Exebacase, in Addition to Daptomycin against MRSA

2021 ◽  
Author(s):  
Razieh Kebriaei ◽  
Kyle C. Stamper ◽  
Katherine L. Lev ◽  
Taylor Morrisette ◽  
Jacinda C. Abdul-Mutakabbir ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Cell Wall ◽  
Bactericidal Activity ◽  
Ex Vivo ◽  
Lytic Activity ◽  
Vegetation Model ◽  
Methicillin Resistant ◽  
Initial Inoculum ◽  
Mrsa Strains ◽  
Time Kill

Exebacase is a lysin (cell wall hydrolase) with direct lytic activity against Staphylococcus aureus including methicillin-resistant S. aureus (MRSA). Time kill analysis experiments illustrated bactericidal activity of exebacase-daptomycin, against MRSA strains MW2 and 494. Furthermore, exebacase in addition to daptomycin (10, 6 and 4 mg/kg/d) in a two-compartment ex-vivo pharmacokinetic/pharmacodynamic simulated endocardial vegetation model with humanized doses resulted in reductions of 6.01, 4.99 and 2.81 log 10 CFU/g (from initial inoculum) against MRSA strain MW2.

scholarly journals The Combination of Daptomycin and Fosfomycin Has Synergistic, Potent, and Rapid Bactericidal Activity against Methicillin-ResistantStaphylococcus aureusin a Rabbit Model of Experimental Endocarditis

2018 ◽  
Vol 62 (6) ◽  
Author(s):  
Cristina García-de-la-Mària ◽  
Oriol Gasch ◽  
Javier García-Gonzalez ◽  
Dolors Soy ◽  
Evelyn Shaw ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Bactericidal Activity ◽  
Combined Therapy ◽  
Rabbit Model ◽  
Bactericidal Effect ◽  
Methicillin Resistant ◽  
Content Type ◽  
Mrsa Strains ◽  
Time Kill

ABSTRACTWe investigated whether the addition of fosfomycin or cloxacillin to daptomycin provides better outcomes in the treatment of methicillin-resistantStaphylococcus aureus(MRSA) experimental aortic endocarditis in rabbits. Five MRSA strains were used to performin vitrotime-kill studies using standard (106) and high (108) inocula. Combined therapy was compared to daptomycin monotherapy treatment in the MRSA experimental endocarditis model. A human-like pharmacokinetics model was applied, and the equivalents of cloxacillin at 2 g/4 h, fosfomycin at 2 g/6 h, and daptomycin at 6 to 10 mg/kg/day were administered intravenously. A combination of daptomycin and either fosfomycin or cloxacillin was synergistic in the five strains tested at both inocula. A bactericidal effect was detected in four of five strains tested with both combinations. The MRSA-277 strain (vancomycin MIC, 2 μg/ml) was used for the experimental endocarditis model. Daptomycin plus fosfomycin significantly improved the efficacy of daptomycin monotherapy at 6 mg/kg/day in terms of both the proportion of sterile vegetations (100% versus 72%,P= 0.046) and the decrease in the density of bacteria within the vegetations (P= 0.025). Daptomycin plus fosfomycin was as effective as daptomycin monotherapy at 10 mg/kg/day (100% versus 93%,P= 1.00) and had activity similar to that of daptomycin plus cloxacillin when daptomycin was administered at 6 mg/kg/day (100% versus 88%,P= 0.48). Daptomycin nonsusceptibility was not detected in any of the isolates recovered from vegetations. In conclusion, for the treatment of MRSA experimental endocarditis, the combination of daptomycin plus fosfomycin showed synergistic and bactericidal activity.

scholarly journals In Vitro and In Vivo Synergistic Activities of Linezolid Combined with Subinhibitory Concentrations of Imipenem against Methicillin-Resistant Staphylococcus aureus

2005 ◽  
Vol 49 (1) ◽  
pp. 45-51 ◽  
Author(s):  
Cédric Jacqueline ◽  
Dominique Navas ◽  
Eric Batard ◽  
Anne-Françoise Miegeville ◽  
Virginie Le Mabecque ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Bactericidal Activity ◽  
Methicillin Resistant ◽  
In Vivo Experiments ◽  
Low Concentrations ◽  
Mrsa Strains ◽  
Kill Curve ◽  
Time Kill

ABSTRACT Indifference or moderate antagonism of linezolid combined with other antibiotics in vitro and in vivo have mainly been reported in the literature. We have assessed the in vitro activities of linezolid, alone or in combination with imipenem, against methicillin-resistant Staphylococcus aureus (MRSA) strains using the dynamic checkerboard and time-kill curve methods. Linezolid and low concentrations of imipenem had a synergistic effect, leading us to evaluate the in vivo antibacterial activity of the combination using the rabbit endocarditis experimental model. Two MRSA strains were used for in vivo experiments: one was a heterogeneous glycopeptide-intermediate clinical S. aureus strain isolated from blood cultures, and the other was the S. aureus COL reference strain. Animals infected with one of two MRSA strains were randomly assigned to one of the following treatments: no treatment (controls), linezolid (simulating a dose in humans of 10 mg/kg of body weight every 12 h), a constant intravenous infusion of imipenem (which allowed the steady-state concentration of about 1/32 the MIC of imipenem for each strain to be reached in serum), or the combination of both treatments. Linezolid and imipenem as monotherapies exhibited no bactericidal activity against either strain. The combination of linezolid plus imipenem showed in vivo bactericidal activity that corresponded to a decrease of at least 4.5 log CFU/g of vegetation compared to the counts for the controls. In conclusion, the combination exhibited synergistic and bactericidal activities against two MRSA strains after 5 days of treatment. The combination of linezolid plus imipenem appears to be promising for the treatment of severe MRSA infections and merits further investigations to explore the mechanism underlying the synergy between the two drugs.

scholarly journals Ability of Bicarbonate Supplementation To Sensitize Selected Methicillin-Resistant Staphylococcus aureus Strains to β-Lactam Antibiotics in an Ex Vivo Simulated Endocardial Vegetation Model

2019 ◽  
Vol 64 (3) ◽  
Author(s):  
Warren E. Rose ◽  
Ana M. Bienvenida ◽  
Yan Q. Xiong ◽  
Henry F. Chambers ◽  
Arnold S. Bayer ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Bactericidal Activity ◽  
Ex Vivo ◽  
Rabbit Model ◽  
Luria Bertani ◽  
Growth Media ◽  
Methicillin Resistant ◽  
Content Type ◽  
Mrsa Strains

ABSTRACT Supplementation of standard growth media (cation-adjusted Mueller-Hinton Broth [CAMHB]) with bicarbonate (NaHCO3) increases β-lactam susceptibility of selected methicillin-resistant Staphylococcus aureus (MRSA) strains (“NaHCO3 responsive”). This “sensitization” phenomenon translated to enhanced β-lactam efficacy in a rabbit model of endocarditis. The present study evaluated NaHCO3-mediated β-lactam MRSA sensitization using an ex vivo pharmacodynamic model, featuring simulated endocardial vegetations (SEVs), to more closely mimic the host microenvironment. Four previously described MRSA strains were used: two each exhibiting in vitro NaHCO3-responsive or NaHCO3-nonresponsive phenotypes. Cefazolin (CFZ) and oxacillin (OXA) were evaluated in CAMHB with or without NaHCO3. Intra-SEV MRSA killing was determined over 72-h exposures. In both “responsive” strains, supplementation with 25 mM or 44 mM NaHCO3 significantly reduced β-lactam MICs to below the OXA susceptibility breakpoint (≤4 mg/liter) and resulted in bactericidal activity (≥3-log killing) in the model for both OXA and CFZ. In contrast, neither in vitro-defined nonresponsive MRSA strain showed significant sensitization in the SEV model to either β-lactam. At both NaHCO3 concentrations, the fractional time above MIC was >50% for both CFZ and OXA in the responsive MRSA strains. Also, in media containing RPMI plus 10% Luria-Bertani broth (proposed as a more host-mimicking microenvironment and containing 25 mM NaHCO3), both CFZ and OXA exhibited enhanced bactericidal activity against NaHCO3-responsive strains in the SEV model. Neither CFZ nor OXA exposures selected for emergence of high-level β-lactam-resistant mutants within SEVs. Thus, in this ex vivo model of endocarditis, in the presence of NaHCO3 supplementation, both CFZ and OXA are highly active against MRSA strains that demonstrate similar enhanced susceptibility in NaHCO3-supplemented media in vitro.

scholarly journals Evaluation of Ceftaroline Activity versus Daptomycin (DAP) against DAP-Nonsusceptible Methicillin-Resistant Staphylococcus aureus Strains in anIn VitroPharmacokinetic/Pharmacodynamic Model

2011 ◽  
Vol 55 (7) ◽  
pp. 3522-3526 ◽  
Author(s):  
Molly Steed ◽  
Celine Vidaillac ◽  
Michael J. Rybak
Keyword(s):  
Staphylococcus Aureus ◽  
Bactericidal Activity ◽  
Therapeutic Option ◽  
Pharmacodynamic Model ◽  
Methicillin Resistant ◽  
Content Type ◽  
Initial Inoculum ◽  
Mrsa Strains ◽  
Post Hoc

ABSTRACTThe objective of this study was to investigate the potential role of ceftaroline, a new broad-spectrum cephalosporin, as a therapeutic option for the treatment of daptomycin-nonsusceptible (DNS) methicillin-resistantStaphylococcus aureus(MRSA) infections. Four clinical DNS MRSA strains, R5717, R5563, R5996 (heteroresistant vancomycin-intermediateS. aureus) and R5995 (vancomycin-intermediateS. aureus) were evaluated in a two-compartment hollow-fiberin vitropharmacokinetic/pharmacodynamic model at a starting inoculum of 107CFU/ml for 96 h. Simulated regimens were ceftaroline at 600 mg every 12 h (q12h) (maximum free-drug concentration [fCmax], 15.2 μg/ml; serum half-life [t1/2], 2.3 h), daptomycin at 6 mg/kg q24h (fCmax, 7.9 μg/ml;t1/2, 8 h), and daptomycin at 10 mg/kg q24h (fCmax, 15.2 μg/ml;t1/2, 8 h). Differences in CFU/ml between 24 and 96 h were evaluated by analysis of variance with Tukey's post-hoc test. Bactericidal activity was defined as a ≥3-log10CFU/ml decrease in the colony count from the initial inoculum. The ceftaroline MIC values were 0.25, 0.5, 0.5, and 0.5 μg/ml, and the daptomycin MIC values were 2, 2, 4, and 4 μg/ml for R5717, R5563, R5996, and R5995, respectively. Ceftaroline displayed sustained bactericidal activity against 3 of the 4 strains at 96 h (R5717, −3.1 log10CFU/ml; R5563, −2.5 log10CFU/ml; R5996, −5.77 log10CFU/ml; R5995, −6.38 log10CFU/ml). Regrowth occurred during the daptomycin at 6-mg/kg q24h regimen (4 strains) and the daptomycin at 10-mg/kg q24h regimen (3 strains). At 96 h, ceftaroline was significantly more active, resulting in CFU/ml counts lower than those obtained with daptomycin at 6 mg/kg q24h (4 strains,P≤ 0.008) and daptomycin at 10 mg/kg q24 h (3 strains,P≤ 0.001). Isolates with increased MIC values for daptomycin (all 4 strains) but not for ceftaroline were recovered. Ceftaroline was effective against the 4 isolates tested and may provide a clinical option for the treatment of DNS MRSA infections.

scholarly journals Novel Combinations of Vancomycin plus Ceftaroline or Oxacillin against Methicillin-Resistant Vancomycin-Intermediate Staphylococcus aureus (VISA) and Heterogeneous VISA

2013 ◽  
Vol 57 (5) ◽  
pp. 2376-2379 ◽  
Author(s):  
B. J. Werth ◽  
C. Vidaillac ◽  
K. P. Murray ◽  
K. L. Newton ◽  
G. Sakoulas ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Cell Wall ◽  
Inverse Correlation ◽  
Fluorescent Dye ◽  
Beta Lactam ◽  
Significant Inverse Correlation ◽  
Methicillin Resistant ◽  
Content Type ◽  
Time Kill ◽  
Wall Interactions

ABSTRACTWe demonstrated a significant inverse correlation between vancomycin and beta-lactam susceptibilities in vancomycin-intermediateStaphylococcus aureus(VISA) and heterogeneous VISA (hVISA) isolates. Using time-kill assays, vancomycin plus oxacillin or ceftaroline was synergistic against 3 of 5 VISA and 1 of 5 hVISA isolates or 5 of 5 VISA and 4 of 5 hVISA isolates, respectively. Beta-lactam exposure reduced overall vancomycin-Bodipy (dipyrrometheneboron difluoride [4,4-difluoro-4-bora-3a,4a-diaza-s-indacene] fluorescent dye) binding but may have improved vancomycin-cell wall interactions to improve vancomycin activity. Further research is warranted to elucidate the mechanism behind vancomycin and beta-lactam synergy.

scholarly journals Telavancin, a Multifunctional Lipoglycopeptide, Disrupts both Cell Wall Synthesis and Cell Membrane Integrity in Methicillin-Resistant Staphylococcus aureus

2005 ◽  
Vol 49 (3) ◽  
pp. 1127-1134 ◽  
Author(s):  
Deborah L. Higgins ◽  
Ray Chang ◽  
Dmitri V. Debabov ◽  
Joey Leung ◽  
Terry Wu ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Cell Wall ◽  
Membrane Potential ◽  
Cell Membrane ◽  
Bactericidal Activity ◽  
Bacterial Cell ◽  
Cell Membrane Potential ◽  
Gram Positive ◽  
Methicillin Resistant ◽  
Bacterial Cell Membrane

ABSTRACTThe emergence and spread of multidrug-resistant gram-positive bacteria represent a serious clinical problem. Telavancin is a novel lipoglycopeptide antibiotic that possesses rapid in vitro bactericidal activity against a broad spectrum of clinically relevant gram-positive pathogens. Here we demonstrate that telavancin's antibacterial activity derives from at least two mechanisms. As observed with vancomycin, telavancin inhibited late-stage peptidoglycan biosynthesis in a substrate-dependent fashion and bound the cell wall, as it did the lipid II surrogate tripeptideN,N′-diacetyl-l-lysinyl-d-alanyl-d-alanine, with high affinity. Telavancin also perturbed bacterial cell membrane potential and permeability. In methicillin-resistantStaphylococcus aureus, telavancin caused rapid, concentration-dependent depolarization of the plasma membrane, increases in permeability, and leakage of cellular ATP and K+. The timing of these changes correlated with rapid , concentration-dependent loss of bacterial viability, suggesting that the early bactericidal activity of telavancin results from dissipation of cell membrane potential and an increase in membrane permeability. Binding and cell fractionation studies provided direct evidence for an interaction of telavancin with the bacterial cell membrane; stronger binding interactions were observed with the bacterial cell wall and cell membrane relative to vancomycin. We suggest that this multifunctional mechanism of action confers advantageous antibacterial properties.

scholarly journals SpoVG Regulates Cell Wall Metabolism and Oxacillin Resistance in Methicillin-Resistant Staphylococcus aureus Strain N315

2016 ◽  
Vol 60 (6) ◽  
pp. 3455-3461 ◽  
Author(s):  
Xiaoyu Liu ◽  
Shijie Zhang ◽  
Baolin Sun
Keyword(s):  
Staphylococcus Aureus ◽  
Cell Wall ◽  
Aureus Strain ◽  
Cell Wall Metabolism ◽  
Mobility Shift ◽  
Entire Family ◽  
Positive Role ◽  
Methicillin Resistant ◽  
Oxacillin Resistance ◽  
Mrsa Strains

Increasing cases of infections caused by methicillin-resistantStaphylococcus aureus(MRSA) strains in healthy individuals have raised concerns worldwide. MRSA strains are resistant to almost the entire family of β-lactam antibiotics due to the acquisition of an extra penicillin-binding protein, PBP2a. Studies have shown thatspoVGis involved in oxacillin resistance, while the regulatory mechanism remains elusive. In this study, we have found that SpoVG plays a positive role in oxacillin resistance through promoting cell wall synthesis and inhibiting cell wall degradation in MRSA strain N315. Deletion ofspoVGin strain N315 led to a significant decrease in oxacillin resistance and a dramatic increase in Triton X-100-induced autolytic activity simultaneously. Real-time quantitative reverse transcription-PCR revealed that the expression of 8 genes related to cell wall metabolism or oxacillin resistance was altered in thespoVGmutant. Electrophoretic mobility shift assay indicated that SpoVG can directly bind to the putative promoter regions oflytN(murein hydrolase),femA, andlytSR(the two-component system). These findings suggest a molecular mechanism in which SpoVG modulates oxacillin resistance by regulating cell wall metabolism in MRSA.

scholarly journals 204. Antagonistic Effect of Colistin on Vancomycin Activity Against Methicillin-Resistant Staphylococcus aureus in in vitro and in vivo Studies

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S120-S121
Author(s):  
Sungim Choi ◽  
Taeeun Kim ◽  
Seongman Bae ◽  
Eunmi Yang ◽  
Su-Jin Park ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Methicillin Resistant Staphylococcus Aureus ◽  
Antagonistic Effect ◽  
In Vivo Studies ◽  
Infection Model ◽  
Methicillin Resistant ◽  
Checkerboard Assay ◽  
Mrsa Strains ◽  
Time Kill

Abstract Background There is a concern that the vancomycin MIC of methicillin-resistant Staphylococcus aureus (MRSA) could be increased by concomitant colistin administered against multidrug-resistant gram-negative pathogen. Methods We confirmed the molecular genotypes of MRSA blood isolates collected in a tertiary hospital in Seoul, South Korea, and selected representative strains from the community-associated MRSA strains (CA-MRSA, ST72-SCCmec IV) and hospital-acquired MRSA strains (HA-MRSA, ST5-SCCmec II). USA CA-MRSA (USA300, ST8-SCCmec IV) and MRSA standard strain (ATCC 43300, ST39-SCCmec II) were also used for comparison with representative. We identified changes of the vancomycin MIC in MRSA by colistin exposure in a checkerboard assay and performed a time-kill assay to evaluate the combined effect of vancomycin and colistin on MRSA. In addition, we administered vancomycin, colistin, and combination of two antibiotics, respectively, to a neutropenic murine thigh infection model to evaluate the in vivo antagonistic effect of colistin on vancomycin treatment. Results In the checkerboard assay, all 4 MRSA strains showed a tendency for the vancomycin MIC to increase along with increasing concentrations of colistin. However, the time-kill assay showed the antagonism of vancomycin and colistin only against ST5-MRSA, when vancomycin concentration was 2 times the vancomycin MIC (Figure 1). No antagonism was observed in other strains. In the murine thigh infection model of ST5-MRSA, vancomycin monotherapy showed a significant log CFU reduction compared with a combination of vancomycin and colistin at 24 hours, demonstrating the antagonistic effect of vancomycin and colistin combination (Figure 2). Conclusion This study showed that exposure of colistin to certain MRSA strains may reduce the susceptibility to vancomycin. Combination therapy with vancomycin and colistin for MDR pathogens infections might result in treatment failure for concurrent MRSA infection. Disclosures All authors: No reported disclosures.

scholarly journals Ceftobiprole EfficacyIn Vitroagainst Panton-Valentine Leukocidin Production andIn Vivoagainst Community-Associated Methicillin-Resistant Staphylococcus aureus Osteomyelitis in Rabbits

2012 ◽  
Vol 56 (12) ◽  
pp. 6291-6297 ◽  
Author(s):  
Azzam Saleh-Mghir ◽  
Oana Dumitrescu ◽  
Aurélien Dinh ◽  
Yassine Boutrad ◽  
Laurent Massias ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Methicillin Resistant ◽  
Content Type ◽  
The Mean ◽  
Mrsa Strains ◽  
Time Kill ◽  
Panton Valentine Leukocidin ◽  
Valentine Leukocidin

ABSTRACTCommunity-associated methicillin-resistantStaphylococcus aureus(CA-MRSA) can cause osteomyelitis with severe sepsis and/or local complications in which a Panton-Valentine leukocidin (PVL) role is suspected.In vitrosub-MIC antibiotic effects on growth and PVL production by 11 PVL+MRSA strains, including the major CA-MRSA clones (USA300, including the LAC strain; USA400; and USA1000), and 11 PVL+methicillin-susceptibleS. aureus(MSSA) strains were tested in microplate culture. Time-kill analyses with ceftobiprole at its MIC were also run with LAC. Efficacies of ceftobiprole (40 mg/kg of body weight subcutaneously [s.c.] four times a day [q.i.d.]) or vancomycin (60 mg/kg intramuscularly [i.m.] twice a day [b.i.d.]) alone or combined with rifampin (10 mg/kg b.i.d.) against rabbit CA-MRSA osteomyelitis, induced by tibial injection of 3.4 × 107CFU of LAC, were compared. Treatment, started 14 days postinoculation, lasted 14 days.In vitro, 6/11 strains cultured with sub-MICs of ceftobiprole produced 1.6- to 4.8-fold more PVL than did the controls, with no link to specific clones. Rifampin decreased PVL production by all tested strains. In time-kill analyses at the LAC MIC (0.75 mg/liter), PVL production rose transiently at 6 and 8 h and then declined 2-fold at 16 h, concomitant with a 2-log10-CFU-count decrease.In vivo, the mean log10CFU/g of bone for ceftobiprole (1.44 ± 0.40) was significantly lower than that for vancomycin (2.37 ± 1.22) (P= 0.034), with 7/10 versus 5/11 bones sterilized, respectively. Combination with rifampin enhanced ceftobiprole (1.16 ± 0.04 CFU/g of bone [P= 0.056], 11/11 sterile bones) and vancomycin (1.23 ± 0.06 CFU/g [P= 0.011], 11/11 sterile bones) efficacies. Ceftobiprole bactericidal activity and the rifampin anti-PVL effect could play a role in these findings, which should be of interest for treating CA-MRSA osteomyelitis.

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