Clinical Infectious Diseases Advance Access published May 27, 2014
1 Vancomycin Exposure in Patients with MRSA Bloodstream Infections: How much is enough?
1
Albany College of Pharmacy and Health Sciences, Albany, NY
2
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T.P. Lodise1, G.L. Drusano2, E. Zasowski1, A. Dihmess1, V. Lazariu3, L. Cosler1, L.A. McNutt3
Institute for Therapeutic Innovation, College of Medicine, University of Florida, Lake Nona, FL
3
University at Albany, State University of New York, Albany, NY
us
Albany College of Pharmacy and Health Sciences, Albany, NY 12208‐3492, Phone: 518‐694‐
an
7292; Fax: 518‐694‐7032; E‐mail: [email protected]
M
Alternative corresponding author: Louise‐Anne McNutt, M.S., Ph.D. Associate Professor of Epidemiology and Biostatistics, Associate Director, Institute for Health and the Environment, University at Albany, State University of New York, Rensselaer, NY 12144, (518) 402‐0403; E‐ mail: [email protected]
pt ed
Summary: Using a validate Bayesian method to estimate vancomycin exposure profiles among patients with limited pharmacokinetic data, the findings suggest that that AUC/MIC, not trough, is the pharmacodynamic index most closely linked to outcomes for patients with MRSA
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bloodstream infections.
© The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: [email protected].
Downloaded from http://cid.oxfordjournals.org/ at University of Utah on May 28, 2014
Corresponding author: Thomas Lodise, Pharm.D., Ph.D. Associate Professor, Pharmacy Practice,
2 Abstract Background: Contemporary vancomycin dosing schemes are designed to achieve an area under
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the curve (AUC) to minimum inhibitory concentration (MIC) [AUC/MIC ratio] ≥ 400. However, scant clinical data exist to support this target and available data relied on pharmacokinetic formulas based on daily vancomycin dose and estimated renal function (demographic pharmacokinetic model) to estimate AUCs.
us
infections treated with vancomycin was performed to quantitatively evaluate the relationship
an
between vancomycin exposure and outcomes. Bayesian techniques were used to estimate vancomycin exposure for day 1 and 2 of therapy for each patient based on their dosing
M
schedule and collected concentrations. Classification and Regression Tree Analysis (CART) was used to identify day 1 and 2 exposure thresholds associated with an increased risk of failure.
pt ed
Results: During the study period, 123 cases met criteria. Failure was uniformly less pronounced (approximately 20% less in absolute value) in patients who achieved the CART‐derived day 1 and 2 thresholds for AUC/ MICBMD, and AUC/ MICETEST. In the multivariate analyses, all risk ratios were circa 0.5 for all CART‐derived AUC exposure thresholds, indicating that achievement
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of CART‐derived AUC/MIC exposure thresholds was associated with a two‐fold decrease in failure.
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Conclusions: These findings establish the critical importance of daily AUC/MIC ratios during the first two days of therapy. As with all observational studies, these findings should be interpreted
cautiously and validated in a multi‐center randomized trial before adoption into practice.
Downloaded from http://cid.oxfordjournals.org/ at University of Utah on May 28, 2014
Methods: A cohort study of hospitalized, adult, non‐dialysis patients with MRSA bloodstream
3 Introduction
Despite its introduction over a half century ago, the optimal dosing strategy for
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vancomycin remains undefined. Contemporary vancomycin dosing schemes are designed to
achieve an area under the curve (AUC) to minimum inhibitory concentration (MIC) (AUC/MIC) ratio ≥ 400 for serious MRSA infections [1, 2]. Although this target is based on the best
data[3]. The best clinical evidence supporting AUC/MIC ratio ≥ 400 is drawn from a retrospective evaluation of patients with Staphylococcus aureus pneumonia [5]. Two recent
an
studies of patients with MRSA bloodstream infections (BSIs) have also identified similar vancomycin AUC/MIC ratio targets [7, 8]. While these evaluations provide further evidence
M
that the vancomycin pharmacodynamic target is an AUC/MIC ratio of at least 400, all evaluations used a simple formula based on daily vancomycin dose and estimated renal
pt ed
function to estimate AUC values [5, 7, 8]. In most cases, they used the Cockcroft‐Gault (G‐C) creatinine clearance formula. There is considerable inter‐patient variability in vancomycin exposure profiles in clinical practice and it is difficult to generate valid estimates of exposure variables in a given individual based on glomerular filtration estimation formulas alone [9‐11].
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To date, we are only aware of two small‐scale vancomycin exposure‐response clinical evaluations that considered individualized estimates of the vancomycin AUC based on collected
Ac
levels and doses received [12, 13]. Thus, there is a critical need for additional, larger‐scale clinical studies which utilize individualized estimates of exposure profiles based on measured concentrations.
Downloaded from http://cid.oxfordjournals.org/ at University of Utah on May 28, 2014
us
available evidence [1‐6], it is largely derived from neutropenic mouse thigh infection model
4
Although AUC/MIC ratio is the prevailing vancomycin exposure target, AUCs are not
determined in clinical practice due to the perceived difficulty in calculating the AUC [2]. Expert
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guidelines recommend maintaining troughs (Cmin) between 15 and 20 mg/L as a surrogate
marker for an AUC/MIC ratio ≥ 400 [1, 2]. However, the clinical benefits of maintaining higher
vancomycin trough values have not been well described [14‐19]. The intent of this study was to
Cmin/MIC, AUC/MIC) and outcomes among patients with MRSA BSIs. Bayesian techniques [20‐ 22] were used to estimate the vancomycin concentration‐time profile for each patient. The
an
Bayesian approach used in this study to estimate exposure profiles has recently been validated as a method to estimate vancomycin exposure values with low bias and high precision in
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situations where trough‐only pharmacokinetic (PK) data are available [22]. As a secondary objective, this study compared the predictive performance of the Bayesian relative to the
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formula‐based approach for estimating exposure profiles.
Research Design and Methods
Experimental Design and Study Population
A retrospective cohort study was performed among hospitalized patients with MRSA
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BSIs treated with vancomycin at Albany Medical Center Hospital (AMCH) between January 2005
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and June 2009. Patients meeting the following criteria were included: (i) age ≥ 18 years; (ii) absolute neutrophil count ≥ 1,000 cells/mm; (iii) MRSA culture met the CDC criteria for BSI[23]; (iv) index MRSA isolate available for phenotypic characterization; (v) non‐dialysis; (vi) received vancomycin within 48 hours of index culture; (vii) received vancomycin for at least 2 days; and
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quantitatively evaluate the relationship between vancomycin exposure variables (i.e.,
5 (viii) had ≥ 1 vancomycin level collected within the first 5 days of therapy. If a patient had > 1 MRSA BSI during the study period, additional episodes were included if they occurred > 60 days
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after completion of antibiotic therapy for the previous BSI. The study was limited to patients
who received vancomycin within 48 hours of index culture collection as this has been identified as the critical time window for delivery of appropriate antibiotics for patients with MRSA BSIs
and a HIPAA waiver was obtained.
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Patient data
Data elements included: demographics, medical history and comorbidities [18], recent
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healthcare institution exposure in the past 6 months, receipt of antibiotics in the 30 days prior to the index culture collection, hospitalization history, and creatinine clearance (CLCR) estimated
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by the C‐G formula [25] at index culture collection. Illness severity was defined by the Acute Physiological and Chronic Health Evaluation (APACHE II) score (based on the worst physiological score in the 48 hours prior to index culture collection) [26] and the Chronic Disease Score‐ Infectious Diseases (CDS‐ID) score (determined at admission) [27]. Additional data elements
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included source of MRSA BSI, mortality risk associated with infection source [24, 28, 29], presence of infective endocarditis [30], infection source control intervention, microbiologic
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data, treatment data, occurrence of nephrotoxicity (defined as either a 50% or 0.5 mg/dL increase in serum creatinine (SCR), whichever was greater, from initiation of vancomycin to 48
hours post‐completion among patients with a baseline SCR 1
mg/L. The current paradigm in PK/PD is that a doubling of exposure is required with each log2
increase in MIC values. Before we definitively recommend a daily AUC of 1300 for an MICBMD of
consistent with the AUC/ MICBMD targets observed in this study when the MICBMD is 2 mg/L, it will be difficult to use vancomycin in these instances since the vancomycin AUC needed for
an
effect will be associated with nephrotoxicity rates in excess of 30% [21].
We did not attempt to determine if 30‐day mortality was attributable to the MRSA
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bloodstream infection. Rather than basing microbiological failure on persistent signs and symptoms of infection, treatment was considered a microbiological failure only if the duration
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of bacteremia was ≥ 7 days, as proposed by a number of authors [18, 27, 38]. We believe these aforementioned definitions allow for an objective assessment of the end points and minimize any subjective biases that may result from assessing and interpreting retrospective clinical data. Another consideration in the evaluation of MRSA bloodstream infection studies is the adequacy
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of source control. In situations when source control was warranted, there was an attempt to remove the catheter/debride the wound in almost all cases. Among patients who experienced
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a failure, there was a documented intervention in the medical record to “control the source” in >95% of cases. The frequency of source control attempts were not different between CART‐ derive exposure groups.
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2 mg/L, additional research is needed. If future studies indicate the pharmacodynamic target is
14 In conclusion, our findings suggest that that AUC/MIC, not Cmin/MIC, is the pharmacodynamic index most closely linked to outcomes for patients with MRSA BSIs.
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Clinicians should conservatively target AUC values needed to provide adequate exposure against the common MIC values observed in their institution given that MICs are largely
unknown until therapy day 3. Further research is still needed among patients with MRSA BSIs
findings need to be validated in a multi‐center vancomycin AUC dose‐optimized randomized
Acknowledgements
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outcomes trial before they can be incorporated into clinical practice.
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We also extend gratitude to the following individuals for data collection and database entry: Nadia El‐Fawal, Jill Butterfield, Benjamin Woo, and Rasha Masoud. We like to thank Ron Jones,
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M.D., and Rodrigo E. Mendes, Ph.D, at JMI Laboratories (North Liberty, IA) for characterizing the phenotypic and genotypic profiles of the MRSA isolates. This article has greatly benefited from the thoughtful editing (grammar and spelling) of Allison Krug. Allison Krug was paid by grant.
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Funding
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This work was supported by an investigator‐initiated research grant from Cubist Pharmaceuticals. T.P.L. was the principal investigator for this grant. Please note that Cubist
only provided support to complete the project and was not involved in the following: design and conduct of the study; collection, management, analysis, and interpretation of the data; and
Downloaded from http://cid.oxfordjournals.org/ at University of Utah on May 28, 2014
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with vancomycin MICBMD > 1 mg/L. As this was a retrospective observational study, these
15 preparation and review of the manuscript. T.P.L. is also a consultant for Cubist. No other conflicts of interest exist for any of the authors.
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with methicillin‐resistant staphylococcus aureus pneumonia. Chemotherapy
22 Figure 1. Observed vs. Predicted for (A) Bayesian Estimation Approach and (B) Formula‐Based Approach
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an
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23 FIGURE 2. Bivariate relationship between CART‐derived Day 1 and Day 2 Cmin/MIC exposure variables and failure (A) and CART‐derived Day 1 and Day 2 AUC/MIC exposure variables and
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failure (B).
24 Table 1. Distribution of microbiologic phenotypes, exposure variables, and outcomes in study cohort Value
Microbiologic Phenotypes
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Characteristic
Range
0.38 to 3.0 mg/L
MIC50/90
1.5/1.5 mg/L
Range
0.38 to 3.0 mg/L
MIC50/90
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MICBMD
0.75/1 mg/L
Range
MBC/MIC50/90
M
MBC/MIC ratio
pt ed
1 to 21.33 1.3/2.4
hVISA phenotype
4 (3.3%)
Agr dysfunctional
62 (50.4%)
Mean (SD) Vancomycin Exposure Variables
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Cmin24h
8.6 (4.7) 11.2 (5.9)
Cmin24h/ MICBMD
11.2 (6.6)
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Cmin48h
Cmin48h/MICBMD
14.8 (8.5)
Cmin24h/MICETEST
7.4 (5.3)
Cmin48h/ MICETEST
9.7 (6.8)
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MICETEST values
25 436.4 (162.5)
AUC24‐48h
517.3 (197.3)
AUC0‐24h/MICBMD
571.6 (245.8)
AUC24‐48h/MICBMD
680.0 (302.2)
AUC0‐24h/MICETEST
380.1 (215.4)
AUC24‐48h/ MICTEST
453.9 (273.6)
Outcomes
40 (32.5%)
30‐day mortality
Microbiologic failure
Recurrence
Nephrotoxicity**
25 (20.3%)
15 (12.2%)
10 (8.1%)
M
an
Failure*
19 (17.9%)
pt ed
* Of the 40 failures, 30 met 1 failure criterion and 10 met 2.
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** Nephrotoxicity occurrences among the 106 patients with a SCR
1 Vancomycin Exposure in Patients with MRSA Bloodstream Infections: How much is enough?
1
Albany College of Pharmacy and Health Sciences, Albany, NY
2
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T.P. Lodise1, G.L. Drusano2, E. Zasowski1, A. Dihmess1, V. Lazariu3, L. Cosler1, L.A. McNutt3
Institute for Therapeutic Innovation, College of Medicine, University of Florida, Lake Nona, FL
3
University at Albany, State University of New York, Albany, NY
us
Albany College of Pharmacy and Health Sciences, Albany, NY 12208‐3492, Phone: 518‐694‐
an
7292; Fax: 518‐694‐7032; E‐mail: [email protected]
M
Alternative corresponding author: Louise‐Anne McNutt, M.S., Ph.D. Associate Professor of Epidemiology and Biostatistics, Associate Director, Institute for Health and the Environment, University at Albany, State University of New York, Rensselaer, NY 12144, (518) 402‐0403; E‐ mail: [email protected]
pt ed
Summary: Using a validate Bayesian method to estimate vancomycin exposure profiles among patients with limited pharmacokinetic data, the findings suggest that that AUC/MIC, not trough, is the pharmacodynamic index most closely linked to outcomes for patients with MRSA
Ac
ce
bloodstream infections.
© The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: [email protected].
Downloaded from http://cid.oxfordjournals.org/ at University of Utah on May 28, 2014
Corresponding author: Thomas Lodise, Pharm.D., Ph.D. Associate Professor, Pharmacy Practice,
2 Abstract Background: Contemporary vancomycin dosing schemes are designed to achieve an area under
cr ipt
the curve (AUC) to minimum inhibitory concentration (MIC) [AUC/MIC ratio] ≥ 400. However, scant clinical data exist to support this target and available data relied on pharmacokinetic formulas based on daily vancomycin dose and estimated renal function (demographic pharmacokinetic model) to estimate AUCs.
us
infections treated with vancomycin was performed to quantitatively evaluate the relationship
an
between vancomycin exposure and outcomes. Bayesian techniques were used to estimate vancomycin exposure for day 1 and 2 of therapy for each patient based on their dosing
M
schedule and collected concentrations. Classification and Regression Tree Analysis (CART) was used to identify day 1 and 2 exposure thresholds associated with an increased risk of failure.
pt ed
Results: During the study period, 123 cases met criteria. Failure was uniformly less pronounced (approximately 20% less in absolute value) in patients who achieved the CART‐derived day 1 and 2 thresholds for AUC/ MICBMD, and AUC/ MICETEST. In the multivariate analyses, all risk ratios were circa 0.5 for all CART‐derived AUC exposure thresholds, indicating that achievement
ce
of CART‐derived AUC/MIC exposure thresholds was associated with a two‐fold decrease in failure.
Ac
Conclusions: These findings establish the critical importance of daily AUC/MIC ratios during the first two days of therapy. As with all observational studies, these findings should be interpreted
cautiously and validated in a multi‐center randomized trial before adoption into practice.
Downloaded from http://cid.oxfordjournals.org/ at University of Utah on May 28, 2014
Methods: A cohort study of hospitalized, adult, non‐dialysis patients with MRSA bloodstream
3 Introduction
Despite its introduction over a half century ago, the optimal dosing strategy for
cr ipt
vancomycin remains undefined. Contemporary vancomycin dosing schemes are designed to
achieve an area under the curve (AUC) to minimum inhibitory concentration (MIC) (AUC/MIC) ratio ≥ 400 for serious MRSA infections [1, 2]. Although this target is based on the best
data[3]. The best clinical evidence supporting AUC/MIC ratio ≥ 400 is drawn from a retrospective evaluation of patients with Staphylococcus aureus pneumonia [5]. Two recent
an
studies of patients with MRSA bloodstream infections (BSIs) have also identified similar vancomycin AUC/MIC ratio targets [7, 8]. While these evaluations provide further evidence
M
that the vancomycin pharmacodynamic target is an AUC/MIC ratio of at least 400, all evaluations used a simple formula based on daily vancomycin dose and estimated renal
pt ed
function to estimate AUC values [5, 7, 8]. In most cases, they used the Cockcroft‐Gault (G‐C) creatinine clearance formula. There is considerable inter‐patient variability in vancomycin exposure profiles in clinical practice and it is difficult to generate valid estimates of exposure variables in a given individual based on glomerular filtration estimation formulas alone [9‐11].
ce
To date, we are only aware of two small‐scale vancomycin exposure‐response clinical evaluations that considered individualized estimates of the vancomycin AUC based on collected
Ac
levels and doses received [12, 13]. Thus, there is a critical need for additional, larger‐scale clinical studies which utilize individualized estimates of exposure profiles based on measured concentrations.
Downloaded from http://cid.oxfordjournals.org/ at University of Utah on May 28, 2014
us
available evidence [1‐6], it is largely derived from neutropenic mouse thigh infection model
4
Although AUC/MIC ratio is the prevailing vancomycin exposure target, AUCs are not
determined in clinical practice due to the perceived difficulty in calculating the AUC [2]. Expert
cr ipt
guidelines recommend maintaining troughs (Cmin) between 15 and 20 mg/L as a surrogate
marker for an AUC/MIC ratio ≥ 400 [1, 2]. However, the clinical benefits of maintaining higher
vancomycin trough values have not been well described [14‐19]. The intent of this study was to
Cmin/MIC, AUC/MIC) and outcomes among patients with MRSA BSIs. Bayesian techniques [20‐ 22] were used to estimate the vancomycin concentration‐time profile for each patient. The
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Bayesian approach used in this study to estimate exposure profiles has recently been validated as a method to estimate vancomycin exposure values with low bias and high precision in
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situations where trough‐only pharmacokinetic (PK) data are available [22]. As a secondary objective, this study compared the predictive performance of the Bayesian relative to the
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formula‐based approach for estimating exposure profiles.
Research Design and Methods
Experimental Design and Study Population
A retrospective cohort study was performed among hospitalized patients with MRSA
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BSIs treated with vancomycin at Albany Medical Center Hospital (AMCH) between January 2005
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and June 2009. Patients meeting the following criteria were included: (i) age ≥ 18 years; (ii) absolute neutrophil count ≥ 1,000 cells/mm; (iii) MRSA culture met the CDC criteria for BSI[23]; (iv) index MRSA isolate available for phenotypic characterization; (v) non‐dialysis; (vi) received vancomycin within 48 hours of index culture; (vii) received vancomycin for at least 2 days; and
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quantitatively evaluate the relationship between vancomycin exposure variables (i.e.,
5 (viii) had ≥ 1 vancomycin level collected within the first 5 days of therapy. If a patient had > 1 MRSA BSI during the study period, additional episodes were included if they occurred > 60 days
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after completion of antibiotic therapy for the previous BSI. The study was limited to patients
who received vancomycin within 48 hours of index culture collection as this has been identified as the critical time window for delivery of appropriate antibiotics for patients with MRSA BSIs
and a HIPAA waiver was obtained.
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Patient data
Data elements included: demographics, medical history and comorbidities [18], recent
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healthcare institution exposure in the past 6 months, receipt of antibiotics in the 30 days prior to the index culture collection, hospitalization history, and creatinine clearance (CLCR) estimated
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by the C‐G formula [25] at index culture collection. Illness severity was defined by the Acute Physiological and Chronic Health Evaluation (APACHE II) score (based on the worst physiological score in the 48 hours prior to index culture collection) [26] and the Chronic Disease Score‐ Infectious Diseases (CDS‐ID) score (determined at admission) [27]. Additional data elements
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included source of MRSA BSI, mortality risk associated with infection source [24, 28, 29], presence of infective endocarditis [30], infection source control intervention, microbiologic
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data, treatment data, occurrence of nephrotoxicity (defined as either a 50% or 0.5 mg/dL increase in serum creatinine (SCR), whichever was greater, from initiation of vancomycin to 48
hours post‐completion among patients with a baseline SCR 1
mg/L. The current paradigm in PK/PD is that a doubling of exposure is required with each log2
increase in MIC values. Before we definitively recommend a daily AUC of 1300 for an MICBMD of
consistent with the AUC/ MICBMD targets observed in this study when the MICBMD is 2 mg/L, it will be difficult to use vancomycin in these instances since the vancomycin AUC needed for
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effect will be associated with nephrotoxicity rates in excess of 30% [21].
We did not attempt to determine if 30‐day mortality was attributable to the MRSA
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bloodstream infection. Rather than basing microbiological failure on persistent signs and symptoms of infection, treatment was considered a microbiological failure only if the duration
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of bacteremia was ≥ 7 days, as proposed by a number of authors [18, 27, 38]. We believe these aforementioned definitions allow for an objective assessment of the end points and minimize any subjective biases that may result from assessing and interpreting retrospective clinical data. Another consideration in the evaluation of MRSA bloodstream infection studies is the adequacy
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of source control. In situations when source control was warranted, there was an attempt to remove the catheter/debride the wound in almost all cases. Among patients who experienced
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a failure, there was a documented intervention in the medical record to “control the source” in >95% of cases. The frequency of source control attempts were not different between CART‐ derive exposure groups.
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2 mg/L, additional research is needed. If future studies indicate the pharmacodynamic target is
14 In conclusion, our findings suggest that that AUC/MIC, not Cmin/MIC, is the pharmacodynamic index most closely linked to outcomes for patients with MRSA BSIs.
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Clinicians should conservatively target AUC values needed to provide adequate exposure against the common MIC values observed in their institution given that MICs are largely
unknown until therapy day 3. Further research is still needed among patients with MRSA BSIs
findings need to be validated in a multi‐center vancomycin AUC dose‐optimized randomized
Acknowledgements
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outcomes trial before they can be incorporated into clinical practice.
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We also extend gratitude to the following individuals for data collection and database entry: Nadia El‐Fawal, Jill Butterfield, Benjamin Woo, and Rasha Masoud. We like to thank Ron Jones,
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M.D., and Rodrigo E. Mendes, Ph.D, at JMI Laboratories (North Liberty, IA) for characterizing the phenotypic and genotypic profiles of the MRSA isolates. This article has greatly benefited from the thoughtful editing (grammar and spelling) of Allison Krug. Allison Krug was paid by grant.
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Funding
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This work was supported by an investigator‐initiated research grant from Cubist Pharmaceuticals. T.P.L. was the principal investigator for this grant. Please note that Cubist
only provided support to complete the project and was not involved in the following: design and conduct of the study; collection, management, analysis, and interpretation of the data; and
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with vancomycin MICBMD > 1 mg/L. As this was a retrospective observational study, these
15 preparation and review of the manuscript. T.P.L. is also a consultant for Cubist. No other conflicts of interest exist for any of the authors.
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22 Figure 1. Observed vs. Predicted for (A) Bayesian Estimation Approach and (B) Formula‐Based Approach
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23 FIGURE 2. Bivariate relationship between CART‐derived Day 1 and Day 2 Cmin/MIC exposure variables and failure (A) and CART‐derived Day 1 and Day 2 AUC/MIC exposure variables and
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failure (B).
24 Table 1. Distribution of microbiologic phenotypes, exposure variables, and outcomes in study cohort Value
Microbiologic Phenotypes
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Characteristic
Range
0.38 to 3.0 mg/L
MIC50/90
1.5/1.5 mg/L
Range
0.38 to 3.0 mg/L
MIC50/90
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MICBMD
0.75/1 mg/L
Range
MBC/MIC50/90
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MBC/MIC ratio
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1 to 21.33 1.3/2.4
hVISA phenotype
4 (3.3%)
Agr dysfunctional
62 (50.4%)
Mean (SD) Vancomycin Exposure Variables
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Cmin24h
8.6 (4.7) 11.2 (5.9)
Cmin24h/ MICBMD
11.2 (6.6)
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Cmin48h
Cmin48h/MICBMD
14.8 (8.5)
Cmin24h/MICETEST
7.4 (5.3)
Cmin48h/ MICETEST
9.7 (6.8)
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MICETEST values
25 436.4 (162.5)
AUC24‐48h
517.3 (197.3)
AUC0‐24h/MICBMD
571.6 (245.8)
AUC24‐48h/MICBMD
680.0 (302.2)
AUC0‐24h/MICETEST
380.1 (215.4)
AUC24‐48h/ MICTEST
453.9 (273.6)
Outcomes
40 (32.5%)
30‐day mortality
Microbiologic failure
Recurrence
Nephrotoxicity**
25 (20.3%)
15 (12.2%)
10 (8.1%)
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Failure*
19 (17.9%)
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* Of the 40 failures, 30 met 1 failure criterion and 10 met 2.
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** Nephrotoxicity occurrences among the 106 patients with a SCR
