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Michael J Rybak - One of the best experts on this subject based on the ideXlab platform.
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a quasi experiment to study the impact of vancomycin area under the Concentration time curve guided dosing on vancomycin associated nephrotoxicity
Antimicrobial Agents and Chemotherapy, 2017Co-Authors: Natalie A Finch, Evan J Zasowski, Kyle P Murray, Ryan P Mynatt, Jing J Zhao, Raymond Yost, Jason M Pogue, Michael J RybakAbstract:Evidence suggests that maintenance of vancomycin Trough Concentrations at between 15 and 20 mg/liter, as currently recommended, is frequently unnecessary to achieve the daily area under the Concentration-time curve (AUC24) target of ≥400 mg · h/liter. Many patients with Trough Concentrations in this range have AUC24 values in excess of the therapeutic threshold and within the exposure range associated with nephrotoxicity. On the basis of this, the Detroit Medical Center switched from Trough Concentration-guided dosing to AUC-guided dosing to minimize potentially unnecessary vancomycin exposure. The primary objective of this analysis was to assess the impact of this intervention on vancomycin-associated nephrotoxicity in a single-center, retrospective quasi-experiment of hospitalized adult patients receiving intravenous vancomycin from 2014 to 2015. The primary analysis compared the incidence of nephrotoxicity between patients monitored by assessment of the AUC24 and those monitored by assessment of the Trough Concentration. Multivariable logistic and Cox proportional hazards regression examined the independent association between the monitoring strategy and nephrotoxicity. Secondary analysis compared vancomycin exposures (total daily dose, AUC, and Trough Concentrations) between monitoring strategies. Overall, 1,280 patients were included in the analysis. After adjusting for severity of illness, comorbidity, duration of vancomycin therapy, and concomitant receipt of nephrotoxins, AUC-guided dosing was independently associated with lower nephrotoxicity by both logistic regression (odds ratio, 0.52; 95% confidence interval [CI], 0.34 to 0.80; P = 0.003) and Cox proportional hazards regression (hazard ratio, 0.53; 95% CI, 0.35 to 0.78; P = 0.002). AUC-guided dosing was associated with lower total daily vancomycin doses, AUC values, and Trough Concentrations. Vancomycin AUC-guided dosing was associated with reduced nephrotoxicity, which appeared to be a result of reduced vancomycin exposure.
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a quasi experiment to study the impact of vancomycin area under the Concentration time curve guided dosing on vancomycin associated nephrotoxicity
Antimicrobial Agents and Chemotherapy, 2017Co-Authors: Natalie A Finch, Evan J Zasowski, Kyle P Murray, Ryan P Mynatt, Jing J Zhao, Raymond Yost, Jason M Pogue, Michael J RybakAbstract:Background: Evidence suggests maintaining vancomycin Trough Concentrations between 15 and 20 mg/L, as currently recommended, is frequently unnecessary to achieve the daily area under the Concentration-time curve (AUC 24h ) target of ≥ 400 mg*h/L. Many patients with Trough Concentrations in this range have AUC 24h in excess of the therapeutic threshold and within the exposure range associated with nephrotoxicity. Based on this, the Detroit Medical Center switched from Trough Concentration to AUC-guided dosing to minimize potentially unnecessary vancomycin exposure. The primary objective of this analysis was to assess the impact of this intervention on vancomycin-associated nephrotoxicity. Methods: Single center, retrospective quasi-experiment of hospitalized adult patients receiving intravenous vancomycin from 2014 to 2015. The primary analysis compared the incidence of nephrotoxicity between patients monitored by AUC 24h versus Trough Concentration. Multivariable logistic and Cox-proportional hazard regression examined the independent association between monitoring strategy and nephrotoxicity. Secondary analysis compared vancomycin exposures (total daily dose, AUC, and Trough Concentrations) between monitoring strategies. Results: Overall, 1,280 patients were included in the analysis. After adjusting for severity of illness, comorbidity, duration of vancomycin therapy, and concomitant nephrotoxins, AUC-guided dosing was independently associated with lower nephrotoxicity in both logistic regression (OR, 0.52; 95% CI, 0.34-0.80; P =0.003) and Cox-proportional hazards regression (HR, 0.53; 95% CI, 0.35-0.78; P =0.002). AUC-guided dosing was associated with lower total daily vancomycin doses, AUC values, and Trough Concentrations. Conclusion: Vancomycin AUC-guided dosing was associated with reduced nephrotoxicity which appears to be a result of reduced vancomycin exposure.
Michael Neely - One of the best experts on this subject based on the ideXlab platform.
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prospective trial on the use of Trough Concentration versus area under the curve to determine therapeutic vancomycin dosing
Antimicrobial Agents and Chemotherapy, 2017Co-Authors: Michael Neely, Lauren Kato, Gilmer Youn, Lironn Kraler, David S Bayard, Michael Van Guilder, Alan Schumitzky, Walter M Yamada, Brenda E JonesAbstract:: We hypothesized that dosing vancomycin to achieve Trough Concentrations of >15 mg/liter overdoses many adults compared to area under the Concentration-time curve (AUC)-guided dosing. We conducted a 3-year, prospective study of vancomycin dosing, plasma Concentrations, and outcomes. In year 1, nonstudy clinicians targeted Trough Concentrations of 10 to 20 mg/liter (infection dependent) and controlled dosing. In years 2 and 3, the study team controlled vancomycin dosing with BestDose Bayesian software to achieve a daily, steady-state AUC/MIC ratio of ≥400, with a maximum AUC value of 800 mg · h/liter, regardless of Trough Concentration. For Bayesian estimation of AUCs, we used Trough samples in years 1 and 2 and optimally timed samples in year 3. We enrolled 252 adults who were ≥18 years old with ≥1 available vancomycin Concentration. Only 19% of all Trough Concentrations were therapeutic versus 70% of AUCs (P < 0.0001). After enrollment, median Trough Concentrations by year were 14.4, 9.7, and 10.9 mg/liter (P = 0.005), with 36%, 7%, and 6% over 15 mg/liter (P < 0.0001). Bayesian AUC-guided dosing in years 2 and 3 was associated with fewer additional blood samples per subject (3.6, 2.0, and 2.4; P = 0.003), shorter therapy durations (8.2, 5.4, and 4.7 days; P = 0.03), and reduced nephrotoxicity (8%, 0%, and 2%; P = 0.01). The median inpatient stay was 20 days among nephrotoxic patients versus 6 days (P = 0.002). There was no difference in efficacy by year, with 42% of patients having microbiologically proven infections. Compared to Trough Concentration targets, AUC-guided, Bayesian estimation-assisted vancomycin dosing was associated with decreased nephrotoxicity, reduced per-patient blood sampling, and shorter length of therapy, without compromising efficacy. These benefits have the potential for substantial cost savings. (This study has been registered at ClinicalTrials.gov under registration no. NCT01932034.).
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an exploratory analysis of the ability of a cefepime Trough Concentration greater than 22 mg l to predict neurotoxicity
Journal of Infection and Chemotherapy, 2016Co-Authors: Nathaniel J Rhodes, Joseph L Kuti, David P Nicolau, Michael Neely, Anthony M Nicasio, Marc H ScheetzAbstract:Abstract Introduction Cefepime Trough Concentrations >22 mg/L (T>22) have been associated with neurotoxicity in a single study. Patients and methods Neurotoxicity outcomes for 28 cefepime-treated adult patients with febrile neutropenia were abstracted from the literature. The precision of T>22 to predict neurotoxicity was quantified using 95% confidence intervals. Thirty-two cefepime-treated patients contributed serum Concentrations for a pharmacokinetic model, fit using the Nonparametric Adaptive Grid algorithm within the Pmetrics package for R. Concentration-time curves were simulated for common dosing schemes and 3 renal dispositions. Probabilities of neurotoxicity and numbers needed to harm were calculated from simulations according to the proposed pharmacokinetic/toxicodynamic threshold of T>22. Bayesian modeling was utilized to explore other pharmacokinetic parameters relationships with neurotoxicity. Results The mean probability of neurotoxicity at T>22 was 51.4% (95% CI: 16.4–85.0%). Among the schemes and renal dispositions simulated, the combination of cefepime 2 g every 8 h and a creatinine clearance of 60 mL/min produced the greatest probability of neurotoxicity (48.3%). Estimated numbers needed to harm according to T>22 ranged from 2.1 to 18.5 persons. Explorations of maximal serum Concentration and area under the curve demonstrated high levels of collinearity, making it impossible to identify Trough Concentrations as the driver of neurotoxicity. Discussion T>22 had low precision as a predictive neurotoxic threshold. When a neurotoxic threshold of T>22 was assumed, projected neurotoxicity rates and numbers needed to harm greatly exceeded observed neurotoxicity rates in the general population and in high risk subpopulations. Other drug exposure metrics should be explored.
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are vancomycin Trough Concentrations adequate for optimal dosing
Antimicrobial Agents and Chemotherapy, 2014Co-Authors: Michael Neely, Gilmer Youn, Brenda E Jones, Roger W Jelliffe, George L Drusano, Keith A Rodvold, Thomas P LodiseAbstract:The current vancomycin therapeutic guidelines recommend the use of only Trough Concentrations to manage the dosing of adults with Staphylococcus aureus infections. Both vancomycin efficacy and toxicity are likely to be related to the area under the plasma Concentration-time curve (AUC). We assembled richly sampled vancomycin pharmacokinetic data from three studies comprising 47 adults with various levels of renal function. With Pmetrics, the nonparametric population modeling package for R, we compared AUCs estimated from models derived from Trough-only and peak-Trough depleted versions of the full data set and characterized the relationship between the vancomycin Trough Concentration and AUC. The Trough-only and peak-Trough depleted data sets underestimated the true AUCs compared to the full model by a mean (95% confidence interval) of 23% (11 to 33%; P = 0.0001) and 14% (7 to 19%; P < 0.0001), respectively. In contrast, using the full model as a Bayesian prior with Trough-only data allowed 97% (93 to 102%; P = 0.23) accurate AUC estimation. On the basis of 5,000 profiles simulated from the full model, among adults with normal renal function and a therapeutic AUC of ≥400 mg · h/liter for an organism for which the vancomycin MIC is 1 mg/liter, approximately 60% are expected to have a Trough Concentration below the suggested minimum target of 15 mg/liter for serious infections, which could result in needlessly increased doses and a risk of toxicity. Our data indicate that adjustment of vancomycin doses on the basis of Trough Concentrations without a Bayesian tool results in poor achievement of maximally safe and effective drug exposures in plasma and that many adults can have an adequate vancomycin AUC with a Trough Concentration of <15 mg/liter.
Bruce K Bayley - One of the best experts on this subject based on the ideXlab platform.
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increasing vancomycin serum Trough Concentrations and incidence of nephrotoxicity
The American Journal of Medicine, 2010Co-Authors: Lindsey Pritchard, Catherine A Baker, James Leggett, Paul Sehdev, Allen Brown, Bruce K BayleyAbstract:Abstract Background Conflicting evidence regarding the association of vancomycin serum Concentrations with efficacy and toxicity has resulted in controversy regarding optimal target Concentrations. Recent publications recommend attaining higher vancomycin Trough Concentrations of 15 to 20 mg/L for target infections, yet limited research is available assessing the correlation of vancomycin serum Concentrations with toxicity. The aim of this study was to evaluate the association between vancomycin serum Trough Concentrations and nephrotoxicity. Methods A 2-phase retrospective analysis was completed. Phase 1 evaluated 2493 courses of vancomycin completed between January 2003 and December 2007. The analysis describes a 5-year trend in vancomycin prescribing practices and assesses the association of nephrotoxicity with baseline serum creatinine, vancomycin serum Trough Concentrations, and duration of vancomycin therapy. Phase 2 examined patients receiving vancomycin therapy during 2007 to evaluate specific risk factors for development of nephrotoxicity. Results The proportion of vancomycin serum Trough Concentrations ≥15 mg/L and ≥20 mg/L increased significantly over time. Statistical analysis identified vancomycin serum Trough Concentrations ≥14 mg/L, duration of vancomycin therapy ≥7 days, and baseline serum creatinine levels ≥1.7 mg/dL as independent predictors of nephrotoxicity. Phase 2 analysis again implicated mean vancomycin serum Trough Concentration as a significant predictor of nephrotoxicity. Nephrotoxicity resolved in 81% (17/21) of cases evaluated. Conclusions A higher vancomycin serum Trough Concentration and prolonged vancomycin therapy are associated with an increased risk of nephrotoxicity. The decision to target increased vancomycin Trough Concentrations should be based on an assessment of the severity of the infection and must consider the nephrotoxicity risk associated with increased vancomycin levels.
Katsushi Yamada - One of the best experts on this subject based on the ideXlab platform.
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an initial dosing method for teicoplanin based on the area under the serum Concentration time curve required for mrsa eradication
Journal of Infection and Chemotherapy, 2011Co-Authors: Naoko Kanazawa, Kazuaki Matsumoto, Kazuro Ikawa, Tomohide Fukamizu, Akari Shigemi, Keiko Yaji, Yoshihiro Shimodozono, Norifumi Morikawa, Yasuo Takeda, Katsushi YamadaAbstract:Teicoplanin is a glycopeptide antibacterial agent that has a long serum half-life and therefore takes time to achieve steady-state conditions. An appropriate initial dosing is needed for teicoplanin to promptly reach an effective serum Trough Concentration. However, little information is available on tailoring the initial dosing for patients with various characteristics. The objective of this study was to develop a nomogram for determining teicoplanin initial dose to promptly reach an effective Trough Concentration (≥13 μg/mL). A logistic regression analysis was performed to test whether the area under the Concentration time curve (AUC) is a significant predictor of microbiological response (persistence 0; eradication 1). The study included 24 adult patients with methicillin-resistant Staphylococcus aureus infections [minimal inhibitory Concentration (MIC) for the isolates was <2 μg/mL). Each AUC was estimated using individual dose, creatinine clearance (CLcr), and body weight data. The target value, which gives about a 0.9 microbiological eradication probability, was 750 μg h/mL for AUC from zero to 24 h (AUC0–24 h). Using published population pharmacokinetic parameters, the dose required to achieve the AUC0–24 h target was calculated as dose (mg) = 750 × (0.00498 × CLcr (mL/min) + 0.00426 × body weight (kg). For various combinations of CLcr and body weight, we checked the calculated doses using a therapeutic drug monitoring (TDM)-supporting software and developed a nomogram. The nomogram would be useful for initial dose adjustment to promptly reach an effective serum Trough Concentration and avoid adverse events of teicoplanin.
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higher linezolid exposure and higher frequency of thrombocytopenia in patients with renal dysfunction
International Journal of Antimicrobial Agents, 2010Co-Authors: Kazuaki Matsumoto, Kazuro Ikawa, Akari Shigemi, Keiko Yaji, Yoshihiro Shimodozono, Norifumi Morikawa, Yasuo Takeda, Ayumi Takeshita, Katsushi YamadaAbstract:The major adverse event associated with linezolid treatment is reversible myelosuppression, mostly thrombocytopenia. Recent studies have reported that the incidence of linezolid-induced thrombocytopenia was higher in patients with renal failure than in patients with normal renal function, although the underlying mechanisms of this toxicity are still unknown. The present study thus aimed to investigate the relationship between renal function and linezolid exposure as well as the effects of drug exposure on thrombocytopenia. A statistically significant (P<0.01) strong correlation (r=0.933) was observed between linezolid clearance and creatinine clearance. A negative correlation (r=-0.567) was also shown between linezolid clearance and blood urea nitrogen, although the correlation was not statistically significant. In thrombocytopenic patients, the Trough Concentration was 14.4-35.6 mg/L and the area under the plasma linezolid Concentration-time curve for 24h (AUC(24h)) was 513.1-994.6 mg h/L; in non-thrombocytopenic patients, drug exposure was relatively low (6.9 mg/L and 7.2mg/L for Trough Concentration and 294.3 mg h/L and 323.6 mg h/L for AUC(24h)). These results provide a pharmacokinetic explanation for the mechanism of the adverse event that renal dysfunction increased linezolid Trough Concentration and AUC and that higher drug exposure induced thrombocytopenia.
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determination of teicoplanin Trough Concentration target and appropriate total dose during the first 3 days a retrospective study in patients with mrsa infections
Journal of Infection and Chemotherapy, 2010Co-Authors: Kazuaki Matsumoto, Naoko Kanazawa, Kazuro Ikawa, Tomohide Fukamizu, Akari Shigemi, Keiko Yaji, Yoshihiro Shimodozono, Norifumi Morikawa, Yasuo Takeda, Katsushi YamadaAbstract:An initial loading procedure has been recommended to enable teicoplanin to promptly reach an effective serum Concentration for the treatment of methicillin-resistant Staphylococcus aureus (MRSA). This study aimed to retrospectively evaluate the pharmacokinetics and pharmacodynamics of teicoplanin to determine the therapeutic target for the teicoplanin Trough Concentration and an appropriate dosing method during the first 3 days. The mean Trough Concentrations were 13.2 mg/L for patients with eradication of MRSA. Moreover, logistic regression analysis showed that the teicoplanin Trough Concentration was 13 mg/L to achieve MRSA eradication with a probability of 89.0%. The rates of achieving ≥13 mg/L in ≤24, 24–36 and ≥36 mg/kg (total dose during the first 3 days) groups were 9.1, 48.4 and 87.5%, respectively. These results suggest that the administration of ≥36 mg/kg during the first 3 days is appropriate to promptly obtain a Trough Concentration target of ≥13 mg/L for the initial treatment of MRSA infections.
Patrick D Mauldin - One of the best experts on this subject based on the ideXlab platform.
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tacrolimus Trough Concentration variability and disparities in african american kidney transplantation
Transplantation, 2017Co-Authors: David J Taber, Patrick D Mauldin, James N Fleming, John W Mcgillicuddy, Maria Posadassalas, Frank A Treiber, Derek Dubay, Titte R Srinivas, William P Moran, Prabhakar K BaligaAbstract:BackgroundLow tacrolimus Concentrations have been associated with higher risk of acute rejection, particularly within African American (AA) kidney transplant recipients; little is known about intrapatient tacrolimus variabilities impact on racial disparities.MethodsTen year, single-center, longitudi
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relationship between vancomycin Trough Concentrations and nephrotoxicity a prospective multicenter trial
Antimicrobial Agents and Chemotherapy, 2011Co-Authors: John A Bosso, Jean M Nappi, Celeste N Rudisill, Marlea Wellein, Brandon P Bookstaver, Jenna Swindler, Patrick D MauldinAbstract:Several single-center studies have suggested that higher doses of vancomycin, aimed at producing Trough Concentrations of >15 mg/liter, are associated with increased risk of nephrotoxicity. We prospectively assessed the relative incidence of nephrotoxicity in relation to Trough Concentration in patients with documented methicillin-resistant Staphylococcus aureus (MRSA) infections at seven hospitals throughout South Carolina. Adult patients receiving vancomycin for at least 72 h with at least one vancomycin Trough Concentration determined under steady-state conditions were prospectively studied. The relationship between vancomycin Trough Concentrations of >15 mg/ml and the occurrence of nephrotoxicity was assessed using univariate and multivariate analyses, controlling for age, gender, race, dose, length of therapy, use of other nephrotoxins (including contrast media), intensive care unit (ICU) residence, episodes of hypotension, and comorbidities. Nephrotoxicity was defined as an increase in serum creatinine of 0.5 mg/dl or a ≥50% increase from the baseline for two consecutive measurements. MICs of vancomycin for the MRSA isolates were also determined. A total of 288 patients were studied between February 2008 and June 2010, with approximately one-half having initial Trough Concentrations of ≥15 mg/ml. Nephrotoxicity was observed for 42 patients (29.6%) with Trough Concentrations >15 mg/ml and for 13 (8.9%) with Trough Concentrations of ≤15 mg/ml. Multivariate analysis revealed vancomycin Trough Concentrations of >15 mg/ml and race (black) as risk factors for nephrotoxicity in this population. Vancomycin Trough Concentrations of >15 mg/ml appear to be associated with a 3-fold increased risk of nephrotoxicity.