Impact of Daptomycin Dose Exposure Alone or in Combination with β-Lactams or Rifampin against Vancomycin-Resistant Enterococci in an In Vitro Biofilm Model

ABSTRACT Enterococcus faecium strains are commonly resistant to vancomycin and β-lactams. In addition, E. faecium often causes biofilm-associated infections and these infections are difficult to treat. In this context, we investigated the activity of dosing regimens using daptomycin (DAP) (8, 10, 12, and 14 mg/kg of body weight/day) alone and in combination with ceftaroline (CPT), ampicillin (AMP), ertapenem (ERT), and rifampin (RIF) against 2 clinical strains of biofilm-producing vancomycin-resistant Enterococcus faecium (VREfm), namely, strains S447 and HOU503, in an in vitro biofilm model. HOU503 harbors common LiaS and LiaR substitutions, whereas S447 lacks mutations associated with the LiaFSR pathway. MIC results demonstrated that both strains were susceptible to DAP and resistant to CPT, AMP, ERT, and RIF. The 168-h pharmacokinetic/pharmacodynamic (PK/PD) CDC biofilm reactor models (simulating human antibiotic exposures) were used with titanium and polyurethane coupons to evaluate the efficacy of antibiotic combinations. DAP 12 and 14 achieved bactericidal activity against S447 but lacked such effect against HOU503. Addition of ERT and RIF enhanced DAP activity, allowing DAP 8 and 10 plus ERT or RIF to produce bactericidal activity against both strains at 168 h. While DAP 8 and 10 plus CPT improved killing, they did not reach bactericidal reduction against S447. Combination of AMP, CPT, ERT, or RIF resulted in enhanced and bactericidal activity for DAP against HOU503 at 168 h. Our data provide further support for the use of combinations of DAP with AMP, ERT, CPT, and RIF in infections caused by biofilm producing VREfm. Further research involving DAP combinations against biofilm-producing enterococci is warranted.

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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

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01873-17 ◽

2017 ◽

Vol 62 (1) ◽

Cited By ~ 5

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.

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Evaluation of Telavancin Alone and Combined with Ceftaroline or Rifampin against Methicillin-ResistantStaphylococcus aureusin anIn VitroBiofilm Model

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00567-18 ◽

2018 ◽

Vol 62 (8) ◽

Cited By ~ 3

Author(s):

Seyedehameneh Jahanbakhsh ◽

Nivedita B. Singh ◽

Juwon Yim ◽

Warren E. Rose ◽

Michael J. Rybak

Keyword(s):

Rapid Decrease ◽

Biofilm Reactor ◽

Content Type ◽

Development Of Resistance ◽

Dosage Regimens ◽

Enhanced Activity ◽

Dosing Regimens ◽

Mrsa Strains ◽

Reactor Models

ABSTRACTInfections caused by biofilm-producing methicillin-resistantStaphylococcus aureus(MRSA) bacteria are challenging due to increasing antibiotic resistance. Synergistic activities of lipopeptides and lipoglycopeptides with β-lactams have been demonstrated for MRSA, but little is known about biofilm-embedded organisms. Our objective was to evaluate two telavancin (TLV) dosage regimens (7.5 mg/kg of body weight and 10 mg/kg every 24 h [q24h]) alone and in combination with ceftaroline (CPT) (600 mg every 8 h [q8h]) or rifampin (RIF) (450 mg every 12 h [q12h]) against two biofilm-producing MRSA strains (494 and N315). Pharmacokinetic/pharmacodynamic CDC biofilm reactor models with polyurethane coupons were used to evaluate the efficacies of the antibiotic combinations over 72 h. Overall, there were no significant differences observed between the two TLV dosing regimens either alone or in combination with RIF or CPT against these strains. Both TLV dosing regimens and CPT alone demonstrated killing but did not reach bactericidal reduction at 72 h. However, both TLV regimens in combination with RIF demonstrated enhanced activity against both strains, with a rapid decrease in CFU/ml at 4 h that was bactericidal and maintained over the 72-h experiment (−Δ3.75 log10CFU/ml from baseline;P< 0.0001). Of interest, no enhanced activity was observed for TLV combined with CPT. No development of resistance was observed in any of the combination models. However, resistance to RIF developed as early as 24 h, with MIC values exceeding 32 mg/liter. Our results show that TLV plus RIF displayed therapeutic improvement against biofilm-producing MRSA. These results suggest that TLV at 7.5 and 10 mg/kg q24h are equally effective in eradicating biofilm-associated MRSA strainsin vitro.

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

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.06439-11 ◽

2012 ◽

Vol 56 (6) ◽

pp. 3174-3180 ◽

Cited By ~ 73

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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Oritavancin Activity against Vancomycin-Susceptible and Vancomycin-Resistant Enterococci with Molecularly Characterized Glycopeptide Resistance Genes Recovered from Bacteremic Patients, 2009-2010

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.06067-11 ◽

2011 ◽

Vol 56 (3) ◽

pp. 1639-1642 ◽

Cited By ~ 23

Author(s):

Rodrigo E. Mendes ◽

Leah N. Woosley ◽

David J. Farrell ◽

Helio S. Sader ◽

Ronald N. Jones

Keyword(s):

Resistance Genes ◽

Glycopeptide Resistance ◽

Content Type ◽

Vancomycin Resistant Enterococci ◽

Vancomycin Resistant

ABSTRACTOritavancin exhibited potent activity against vancomycin-susceptible (MIC50and MIC90, 0.015/0.03 μg/ml) andvanB-carryingE. faecalisisolates (MIC50and MIC90, 0.015 and 0.015 μg/ml). Higher (16- to 32-fold) MIC50s and MIC90s forvanA-harboringE. faecaliswere noted (MIC50and MIC90, 0.25 and 0.5 μg/ml), although oritavancin inhibited all strains at ≤0.5 μg/ml. Vancomycin-susceptible andvanB-carryingE. faeciumstrains (MIC50and MIC90, ≤0.008 and ≤0.008 μg/ml for both) were very susceptible to oritavancin, as were VanA-producing isolates (MIC50and MIC90, 0.03 and 0.06 μg/ml). Oritavancin exhibited goodin vitropotency against this collection of organisms, including vancomycin-resistant enterococci.

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

Journal of Clinical Microbiology ◽

10.1128/jcm.03395-15 ◽

2016 ◽

Vol 54 (9) ◽

pp. 2225-2232 ◽

Cited By ~ 23

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.

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ddcP, pstB, and excess D-lactate impact synergism between vancomycin and chlorhexidine against Enterococcus faecium 1,231,410

PLoS ONE ◽

10.1371/journal.pone.0249631 ◽

2021 ◽

Vol 16 (4) ◽

pp. e0249631

Author(s):

Pooja Bhardwaj ◽

Moutusee Z. Islam ◽

Christi Kim ◽

Uyen Thy Nguyen ◽

Kelli L. Palmer

Keyword(s):

Enterococcus Faecium ◽

Whole Genome ◽

Vancomycin Resistant Enterococci ◽

Control Hospital ◽

Skin Antisepsis ◽

Life Threatening ◽

Membrane Bound ◽

Vancomycin Resistant ◽

Hospital Associated Infections

Vancomycin-resistant enterococci (VRE) are important nosocomial pathogens that cause life-threatening infections. To control hospital-associated infections, skin antisepsis and bathing utilizing chlorhexidine is recommended for VRE patients in acute care hospitals. Previously, we reported that exposure to inhibitory chlorhexidine levels induced the expression of vancomycin resistance genes in VanA-type Enterococcus faecium. However, vancomycin susceptibility actually increased for VanA-type E. faecium in the presence of chlorhexidine. Hence, a synergistic effect of the two antimicrobials was observed. In this study, we used multiple approaches to investigate the mechanism of synergism between chlorhexidine and vancomycin in the VanA-type VRE strain E. faecium 1,231,410. We generated clean deletions of 7 of 11 pbp, transpeptidase, and carboxypeptidase genes in this strain (ponA, pbpF, pbpZ, pbpA, ddcP, ldtfm, and vanY). Deletion of ddcP, encoding a membrane-bound carboxypeptidase, altered the synergism phenotype. Furthermore, using in vitro evolution, we isolated a spontaneous synergy escaper mutant and utilized whole genome sequencing to determine that a mutation in pstB, encoding an ATPase of phosphate-specific transporters, also altered synergism. Finally, addition of excess D-lactate, but not D-alanine, enhanced synergism to reduce vancomycin MIC levels. Overall, our work identified factors that alter chlorhexidine and vancomycin synergism in a model VanA-type VRE strain.

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

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00053-15 ◽

2015 ◽

Vol 59 (5) ◽

pp. 2842-2848 ◽

Cited By ~ 27

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.

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A Phenotypically Silent vanB2 Operon Carried on a Tn1549-Like Element in Clostridium difficile

mSphere ◽

10.1128/msphere.00177-16 ◽

2016 ◽

Vol 1 (4) ◽

Cited By ~ 13

Author(s):

Daniel R. Knight ◽

Grace O. Androga ◽

Susan A. Ballard ◽

Benjamin P. Howden ◽

Thomas V. Riley

Keyword(s):

Health Care ◽

Clostridium Difficile ◽

Resistance Genes ◽

Vancomycin Resistance ◽

Content Type ◽

Vancomycin Resistant Enterococci ◽

Vancomycin Resistant ◽

Emergence Of Resistance ◽

First Time

ABSTRACT In an era when the development of new antimicrobial drugs is slow, vancomycin remains the preferred antimicrobial therapy for Clostridium difficile infection (CDI), the most important health care-related infection in the world today. The emergence of resistance to vancomycin would have significant consequences in relation to treating patients with CDI. In this paper, we describe for the first time a complete set of vancomycin resistance genes in C. difficile. The genes were very similar to genes found in vancomycin-resistant enterococci (VRE) that were associated with the emergence and global dissemination of this organism. Fortunately, the C. difficile strain did not show any reduced susceptibility to vancomycin in vitro (MIC, 1 mg/liter), possibly because of a small difference in one gene. However, this observation signals that we may be very close to seeing a fully vancomycin-resistant strain of C. difficile. In the last decade, Clostridium difficile infection (CDI) has reached an epidemic state with increasing incidence and severity in both health care and community settings. Vancomycin is an important first-line therapy for CDI, and the emergence of resistance would have significant clinical consequences. In this study, we describe for the first time a vanB2 vancomycin resistance operon in C. difficile, isolated from an Australian veal calf at slaughter. The operon was carried on an ~42-kb element showing significant homology and synteny to Tn1549, a conjugative transposon linked with the emergence and global dissemination of vancomycin-resistant enterococci (VRE). Notably, the C. difficile strain did not show any reduced susceptibility to vancomycin in vitro (MIC, 1 mg/liter), possibly as a result of an aberrant vanRB gene. As observed for other anaerobic species of the animal gut microbiota, C. difficile may be a reservoir of clinically important vancomycin resistance genes. IMPORTANCE In an era when the development of new antimicrobial drugs is slow, vancomycin remains the preferred antimicrobial therapy for Clostridium difficile infection (CDI), the most important health care-related infection in the world today. The emergence of resistance to vancomycin would have significant consequences in relation to treating patients with CDI. In this paper, we describe for the first time a complete set of vancomycin resistance genes in C. difficile. The genes were very similar to genes found in vancomycin-resistant enterococci (VRE) that were associated with the emergence and global dissemination of this organism. Fortunately, the C. difficile strain did not show any reduced susceptibility to vancomycin in vitro (MIC, 1 mg/liter), possibly because of a small difference in one gene. However, this observation signals that we may be very close to seeing a fully vancomycin-resistant strain of C. difficile.

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Ceftaroline Restores Daptomycin Activity against Daptomycin-Nonsusceptible Vancomycin-Resistant Enterococcus faecium

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02274-13 ◽

2013 ◽

Vol 58 (3) ◽

pp. 1494-1500 ◽

Cited By ~ 61

Author(s):

George Sakoulas ◽

Warren Rose ◽

Poochit Nonejuie ◽

Joshua Olson ◽

Joseph Pogliano ◽

...

Keyword(s):

Membrane Fluidity ◽

Enterococcus Faecium ◽

Surface Binding ◽

Host Defense Peptides ◽

Content Type ◽

Invasive Infections ◽

Vancomycin Resistant ◽

Biophysical Changes

ABSTRACTDaptomycin-nonsusceptible vancomycin-resistantEnterococcus faecium(VRE) strains are a formidable emerging threat to patients with comorbidities, leaving few therapeutic options in cases of severe invasive infections. Using a previously characterized isogenic pair of VRE strains from the same patient differing in their daptomycin susceptibilities (Etest MICs of 0.38 mg/liter and 10 mg/liter), we examined the effect of ceftaroline, ceftriaxone, and ampicillin on membrane fluidity and susceptibility of VRE to surface binding and killing by daptomycin and human cathelicidin antimicrobial peptide LL37. Synergy was notedin vitrobetween daptomycin, ampicillin, and ceftaroline for the daptomycin-susceptible VRE strain, but only ceftaroline showed synergy against the daptomycin-nonsusceptible VRE strain (∼2 log10CFU reduction at 24 h). Ceftaroline cotreatment increased daptomycin surface binding with an associated increase in membrane fluidity and an increase in the net negative surface charge of the bacteria as evidenced by increased poly-l-lysine binding. Consistent with the observed biophysical changes, ceftaroline resulted in increased binding and killing of daptomycin-nonsusceptible VRE by human cathelicidin LL37. Using a pair of daptomycin-susceptible/nonsusceptible VRE strains, we noted that VRE is ceftaroline resistant, yet ceftaroline confers significant effects on growth rate as well as biophysical changes on the cell surface of VRE that can potentiate the activity of daptomycin and innate cationic host defense peptides, such as cathelicidin. Although limited to just 2 strains, these finding suggest that additionalin vivoandin vitrostudies need to be done to explore the possibility of using ceftaroline as adjunctive anti-VRE therapy.

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

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.03006-15 ◽

2016 ◽

Vol 60 (4) ◽

pp. 2352-2358 ◽

Cited By ~ 14

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.

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