scholarly journals Ceftaroline Increases Membrane Binding and Enhances the Activity of Daptomycin against Daptomycin-Nonsusceptible Vancomycin-Intermediate Staphylococcus aureus in a Pharmacokinetic/Pharmacodynamic Model

2012 ◽  
Vol 57 (1) ◽  
pp. 66-73 ◽  
Author(s):  
Brian J. Werth ◽  
George Sakoulas ◽  
Warren E. Rose ◽  
Joseph Pogliano ◽  
Ryan Tewhey ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Cell Wall ◽  
Wall Thickness ◽  
Antimicrobial Agents ◽  
Single Agent ◽  
Pharmacodynamic Model ◽  
Cell Wall Thickness ◽  
Ceftaroline Fosamil ◽  
Content Type

ABSTRACTNew antimicrobial agents and novel combination therapies are needed to treat serious infections caused by methicillin-resistantStaphylococcus 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 anin vitropharmacokinetic/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-compartmentin vitropharmacokinetic/pharmacodynamic model over 96 h. Therapeutic enhancement of combinations was defined as ≥2 log10CFU/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 anfmtC(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.

scholarly journals In VitroActivity of Ceftaroline against Staphylococcus aureus Isolated in 2012 from Asia-Pacific Countries as Part of the AWARE Surveillance Program

2015 ◽  
Vol 60 (1) ◽  
pp. 343-347 ◽  
Author(s):  
Douglas J. Biedenbach ◽  
Richard A. Alm ◽  
Sushmita D. Lahiri ◽  
Edina Reiszner ◽  
Daryl J. Hoban ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Antimicrobial Agents ◽  
Generation Cephalosporin ◽  
Sequence Type ◽  
Asia Pacific ◽  
Surveillance Program ◽  
Ceftaroline Fosamil ◽  
Content Type ◽  
Susceptibility Data

ABSTRACTCeftaroline, the active metabolite of the prodrug ceftaroline-fosamil, is an advanced-generation cephalosporin with activity against methicillin-resistantStaphylococcus aureus(MRSA). This investigation providesin vitrosusceptibility data for ceftaroline against 1,971S. aureusisolates collected in 2012 from seven countries (26 centers) in the Asia-Pacific region as part of the Assessing Worldwide Antimicrobial Resistance and Evaluation (AWARE) program. Broth microdilution as recommended by the CLSI was used to determine susceptibility. In all, 62% of the isolates studied were MRSA, and the ceftaroline MIC90for allS. aureusisolates was 2 μg/ml (interpretive criteria: susceptible, ≤1 μg/ml). The overall ceftaroline susceptibility rate forS. aureuswas 86.9%, with 100% of methicillin-sensitiveS. aureusisolates and 78.8% of MRSA isolates susceptible to this agent. The highest percentages of ceftaroline-nonsusceptible MRSA isolates came from China (47.6%), all of which showed intermediate susceptibility, and Thailand (37.1%), where over half (52.8%) of isolates were resistant to ceftaroline (MIC, 4 μg/ml). Thirty-eight ceftaroline-nonsusceptible isolates (MIC values of 2 to 4 μg/ml) were selected for molecular characterization. Among the isolates analyzed, sequence type 5 (ST-5) was the most common sequence type encountered; however, all isolates analyzed from Thailand were ST-228. Penicillin-binding protein 2a (PBP2a) substitution patterns varied by country, but all isolates from Thailand had the Glu239Lys substitution, and 12 of these also carried an additional Glu447Lys substitution. Ceftaroline-fosamil is a useful addition to the antimicrobial agents that can be used to treatS. aureusinfections. However, with the capability of this species to develop resistance to new agents, it is important to recognize and monitor regional differences in trends as they emerge.

scholarly journals Characterizing Vancomycin-Resistant Enterococcus Strains with Various Mechanisms of Daptomycin Resistance Developed in anIn VitroPharmacokinetic/Pharmacodynamic Model

2011 ◽  
Vol 55 (10) ◽  
pp. 4748-4754 ◽  
Author(s):  
Molly E. Steed ◽  
Celine Vidaillac ◽  
Warren E. Rose ◽  
Patricia Winterfield ◽  
Glenn W. Kaatz ◽  
...  
Keyword(s):  
Cell Wall ◽  
Surface Charge ◽  
Wall Thickness ◽  
Membrane Depolarization ◽  
Cell Wall Thickness ◽  
Content Type ◽  
Dosing Regimens ◽  
Mueller Hinton Agar ◽  
Vancomycin Resistant

ABSTRACTTwo daptomycin (DAP) regimens were evaluated in a pharmacokinetic/pharmacodynamic (PK/PD) model, and the mutants recovered were examined for changes in phenotypic characteristics. ThreeEnterococcus faeciumstrains (vancomycin-resistantEnterococcus[VRE] ATCC 51559, VRE 12311, and VRE SF 12047) were utilized in a 7-day, 1-compartmentin vitroPK/PD model. The simulated dosing regimens were DAP at 6 mg/kg/day (freeCmax[fCmax] = 7.9 μg/ml, half-life [t1/2] = 8 h) and DAP at 10 mg/kg/day (fCmax= 13.17 μg/ml,t1/2= 8 h). Samples were plated daily on Mueller-Hinton agar containing DAP at 16 μg/ml and 50 mg/liter Ca2+to assess the emergence of DAP resistance. For each strain, the mutant with the highest DAP MIC was then evaluated for changes in relative surface charge, cell wall thickness, and cytoplasmic membrane depolarization induced by DAP. The initial DAP MICs were 4 μg/ml for all 3 strains. A dose-dependent response and regrowth were observed for DAP 6 mg/kg/day and DAP 10 mg/kg/day against all 3 strains. Mutants of VRE ATCC 51559 (MIC = 128 and 64 μg/ml) and VRE 12311 (MIC = 256 and 32 μg/ml) were recovered from the DAP 6 mg and DAP 10 mg regimen, respectively. For VRE SF 12047, a mutant (MIC = 64 μg/ml) was recovered from the DAP 6 mg model. All mutants displayed an increase in relative surface charge compared to those of their respective parent strains. The DAP-resistant mutants displayed a 43 to 58% increase in cell wall thickness (P< 0.0001), while DAP membrane depolarization decreased by 53 to 65% compared to that of the susceptible strains. VRE with DAP resistance displayed increased surface charge, increased cell wall thickness, and decreased depolarization induced by DAP, consistent with previous observations inStaphylococcus aureuswith reduced DAP susceptibility. Further characterization of DAP-resistant VRE is warranted.

scholarly journals Reduced Vancomycin Susceptibility in anIn VitroCatheter-Related Biofilm Model Correlates with Poor Therapeutic Outcomes in Experimental Endocarditis Due to Methicillin-Resistant Staphylococcus aureus

2013 ◽  
Vol 57 (3) ◽  
pp. 1447-1454 ◽  
Author(s):  
Wessam Abdelhady ◽  
Arnold S. Bayer ◽  
Kati Seidl ◽  
Cynthia C. Nast ◽  
Megan R. Kiedrowski ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Cell Wall ◽  
Wall Thickness ◽  
Biofilm Formation ◽  
Methicillin Resistant ◽  
Content Type ◽  
Biofilm Model ◽  
Mrsa Strains

ABSTRACTStaphylococcus aureusis the most common cause of endovascular infections, including catheter sepsis and infective endocarditis (IE). Vancomycin (VAN) is the primary choice for treatment of methicillin-resistantS. aureus(MRSA) infections. However, high rates of VAN treatment failure in MRSA infections caused by VAN-susceptible strains have been increasingly reported. Biofilm-associated MRSA infections are especially prone to clinical antibiotic failure. The present studies examined potential relationships between MRSA susceptibility to VAN in biofilmsin vitroand nonsusceptibility to VAN in endovascular infectionin vivo. Using 10 “VAN-susceptible” MRSA bloodstream isolates previously investigated for VAN responsiveness in experimental IE, we studied the mechanism(s) of suchin vivoVAN resistance, including: (i) VAN binding to MRSA organisms; (ii) the impact of VAN on biofilm formation and biofilm composition; (iii) VAN efficacy in anin vitrocatheter-related biofilm model; (iv) effects on cell wall thickness. As a group, the five strains previously categorized as VAN nonresponders (non-Rsp) in the experimental IE model differed from the five responders (Rsp) in terms of lower VAN binding, increased biofilm formation, higher survival in the presence of VAN within biofilms in the presence or absence of catheters, and greater biofilm reduction upon proteinase K treatment. Interestingly, sub-MICs of VAN significantly promoted biofilm formation only in the non-Rsp isolates. Cell wall thickness was similar among all MRSA strains. These results suggest that sublethal VAN levels that induce biofilm formation and reduce efficacy of VAN in thein vitrocatheter-associated biofilms may contribute to suboptimal treatment outcomes for endovascular infections caused by “VAN-susceptible” MRSA strains.

scholarly journals In VitroPharmacodynamics of Human Simulated Exposures of Ceftaroline and Daptomycin against MRSA, hVISA, and VISA with and without Prior Vancomycin Exposure

2013 ◽  
Vol 58 (2) ◽  
pp. 672-677 ◽  
Author(s):  
Amira A. Bhalodi ◽  
Mao Hagihara ◽  
David P. Nicolau ◽  
Joseph L. Kuti
Keyword(s):  
Staphylococcus Aureus ◽  
Body Weight ◽  
Sequential Therapy ◽  
Free Drug ◽  
Pharmacodynamic Model ◽  
Prior Exposure ◽  
Methicillin Resistant ◽  
Content Type ◽  
Mrsa Infection

ABSTRACTThe effects of prior vancomycin exposure on ceftaroline and daptomycin therapy against methicillin-resistantStaphylococcus aureus(MRSA) have not been widely studied. Humanized free-drug exposures of vancomycin at 1 g every 12 h (q12h), ceftaroline at 600 mg q12h, and daptomycin at 10 mg/kg of body weight q24h were simulated in a 96-hin vitropharmacodynamic model against three MRSA isolates, including one heteroresistant vancomycin-intermediateS. aureus(hVISA) isolate and one VISA isolate. A total of five regimens were tested: vancomycin, ceftaroline, and daptomycin alone for the entire 96 h, and then sequential therapy with vancomycin for 48 h followed by ceftaroline or daptomycin for 48 h. Microbiological responses were measured by the changes in log10CFU during 96 h from baseline. Control isolates grew to 9.16 ± 0.32, 9.13 ± 0.14, and 8.69 ± 0.28 log10CFU for MRSA, hVISA, and VISA, respectively. Vancomycin initially achieved ≥3 log10CFU reductions against the MRSA and hVISA isolates, followed by regrowth beginning at 48 h; minimal activity was observed against VISA. The change in 96-h log10CFU was largest for sequential therapy with vancomycin followed by ceftaroline (−5.22 ± 1.2,P= 0.010 versus ceftaroline) and for sequential therapy with vancomycin followed by ceftaroline (−3.60 ± 0.6,P= 0.037 versus daptomycin), compared with daptomycin (−2.24 ± 1.0), vancomycin (−1.40 ± 1.8), and sequential therapy with vancomycin followed by daptomycin (−1.32 ± 1.0,P> 0.5 for the last three regimens). Prior exposure of vancomycin at 1 g q12h reduced the initial microbiological response of daptomycin, particularly for hVISA and VISA isolates, but did not affect the response of ceftaroline. In the scenario of poor vancomycin response for high-inoculum MRSA infection, a ceftaroline-containing regimen may be preferred.

scholarly journals In Vitro Activity of Tedizolid Compared to Linezolid and Five Other Antimicrobial Agents against 332 Anaerobic Isolates, Including Bacteroides fragilis Group, Prevotella, Porphyromonas, and Veillonella Species

2020 ◽  
Vol 64 (9) ◽  
Author(s):  
Ellie J. C. Goldstein ◽  
C. Vreni Merriam ◽  
Diane M. Citron
Keyword(s):  
Staphylococcus Aureus ◽  
Antimicrobial Agents ◽  
Bacteroides Fragilis ◽  
Vitro Activity ◽  
Mixed Infections ◽  
In Vitro Activity ◽  
Content Type ◽  
Bacteroides Fragilis Group ◽  
Group Species

ABSTRACT Tedizolid’s anaerobic activity is unappreciated. In this study, it was active against all 332 anaerobic isolates tested at ≤2 μg/ml except Bilophila wadsworthia and was more active than linezolid against Bacteroides fragilis group species (MIC90, 1 μg/ml versus 2 to 4 μg/ml). Tedizolid was active against Gram-positive anaerobes (MIC90 for clostridia, 0.25 to 1 μg/ml; MIC90 for anaerobic cocci, ≤0.06 to 0.25 μg/ml). Our data coupled with clinical reports indicate that clinicians should consider its use in mixed infections where Staphylococcus aureus and anaerobes are involved.

Increase in the in vitro susceptibility of Staphylococcus aureus to antimicrobial agents in the presence of Candida albicans

1979 ◽  
Vol 25 (4) ◽  
pp. 429-435 ◽  
Author(s):  
J. deRepentigny ◽  
R. Lévesque ◽  
L. G. Mathieu
Keyword(s):  
Staphylococcus Aureus ◽  
Cell Wall ◽  
Candida Albicans ◽  
Inhibitory Activity ◽  
Antimicrobial Agents ◽  
Mixed Cultures ◽  
Alpha Toxin ◽  
In Vitro Susceptibility ◽  
Pure Cultures

In experiments with mixed cultures of Staphylococcus aureus and Candida albicans both in the absence and in the presence of 5-fluorocytosine (5-FC), we have observed that (1) there is an inhibition of S. aureus growth in mixed cultures with C. albicans in media supplemented with 1 μg/mL of 5-FC and that 5-FC has no effect on staphylococci in pure cultures; (2) this inhibition occurred with clinically isolated and laboratory strains and could be reversed by specific metabolites; (3) Staphylococcus aureus was inhibited by filtrates of C. albicans cultures treated with 5-FC and this seemed to be favored by some C. albicans filterable product which can affect the cell wall and the permeability of the staphylococcal cells since they become sensitive to 5-FC; (4) nine other commonly used antimicrobials showed an increased inhibitory activity against S. aureus in mixed cultures with C. albicans; and (5) there is a decrease in the number of precipitating antigens of S. aureus and of the activity of alpha toxin when this species was grown with both C. albicans and 5-FC. Our results indicate that the susceptibility of some species to antimicrobials could be significantly modified in the presence of other species. One cannot exclude that a similar phenomenon could happen in hosts under treatment with antibiotics against infection.

scholarly journals Altering the Proclivity towards Daptomycin Resistance in Methicillin-Resistant Staphylococcus aureus Using Combinations with Other Antibiotics

2012 ◽  
Vol 56 (10) ◽  
pp. 5046-5053 ◽  
Author(s):  
Andrew D. Berti ◽  
Justine E. Wergin ◽  
Gary G. Girdaukas ◽  
Scott J. Hetzel ◽  
George Sakoulas ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Cell Wall ◽  
Cell Membrane ◽  
Membrane Integrity ◽  
Wall Thickening ◽  
Methicillin Resistant ◽  
Content Type ◽  
Cell Membrane Integrity ◽  
Cell Membrane Fluidity

ABSTRACTDaptomycin (DAP) is increasingly used as a part of combination therapy, particularly in complex methicillin-resistantStaphylococcus aureus(MRSA) infections. While multiple studies have reported the potential for synergy between DAP and adjunctive anti-infectives, few have examined the influence of adjunctive therapy on the emergence of DAP resistance. This study examined eight adjunctive antimicrobial combinations with DAPin vitroand the emergence of DAP resistance over time (up to 4 weeks) using clinical isolates of DAP-susceptible MRSA (MIC, 0.5 μg/ml) in which DAP resistance subsequently developed during patient therapy (MIC, 3 μg/ml). In addition to DAP susceptibility testing, selected strains were examined for phenotypic changes associated with DAP resistance, including changes to cell wall thickness (CWT) and cell membrane alterations. The addition of either oxacillin or clarithromycin in medium containing DAP significantly inhibited the development of DAP resistance through the entirety of the 4-week exposure (10- to 32-fold MIC reduction from that of DAP alone). Combinations with rifampin or fosfomycin were effective in delaying the emergence of DAP resistance through the end of week one only (week one MIC, 0.5 μg/ml; week four MIC, 24 μg/ml). Cell wall thickening was observed for all antibiotic combinations regardless of their effect on the DAP MIC (14 to 70% increase in CWT), while changes in cell membrane fluidity were variable and treatment dependent. DAP showed reduced activity against strains with DAP MICs of 1 to 12 μg/ml, but cell membrane integrity was still disrupted at concentrations achieved with doses greater than 10 mg/kg of body weight. The emergence of DAP resistance in MRSA is strongly influenced by the presence of subinhibitory concentrations of adjunctive antimicrobials. These data suggest that combining DAP with oxacillin or clarithromycin may delay the development of DAP resistance in cases requiring prolonged antibiotic therapy.

scholarly journals Pharmacodynamics of Ceftaroline against Staphylococcus aureus Studied in anIn VitroPharmacokinetic Model of Infection

2013 ◽  
Vol 57 (6) ◽  
pp. 2451-2456 ◽  
Author(s):  
Alasdair P. MacGowan ◽  
Alan R. Noel ◽  
Sharon Tomaselli ◽  
Karen E. Bowker
Keyword(s):  
Staphylococcus Aureus ◽  
Drug Exposure ◽  
Population Analysis ◽  
Intermediate Phenotype ◽  
Ceftaroline Fosamil ◽  
Content Type ◽  
Dose Ranging ◽  
Mrsa Strains ◽  
Emergence Of Resistance

ABSTRACTAnin vitrosingle-compartment dilutional pharmacokinetic model was used to study the pharmacodynamics of ceftaroline againstStaphylococcus aureus(both methicillin-susceptibleS. aureus[MSSA] and methicillin-resistantS. aureus[MRSA]). Mean serum free concentrations of ceftaroline (the active metabolite of the prodrug ceftaroline fosamil) dosed in humans at 600 mg every 12 h (q12h) were simulated, and activities against 12S. aureusstrains (3 MSSA strains and 9 MRSA strains, 3 of which had a vancomycin-intermediate phenotype) were determined. Ceftaroline produced 2.5- to 4.0-log10-unit reductions in viable counts by 24 h with all strains and a 0.5- to 4.0-log-unit drop in counts at 96 h. The antibacterial effect could not be related to the strain MIC across the ceftaroline MIC range from 0.12 to 2.0 μg/ml. In dose-ranging studies, the cumulative percentage of a 24-h period that the free drug concentration exceeded the MIC under steady-state pharmacokinetic conditions (fTMIC) of 24.5% ± 8.9% was associated with a 24-h bacteriostatic effect, one of 27.8% ± 9.5% was associated with a −1-log-unit drop, and one of 32.1% ± 8.1% was associated with a −2-log-unit drop. The MSSA and MRSA strains had similarfTMICvalues.fTMICvalues increased with increasing duration of exposure up to 96 h. Changes in ceftaroline population analysis profiles were related tofTMIC.fTMICs of <50% were associated with growth on 4× MIC recovery plates at 96 h of drug exposure. These data support the use of ceftaroline fosamil at doses of 600 mg q12h to treatS. aureusstrains with MICs of ≤2 μg/ml. AnfTMICof 25 to 30% would make a suitable pharmacodynamic index target, butfTMICvalues of ≥50% are needed to suppress the emergence of resistance and require clinical evaluation.

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