scholarly journals Pharmacodynamic comparison of different antimicrobial regimens against Staphylococcus aureus bloodstream infections with elevated vancomycin minimum inhibitory concentration

2019 ◽  
Author(s):  
Thaina Miranda da Costa ◽  
Gabriel Trova Cuba ◽  
Priscylla Guimarães Migueres Morgado ◽  
David P. Nicolau ◽  
Simone Aranha Nouér ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Monte Carlo ◽  
Inhibitory Concentration ◽  
Area Under The Curve ◽  
Bloodstream Infections ◽  
Stochastic Simulations ◽  
High Dose ◽  
Percent Time ◽  
High Prevalence ◽  
Total Growth

Abstract Background Staphylococcus aureus is one of the major causes of bloodstream infections (BSI) worldwide, representing a major challenge for public health due to its resistance profile. Higher vancomycin minimum inhibitory concentrations (MIC) in S. aureus are associated with treatment failure and defining optimal empiric options for BSIs in settings where these isolates are prevalent is rather challenging. In silico pharmacodynamic models based on stochastic simulations (Monte Carlo) are important tools to estimate best antimicrobial regimens in different scenarios. We aimed to compare the pharmacodynamic profiles of different antimicrobials regimens for the treatment of S. aureus BSI in an environment with high vancomycin MIC. Methods Steady-state drug area under the curve ratio to MIC (AUC⁄MIC) or the percent time above MIC (fT>MIC) were modeled using a 5000-patient Monte Carlo simulation to achieve pharmacodynamic exposures against 110 consecutive S. aureus isolates associated with BSI. Results Cumulative fractions of response (CFRs) against all S. aureus isolates were 98% for ceftaroline; 79% and 92% for daptomycin 6 mg/kg q24h and for the high dose of 10 mg/kg q24h, respectively; 77% for linezolid 600 mg every 12h when MIC was read according to CLSI M100-S26 instructions, and 64% when MIC was considered at the total growth inhibition; 65% and 86% for teicoplanin, three loading doses of 400 mg every 12h followed by 400 mg every 24h and for teicoplanin 400 mg every 12h, respectively; 61% and 76% for vancomycin 1000 mg every 12h and every 8h, respectively. Conclusions Based on this model, ceftaroline and high-dose daptomycin regimens delivered best pharmacodynamic exposures against S. aureus BSIs. Teicoplanin higher dose regimen achieves the best CFR (86%) among glycopeptides, although optimal threshold was not achieved, and vancomycin performance is critically affected by S. aureus vancomycin MIC ≥ 2 mg/L. Linezolid effectiveness (CFR of 73%) is also affected by high prevalence of isolates with higher MICs. These data show the need to continually evaluate the pharmacodynamic profiles of antimicrobials for empiric treatment of these infections.

scholarly journals Pharmacodynamic comparison of different antimicrobial regimens against Staphylococcus aureus bloodstream infections with elevated vancomycin minimum inhibitory concentration

2019 ◽  
Author(s):  
Thaina Miranda da Costa ◽  
Gabriel Trova Cuba ◽  
Priscylla Guimarães Migueres Morgado ◽  
David P. Nicolau ◽  
Simone Aranha Nouér ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Monte Carlo ◽  
Inhibitory Concentration ◽  
Area Under The Curve ◽  
Bloodstream Infections ◽  
Stochastic Simulations ◽  
High Dose ◽  
Percent Time ◽  
High Prevalence ◽  
Total Growth

Abstract Background: Staphylococcus aureus is one of the major causes of bloodstream infections (BSI) worldwide, representing a major challenge for public health due to its resistance profile. Higher vancomycin minimum inhibitory concentrations (MIC) in S. aureus are associated with treatment failure and defining optimal empiric options for BSIs in settings where these isolates are prevalent is rather challenging. I n silico pharmacodynamic models based on stochastic simulations (Monte Carlo) are important tools to estimate best antimicrobial regimens in different scenarios. We aimed to compare the pharmacodynamic profiles of different antimicrobials regimens for the treatment of S. aureus BSI in an environment with high vancomycin MIC . Methods: Steady-state drug area under the curve ratio to MIC (AUC⁄MIC) or the percent time above MIC ( f T>MIC) were modeled using a 5000-patient Monte Carlo simulation to achieve pharmacodynamic exposures against 110 consecutive S. aureus isolates associated with BSI. Results: Cumulative fractions of response (CFRs) against all S. aureus isolates were 98% for ceftaroline; 79% and 92% for daptomycin 6 mg/kg q24h and for the high dose of 10 mg/kg q24h, respectively; 77% for linezolid 600 mg q12h when MIC was read according to CLSI M100-S26 instructions, and 64% when MIC was considered at the total growth inhibition; 65% and 86% for teicoplanin, three loading doses of 400 mg every 12h followed by 400 mg every 24h and for teicoplanin 400 mg every 12h, respectively; 61% and 76% for vancomycin 1000 mg every 12h and every 8h, respectively. Conclusions: Based on this model, ceftaroline and high-dose daptomycin regimens delivered best pharmacodynamic exposures against S. aureus BSIs. Teicoplanin higher dose regimen achieved the best CFR (86%) among glycopeptides, although optimal threshold was not achieved, and vancomycin performance was critically affected by the S. aureus vancomycin MIC ≥ 2 mg/L. Linezolid effectiveness (CFR of 73%) is also affected by high prevalence of isolates with linezolid MIC ≥ 2 mg/L. These data show the need to continually evaluate the pharmacodynamic profiles of antimicrobials for empiric treatment of these infections.

scholarly journals Pharmacodynamic comparison of different antimicrobial regimens against Staphylococcus aureus bloodstream infections with elevated vancomycin minimum inhibitory concentration

2019 ◽  
Author(s):  
Thaina Miranda da Costa ◽  
Gabriel Trova Cuba ◽  
Priscylla Guimarães Migueres Morgado ◽  
David P. Nicolau ◽  
Simone Aranha Nouér ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Monte Carlo ◽  
Inhibitory Concentration ◽  
Area Under The Curve ◽  
Bloodstream Infections ◽  
Stochastic Simulations ◽  
High Dose ◽  
Percent Time ◽  
High Prevalence ◽  
Total Growth

Abstract Background: Staphylococcus aureus is one of the major causes of bloodstream infections (BSI) worldwide, representing a major challenge for public health due to its resistance profile. Higher vancomycin minimum inhibitory concentrations (MIC) in S. aureus are associated with treatment failure and defining optimal empiric options for BSIs in settings where these isolates are prevalent is rather challenging. I n silico pharmacodynamic models based on stochastic simulations (Monte Carlo) are important tools to estimate best antimicrobial regimens in different scenarios. We aimed to compare the pharmacodynamic profiles of different antimicrobials regimens for the treatment of S. aureus BSI in an environment with high vancomycin MIC . Methods: Steady-state drug area under the curve ratio to MIC (AUC⁄MIC) or the percent time above MIC ( f T>MIC) were modeled using a 5000-patient Monte Carlo simulation to achieve pharmacodynamic exposures against 110 consecutive S. aureus isolates associated with BSI. Results: Cumulative fractions of response (CFRs) against all S. aureus isolates were 98% for ceftaroline; 79% and 92% for daptomycin 6 mg/kg q24h and for the high dose of 10 mg/kg q24h, respectively; 77% for linezolid 600 mg q12h when MIC was read according to CLSI M100-S26 instructions, and 64% when MIC was considered at the total growth inhibition; 65% and 86% for teicoplanin, three loading doses of 400 mg every 12h followed by 400 mg every 24h and for teicoplanin 400 mg every 12h, respectively; 61% and 76% for vancomycin 1000 mg every 12h and every 8h, respectively. Conclusions: Based on this model, ceftaroline and high-dose daptomycin regimens delivered best pharmacodynamic exposures against S. aureus BSIs. Teicoplanin higher dose regimen achieved the best CFR (86%) among glycopeptides, although optimal threshold was not achieved, and vancomycin performance was critically affected by the S. aureus vancomycin MIC ≥ 2 mg/L. Linezolid effectiveness (CFR of 73%) is also affected by high prevalence of isolates with linezolid MIC ≥ 2 mg/L. These data show the need to continually evaluate the pharmacodynamic profiles of antimicrobials for empiric treatment of these infections.

scholarly journals Use of Pharmacokinetic and Pharmacodynamic Principles To Determine Optimal Administration of Daptomycin in Patients Receiving Standardized Thrice-Weekly Hemodialysis

2011 ◽  
Vol 55 (4) ◽  
pp. 1677-1683 ◽  
Author(s):  
Nimish Patel ◽  
Katie Cardone ◽  
Darren W. Grabe ◽  
Shari Meola ◽  
Christopher Hoy ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Monte Carlo ◽  
Body Weight ◽  
Infective Endocarditis ◽  
Population Model ◽  
Area Under The Curve ◽  
Compartment Model ◽  
Population Pharmacokinetic ◽  
Exposure Profile ◽  
Trough Concentrations

ABSTRACTThis study identified optimal daptomycin dosing for patients receiving thrice-weekly hemodialysis (HD). Twelve adult patients on HD received daptomycin at 6 mg/kg of body weight intravenously (i.v.) one time; plasma and dialysate samples were collected over 3 days. A 2-compartment model with separate HD and non-HD clearance terms was fit to the data. A series of 9,999-subject Monte Carlo simulations (MCS) was performed to identify HD dosing schemes providing efficacy and toxicity profiles comparable to those obtained for MCS employing the daptomycin population pharmacokinetic (PK) model derived from patients in theStaphylococcus aureusbacteremia-infective endocarditis (SAB-IE) study. For efficacy, we selected the HD dosing scheme which generated an area-under-the-curve (AUC) exposure profile comparable to that for the SAB-IE population model. For toxicity, we selected HD dosing schemes that minimized trough concentrations of ≥24.3 mg/liter. Separate HD dosing schemes were developed for each FDA-approved regimen and for two weekly interdialytic periods (48 and 72 h). Administration of the same parent daptomycin dose intra-HD and post-HD resulted in AUC, maximum concentration of drug in serum (Cmax), andCminvalues most comparable to those for SAB-IE simulations for the 48-hour interdialytic period. In contrast, all candidate HD dosing schemes provided AUC48-72values that were at least 50% lower than the SAB-IE AUC48-72values. Increasing the parent dose by 50% provided more comparable AUC48-72values while maintaining acceptableCminvalues. Administration of the daptomycin parent dose intra-HD or post-HD was optimal for the 48-h interdialytic period. For the 72-h interdialytic period, clinicians should consider increasing the dose by 50% to achieve more comparable AUC48-72values.

scholarly journals Reduced susceptibility to daptomycin in methicillin-resistant Staphylococcus aureus isolated from catheter-related bloodstream infections

2021 ◽  
Author(s):  
Sho Ohyatsu ◽  
Tomoyuki Nariyama ◽  
Kotaro Matsumoto ◽  
Yuki Moritoki ◽  
Kentaro Kikuchi
Keyword(s):  
Staphylococcus Aureus ◽  
Blood Culture ◽  
Drug Treatment ◽  
Methicillin Resistant Staphylococcus Aureus ◽  
Bloodstream Infections ◽  
High Dose ◽  
Methicillin Resistant ◽  
Treatment Methods ◽  
History Of ◽  
The Mean

Abstract Background The appearance of reduced susceptibility to daptomycin in methicillin-resistant Staphylococcus aureus (MRSA) has recently been reported. It is unclear how likely MRSA involved in catheter-related bloodstream infections (CRBSI) is to dampen susceptibility to daptomycin. We investigated the minimum inhibitory concentrations (MIC) of daptomycin in MRSA isolated from the blood of patients with CRBSI and examined how it was affected by previous anti-MRSA drug treatment. Methods A total of 115 patients whose blood culture samples were found to contain MRSA were enrolled in this study. The MIC of daptomycin and vancomycin and whether the subjects had a history of anti-MRSA drug treatment were investigated and compared between the CRBSI and non-CRBSI groups. Results The mean MIC of daptomycin was significantly higher for the 46 CRBSI-related MRSA isolates than for the 69 non-CRBSI-related MRSA isolates (0.78 vs. 0.33, respectively; p<0.0001). Among the CRBSI-related MRSA isolates, those collected from patients with a history of anti-MRSA drug treatment had significantly higher MIC (1.27 vs. 0.53, respectively; p <0.01). During treatment, MRSA was detected again in 10 CRBSI and 4 non-CRBSI patients, and all of the CRBSI-related MRSA isolates exhibited 1-2 log2 increases in their daptomycin MIC. Conclusions It is considered that when MRSA in catheter biofilms is exposed to anti-MRSA drugs, strains with reduced susceptibility to daptomycin are able to survive and disperse into the blood. Catheters should be removed if an MRSA-induced CRBSI is suspected. Further study of whether high-dose daptomycin treatment is effective when catheters cannot be immediately removed is needed.

scholarly journals Pharmacodynamic comparison of different antimicrobial regimens against Staphylococcus aureus bloodstream infections with elevated vancomycin minimum inhibitory concentration

2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Thaina Miranda da Costa ◽  
Gabriel Trova Cuba ◽  
Priscylla Guimarães Migueres Morgado ◽  
David P. Nicolau ◽  
Simone Aranha Nouér ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Minimum Inhibitory Concentration ◽  
Inhibitory Concentration ◽  
Bloodstream Infections ◽  
Vancomycin Minimum Inhibitory Concentration

scholarly journals High Prevalence of Isolates with Reduced Glycopeptide Susceptibility in Persistent or Recurrent Bloodstream Infections Due to Methicillin-Resistant Staphylococcus aureus

2011 ◽  
Vol 56 (3) ◽  
pp. 1258-1264 ◽  
Author(s):  
Ilker Uçkay ◽  
Louis Bernard ◽  
Marta Buzzi ◽  
Stephan Harbarth ◽  
Patrice François ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Methicillin Resistant Staphylococcus Aureus ◽  
Bloodstream Infections ◽  
Poor Response ◽  
University Hospital ◽  
Methicillin Resistant ◽  
Content Type ◽  
Vancomycin Mics ◽  
High Prevalence ◽  
The University

ABSTRACTReduced susceptibility to glycopeptides in methicillin-resistantStaphylococcus aureus(MRSA) clinical isolates is considered a risk factor for failure of glycopeptide therapy. We compared the prevalences of MRSA isolates with reduced glycopeptide susceptibility in patients with versus without persistent or recurrent MRSA bloodstream infections. A retrospective cohort study at the University Hospital of Geneva identified 27 patients with persistent or recurrent clonally related MRSA bacteremic episodes over an 8-year period, which included 208 consecutive nosocomial MRSA bacteremic episodes. Vancomycin and teicoplanin MICs were determined by a modified macrodilution assay allowing improved detection of glycopeptide-intermediate MRSA isolates (GISA), characterized by elevated teicoplanin or/and vancomycin MICs (≥4 μg/ml). For 16 patients (59%), their pretherapy and/or posttherapy MRSA isolates showed elevated teicoplanin MICs, among which 10 (37%) concomitantly displayed elevated vancomycin MICs. In contrast, 11 other patients (41%) were persistently or recurrently infected with non-GISA isolates. In comparison, only 39 (22%) of 181 single isolates from patients with no microbiological evidence of persistent or recurrent infections showed elevated teicoplanin MICs, among which 14 (8%) concomitantly displayed elevated vancomycin MICs. Clinical, microbiological, and pharmacokinetic variables for patients persistently or recurrently infected with GISA or non-GISA isolates were similar. Bacteremic patients with a poor response to glycopeptide therapy had a 2.8-fold- and 4.8-fold-higher rates of MRSA isolates displaying elevated teicoplanin and vancomycin MICs, respectively, than patients with single isolates (P< 0.0001). Detection of elevated teicoplanin MICs may help to predict a poor response to glycopeptide therapy in MRSA bacteremic patients.

scholarly journals The Emperor’s New Clothes: PRospective Observational Evaluation of the Association Between Initial VancomycIn Exposure and Failure Rates Among ADult HospitalizEd Patients With Methicillin-resistant Staphylococcus aureus Bloodstream Infections (PROVIDE)

2019 ◽  
Vol 70 (8) ◽  
pp. 1536-1545 ◽  
Author(s):  
Thomas P Lodise ◽  
Susan L Rosenkranz ◽  
Matthew Finnemeyer ◽  
Scott Evans ◽  
Matthew Sims ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Treatment Failure ◽  
Methicillin Resistant Staphylococcus Aureus ◽  
Area Under The Curve ◽  
Kidney Injury ◽  
Bloodstream Infections ◽  
Hospitalized Patients ◽  
Methicillin Resistant ◽  
Primary Endpoints ◽  
Persistent Bacteremia

Abstract Background Vancomycin is the most commonly administered antibiotic in hospitalized patients, but optimal exposure targets remain controversial. To clarify the therapeutic exposure range, this study evaluated the association between vancomycin exposure and outcomes in patients with methicillin-resistant Staphylococcus aureus (MRSA) bacteremia. Methods This was a prospective, multicenter (n = 14), observational study of 265 hospitalized adults with MRSA bacteremia treated with vancomycin. The primary outcome was treatment failure (TF), defined as 30-day mortality or persistent bacteremia ≥7 days. Secondary outcomes included acute kidney injury (AKI). The study was powered to compare TF between patients who achieved or did not achieve day 2 area under the curve to minimum inhibitory concentration (AUC/MIC) thresholds previously found to be associated with lower incidences of TF. The thresholds, analyzed separately as co-primary endpoints, were AUC/MIC by broth microdilution ≥650 and AUC/MIC by Etest ≥320. Results Treatment failure and AKI occurred in 18% and 26% of patients, respectively. Achievement of the prespecified day 2 AUC/MIC thresholds was not associated with less TF. Alternative day 2 AUC/MIC thresholds associated with lower TF risks were not identified. A relationship between the day 2 AUC and AKI was observed. Patients with day 2 AUC ≤515 experienced the best global outcomes (no TF and no AKI). Conclusions Higher vancomycin exposures did not confer a lower TF risk but were associated with more AKI. The findings suggest that vancomycin dosing should be guided by the AUC and day 2 AUCs should be ≤515. As few patients had day 2 AUCs &lt;400, further study is needed to define the lower bound of the therapeutic range.

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