scholarly journals β-Lactams Enhance Daptomycin Activity against Vancomycin-Resistant Enterococcus faecalis and Enterococcus faecium inIn VitroPharmacokinetic/Pharmacodynamic Models

2015 ◽  
Vol 59 (5) ◽  
pp. 2842-2848 ◽  
Author(s):  
Jordan R. Smith ◽  
Katie E. Barber ◽  
Animesh Raut ◽  
Michael J. Rybak
Keyword(s):  
Body Weight ◽  
Combination Therapy ◽  
Enterococcus Faecalis ◽  
Enterococcus Faecium ◽  
Single Agent ◽  
Vancomycin Resistant Enterococcus ◽  
Content Type ◽  
Vancomycin Resistant ◽  
Combination Regimens

ABSTRACTEnterococcus faecalisandEnterococcus faeciumare frequently resistant to vancomycin and β-lactams. In enterococcal infections with reduced glycopeptide susceptibility, combination therapy is often administered. Our objective was to conduct pharmacokinetic/pharmacodynamic (PK/PD) models to evaluate β-lactam synergy with daptomycin (DAP) against resistant enterococci. OneE. faecalisstrain (R6981) and twoE. faeciumstrains (R6370 and 8019) were evaluated. DAP MICs were obtained. All strains were evaluated for response to LL37, an antimicrobial peptide, in the presence and absence of ceftaroline (CPT), ertapenem (ERT), and ampicillin (AMP). After 96 h,in vitromodels were run simulating 10 mg DAP/kg body weight/day, 600 mg CPT every 8 h (q8h), 2 g AMP q4h, and 1 g ERT q24h, both alone and in combination against all strains. DAP MICs were 2, 4, and 4 μg/ml for strains R6981, R6370, and 8019, respectively. PK/PD models demonstrated bactericidal activity with DAP-CPT, DAP-AMP, and DAP-ERT combinations against strain 8019 (P< 0.001 and log10CFU/ml reduction of >2 compared to any single agent). Against strains R6981 and R6370, the DAP-AMP combination demonstrated enhancement against R6370 but not R6981, while the combinations of DAP-CPT and DAP-ERT were bactericidal, demonstrated enhancement, and were statistically superior to all other regimens at 96 h (P< 0.001) against both strains. CPT, ERT, and AMP similarly augmented LL37 killing against strain 8019. In strains R6981 and R6370, CPT and ERT aided LL37 more than AMP (P< 0.001). Compared to DAP alone, combination regimens provide better killing and prevent resistance. Clinical research involving DAP combinations is warranted.

scholarly journals Ampicillin in Combination with Ceftaroline, Cefepime, or Ceftriaxone Demonstrates Equivalent Activities in a High-Inoculum Enterococcus faecalis Infection Model

2016 ◽  
Vol 60 (5) ◽  
pp. 3178-3182 ◽  
Author(s):  
Megan K. Luther ◽  
Louis B. Rice ◽  
Kerry L. LaPlante
Keyword(s):  
Combination Therapy ◽  
Enterococcus Faecalis ◽  
Pharmacodynamic Model ◽  
Infection Model ◽  
Vancomycin Resistant Enterococcus ◽  
Content Type ◽  
Time Profiles ◽  
Concentration Time ◽  
Vancomycin Resistant

ABSTRACTAmpicillin-ceftriaxone combination therapy has become a predominant treatment for seriousEnterococcus faecalisinfections, such as endocarditis. Unfortunately, ceftriaxone use is associated with future vancomycin-resistant enterococcus colonization. We evaluatedE. faecalisin anin vitropharmacodynamic model against simulated human concentration-time profiles of ampicillin plus ceftaroline, cefepime, ceftriaxone, or gentamicin. Ampicillin-cefepime and ampicillin-ceftaroline demonstrated activities similar to those of ampicillin-ceftriaxone againstE. faecalis.

scholarly journals Treatment of Multidrug-Resistant Vancomycin-Resistant Enterococcus faecium Hardware-Associated Vertebral Osteomyelitis with Oritavancin plus Ampicillin

2019 ◽  
Vol 63 (7) ◽  
Author(s):  
Samira Dahesh ◽  
Brian Wong ◽  
Victor Nizet ◽  
George Sakoulas ◽  
Truc T. Tran ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Antimicrobial Peptide ◽  
Continuous Infusion ◽  
Enterococcus Faecium ◽  
Vertebral Osteomyelitis ◽  
Multidrug Resistant ◽  
Vancomycin Resistant Enterococcus ◽  
Content Type ◽  
Vancomycin Resistant ◽  
Time Kill

ABSTRACT Weekly oritavancin plus ampicillin continuous infusion combination therapy was used to successfully treat a deep spine vancomycin-resistant Enterococcus faecium infection associated with hardware. Checkerboard and time-kill assays confirmed synergy between these two antibiotics. Further synergies of oritavancin and ampicillin with rifampin or the endogenous human antimicrobial peptide cathelicidin LL-37 were demonstrated.

scholarly journals Evaluation of Oritavancin Dosing Strategies against Vancomycin-Resistant Enterococcus faecium Isolates with or without Reduced Susceptibility to Daptomycin in an In Vitro Pharmacokinetic/Pharmacodynamic Model

2017 ◽  
Vol 62 (1) ◽  
Author(s):  
Adam Belley ◽  
Francis F. Arhin ◽  
Greg Moeck
Keyword(s):  
Enterococcus Faecium ◽  
Pharmacodynamic Model ◽  
Vancomycin Resistant Enterococcus ◽  
Content Type ◽  
Dosing Regimens ◽  
Dosing Strategies ◽  
Vancomycin Resistant ◽  
Lipopeptide Antibiotic ◽  
Long Acting

ABSTRACT The clinical development of nonsusceptibility to the lipopeptide antibiotic daptomycin remains a serious concern during therapy for infections caused by vancomycin-resistant Enterococcus faecium (VREfm). The long-acting lipoglycopeptide oritavancin exhibits potent in vitro activity against VREfm, although its safety and efficacy for treating clinical VREfm infections have not been established. In this study, novel dosing regimens of daptomycin and oritavancin were assessed against both VREfm and daptomycin-nonsusceptible VREfm isolates in an in vitro pharmacokinetic/pharmacodynamic model.

scholarly journals Activities of the Oxazolidinones Linezolid and Eperezolid in Experimental Intra-Abdominal Abscess Due to Enterococcus faecalis or Vancomycin-Resistant Enterococcus faecium

1999 ◽  
Vol 43 (12) ◽  
pp. 2873-2876 ◽  
Author(s):  
T. Schülin ◽  
C. Thauvin-Eliopoulos ◽  
R. C. Moellering ◽  
G. M. Eliopoulos
Keyword(s):  
Body Weight ◽  
Enterococcus Faecalis ◽  
Enterococcus Faecium ◽  
Abdominal Abscess ◽  
Vancomycin Resistant Enterococcus ◽  
Viable Cells ◽  
Fold Reduction ◽  
Dosing Regimens ◽  
Vancomycin Resistant

ABSTRACT The in vivo effectiveness of oxazolidinones eperezolid (U-100592) and linezolid (U-100766) against one strain each ofEnterococcus faecalis and vancomycin-resistantEnterococcus faecium was examined in a rat model of intra-abdominal abscess. MICs of both drugs were 2 μg/ml for each strain. At doses of 25 mg/kg of body weight twice daily intravenously or orally, linezolid produced small but statistically significant reductions in abscess bacterial density for E. faecalis. The reduction in viable cells observed would not likely be clinically relevant. Eperezolid was ineffective at this dose. At a dosage of 100 mg/kg/day, linezolid treatment led to an approximately 100-fold reduction in viable cells per gram of abscess. Against E. faecium infections, intravenous eperezolid and oral linezolid were effective, reducing densities approximately 2 log10 CFU/g. Both oxazolidinones demonstrated activity against enterococci in this model. However, results were modest with the dosing regimens employed.

scholarly journals Genetic Variability of Vancomycin-Resistant Enterococcus faecium and Enterococcus faecalis Isolates from Humans, Chickens, and Pigs in Malaysia

2013 ◽  
Vol 79 (15) ◽  
pp. 4528-4533 ◽  
Author(s):  
Yitbarek Getachew ◽  
Latiffah Hassan ◽  
Zunita Zakaria ◽  
Saleha Abdul Aziz
Keyword(s):  
Enterococcus Faecalis ◽  
Enterococcus Faecium ◽  
Clonal Complex ◽  
Housekeeping Genes ◽  
Vancomycin Resistant Enterococcus ◽  
Content Type ◽  
Vancomycin Resistant Enterococci ◽  
Vancomycin Resistant ◽  
Sequence Types ◽  
Representative Samples

ABSTRACTVancomycin-resistant enterococci (VRE) have been reported to be present in humans, chickens, and pigs in Malaysia. In the present study, representative samples of VRE isolated from these populations were examined for similarities and differences by using the multilocus sequence typing (MLST) method. Housekeeping genes ofEnterococcus faecium(n= 14) andEnterococcus faecalis(n= 11) isolates were sequenced and analyzed using the MLST databases eBURST and goeBURST. We found five sequence types (STs) ofE. faeciumand six STs ofE. faecalisexisting in Malaysia.Enterococcus faeciumisolates belonging to ST203, ST17, ST55, ST79, and ST29 were identified, andE. faeciumST203 was the most common among humans. The MLST profiles ofE. faeciumfrom humans in this study were similar to the globally reported nosocomial-related strain lineage belonging to clonal complex 17 (CC17). Isolates from chickens and pigs have few similarities to those from humans, except for one isolate from a chicken, which was identified as ST203.E. faecalisisolates were more diverse and were identified as ST4, ST6, ST87, ST108, ST274, and ST244, which were grouped as specific to the three hosts.E. faecalis, belonging to the high-risk CC2 and CC87, were detected among isolates from humans. In conclusion, even though one isolate from a chicken was found clonal to that of humans, the MLST analysis ofE. faeciumandE. faecalissupports the findings of others who suggest VRE to be predominantly host specific and that clinically important strains are found mainly among humans. The infrequent detection of a human VRE clone in a chicken may in fact suggest a reverse transmission of VRE from humans to animals.

scholarly journals Comparative Pharmacodynamics of Single-Dose Oritavancin and Daily High-Dose Daptomycin Regimens against Vancomycin-Resistant Enterococcus faecium Isolates in an In Vitro Pharmacokinetic/Pharmacodynamic Model of Infection

2017 ◽  
Vol 61 (10) ◽  
Author(s):  
Adam Belley ◽  
David Lalonde-Séguin ◽  
Francis F. Arhin ◽  
Greg Moeck
Keyword(s):  
Single Dose ◽  
Enterococcus Faecium ◽  
Free Drug ◽  
Pharmacodynamic Model ◽  
High Dose ◽  
Vancomycin Resistant Enterococcus ◽  
Content Type ◽  
Drug Levels ◽  
Vancomycin Resistant

ABSTRACT There are limited therapeutic options to treat infections caused by vancomycin-resistant Enterococcus faecium (VREfm). The lipoglycopeptide oritavancin exhibits in vitro activity against this pathogen, although its utility against infections caused by VREfm has not been clinically established. In this study, the pharmacodynamic activity of free-drug levels associated with 12 mg/kg/day of daptomycin and a single 1,200-mg dose of oritavancin were determined against three VanA VREfm isolates in an in vitro pharmacokinetic/pharmacodynamic model.

scholarly journals Evaluation of Standard- and High-Dose Daptomycin versus Linezolid against Vancomycin-Resistant Enterococcus Isolates in anIn VitroPharmacokinetic/Pharmacodynamic Model with Simulated Endocardial Vegetations

2012 ◽  
Vol 56 (6) ◽  
pp. 3174-3180 ◽  
Author(s):  
Ashley D. Hall ◽  
Molly E. Steed ◽  
Cesar A. Arias ◽  
Barbara E. Murray ◽  
Michael J. Rybak
Keyword(s):  
Bactericidal Activity ◽  
Optimal Dose ◽  
Pharmacodynamic Model ◽  
Colony Count ◽  
High Dose ◽  
Vancomycin Resistant Enterococcus ◽  
Content Type ◽  
Sustained Reduction ◽  
Vancomycin Resistant

ABSTRACTDaptomycin MICs for enterococci are typically 1- to 2-fold higher than those forStaphylococcus aureus, and there is an imminent need to establish the optimal dose for appropriate treatment of enterococcal infections. We investigated the bactericidal activity of daptomycin at various dose exposures compared to that of linezolid against vancomycin-resistant enterococcus (VRE) in anin vitropharmacokinetic/pharmacodynamic model utilizing simulated endocardial vegetations over 96 h. Daptomycin at doses of 6, 8, 10, and 12 mg/kg of body weight/day and linezolid at a dose of 600 mg every 12 h were evaluated against two clinical vancomycin-resistantEnterococcus faeciumstrains (EFm11499 and 09-184D1051), one of which was linezolid resistant (09-184D1051), and one clinical vancomycin-resistantEnterococcus faecalisstrain (EFs11496). Daptomycin MICs were 4, 2, and 0.5 μg/ml for EFm11499, 09-184D1051, and EFs11496, respectively. Bactericidal activity, defined as a ≥3 log10CFU/g reduction from the initial colony count, was demonstrated against all three isolates with all doses of daptomycin; however, bactericidal activity was not sustained with the daptomycin 6- and 8-mg/kg/day regimens. Linezolid was bacteriostatic against EFm11499 and displayed no appreciable activity against 09-184D1051 or EFs11496. Concentration-dependent killing was displayed with more sustained reduction in colony count (3.58 to 6.46 and 5.89 to 6.56 log10CFU/g) at 96 h for the simulated regimen of daptomycin at doses of 10 and 12 mg/kg/day, respectively (P≤ 0.012). NoE. faeciummutants with reduced susceptibility were recovered at any dosage regimen; however, theE. faecalisstrain developed reduced daptomycin susceptibility with daptomycin at 6, 8, and 10 but not at 12 mg/kg/day. Daptomycin displayed a dose-dependent response against three VRE isolates, with high-dose daptomycin producing sustained bactericidal activity. Further research is warranted.

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