Daptomycin

14,000,000 Leading Edge Experts on the ideXlab platform

Scan Science and Technology

Contact Leading Edge Experts & Companies

Scan Science and Technology

Contact Leading Edge Experts & Companies

The Experts below are selected from a list of 6957 Experts worldwide ranked by ideXlab platform

Michael J Rybak - One of the best experts on this subject based on the ideXlab platform.

  • Biofilm Time-Kill Curves to Assess the Bactericidal Activity of Daptomycin Combinations against Biofilm-Producing Vancomycin-Resistant Enterococcus faecium and faecalis
    'MDPI AG', 2021
    Co-Authors: Katie E Barber, Jordan R Smith, Zade Shammout, Razieh Kebriaei, Taylor Morrisette, Michael J Rybak
    Abstract:

    Introduction: E. faecium and E. faecalis are responsible for 13.9% of hospital-acquired infections with frequent resistance to vancomycin (82.6% of E. faecium, 9.5% of E. faecalis). Medical device infections secondary to enterococci often require combination therapy due to impaired activity against biofilm embedded cells. In vitro data demonstrate synergistic activity of Daptomycin combinations. Using a novel, biofilm time-kill approach, we evaluated whether Daptomycin combinations maintained synergy against biofilm-producing E. faecium and E. faecalis. Methods: Broth microdilution (BMD) and biofilm MIC (bMIC) values for Daptomycin, ampicillin, ceftriaxone, fosfomycin, and rifampin were determined against biofilm-producing E. faecium and E. faecalis. Daptomycin combination bMIC values were determined in the presence of biologic concentrations of other antimicrobials. Synergy was evaluated against two E. faecalis (R6981, R7808) and two E. faecium (5938 and 8019) using a previously described biofilm time-kill method. Synergy was defined as ≥2 log10 CFU/cm2 reduction over the most active agent alone. Bactericidal activity was defined as ≥3 log10 CFU/cm2 reduction. Results: Daptomycin bMICs were 2–8-fold higher than BMD. In the presence of other antimicrobials, Daptomycin bMICs were reduced ≥ two-fold in dilutions. Ceftriaxone and ampicillin demonstrated the most potent combinations with Daptomycin, yielding synergy against three of four strains. Daptomycin plus rifampin was synergistic against E. faecium 5938 and E. faecalis 6981 and produced bactericidal kill. The combination of Daptomycin plus fosfomycin displayed synergy solely against E. faecalis 6981. Conclusions: Daptomycin combinations with beta-lactams demonstrated promising synergistic activity against both E. faecium and E. faecalis. While Daptomycin plus rifampin yielded bactericidal results, the effect was not seen across all organisms. These combinations warrant further evaluation to determine the optimal dose and response

  • ceftobiprole and ampicillin increase Daptomycin susceptibility of Daptomycin susceptible and resistant vre
    Journal of Antimicrobial Chemotherapy, 2015
    Co-Authors: Brian J Werth, Poochit Nonejuie, Joe Pogliano, George Sakoulas, Michael J Rybak, Katie E Barber, Kieu Nhi T Tran
    Abstract:

    OBJECTIVES The synergistic combination of Daptomycin plus ampicillin has proven to be effective against VRE including Daptomycin-non-susceptible strains. Ceftobiprole is a cephalosporin with broad binding affinity for enterococcal PBP subtypes including PBP5. Given the synergy between β-lactams and Daptomycin against VRE, it was of interest to determine whether ceftobiprole offered any synergistic advantage with Daptomycin compared with ampicillin. METHODS MICs were determined by broth microdilution in the presence and absence of ampicillin or ceftobiprole for 20 ampicillin-resistant VRE. Six strains, including two isogenic pairs of vancomycin-resistant Enterococcus faecium and two vancomycin-resistant Enterococcus faecalis, were evaluated for synergy using time-kill methods. Synergy was defined as a ≥2 log10 cfu/mL reduction of the combination over the most active single agent. Binding of Daptomycin-bodipy in the presence and absence of ceftobiprole was quantified. RESULTS Daptomycin MICs ranged from 2 to 256 mg/L. The addition of ceftobiprole and ampicillin reduced Daptomycin MICs by a median of 3 and 4 log2 dilutions, respectively. In time-kill studies, Daptomycin plus either ceftobiprole or ampicillin was synergistic against four of six strains, but not the same strains. Both combinations were synergistic against the vancomycin-resistant E. faecalis strains. Ceftobiprole exposure increased Daptomycin-bodipy binding by 2.8 times (P<0.0001). CONCLUSIONS Ceftobiprole appears to offer a similar degree of synergistic activity to ampicillin when combined with Daptomycin against VRE. Further research should explore the genetic and phenotypic qualities of strains that respond preferentially to ceftobiprole as opposed to ampicillin.

  • antimicrobial salvage therapy for persistent staphylococcal bacteremia using Daptomycin plus ceftaroline
    Clinical Therapeutics, 2014
    Co-Authors: George Sakoulas, Pamela A Moise, Poochit Nonejuie, Joshua Olson, Cheryl Y M Okumura, Ravina Kullar, Abhay Dhand, Anthony M Casapao, Michael J Rybak, Warren E Rose
    Abstract:

    Abstract Purpose Guidelines recommend Daptomycin combination therapy as an option for methicillin-resistant Staphylococcus aureus (MRSA) bacteremia after vancomycin failure. Recent data suggest that combining Daptomycin with a β-lactam may have unique benefits; however, there are very limited clinical data regarding the use of ceftaroline with Daptomycin. Methods All 26 cases from the 10 medical centers in which ceftaroline plus Daptomycin was used for treatment of documented refractory staphylococcal bacteremia from March 2011 to November 2012 were included. In vitro (synergy studies, binding assays, cathelicidin LL-37 killing assays), and in vivo (virulence assays using a murine subcutaneous infection model) studies examining the effects of ceftaroline with Daptomycin were also performed. Findings Daptomycin plus ceftaroline was used in 26 cases of staphylococcal bacteremia (20 MRSA, 2 vancomycin-intermediate S aureus , 2 methicillin-susceptible S aureus [MSSA], 2 methicillin-resistant S epidermidis ). Bacteremia persisted for a median of 10 days (range, 3–23 days) on previous antimicrobial therapy. After Daptomycin plus ceftaroline was started, the median time to bacteremia clearance was 2 days (range, 1–6 days). In vitro studies showed ceftaroline synergy against MRSA and enhanced MRSA killing by cathelicidin LL-37 and neutrophils. Ceftaroline also induced Daptomycin binding in MSSA and MRSA to a comparable degree as nafcillin. MRSA grown in subinhibitory concentrations of ceftaroline showed attenuated virulence in a murine subcutaneous infection model. Implications Ceftaroline plus Daptomycin may be an option to hasten clearance of refractory staphylococcal bacteremia. Ceftaroline offers dual benefit via synergy with both Daptomycin and sensitization to innate host defense peptide cathelicidin LL37, which could attenuate virulence of the pathogen.

  • evaluation of the novel combination of Daptomycin plus ceftriaxone against vancomycin resistant enterococci in an in vitro pharmacokinetic pharmacodynamic simulated endocardial vegetation model
    Journal of Antimicrobial Chemotherapy, 2014
    Co-Authors: Ashley Hall D Snyder, Brian J Werth, George Sakoulas, Michael J Rybak, Katie E Barber
    Abstract:

    OBJECTIVES: Daptomycin has demonstrated synergy with β-lactams against Enterococcus faecium and this combination has been used successfully to treat infections refractory to Daptomycin. We investigated Daptomycin alone and combined with ceftriaxone against vancomycin-resistant enterococci (VRE) in an in vitro pharmacokinetic/pharmacodynamic simulated endocardial vegetation (SEV) model. METHODS: Daptomycin (6 and 12 mg/kg/day) with and without 2 g of ceftriaxone every 24 h were evaluated against two clinical E. faecium strains (8019 and 5938) and one Enterococcus faecalis (6981) in a 96 h in vitro pharmacokinetic/pharmacodynamic SEV model. FITC-labelled poly-l-lysine was used to assess β-lactam-induced changes in cell surface charge. RESULTS: For 8019 and 6981, Daptomycin 6 mg/kg with ceftriaxone and Daptomycin 12 mg/kg alone and in combination with ceftriaxone displayed significantly more activity than Daptomycin 6 mg/kg alone from 48 to 96 h (P ≤ 0.005). The addition of ceftriaxone significantly enhanced activity of Daptomycin 6 mg/kg against both strains at 96 h (8019, reductions -0.55 versus 3.64 log10 cfu/g; 6981, reductions 1.11 versus 5.67 log10 cfu/g; P < 0.001) and improved Daptomycin 12 mg/kg against 8019 at 96 h. Daptomycin 12 mg/kg plus ceftriaxone displayed no appreciable activity against 5938 (Daptomycin MIC 32 mg/L). Daptomycin non-susceptibility developed in 8019 and 6981 versus Daptomycin 6 mg/kg by 96 h. Ampicillin or ceftriaxone exposure reduced Daptomycin surface charge in 8019, resulting in significantly increased FITC-poly-l-lysine binding. CONCLUSIONS: The combination of Daptomycin and ceftriaxone may be promising for eradicating high-inoculum, deep-seated enterococcal infections. Further research is warranted to examine the enhancement of Daptomycin and innate immunity killing of VRE by ceftriaxone and other β-lactams.

  • ceftaroline increases membrane binding and enhances the activity of Daptomycin against Daptomycin nonsusceptible vancomycin intermediate staphylococcus aureus in a pharmacokinetic pharmacodynamic model
    Antimicrobial Agents and Chemotherapy, 2013
    Co-Authors: Brian J Werth, Joe Pogliano, Ryan Tewhey, Warren E Rose, George Sakoulas, Michael J Rybak
    Abstract:

    New antimicrobial agents and novel combination therapies are needed to treat serious infections caused by methicillin-resistant Staphylococcus aureus (MRSA) with reduced susceptibility to Daptomycin and vancomycin. The purpose of this study was to evaluate the combination of ceftaroline plus Daptomycin or vancomycin in an in vitro pharmacokinetic/pharmacodynamic model. Simulations of ceftaroline-fosamil at 600 mg per kg of body weight every 8 h (q8h) (maximum free-drug concentration in serum [fCmax], 15.2 mg/liter; half-life [t1/2], 2.3 h), Daptomycin at 10 mg/kg/day (fCmax, 11.3 mg/liter; t1/2, 8 h), vancomycin at 2 g q12h (fCmax, 30 mg/liter; t1/2, 6 h), ceftaroline plus Daptomycin, and ceftaroline plus vancomycin were evaluated against a clinical, isogenic MRSA strain pair: D592 (Daptomycin susceptible and heterogeneous vancomycin intermediate) and D712 (Daptomycin nonsusceptible and vancomycin intermediate) in a one-compartment in vitro pharmacokinetic/pharmacodynamic model over 96 h. Therapeutic enhancement of combinations was defined as ≥2 log10 CFU/ml reduction over the most active single agent. The effect of ceftaroline on the membrane charge, cell wall thickness, susceptibility to killing by the human cathelicidin LL37, and Daptomycin binding were evaluated. Therapeutic enhancement was observed with Daptomycin plus ceftaroline in both strains and vancomycin plus ceftaroline against D592. Ceftaroline exposure enhanced Daptomycin-induced depolarization (81.7% versus 72.3%; P = 0.03) and killing by cathelicidin LL37 (P < 0.01) and reduced cell wall thickness (P < 0.001). Fluorescence-labeled Daptomycin was bound over 7-fold more in ceftaroline-exposed cells. Whole-genome sequencing and mutation analysis of these strains indicated that change in Daptomycin susceptibility is related to an fmtC (mprF) mutation. The combination of Daptomycin plus ceftaroline appears to be potent, with rapid and sustained bactericidal activity against both Daptomycin-susceptible and -nonsusceptible strains of MRSA.

George Sakoulas - One of the best experts on this subject based on the ideXlab platform.

  • ceftobiprole and ampicillin increase Daptomycin susceptibility of Daptomycin susceptible and resistant vre
    Journal of Antimicrobial Chemotherapy, 2015
    Co-Authors: Brian J Werth, Poochit Nonejuie, Joe Pogliano, George Sakoulas, Michael J Rybak, Katie E Barber, Kieu Nhi T Tran
    Abstract:

    OBJECTIVES The synergistic combination of Daptomycin plus ampicillin has proven to be effective against VRE including Daptomycin-non-susceptible strains. Ceftobiprole is a cephalosporin with broad binding affinity for enterococcal PBP subtypes including PBP5. Given the synergy between β-lactams and Daptomycin against VRE, it was of interest to determine whether ceftobiprole offered any synergistic advantage with Daptomycin compared with ampicillin. METHODS MICs were determined by broth microdilution in the presence and absence of ampicillin or ceftobiprole for 20 ampicillin-resistant VRE. Six strains, including two isogenic pairs of vancomycin-resistant Enterococcus faecium and two vancomycin-resistant Enterococcus faecalis, were evaluated for synergy using time-kill methods. Synergy was defined as a ≥2 log10 cfu/mL reduction of the combination over the most active single agent. Binding of Daptomycin-bodipy in the presence and absence of ceftobiprole was quantified. RESULTS Daptomycin MICs ranged from 2 to 256 mg/L. The addition of ceftobiprole and ampicillin reduced Daptomycin MICs by a median of 3 and 4 log2 dilutions, respectively. In time-kill studies, Daptomycin plus either ceftobiprole or ampicillin was synergistic against four of six strains, but not the same strains. Both combinations were synergistic against the vancomycin-resistant E. faecalis strains. Ceftobiprole exposure increased Daptomycin-bodipy binding by 2.8 times (P<0.0001). CONCLUSIONS Ceftobiprole appears to offer a similar degree of synergistic activity to ampicillin when combined with Daptomycin against VRE. Further research should explore the genetic and phenotypic qualities of strains that respond preferentially to ceftobiprole as opposed to ampicillin.

  • antimicrobial salvage therapy for persistent staphylococcal bacteremia using Daptomycin plus ceftaroline
    Clinical Therapeutics, 2014
    Co-Authors: George Sakoulas, Pamela A Moise, Poochit Nonejuie, Joshua Olson, Cheryl Y M Okumura, Ravina Kullar, Abhay Dhand, Anthony M Casapao, Michael J Rybak, Warren E Rose
    Abstract:

    Abstract Purpose Guidelines recommend Daptomycin combination therapy as an option for methicillin-resistant Staphylococcus aureus (MRSA) bacteremia after vancomycin failure. Recent data suggest that combining Daptomycin with a β-lactam may have unique benefits; however, there are very limited clinical data regarding the use of ceftaroline with Daptomycin. Methods All 26 cases from the 10 medical centers in which ceftaroline plus Daptomycin was used for treatment of documented refractory staphylococcal bacteremia from March 2011 to November 2012 were included. In vitro (synergy studies, binding assays, cathelicidin LL-37 killing assays), and in vivo (virulence assays using a murine subcutaneous infection model) studies examining the effects of ceftaroline with Daptomycin were also performed. Findings Daptomycin plus ceftaroline was used in 26 cases of staphylococcal bacteremia (20 MRSA, 2 vancomycin-intermediate S aureus , 2 methicillin-susceptible S aureus [MSSA], 2 methicillin-resistant S epidermidis ). Bacteremia persisted for a median of 10 days (range, 3–23 days) on previous antimicrobial therapy. After Daptomycin plus ceftaroline was started, the median time to bacteremia clearance was 2 days (range, 1–6 days). In vitro studies showed ceftaroline synergy against MRSA and enhanced MRSA killing by cathelicidin LL-37 and neutrophils. Ceftaroline also induced Daptomycin binding in MSSA and MRSA to a comparable degree as nafcillin. MRSA grown in subinhibitory concentrations of ceftaroline showed attenuated virulence in a murine subcutaneous infection model. Implications Ceftaroline plus Daptomycin may be an option to hasten clearance of refractory staphylococcal bacteremia. Ceftaroline offers dual benefit via synergy with both Daptomycin and sensitization to innate host defense peptide cathelicidin LL37, which could attenuate virulence of the pathogen.

  • evaluation of the novel combination of Daptomycin plus ceftriaxone against vancomycin resistant enterococci in an in vitro pharmacokinetic pharmacodynamic simulated endocardial vegetation model
    Journal of Antimicrobial Chemotherapy, 2014
    Co-Authors: Ashley Hall D Snyder, Brian J Werth, George Sakoulas, Michael J Rybak, Katie E Barber
    Abstract:

    OBJECTIVES: Daptomycin has demonstrated synergy with β-lactams against Enterococcus faecium and this combination has been used successfully to treat infections refractory to Daptomycin. We investigated Daptomycin alone and combined with ceftriaxone against vancomycin-resistant enterococci (VRE) in an in vitro pharmacokinetic/pharmacodynamic simulated endocardial vegetation (SEV) model. METHODS: Daptomycin (6 and 12 mg/kg/day) with and without 2 g of ceftriaxone every 24 h were evaluated against two clinical E. faecium strains (8019 and 5938) and one Enterococcus faecalis (6981) in a 96 h in vitro pharmacokinetic/pharmacodynamic SEV model. FITC-labelled poly-l-lysine was used to assess β-lactam-induced changes in cell surface charge. RESULTS: For 8019 and 6981, Daptomycin 6 mg/kg with ceftriaxone and Daptomycin 12 mg/kg alone and in combination with ceftriaxone displayed significantly more activity than Daptomycin 6 mg/kg alone from 48 to 96 h (P ≤ 0.005). The addition of ceftriaxone significantly enhanced activity of Daptomycin 6 mg/kg against both strains at 96 h (8019, reductions -0.55 versus 3.64 log10 cfu/g; 6981, reductions 1.11 versus 5.67 log10 cfu/g; P < 0.001) and improved Daptomycin 12 mg/kg against 8019 at 96 h. Daptomycin 12 mg/kg plus ceftriaxone displayed no appreciable activity against 5938 (Daptomycin MIC 32 mg/L). Daptomycin non-susceptibility developed in 8019 and 6981 versus Daptomycin 6 mg/kg by 96 h. Ampicillin or ceftriaxone exposure reduced Daptomycin surface charge in 8019, resulting in significantly increased FITC-poly-l-lysine binding. CONCLUSIONS: The combination of Daptomycin and ceftriaxone may be promising for eradicating high-inoculum, deep-seated enterococcal infections. Further research is warranted to examine the enhancement of Daptomycin and innate immunity killing of VRE by ceftriaxone and other β-lactams.

  • ceftaroline restores Daptomycin activity against Daptomycin nonsusceptible vancomycin resistant enterococcus faecium
    Antimicrobial Agents and Chemotherapy, 2014
    Co-Authors: George Sakoulas, Poochit Nonejuie, Joshua Olson, Joe Pogliano, Warren E Rose, Romney M. Humphries, Victor Nizet
    Abstract:

    Daptomycin-nonsusceptible vancomycin-resistant Enterococcus 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 membranefluidity and susceptibility of VRE to surface binding and killing by Daptomycin and human cathelicidin antimicrobial peptide LL37. Synergy was noted in vitro between 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 membranefluidity 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 Daptomycinsusceptible/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, thesefinding suggest that additional in vivo and in vitro studies need to be done to explore the possibility of using ceftaroline as adjunctive anti-VRE therapy.

  • multicenter evaluation of the clinical outcomes of Daptomycin with and without concomitant β lactams in patients with staphylococcus aureus bacteremia and mild to moderate renal impairment
    Antimicrobial Agents and Chemotherapy, 2013
    Co-Authors: Pamela A Moise, George Sakoulas, Maria Amodiogroton, Mohamad Rashid, Kenneth C Lamp, Holly L Hoffmanroberts, Min J Yoon, Suzanne U Schweitzer, Anjay Rastogi
    Abstract:

    Patients with underlying renal disease may be vulnerable to vancomycin-mediated nephrotoxicity and Staphylococcus aureus bacteremia treatment failure. In light of recent data demonstrating the successful use of β-lactam plus Daptomycin in very difficult cases of S. aureus bacteremia, we examined safety and clinical outcomes for patients who received Daptomycin with or without concomitant β-lactams. We identified 106 patients who received Daptomycin for S. aureus bacteremia, had mild or moderate renal insufficiency according to FDA criteria, and enrolled in the Cubicin Outcomes Registry and Experience (CORE), a multicenter registry, from 2005 to 2009. Daptomycin treatment success was 81%. Overall treatment efficacy was slightly enhanced with the addition of a β-lactam (87% versus 78%; P = 0.336), but this trend was most pronounced for bacteremia associated with endocarditis or bone/joint infection or bacteremia from an unknown source (90% versus 57%; P = 0.061). Factors associated with reduced Daptomycin efficacy (by logistic regression) were an unknown source of bacteremia (odds ratio [OR] = 7.59; 95% confidence interval [CI] = 1.55 to 37.2), moderate renal impairment (OR = 9.11; 95% CI = 1.46 to 56.8), and prior vancomycin failure (OR = 11.2; 95% CI = 1.95 to 64.5). Two patients experienced an increase in creatine phosphokinase (CPK) that resolved after stopping Daptomycin. No patients developed worsening renal insufficiency related to Daptomycin. In conclusion, Daptomycin appeared to be effective and well tolerated in patients with S. aureus bacteremia and mild to moderate renal insufficiency. Daptomycin treatment efficacy might be enhanced with β-lactam combination therapy in primary endovascular and bone/joint infections. Additional studies will be necessary to confirm these findings.

Soojin Yang - One of the best experts on this subject based on the ideXlab platform.

  • increased cell wall teichoic acid production and d alanylation are common phenotypes among Daptomycin resistant methicillin resistant staphylococcus aureus mrsa clinical isolates
    PLOS ONE, 2013
    Co-Authors: Ute Bertsche, Soojin Yang, Daniel Kuehner, Stefanie Wanner, Nagendra N Mishra, Tobias Roth, Mulugeta Nega, Alexander W Schneider, Christoph Mayer
    Abstract:

    Multiple mechanisms have been correlated with Daptomycin-resistance (DAP-R) in Staphylococcus aureus. However, one common phenotype observed in many DAP-R S. Aureus strains is a thickened cell wall (CW). The first evidence for an impact of CW-linked glycopolymers on this phenotype was recently demonstrated in a single, well-characterized DAP-R methicillin-susceptible S. aureus (MSSA) strain. In this isolate the thickened CW phenotype was linked to an increased production and D-alanylation of wall teichoic acids (WTA). In the current report, we extended these observations to methicillin-resistant Daptomycin-sensitive/daptomyin-resistant (DAP-S/DAP-R) strain-pairs. These pairs included methicillin-resistant S. aureus (MRSA) isolates with and without single nucleotide polymorphisms (SNPs) in mprF (a genetic locus linked to DAP-R phenotype). We found increased CW dry mass in all DAP-R vs DAP-S isolates. This correlated with an increased expression of the WTA biosynthesis gene tagA, as well as an increased amount of WTA in the DAP-R vs DAP-S isolates. In addition, all DAP-R isolates showed a higher proportion of WTA D-alanylation vs their corresponding DAP-S isolate. We also detected an increased positive surface charge amongst the DAP-R strains (presumably related to the enhanced D-alanylation). In comparing the detailed CW composition of all isolate pairs, substantive differences were only detected in one DAP-S/DAP-R pair. The thickened CW phenotype, together with an increased surface charge most likely contributes to either: i) a charge-dependent repulsion of calcium complexed-DAP; and/or ii) steric-limited access of DAP to the bacterial cell envelope target. Taken together well-defined perturbations of CW structural and functional metrics contribute to the DAP-R phenotype and are common phenotypes in DAP-R S. Aureus isolates, both MSSA and MRSA. Note: Although “Daptomycin-nonsusceptibility” is the generally accepted terminology, we have utilized the term “Daptomycin resistance” for ease of presentation in this manuscript

  • ampicillin enhances Daptomycin and cationic host defense peptide mediated killing of ampicillin and vancomycin resistant enterococcus faecium
    Antimicrobial Agents and Chemotherapy, 2012
    Co-Authors: George Sakoulas, Joe Pogliano, Victor Nizet, Arnold S Bayer, Soojin Yang, Michael R Yeaman, Nagendra N Mishra, Brian T Tsuji
    Abstract:

    We studied an ampicillin- and vancomycin-resistant Enterococcus faecium (VRE) isolate from a patient with endocarditis and bacteremia refractory to treatment with Daptomycin (6 mg/kg of body weight) plus linezolid. Blood cultures cleared within 24 h of changing therapy to Daptomycin (12 mg/kg) plus ampicillin. We examined the effects of ampicillin on Daptomycin-induced growth inhibition and killing, surface charge, and susceptibility to several prototypical host defense cationic antimicrobial peptides. MICs and time-kill curves with Daptomycin were assessed in the presence and absence of ampicillin. The impact of ampicillin on surface charge was assessed by flow cytometry and a poly-l-lysine binding assay. The effects of ampicillin preexposures upon VRE killing by five distinct cationic peptides of different structure, charge, origin, and mechanism of action were analyzed using the epidermal cathelicidin LL-37, thrombin-induced platelet microbicidal proteins (tPMPs), and a synthetic congener modeled after tPMP microbicidal domains (RP-1), human neutrophil peptide-1 (hNP-1), and polymyxin B (bacteria derived). Fluoroscein-Bodipy-labeled Daptomycin was used to evaluate Daptomycin binding to VRE membranes in the presence or absence of ampicillin. In media containing ampicillin (25 to 100 mg/liter), Daptomycin MICs decreased from 1.0 to 0.38 mg/liter. Based on time-kill analysis and an in vitro pharmacodynamic model, ampicillin enhanced Daptomycin activity against the study VRE from a bacteriostatic to a bactericidal profile. VRE grown in ampicillin (25 to 150 mg/liter) demonstrated an incremental reduction in its relative net positive surface charge. When grown in the presence (versus absence) of ampicillin (25 and 100 mg/liter), the VRE strain (i) was more susceptible to killing by LL-37, tPMPs, hNP-1, and RP-1 but not to polymyxin B and (ii) exhibited greater binding to Bodipy-labeled Daptomycin. We conclude that ampicillin induces reductions in net positive bacterial surface charge of VRE, correlating with enhanced bactericidal effects of cationic calcium-Daptomycin and a diverse range of other cationic peptides in vitro. While the mechanism(s) of such β-lactam-mediated shifts in surface charge remains to be defined, these finding suggest a potential for β-lactam-mediated enhancement of activity of both Daptomycin and innate host defense peptides against antibiotic-resistant bacteria.

  • correlation of Daptomycin resistance in a clinical staphylococcus aureus strain with increased cell wall teichoic acid production and d alanylation
    Antimicrobial Agents and Chemotherapy, 2011
    Co-Authors: Ute Bertsche, Soojin Yang, Christopher Weidenmaier, Daniel Kuehner, Stefanie Baur, Stefanie Wanner, Patrice Francois, Jacques Schrenzel, Michael R Yeaman
    Abstract:

    Cell wall thickening is a common feature among Daptomycin-resistant Staphylococcus aureus strains. However, the mechanism(s) leading to this phenotype is unknown. We examined a number of cell wall synthesis pathway parameters in an isogenic strain set of S. aureus bloodstream isolates obtained from a patient with recalcitrant endocarditis who failed Daptomycin therapy, including the initial Daptomycin-susceptible parental strain (strain 616) and two Daptomycin-resistant strains (strains 701 and 703) isolated during Daptomycin therapy. Transmission electron microscopy demonstrated significantly thicker cell walls in the Daptomycin-resistant strains than in the Daptomycin-susceptible strain, a finding which was compatible with significant differences in dry cell weight of strain 616 versus strains 701 to 703 (P < 0.05). Results of detailed analysis of cell wall muropeptide composition, the degree of peptide side chain cross-linkage, and the amount of the peptidoglycan precursor, UDP-MurNAc-pentapeptide, were similar in the Daptomycin-susceptible and Daptomycin-resistant isolates. In contrast, the Daptomycin-resistant strains contained less O-acetylated peptidoglycan. Importantly, both Daptomycin-resistant strains synthesized significantly more wall teichoic acid (WTA) than the parental strain (P < 0.001). Moreover, the proportion of D-alanylated WTA species was substantially higher in the Daptomycin-resistant strains than in the Daptomycin-susceptible parental strain (P < 0.05 in comparing strain 616 versus strain 701). The latter phenotypic findings correlated with (i) enhanced tagA and dltA gene expression, respectively, and (ii) an increase in surface positive charge observed in the Daptomycin-resistant versus Daptomycin-susceptible isolates. Collectively, these data suggest that increases in WTA synthesis and the degree of its D-alanylation may play a major role in the Daptomycin-resistant phenotype in some S. aureus strains.

  • use of antistaphylococcal β lactams to increase Daptomycin activity in eradicating persistent bacteremia due to methicillin resistant staphylococcus aureus role of enhanced Daptomycin binding
    Clinical Infectious Diseases, 2011
    Co-Authors: Abhay Dhand, Joe Pogliano, Victor Nizet, Arnold S Bayer, Soojin Yang, Michael Bolaris, Guiquing Wang, George Sakoulas
    Abstract:

    We used Daptomycin plus antistaphylococcal β-lactams (ASBL) to clear refractory MRSA bacteremia. In vitro studies showed enhanced Daptomycin bactericidal activity, increased membrane Daptomycin binding, and decrease in positive surface charge induced by ASBLs against Daptomycin nonsusceptible MRSA. Addition of ASBLs to Daptomycin may be of benefit in refractory MRSA bacteremia. (Although the official designation is “Daptomycin nonsusceptiblity,” we will use the term “Daptomycin-resistance” in this paper for facility of presentation.)

  • failures in clinical treatment of staphylococcus aureus infection with Daptomycin are associated with alterations in surface charge membrane phospholipid asymmetry and drug binding
    Antimicrobial Agents and Chemotherapy, 2008
    Co-Authors: Tiffanny Jones, George Sakoulas, Soojin Yang, Jacques Schrenzel, Michael R Yeaman, Richard A Proctor, Hansgeorg Sahl, Yan Q Xiong
    Abstract:

    Increasingly frequent reports have described the in vivo loss of Daptomycin susceptibility in association with clinical treatment failures. The mechanism(s) of Daptomycin resistance is not well understood. We studied an isogenic set of Staphylococcus aureus isolates from the bloodstream of a Daptomycin-treated patient with recalcitrant endocarditis in which serial strains exhibited decreasing susceptibility to Daptomycin. Since Daptomycin is a membrane-targeting lipopeptide, we compared a number of membrane parameters in the initial blood isolate (parental) with those in subsequent Daptomycin-resistant strains obtained during treatment. In comparison to the parental strain, resistant isolates demonstrated (i) enhanced membrane fluidity, (ii) increased translocation of the positively charged phospholipid lysyl-phosphotidylglycerol to the outer membrane leaflet, (iii) increased net positive surface charge (P < 0.05 versus the parental strain), (iv) reduced susceptibility to Daptomycin-induced depolarization, permeabilization, and autolysis (P < 0.05 versus the parental strain), (v) significantly lower surface binding of Daptomycin (P < 0.05 versus the parental strain), and (vi) increased cross-resistance to the cationic antimicrobial host defense peptides human neutrophil peptide 1 (hNP-1) and thrombin-induced platelet microbicidal protein 1 (tPMP-1). These data link distinct changes in membrane structure and function with in vivo development of Daptomycin resistance in S. aureus. Moreover, the cross-resistance to hNP-1 and tPMP-1 may also impact the capacity of these Daptomycin-resistant organisms to be cleared from sites of infection, particularly endovascular foci.

Michael R Yeaman - One of the best experts on this subject based on the ideXlab platform.

  • reduced susceptibility to host defense cationic peptides and Daptomycin coemerge in methicillin resistant staphylococcus aureus from Daptomycin naive bacteremic patients
    The Journal of Infectious Diseases, 2012
    Co-Authors: Nagendra N Mishra, Pamela A Moise, Arnold S Bayer, Michael R Yeaman, George Sakoulas
    Abstract:

    Background. We hypothesized that, for methicillin-resistant Staphylococcus aureus (MRSA), in vitro Daptomycin susceptibility could be influenced by exposures to endogenous host defense peptides (HDPs) prior to clinical exposure to Daptomycin. Methods. Two endovascular HDPs were used: thrombin-induced platelet microbicidal protein (tPMP) and human neutrophil defensin-1 (hNP-1) from neutrophils. Forty-seven unique MRSA isolates obtained from bacteremic patients in multicenter prospective clinical trials were studied. Clinical characteristics, microbiologic parameters, prior vancomycin therapy, and susceptibilities to tPMP, hNP-1, and Daptomycin were compared using univariate and multivariate analyses. Results. All strains were Daptomycin susceptible. Daptomycin minimum inhibitory concentrations (MICs) were inversely related to in vitro tPMP (but not hNP-1) killing. Strains with a Daptomycin MIC of 1 mg/L exhibited significantly less killing by tPMP, compared with strains with an MIC of ≤ 0.5 mg/L. Prior vancomycin therapy did not influence this relationship. Regression tree modeling confirmed that reduced tPMP-induced killing in vitro was the strongest predictor of higher Daptomycin MICs within the Daptomycin-susceptible range. Conclusions. Among Daptomycin-susceptible MRSA isolates from patients who had never received Daptomycin, higher Daptomycin MICs tracked with increased resistance to killing by platelet-derived but not neutrophilderived HDPs. These findings support the notion that endogenous exposure of MRSA to specific HDPs may play a role in selecting strains with an intrinsically higher Daptomycin MIC phenotype.

  • ampicillin enhances Daptomycin and cationic host defense peptide mediated killing of ampicillin and vancomycin resistant enterococcus faecium
    Antimicrobial Agents and Chemotherapy, 2012
    Co-Authors: George Sakoulas, Joe Pogliano, Victor Nizet, Arnold S Bayer, Soojin Yang, Michael R Yeaman, Nagendra N Mishra, Brian T Tsuji
    Abstract:

    We studied an ampicillin- and vancomycin-resistant Enterococcus faecium (VRE) isolate from a patient with endocarditis and bacteremia refractory to treatment with Daptomycin (6 mg/kg of body weight) plus linezolid. Blood cultures cleared within 24 h of changing therapy to Daptomycin (12 mg/kg) plus ampicillin. We examined the effects of ampicillin on Daptomycin-induced growth inhibition and killing, surface charge, and susceptibility to several prototypical host defense cationic antimicrobial peptides. MICs and time-kill curves with Daptomycin were assessed in the presence and absence of ampicillin. The impact of ampicillin on surface charge was assessed by flow cytometry and a poly-l-lysine binding assay. The effects of ampicillin preexposures upon VRE killing by five distinct cationic peptides of different structure, charge, origin, and mechanism of action were analyzed using the epidermal cathelicidin LL-37, thrombin-induced platelet microbicidal proteins (tPMPs), and a synthetic congener modeled after tPMP microbicidal domains (RP-1), human neutrophil peptide-1 (hNP-1), and polymyxin B (bacteria derived). Fluoroscein-Bodipy-labeled Daptomycin was used to evaluate Daptomycin binding to VRE membranes in the presence or absence of ampicillin. In media containing ampicillin (25 to 100 mg/liter), Daptomycin MICs decreased from 1.0 to 0.38 mg/liter. Based on time-kill analysis and an in vitro pharmacodynamic model, ampicillin enhanced Daptomycin activity against the study VRE from a bacteriostatic to a bactericidal profile. VRE grown in ampicillin (25 to 150 mg/liter) demonstrated an incremental reduction in its relative net positive surface charge. When grown in the presence (versus absence) of ampicillin (25 and 100 mg/liter), the VRE strain (i) was more susceptible to killing by LL-37, tPMPs, hNP-1, and RP-1 but not to polymyxin B and (ii) exhibited greater binding to Bodipy-labeled Daptomycin. We conclude that ampicillin induces reductions in net positive bacterial surface charge of VRE, correlating with enhanced bactericidal effects of cationic calcium-Daptomycin and a diverse range of other cationic peptides in vitro. While the mechanism(s) of such β-lactam-mediated shifts in surface charge remains to be defined, these finding suggest a potential for β-lactam-mediated enhancement of activity of both Daptomycin and innate host defense peptides against antibiotic-resistant bacteria.

  • correlation of Daptomycin resistance in a clinical staphylococcus aureus strain with increased cell wall teichoic acid production and d alanylation
    Antimicrobial Agents and Chemotherapy, 2011
    Co-Authors: Ute Bertsche, Soojin Yang, Christopher Weidenmaier, Daniel Kuehner, Stefanie Baur, Stefanie Wanner, Patrice Francois, Jacques Schrenzel, Michael R Yeaman
    Abstract:

    Cell wall thickening is a common feature among Daptomycin-resistant Staphylococcus aureus strains. However, the mechanism(s) leading to this phenotype is unknown. We examined a number of cell wall synthesis pathway parameters in an isogenic strain set of S. aureus bloodstream isolates obtained from a patient with recalcitrant endocarditis who failed Daptomycin therapy, including the initial Daptomycin-susceptible parental strain (strain 616) and two Daptomycin-resistant strains (strains 701 and 703) isolated during Daptomycin therapy. Transmission electron microscopy demonstrated significantly thicker cell walls in the Daptomycin-resistant strains than in the Daptomycin-susceptible strain, a finding which was compatible with significant differences in dry cell weight of strain 616 versus strains 701 to 703 (P < 0.05). Results of detailed analysis of cell wall muropeptide composition, the degree of peptide side chain cross-linkage, and the amount of the peptidoglycan precursor, UDP-MurNAc-pentapeptide, were similar in the Daptomycin-susceptible and Daptomycin-resistant isolates. In contrast, the Daptomycin-resistant strains contained less O-acetylated peptidoglycan. Importantly, both Daptomycin-resistant strains synthesized significantly more wall teichoic acid (WTA) than the parental strain (P < 0.001). Moreover, the proportion of D-alanylated WTA species was substantially higher in the Daptomycin-resistant strains than in the Daptomycin-susceptible parental strain (P < 0.05 in comparing strain 616 versus strain 701). The latter phenotypic findings correlated with (i) enhanced tagA and dltA gene expression, respectively, and (ii) an increase in surface positive charge observed in the Daptomycin-resistant versus Daptomycin-susceptible isolates. Collectively, these data suggest that increases in WTA synthesis and the degree of its D-alanylation may play a major role in the Daptomycin-resistant phenotype in some S. aureus strains.

  • failures in clinical treatment of staphylococcus aureus infection with Daptomycin are associated with alterations in surface charge membrane phospholipid asymmetry and drug binding
    Antimicrobial Agents and Chemotherapy, 2008
    Co-Authors: Tiffanny Jones, George Sakoulas, Soojin Yang, Jacques Schrenzel, Michael R Yeaman, Richard A Proctor, Hansgeorg Sahl, Yan Q Xiong
    Abstract:

    Increasingly frequent reports have described the in vivo loss of Daptomycin susceptibility in association with clinical treatment failures. The mechanism(s) of Daptomycin resistance is not well understood. We studied an isogenic set of Staphylococcus aureus isolates from the bloodstream of a Daptomycin-treated patient with recalcitrant endocarditis in which serial strains exhibited decreasing susceptibility to Daptomycin. Since Daptomycin is a membrane-targeting lipopeptide, we compared a number of membrane parameters in the initial blood isolate (parental) with those in subsequent Daptomycin-resistant strains obtained during treatment. In comparison to the parental strain, resistant isolates demonstrated (i) enhanced membrane fluidity, (ii) increased translocation of the positively charged phospholipid lysyl-phosphotidylglycerol to the outer membrane leaflet, (iii) increased net positive surface charge (P < 0.05 versus the parental strain), (iv) reduced susceptibility to Daptomycin-induced depolarization, permeabilization, and autolysis (P < 0.05 versus the parental strain), (v) significantly lower surface binding of Daptomycin (P < 0.05 versus the parental strain), and (vi) increased cross-resistance to the cationic antimicrobial host defense peptides human neutrophil peptide 1 (hNP-1) and thrombin-induced platelet microbicidal protein 1 (tPMP-1). These data link distinct changes in membrane structure and function with in vivo development of Daptomycin resistance in S. aureus. Moreover, the cross-resistance to hNP-1 and tPMP-1 may also impact the capacity of these Daptomycin-resistant organisms to be cleared from sites of infection, particularly endovascular foci.

Warren E Rose - One of the best experts on this subject based on the ideXlab platform.

  • antimicrobial salvage therapy for persistent staphylococcal bacteremia using Daptomycin plus ceftaroline
    Clinical Therapeutics, 2014
    Co-Authors: George Sakoulas, Pamela A Moise, Poochit Nonejuie, Joshua Olson, Cheryl Y M Okumura, Ravina Kullar, Abhay Dhand, Anthony M Casapao, Michael J Rybak, Warren E Rose
    Abstract:

    Abstract Purpose Guidelines recommend Daptomycin combination therapy as an option for methicillin-resistant Staphylococcus aureus (MRSA) bacteremia after vancomycin failure. Recent data suggest that combining Daptomycin with a β-lactam may have unique benefits; however, there are very limited clinical data regarding the use of ceftaroline with Daptomycin. Methods All 26 cases from the 10 medical centers in which ceftaroline plus Daptomycin was used for treatment of documented refractory staphylococcal bacteremia from March 2011 to November 2012 were included. In vitro (synergy studies, binding assays, cathelicidin LL-37 killing assays), and in vivo (virulence assays using a murine subcutaneous infection model) studies examining the effects of ceftaroline with Daptomycin were also performed. Findings Daptomycin plus ceftaroline was used in 26 cases of staphylococcal bacteremia (20 MRSA, 2 vancomycin-intermediate S aureus , 2 methicillin-susceptible S aureus [MSSA], 2 methicillin-resistant S epidermidis ). Bacteremia persisted for a median of 10 days (range, 3–23 days) on previous antimicrobial therapy. After Daptomycin plus ceftaroline was started, the median time to bacteremia clearance was 2 days (range, 1–6 days). In vitro studies showed ceftaroline synergy against MRSA and enhanced MRSA killing by cathelicidin LL-37 and neutrophils. Ceftaroline also induced Daptomycin binding in MSSA and MRSA to a comparable degree as nafcillin. MRSA grown in subinhibitory concentrations of ceftaroline showed attenuated virulence in a murine subcutaneous infection model. Implications Ceftaroline plus Daptomycin may be an option to hasten clearance of refractory staphylococcal bacteremia. Ceftaroline offers dual benefit via synergy with both Daptomycin and sensitization to innate host defense peptide cathelicidin LL37, which could attenuate virulence of the pathogen.

  • ceftaroline restores Daptomycin activity against Daptomycin nonsusceptible vancomycin resistant enterococcus faecium
    Antimicrobial Agents and Chemotherapy, 2014
    Co-Authors: George Sakoulas, Poochit Nonejuie, Joshua Olson, Joe Pogliano, Warren E Rose, Romney M. Humphries, Victor Nizet
    Abstract:

    Daptomycin-nonsusceptible vancomycin-resistant Enterococcus 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 membranefluidity and susceptibility of VRE to surface binding and killing by Daptomycin and human cathelicidin antimicrobial peptide LL37. Synergy was noted in vitro between 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 membranefluidity 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 Daptomycinsusceptible/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, thesefinding suggest that additional in vivo and in vitro studies need to be done to explore the possibility of using ceftaroline as adjunctive anti-VRE therapy.

  • ceftaroline increases membrane binding and enhances the activity of Daptomycin against Daptomycin nonsusceptible vancomycin intermediate staphylococcus aureus in a pharmacokinetic pharmacodynamic model
    Antimicrobial Agents and Chemotherapy, 2013
    Co-Authors: Brian J Werth, Joe Pogliano, Ryan Tewhey, Warren E Rose, George Sakoulas, Michael J Rybak
    Abstract:

    New antimicrobial agents and novel combination therapies are needed to treat serious infections caused by methicillin-resistant Staphylococcus aureus (MRSA) with reduced susceptibility to Daptomycin and vancomycin. The purpose of this study was to evaluate the combination of ceftaroline plus Daptomycin or vancomycin in an in vitro pharmacokinetic/pharmacodynamic model. Simulations of ceftaroline-fosamil at 600 mg per kg of body weight every 8 h (q8h) (maximum free-drug concentration in serum [fCmax], 15.2 mg/liter; half-life [t1/2], 2.3 h), Daptomycin at 10 mg/kg/day (fCmax, 11.3 mg/liter; t1/2, 8 h), vancomycin at 2 g q12h (fCmax, 30 mg/liter; t1/2, 6 h), ceftaroline plus Daptomycin, and ceftaroline plus vancomycin were evaluated against a clinical, isogenic MRSA strain pair: D592 (Daptomycin susceptible and heterogeneous vancomycin intermediate) and D712 (Daptomycin nonsusceptible and vancomycin intermediate) in a one-compartment in vitro pharmacokinetic/pharmacodynamic model over 96 h. Therapeutic enhancement of combinations was defined as ≥2 log10 CFU/ml reduction over the most active single agent. The effect of ceftaroline on the membrane charge, cell wall thickness, susceptibility to killing by the human cathelicidin LL37, and Daptomycin binding were evaluated. Therapeutic enhancement was observed with Daptomycin plus ceftaroline in both strains and vancomycin plus ceftaroline against D592. Ceftaroline exposure enhanced Daptomycin-induced depolarization (81.7% versus 72.3%; P = 0.03) and killing by cathelicidin LL37 (P < 0.01) and reduced cell wall thickness (P < 0.001). Fluorescence-labeled Daptomycin was bound over 7-fold more in ceftaroline-exposed cells. Whole-genome sequencing and mutation analysis of these strains indicated that change in Daptomycin susceptibility is related to an fmtC (mprF) mutation. The combination of Daptomycin plus ceftaroline appears to be potent, with rapid and sustained bactericidal activity against both Daptomycin-susceptible and -nonsusceptible strains of MRSA.

  • addition of ceftaroline to Daptomycin after emergence of Daptomycin nonsusceptible staphylococcus aureus during therapy improves antibacterial activity
    Antimicrobial Agents and Chemotherapy, 2012
    Co-Authors: Warren E Rose, Lucas T Schulz, Rob Striker, Andrew D Berti, David R Andes, Paul R Hutson, Sanjay K Shukla
    Abstract:

    ABSTRACT Antistaphylococcal beta-lactams enhance Daptomycin activity and have been used successfully in combination for refractory methicillin-resistant Staphylococcus aureus (MRSA) infections. Ceftaroline possesses MRSA activity, but it is unknown if it improves the Daptomycin potency comparably to other beta-lactams. We report a complex patient case of endocarditis who was treated with Daptomycin in combination with ceftaroline, which resulted in clearance of a Daptomycin-nonsusceptible strain. An in vitro pharmacokinetic/pharmacodynamic model of renal failure was used to simulate the development of Daptomycin resistance and evaluate the microbiologic effects of Daptomycin plus ceftaroline treatment. Combination therapy with Daptomycin and ceftaroline restored Daptomycin sensitivity in vivo and resulted in clearance of persistent blood cultures. Daptomycin susceptibility in vitro was increased in the presence of either ceftaroline or oxacillin. Daptomycin at 6 mg/kg of body weight every 48 h was bactericidal in the model but resulted in regrowth and Daptomycin resistance (MIC, 2 to 4 μg/ml) with continued monotherapy. The addition of ceftaroline at 200 mg every 12 h after the emergence of Daptomycin resistance enhanced bacterial killing. Importantly, Daptomycin plus ceftaroline as the initial combination therapy produced rapid and sustained bactericidal activity and prevented Daptomycin resistance. Both in vivo - and in vitro -derived Daptomycin resistance resulted in bacteria with more fluid cell membranes. After ceftaroline was added in the model, fluidity was restored to the level of the initial in vivo isolate. Daptomycin-resistant isolates required high Daptomycin exposures (at least 10 mg/kg) to optimize cell membrane damage with Daptomycin alone. Ceftaroline combined with Daptomycin was effective in eliminating Daptomycin-resistant MRSA, and these results further justify the potential use of Daptomycin plus beta-lactam therapy for these refractory infections.

  • evaluation of Daptomycin pharmacodynamics and resistance at various dosage regimens against staphylococcus aureus isolates with reduced susceptibilities to Daptomycin in an in vitro pharmacodynamic model with simulated endocardial vegetations
    Antimicrobial Agents and Chemotherapy, 2008
    Co-Authors: Warren E Rose, Michael J Rybak, Steven N Leonard
    Abstract:

    The need to investigate novel dosing regimens and combinations is essential in combating poor treatment outcomes for Staphylococcus aureus bacteremia and endocarditis. We evaluated the impact of simulated standard- and high-dose Daptomycin in combination with gentamicin or rifampin against Daptomycin-susceptible and nonsusceptible matched strains of S. aureus. These strains were collected from the Daptomycin bacteremia and endocarditis clinical trial and consisted of three susceptible strains (MIC, 0.25 mg/liter) and four nonsusceptible isolates (MICs, 2 to 4 mg/liter). Daptomycin regimens of 6 and 10 mg/kg of body weight daily alone and in combination with gentamicin at 5 mg/kg daily or rifampin at 300 mg every 8 h were evaluated using an in vitro model with simulated endocardial vegetations over 96 h. Rapid bactericidal activity, identified by time to 99.9% kill, was displayed in all regimens with the Daptomycin-susceptible strains. Concentration-dependent activity was noted by more-rapid killing with the 10-mg/kg/day dose. The addition of gentamicin improved activity in the majority of susceptible isolates. Daptomycin 6-mg/kg/day monotherapy displayed bactericidal activity for only one of the nonsusceptible isolates and for only two isolates with increased doses of 10 mg/kg/day. Combination regimens demonstrated improvement with some but not all nonsusceptible isolates. Three isolates developed a reduction in Daptomycin susceptibility with 6-mg/kg/day monotherapy, but this was suppressed with both combination therapy and high-dose Daptomycin. These results suggest that high-dose Daptomycin therapy and combination therapy may be reasonable treatment options for susceptible isolates; however, more investigations are needed to confirm the variability of these regimens with nonsusceptible isolates.

Related terms

Daptomycin - 15 days free trial to Access Experts & Abstracts