scholarly journals Pharmacodynamic Analysis of Daptomycin-treated Enterococcal Bacteremia: It Is Time to Change the Breakpoint

2018 ◽  
Vol 68 (10) ◽  
pp. 1650-1657 ◽  
Author(s):  
Lindsay M Avery ◽  
Joseph L Kuti ◽  
Maja Weisser ◽  
Adrian Egli ◽  
Michael J Rybak ◽  
...  
Keyword(s):  
Regression Tree ◽  
Classification And Regression Tree ◽  
Population Pharmacokinetic ◽  
Time Curve ◽  
Regression Tree Analysis ◽  
Lactam Antibiotic ◽  
Infection Source ◽  
High Doses ◽  
Susceptibility Breakpoint ◽  
Enterococcal Bacteremia

Abstract Background Currently, there is debate over whether the daptomycin susceptibility breakpoint for enterococci (ie, minimum inhibitory concentration [MIC] ≤4 mg/L) is appropriate. In bacteremia, observational data support prescription of high doses (>8 mg/kg). However, pharmacodynamic targets associated with positive patient outcomes are undefined. Methods Data were pooled from observational studies that assessed outcomes in daptomycin-treated enterococcal bacteremia. Patients who received an additional antienterococcal antibiotic and/or a β-lactam antibiotic at any time during treatment were excluded. Daptomycin exposures were calculated using a published population pharmacokinetic model. The free drug area under the concentration-time curve to MIC ratio (fAUC/MIC) threshold predictive of survival at 30 days was identified by classification and regression tree analysis and confirmed with multivariable logistic regression. Monte Carlo simulations determined the probability of target attainment (PTA) at clinically relevant MICs. Results Of 114 patients who received daptomycin monotherapy, 67 (58.8%) were alive at 30 days. A fAUC/MIC >27.43 was associated with survival in low-acuity (n = 77) patients (68.9 vs 37.5%, P = .006), which remained significant after adjusting for infection source and immunosuppression (P = .026). The PTA for a 6-mg/kg/day (every 24 hours) dose was 1.5%–5.5% when the MIC was 4 mg/L (ie, daptomycin-susceptible) and 91.0%–97.9% when the MIC was 1 mg/L. Conclusions For enterococcal bacteremia, a daptomycin fAUC/MIC >27.43 was associated with 30-day survival among low-acuity patients. As pharmacodynamics for the approved dose are optimized only when MIC ≤1 mg/L, these data continue to stress the importance of reevaluation of the susceptibility breakpoint.

scholarly journals Pharmacokinetic/Pharmacodynamic Determinants of Vancomycin Efficacy in Enterococcal Bacteremia

2017 ◽  
Vol 62 (3) ◽  
Author(s):  
Muhammed Taufiq Bin Jumah ◽  
Shawn Vasoo ◽  
Sanjay R. Menon ◽  
Partha Pratim De ◽  
Michael Neely ◽  
...  
Keyword(s):  
Primary Outcome ◽  
Regression Tree ◽  
Classification And Regression Tree ◽  
Vancomycin Therapy ◽  
Content Type ◽  
Regression Tree Analysis ◽  
Gradient Diffusion ◽  
All Cause Mortality ◽  
Mic Value ◽  
Enterococcal Bacteremia

ABSTRACTWhile pharmacokinetic-pharmacodynamic targets for vancomycin therapy are recognized for invasive methicillin-resistantStaphylococcus aureusinfections, scant data are available to guide therapy for other Gram-positive infections. A retrospective single-center cohort of patients withEnterococcusbacteremia hospitalized between 1 January 2009 and 31 May 2015 were studied. The average vancomycin AUC0–24was computed using a Bayesian approach. The MIC was determined by gradient diffusion (Etest; bioMérieux), and the average AUC0–24/MIC value over the initial 72 h of therapy was calculated. We assessed 30-day all-cause mortality as the primary outcome. Classification and regression tree analysis (CART) was used to identify the vancomycin AUC0–24/MIC value associated with 30-day mortality. Fifty-seven patients with enterococcal bacteremia (32E. faecium, 21E. faecalis, and 4 otherEnterococcusspp.) were studied. The median vancomycin MIC was 0.75 mg/liter (range, 0.38 to 3 mg/liter). All-cause 30-day mortality occurred in 10 of 57 patients (17.5%). A CART-derived vancomycin AUC/MICEtestvalue of ≥389 was associated with reduced mortality (P= 0.017); failure to achieve this independently predicted 30-day mortality (odds ratio, 6.83 [95% confidence interval = 1.51 to 30.84];P= 0.01). We found that a vancomycin AUC/MICEtestvalue of ≥389 achieved within 72 h was associated with reduced mortality. Larger, prospective studies are warranted to verify the vancomycin pharmacodynamic targets associated with maximal clinical outcomes and acceptable safety.

scholarly journals Clinical Pharmacodynamics of Antipseudomonal Cephalosporins in Patients with Ventilator-Associated Pneumonia

2013 ◽  
Vol 58 (3) ◽  
pp. 1359-1364 ◽  
Author(s):  
Shawn H. MacVane ◽  
Joseph L. Kuti ◽  
David P. Nicolau
Keyword(s):  
Confidence Interval ◽  
Regression Tree ◽  
Classification And Regression Tree ◽  
Population Pharmacokinetic ◽  
Ventilator Associated Pneumonia ◽  
Gram Negative ◽  
Content Type ◽  
Regression Tree Analysis ◽  
Dosing Regimens ◽  
Predictor Of Success

ABSTRACTAdvanced-generation cephalosporins are frequently used for empirical coverage of ventilator-associated pneumonia (VAP) due to their activity against a broad spectrum of Gram-positive and Gram-negative aerobic bacteria, includingPseudomonas aeruginosaandEnterobacteriaceae. Providing optimal antibiotic exposure is essential to achieving successful response in patients with VAP. We evaluated exposures of two antipseudomonal cephalosporins, ceftazidime and cefepime, in patients with VAP due to Gram-negative bacilli to identify the pharmacodynamic parameter predictive of microbiological success. Population pharmacokinetic models were used to estimate individual free drug exposures. Pharmacodynamic indices were determined for each patient using the baseline Gram-negative bacilli with the highest drug MIC. Classification and regression tree analysis was utilized to partition exposure breakpoints, and multivariate logistic regression was conducted to identify predictors of microbiological success. A total of 73 patients (18 receiving ceftazidime therapy and 55 receiving cefepime therapy) were included. MICs ranged widely from 0.047 to 96 μg/ml. The microbiological success rate was 58.9%. Predictive breakpoints were identified for all pharmacodynamic parameters, including a serumfT > MIC greater than 53% (P= 0.02). When controlling for APACHE II (odds ratio [OR], 1.01; 95% confidence interval, 0.93 to 1.09;P= 0.85) and combination therapy (OR, 0.74; 95% confidence interval, 0.25 to 2.19;P= 0.59), achieving a greater than 53%fT > MIC remained a significant predictor of success (OR, 10.3; 95% confidence interval, 1.1 to 92.3;P= 0.04). In patients with VAP due to Gram-negative bacilli, serum exposure of greater than 53%fT > MIC was found to be a significant predictor of favorable microbiological response for antipseudomonal cephalosporins. These data are useful when determining dosing regimens for cephalosporin agents under development for pneumonia.

scholarly journals Pharmacodynamic Evaluation of Factors Associated with the Development of Bacterial Resistance in Acutely Ill Patients during Therapy

1998 ◽  
Vol 42 (3) ◽  
pp. 521-527 ◽  
Author(s):  
Jennifer K. Thomas ◽  
Alan Forrest ◽  
Sujata M. Bhavnani ◽  
Judith M. Hyatt ◽  
Angela Cheng ◽  
...  
Keyword(s):  
Bacterial Resistance ◽  
Regression Tree ◽  
Classification And Regression Tree ◽  
Type I ◽  
Time Curve ◽  
Factors Associated ◽  
Development Of Resistance ◽  
Regression Tree Analysis ◽  
Gram Negative Organisms ◽  
Selection Of

ABSTRACT The selection of bacterial resistance was examined in relationship to antibiotic pharmacokinetics (PK) and organism MICs in the patients from four nosocomial lower respiratory tract infection clinical trials. The evaluable database included 107 acutely ill patients, 128 pathogens, and five antimicrobial regimens. Antimicrobial pharmacokinetics were characterized by using serum concentrations, and culture and sensitivity tests were performed daily on tracheal aspirates to examine resistance. Pharmacodynamic (PD) models were developed to identify factors associated with the probability of developing bacterial resistance. Overall, in 32 of 128 (25%) initially susceptible cases resistance developed during therapy. An initial univariate screen and a classification and regression tree analysis identified the ratio of the area under the concentration-time curve from 0 to 24 h to the MIC (AUC0–24/MIC) as a significant predictor of the development of resistance (P < 0.001). The final PK/PD model, a variant of the Hill equation, demonstrated that the probability of developing resistance during therapy increased significantly when antimicrobial exposure was at an AUC0–24/MIC ratio of less than 100. This relationship was observed across all treatments and within all organism groupings, with the exception of β-lactamase-producing gram-negative organisms (consistent with type I β-lactamase producers) treated with β-lactam monotherapy. Combination therapy resulted in much lower rates of resistance than monotherapy, probably because all of the combination regimens examined had an AUC0–24/MIC ratio in excess of 100. In summary, the selection of antimicrobial resistance appears to be strongly associated with suboptimal antimicrobial exposure, defined as an AUC0–24/MIC ratio of less than 100.

679: Predicting delivery route in nulliparas with classification and regression tree analysis

2011 ◽  
Vol 204 (1) ◽  
pp. S268
Author(s):  
Michelle Kominiarek ◽  
Paul VanVeldhuisen ◽  
Kimberly Gregory ◽  
Moshe Fridman ◽  
Judith Hibbard
Keyword(s):  
Regression Tree ◽  
Classification And Regression Tree ◽  
Tree Analysis ◽  
Regression Tree Analysis ◽  
Classification And Regression ◽  
Delivery Route
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