating synergy, which was confirmed in growth curve experiments. In the rabbit model of experimental aortic valve endocarditis using an ORSE strain, the combination of lysostaphin and nafcillin was as effective as vancomycin alone and significantly better than lysostaphin or nafcillin alone. We conclude that β-lactam antibiotics given in combination with lysostaphin are synergistic against many strains of ORSE.

scholarly journals Relationship between Susceptibility to Daptomycin In Vitro and Activity In Vivo in a Rabbit Model of Aortic Valve Endocarditis

2009 ◽  
Vol 53 (4) ◽  
pp. 1463-1467 ◽  
Author(s):  
H. F. Chambers ◽  
L. Basuino ◽  
B. A. Diep ◽  
J. Steenbergen ◽  
S. Zhang ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Body Weight ◽  
Aortic Valve ◽  
Rabbit Model ◽  
Dual Infection ◽  
Survival Advantage ◽  
The Other ◽  
Infection Model

ABSTRACT Daptomycin is approved for treatment of Staphylococcus aureus bacteremia and right-sided endocarditis. Increases in daptomycin MICs have been associated with failure. A rabbit model of aortic valve endocarditis was used to determine whether MIC correlates with activity in vivo and whether a higher daptomycin dose can improve efficacy. Two related clinical S. aureus strains, one with a daptomycin MIC of 0.5 μg/ml and the other with a MIC of 2 μg/ml, were used to establish aortic valve endocarditis in rabbits. Daptomycin was administered once a day for 4 days at 12 mg/kg of body weight or 18 mg/kg to simulate doses in humans of 6 mg/kg and 10 mg/kg, respectively. Endocardial vegetations, spleens, and kidneys were harvested and quantitatively cultured. The strain with a MIC of 2 μg/ml had a survival advantage over the strain with a MIC of 0.5 μg/ml with >100 times more organisms of the former in endocardial vegetations at the 12-mg/kg dose in a dual-infection model. Both the 12-mg/kg dose and the 18-mg/kg dose completely eradicated the strain with a MIC of 0.5 from vegetations, spleens, and kidneys. The 12-mg/kg dose was ineffective against the strain with a MIC of 2 in vegetations; the 18-mg/kg dose produced a reduction of 3 log10 units in CFU in vegetations compared to the controls, although in no rabbit were organisms completely eliminated. Increasing the dose of daptomycin may improve its efficacy for infections caused by strains with reduced daptomycin susceptibility.

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 Telavancin Is Active against Experimental Aortic Valve Endocarditis Caused by Daptomycin- and Methicillin-Resistant Staphylococcus aureus Strains

2016 ◽  
Vol 61 (2) ◽  
Author(s):  
Wessam Abdelhady ◽  
Arnold S. Bayer ◽  
Rachelle Gonzales ◽  
Liang Li ◽  
Yan Q. Xiong
Keyword(s):  
Staphylococcus Aureus ◽  
Aortic Valve ◽  
Untreated Control ◽  
Methicillin Resistant Staphylococcus Aureus ◽  
Infection Model ◽  
Methicillin Resistant ◽  
Content Type ◽  
Mrsa Strains ◽  
Culture Negative

ABSTRACT We compared the efficacy of telavancin (TLV) and daptomycin (DAP) in an experimental rabbit endocarditis model caused by two clinically derived daptomycin-resistant (DAPr) methicillin-resistant Staphylococcus aureus (MRSA) strains. TLV treatment significantly reduced MRSA densities in all target tissues and increased the percentage of these organs rendered culture negative compared to those with the untreated control or DAP-treated animals. These results demonstrate that TLV has potent in vivo efficacy against DAPr MRSA isolates in this invasive endovascular infection model.

scholarly journals Teicoplanin-Containing Cement Spacers for Treatment of Experimental Staphylococcus aureus Joint Prosthesis Infection

2003 ◽  
Vol 47 (10) ◽  
pp. 3365-3367 ◽  
Author(s):  
Farid Ismael ◽  
Rémy Bléton ◽  
Azzam Saleh-Mghir ◽  
Sophie Dautrey ◽  
Laurent Massias ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Knee Prosthesis ◽  
Rabbit Model ◽  
Cement Spacer ◽  
Joint Prosthesis ◽  
Prosthesis Infection ◽  
Treatment Groups ◽  
Prosthesis Replacement ◽  
Drug Free ◽  
Systemic Antibiotic Treatment

ABSTRACT Using a rabbit model of methicillin-resistant Staphylococcus aureus knee-prosthesis infection, we studied the efficacy of teicoplanin cement alone or in combination with systemic intramuscular (i.m.) injections of teicoplanin. Seven days after infection, surgical debridement and removal of the infected prostheses were performed, and five rabbits were randomly assigned to one of five different treatment groups: untreated controls, prosthesis replacement by drug-free cement spacer, prosthesis replacement by teicoplanin-loaded cement spacer (1.2 g of teicoplanin/40 g of cement), i.m. injections of teicoplanin (20 mg/kg of body weight, twice a day for 7 days), or systemic antibiotic treatment combined with teicoplanin-loaded spacers. The most effective regimen combined systemic teicoplanin and antibiotic spacers.

scholarly journals Mechanism and Suppression of Lysostaphin Resistance in Oxacillin-Resistant Staphylococcus aureus

2001 ◽  
Vol 45 (5) ◽  
pp. 1431-1437 ◽  
Author(s):  
Michael W. Climo ◽  
Kerstin Ehlert ◽  
Gordon L. Archer
Keyword(s):  
Staphylococcus Aureus ◽  
Aortic Valve ◽  
Rabbit Model ◽  
In Vivo Model ◽  
Nucleotide Sequence Analysis ◽  
Cross Bridge ◽  
Oxacillin Resistance ◽  
Resistant Mutants

ABSTRACT The potential for the development of resistance in oxacillin-resistant Staphylococcus aureus (ORSA) to lysostaphin, a glycylglycine endopeptidase produced byStaphylococcus simulans biovar staphylolyticus, was examined in vitro and in an in vivo model of infection. Following in vitro exposure of ORSA to subinhibitory concentrations of lysostaphin, lysostaphin-resistant mutants were idenitifed among all isolates examined. Resistance to lysostaphin was associated with a loss of resistance to β-lactams and a change in the muropeptide interpeptide cross bridge from pentaglycine to a single glycine. Mutations in femA, the gene required for incorporation of the second and third glycines into the cross bridge, were found following PCR amplification and nucleotide sequence analysis. Complementation of lysostaphin-resistant mutants with pBBB31, which encodes femA, restored the phenotype of oxacillin resistance and lysostaphin susceptibility. Addition of β-lactam antibiotics to lysostaphin in vitro prevented the development of lysostaphin-resistant mutants. In the rabbit model of experimental endocarditis, administration of a low dose of lysostaphin for 3 days led predictably to the appearance of lysostaphin-resistant ORSA mutants in vegetations. Coadministration of nafcillin with lysostaphin prevented the emergence of lysostaphin-resistant mutants and led to a mean reduction in aortic valve vegetation counts of 7.5 log10 CFU/g compared to those for untreated controls and eliminated the isolation of lysostaphin-resistant mutants from aortic valve vegetations. Treatment with nafcillin and lysostaphin given alone led to mean reductions of 1.35 and 1.65 log10 CFU/g respectively. In ORSA, resistance to lysostaphin was associated with mutations in femA, but resistance could be suppressed by the coadministration of β-lactam antibiotics.

scholarly journals Evidence of Less Severe Aortic Valve Destruction after Treatment of Experimental Staphylococcal Endocarditis with Vancomycin and Dexamethasone

2001 ◽  
Vol 45 (12) ◽  
pp. 3531-3537 ◽  
Author(s):  
Peter Siaperas ◽  
Angelos Pefanis ◽  
Dimitrios Iliopoulos ◽  
Ioannis Katsarolis ◽  
Aspassia Kyroudi-Voulgari ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Aortic Valve ◽  
Tissue Damage ◽  
Experimental Studies ◽  
Treated Group ◽  
Control Group ◽  
Beneficial Effects ◽  
Valve Tissue ◽  
Leukocyte Number ◽  
The Mean

ABSTRACT The beneficial effects of therapy combining an antibiotic and dexamethasone have been reported in human studies on meningitis and in experimental studies on septic arthritis, nephritis, and endophthalmitis. Since most patients with staphylococcal endocarditis need a combination of medical and surgical treatment, the purpose of this study was to determine whether the addition of dexamethasone to vancomycin has any beneficial effect regarding the degree of valve tissue damage or the course of experimental aortic valve endocarditis caused by a methicillin-resistant strain of Staphylococcus aureus. Rabbits with catheter-induced aortic valve vegetations were randomly assigned to a control group and to groups receiving dexamethasone (0.5 mg/kg of body weight, intravenously [i.v.], twice a day [b.i.d]), vancomycin (30 mg/kg, i.v., b.i.d), or dexamethasone plus vancomycin, for a total of 10 doses (two doses per day for 5 days). The severity of valve tissue damage was significantly less in groups receiving vancomycin plus dexamethasone compared with that of the group receiving vancomycin alone (P < 0.001). The severity of tissue damage was inversely correlated with the mean polymorphonuclear leukocyte number in valve tissue. No statistically significant differences were observed between the vancomycin-treated group and the vancomycin-plus-dexamethasone-treated group in survival, blood culture sterilization rate, or reduction of the microbial burden (in CFU per gram) in valvular tissue. In conclusion, treatment with a combination of vancomycin and dexamethasone for 5 days reduces the severity of valve tissue damage in experimental staphylococcal aortic valve endocarditis. These findings could have significant implications in the treatment of staphylococcal endocarditis and deserve further confirmation in clinical trials.

scholarly journals Telavancin in Therapy of Experimental Aortic Valve Endocarditis in Rabbits Due to Daptomycin-Nonsusceptible Methicillin-Resistant Staphylococcus aureus

2012 ◽  
Vol 56 (11) ◽  
pp. 5528-5533 ◽  
Author(s):  
Yan Q. Xiong ◽  
Wessam Abdel Hady ◽  
Arnold S. Bayer ◽  
Liang Chen ◽  
Barry N. Kreiswirth ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Aortic Valve ◽  
Rabbit Model ◽  
Methicillin Resistant ◽  
Content Type ◽  
Bacterial Cell Membrane ◽  
Mrsa Strains ◽  
Time Kill

ABSTRACTA number of cases of both methicillin-susceptibleStaphylococcus aureus(MSSA) and methicillin-resistantS. aureus(MRSA) strains that have developed daptomycin resistance (DAP-R) have been reported. Telavancin (TLV) is a lipoglycopeptide agent with a dual mechanism of activity (cell wall synthesis inhibition plus depolarization of the bacterial cell membrane). Five recent daptomycin-susceptible (DAP-S)/DAP-R MRSA isogenic strain pairs were evaluated forin vitroTLV susceptibility. All five DAP-R strains (DAP MICs ranging from 2 to 4 μg/ml) were susceptible to TLV (MICs of ≤0.38 μg/ml).In vitrotime-kill analyses also revealed that several TLV concentrations (1-, 2-, and 4-fold MICs) caused rapid killing against the DAP-R strains. Moreover, for 3 of 5 DAP-R strains (REF2145, A215, and B2.0), supra-MICs of TLV were effective at preventing regrowth at 24 h of incubation. Further, the combination of TLV plus oxacillin (at 0.25× or 0.50× MIC for each agent) increased killing of DAP-R MRSA strains REF2145 and A215 at 24 h (∼2-log and 5-log reductions versus TLV and oxacillin alone, respectively). Finally, using a rabbit model of aortic valve endocarditis caused by DAP-R strain REF2145, TLV therapy produced a mean reduction of >4.5 log10CFU/g in vegetations, kidneys, and spleen compared to untreated or DAP-treated rabbits. Moreover, TLV-treated rabbits had a significantly higher percentage of sterile tissue cultures (87% in vegetations and 100% in kidney and spleen) than all other treatment groups (P< 0.0001). Together, these results demonstrate that TLV has potent bactericidal activityin vitroandin vivoagainst DAP-R MRSA isolates.

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