scholarly journals Oritavancin Combinations with β-Lactams against Multidrug-Resistant Staphylococcus aureus and Vancomycin-Resistant Enterococci

2016 ◽  
Vol 60 (4) ◽  
pp. 2352-2358 ◽  
Author(s):  
Jordan R. Smith ◽  
Juwon Yim ◽  
Animesh Raut ◽  
Michael J. Rybak
Keyword(s):  
Staphylococcus Aureus ◽  
Single Agent ◽  
Multidrug Resistant ◽  
Content Type ◽  
Vancomycin Resistant Enterococci ◽  
Complex Models ◽  
Vancomycin Resistant ◽  
Mrsa Strains ◽  
Time Kill

ABSTRACTOritavancin possesses activity against vancomycin-resistant enterococci (VRE) and methicillin-resistantStaphylococcus aureus(MRSA).In vitrodata suggest synergy between beta-lactams (BLs) and vancomycin or daptomycin, agents similar to oritavancin. We evaluated the activities of BLs combined with oritavancin against MRSA and VRE. Oritavancin MICs were determined for 30 strains, 5 each of MRSA, daptomycin-nonsusceptible (DNS) MRSA, vancomycin-intermediate MRSA (VISA), heteroresistant VISA (hVISA), vancomycin-resistantEnterococcus faecalis, and vancomycin-resistantEnterococcus faecium. Oritavancin MICs were determined in the presence of subinhibitory concentrations of BLs. Oritavancin combined with ceftaroline, cefazolin, or nafcillin was evaluated for lethal synergy against MRSA, and oritavancin combined with ceftaroline, ampicillin, or ertapenem was evaluated for lethal synergy against VRE in 24-h time-kill assays. Oritavancin at 0.5× the MIC was combined with BLs at 0.5× the MIC or the biological free peak concentration, whichever one was lower. Synergy was defined as a ≥2-log10-CFU/ml difference between the killing achieved with the combination and that achieved with the most active single agent at 24 h. Oritavancin MICs were ≤0.125 μg/ml for all MRSA isolates except three VISA isolates with MICs of 0.25 μg/ml. Oritavancin MICs for VRE ranged from 0.03 to 0.125 μg/ml. Oritavancin in combination with ceftaroline was synergistic against all MRSA phenotypes and statistically superior to all other combinations against DNS MRSA, hVISA, and MRSA isolates (P< 0.02). Oritavancin in combination with cefazolin and oritavancin in combination with nafcillin were also synergistic against all MRSA strains. Synergy between oritavancin and all BLs was revealed against VRE strain 8019, while synergy between oritavancin and ampicillin or ertapenem but not ceftaroline was demonstrated against VRE strain R7164. The data support the potential use of oritavancin in combination with BLs, especially oritavancin in combination with ceftaroline, for the treatment of infections caused by MRSA. The data from the present study are not as strong for oritavancin in combination with BLs for VRE. Further study of both MRSA and VRE in more complex models is warranted.

scholarly journals β-Lactam Combinations with Vancomycin Show Synergistic Activity against Vancomycin-SusceptibleStaphylococcus aureus, Vancomycin-IntermediateS. aureus(VISA), and Heterogeneous VISA

2018 ◽  
Vol 62 (6) ◽  
Author(s):  
Kieu-Nhi Tran ◽  
Michael J. Rybak
Keyword(s):  
Staphylococcus Aureus ◽  
Single Agent ◽  
Synergistic Activity ◽  
Beta Lactam ◽  
Beta Lactams ◽  
Content Type ◽  
Fold Reduction ◽  
Mrsa Strains ◽  
Time Kill

ABSTRACTIncreasing utilization of vancomycin due to the high prevalence of methicillin-resistantStaphylococcus aureus(MRSA) infections has led to the emergence of vancomycin-intermediateS. aureus(VISA) and heterogeneous VISA (hVISA) strains.In vitrodata suggest the potential for potent synergy between several beta-lactams and vancomycin. The objective of this study is to evaluate the synergy between beta-lactams and vancomycin against MRSA that is vancomycin susceptible, vancomycin-susceptibleStaphylococcus aureus(VSSA), hVISA, and VISA. Fifty randomly selected clinical MRSA strains with various susceptibility levels to vancomycin were evaluated for vancomycin alone and vancomycin in combination with various concentrations of cefazolin (CFZ), cefepime (FEP), ceftaroline (CPT), and nafcillin (NAF). The potential for synergy was assessed by 24-h time-kill studies. Beta-lactams reduced vancomycin MIC values against all strains (4- to 16-fold reduction). In time-kill studies against MRSA, CFZ, FEP, CPT, and NAF all demonstrated similar degrees of killing at 24 h, and all showed synergistic activity with vancomycin against VSSA, hVISA, and VISA. Each of these combinations was also superior to any single agent against isolates of all three phenotypes, and each was bactericidal (P< 0.001 for all comparisons). All single-agent exposures demonstrated no activity at 24 h. The combination of vancomycin and beta-lactams significantly improved antibacterial activity against VSSA, hVISA, and VISA strains compared to the activity of any agent alone, supporting the potential use of vancomycin–beta-lactam combination therapy in infections caused by MRSA. Further clinical research is warranted to investigate the synergy of vancomycin against theseStaphylococcusstrains.

scholarly journals Activities of Oxadiazole Antibacterials against Staphylococcus aureus and Other Gram-Positive Bacteria

2018 ◽  
Vol 62 (8) ◽  
Author(s):  
Sara Ceballos ◽  
Choon Kim ◽  
Derong Ding ◽  
Shahriar Mobashery ◽  
Mayland Chang ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Gram Positive ◽  
Methicillin Resistant ◽  
Content Type ◽  
Gram Positive Bacteria ◽  
Vancomycin Resistant Enterococci ◽  
Vancomycin Resistant ◽  
Mrsa Strains

ABSTRACT The activities of four oxadiazoles were investigated with 210 methicillin-resistant Staphylococcus aureus (MRSA) strains. MIC50 and MIC90 values of 1 to 2 and 4 μg/ml, respectively, were observed. We also evaluated the activity of oxadiazole ND-421 against other staphylococci and enterococci and in the presence of oxacillin for selected MRSA strains. The MIC for ND-421 is lowered severalfold in combination with oxacillin, as they synergize. The MIC90 of ND-421 against vancomycin-resistant enterococci is ≤1 μg/ml.

scholarly journals New Gram-Positive Agents: the Next Generation of Oxazolidinones and Lipoglycopeptides

2016 ◽  
Vol 54 (9) ◽  
pp. 2225-2232 ◽  
Author(s):  
Matthew P. Crotty ◽  
Tamara Krekel ◽  
Carey-Ann D. Burnham ◽  
David J. Ritchie
Keyword(s):  
Staphylococcus Aureus ◽  
Antimicrobial Resistance ◽  
Next Generation ◽  
Gram Positive ◽  
Content Type ◽  
Skin Structure ◽  
Vancomycin Resistant Enterococci ◽  
Vancomycin Resistant ◽  
The U.S

The growing problem of antimicrobial resistance among bacterial pathogens, including methicillin-resistantStaphylococcus aureus(MRSA) and vancomycin-resistant enterococci (VRE), has reached a critical state. Tedizolid phosphate, dalbavancin, and oritavancin have recently been approved by the U.S. Food and Drug Administration (FDA) for the treatment of acute bacterial skin and skin structure infections (ABSSSI) and represent the next generation of oxazolidinones and lipoglycopeptides. All three agents exhibitin vitroactivity and clinical efficacy against MRSA. Tedizolid phosphate and oritavancin demonstratein vitroactivity against VRE. These new Gram-positive agents are reviewed here.

scholarly journals Antistaphylococcal Activity of TD-1792, a Multivalent Glycopeptide-Cephalosporin Antibiotic

2011 ◽  
Vol 56 (3) ◽  
pp. 1584-1587 ◽  
Author(s):  
Johanne Blais ◽  
Stacey R. Lewis ◽  
Kevin M. Krause ◽  
Bret M. Benton
Keyword(s):  
Staphylococcus Aureus ◽  
Multidrug Resistant ◽  
Postantibiotic Effect ◽  
Content Type ◽  
Gram Positive Bacteria ◽  
Highly Active ◽  
Antistaphylococcal Activity ◽  
Cephalosporin Antibiotic ◽  
Time Kill

ABSTRACTTD-1792 is a new multivalent glycopeptide-cephalosporin antibiotic with potent activity against Gram-positive bacteria. Thein vitroactivity of TD-1792 was tested against 527Staphylococcus aureusisolates, including multidrug-resistant isolates. TD-1792 was highly active against methicillin-susceptibleS. aureus(MIC90, 0.015 μg/ml), methicillin-resistantS. aureus, and heterogeneous vancomycin-intermediateS. aureus(MIC90, 0.03 μg/ml). Time-kill studies demonstrated the potent bactericidal activity of TD-1792 at concentrations of ≤0.12 μg/ml. A postantibiotic effect of >2 h was observed after exposure to TD-1792.

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.

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 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.

scholarly journals Repurposing Thiram and Disulfiram as Antibacterial Agents for Multidrug-Resistant Staphylococcus aureus Infections

2017 ◽  
Vol 61 (9) ◽  
Author(s):  
Timothy E. Long
Keyword(s):  
Staphylococcus Aureus ◽  
Combination Therapy ◽  
Antibacterial Agents ◽  
Multidrug Resistant ◽  
Positive Bacterium ◽  
Content Type ◽  
Spectrum Activity ◽  
Vancomycin Resistant ◽  
Potential Use

ABSTRACT Thiram and disulfiram were evaluated as antibacterial agents against multidrug-resistant Staphylococcus aureus. Against a 30-member panel comprised of vancomycin-susceptible, vancomycin-intermediate, and vancomycin-resistant S. aureus strains, the MIC90 values of the respective test agents were 4 and 16 μg/ml. Additional analyses revealed that thiram and disulfiram are rapid-acting bacteriostatic agents with narrow, Gram-positive-bacterium spectrum activity. Synergy studies further determined that disulfiram increases the vancomycin susceptibility of three clinical vancomycin-resistant S. aureus strains in vitro, thus establishing a potential use in combination therapy.

scholarly journals In Vitro Activities of the Rx-01 Oxazolidinones against Hospital and Community Pathogens

2008 ◽  
Vol 52 (5) ◽  
pp. 1653-1662 ◽  
Author(s):  
Laura Lawrence ◽  
Paul Danese ◽  
Joe DeVito ◽  
Francois Franceschi ◽  
Joyce Sutcliffe
Keyword(s):  
Staphylococcus Aureus ◽  
Moraxella Catarrhalis ◽  
Multidrug Resistant ◽  
Gram Positive ◽  
Gram Negative ◽  
Vancomycin Resistant Enterococci ◽  
The Family ◽  
Vancomycin Resistant ◽  
Gram Negative Organisms

ABSTRACT Rx-01_423 and Rx-01_667 are two members of the family of oxazolidinones that were designed using a combination of computational and medicinal chemistry and conventional biological techniques. The compounds have a two- to eightfold-improved potency over linezolid against serious gram-positive pathogens, including methicillin-resistant Staphylococcus aureus (MRSA), multidrug-resistant streptococci, and vancomycin-resistant enterococci. This enhanced potency extends to the coverage of linezolid-resistant gram-positive microbes, especially multidrug-resistant enterococci and pneumococci. Compounds from this series expand the spectrum compared with linezolid to include fastidious gram-negative organisms like Haemophilus influenzae and Moraxella catarrhalis. Like linezolid, the Rx-01 compounds are bacteriostatic against MRSA and enterococci but are generally bactericidal against S. pneumoniae and H. influenzae.

scholarly journals In Vitro Activities of Daptomycin, Vancomycin, Linezolid, and Quinupristin-Dalfopristin against Staphylococci and Enterococci, Including Vancomycin- Intermediate and -Resistant Strains

2000 ◽  
Vol 44 (4) ◽  
pp. 1062-1066 ◽  
Author(s):  
Michael J. Rybak ◽  
Ellie Hershberger ◽  
Tabitha Moldovan ◽  
Richard G. Grucz
Keyword(s):  
Multidrug Resistant ◽  
Gram Positive ◽  
Gram Positive Bacteria ◽  
Vancomycin Resistant Enterococci ◽  
Alternative Drug ◽  
Potential Alternative ◽  
Resistant Strains ◽  
Vancomycin Resistant ◽  
Time Kill

ABSTRACT The in vitro activity of daptomycin was compared with those of vancomycin, linezolid, and quinupristin-dalfopristin against a variety (n = 203) of gram-positive bacteria, including methicillin-resistant Staphylococcus aureus and S. epidermidis (MRSA and MRSE, respectively), vancomycin-resistant enterococci (VRE), and vancomycin-intermediate S. aureus(VISA). Overall, daptomycin was more active against all organisms tested, except Enterococcus faecium and VISA, against which its activity was similar to that of quinupristin-dalfopristin. In time-kill studies with MRSA, MRSE, VRE, and VISA, daptomycin demonstrated greater bactericidal activity than all other drugs tested, killing ≥3 log CFU/ml by 8 h. Daptomycin may be a potential alternative drug therapy for multidrug-resistant gram-positive organisms and warrants further investigation.

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