Vanquish Thy Troughs: Targeting AUC/MIC for Vancomycin Dosing

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1 Vanquish Thy Troughs: Targeting AUC/MIC for Vancomycin Dosing Jasmin Badwal, PharmD PGY- 1 Pharmacy Resident Department of Pharmacotherapy and Pharmacy Services, University Health System Pharmacotherapy Division, The University of Texas at Austin College of Pharmacy Pharmacotherapy Education and Research Center, UT Health San Antonio March 9, 2018 At the end of this session, the learner will be able to: 1. Summarize pharmacokinetic and pharmacodynamic parameters of vancomycin 2. Analyze current guideline recommendations for vancomycin dosing and monitoring 3. Evaluate the utility and effectiveness of AUC/MIC vs trough guided vancomycin dosing and monitoring on safety and clinical outcomes

2 Assessment Questions 1. Which of the following describes the mechanism leading to vancomycin resistance? A. Target alteration B. Beta- lactamase production C. Increased cell wall thickness D. All of the above E. A and C only 2. Which pharmacodynamic parameter best correlates with vancomycin clinical efficacy? A. T>MIC B. AUC/MIC C. Cmax/MIC D. Cmax 3. True/False: Current guidelines recommend targeting vancomycin troughs of mg/l for MRSA bacteremia. A. True B. False 4. Which of the following is NOT a potential benefit of targeting AUC/MIC when dosing vancomycin? A. Lower risk of nephrotoxicity B. Reduced vancomycin exposure C. Lower risk of resistance D. More efficient serum concentration sampling *** To obtain CE credit for attending this program please sign in. Attendees will be ed a link to an electronic CE Evaluation Form. CE credit will be awarded upon completion of the electronic form. If you do not receive an within 72 hours, please contact the CE Administrator at ana.franco- martinez@uhs- sa.com *** Faculty (Speaker) Disclosure: Jasmin K. Badwal has indicated she has no relevant financial relationships to disclose relative to the content of her presentation Badwal 2

3 Background I. Discovery 1 a. Eli Lilly based program in 1950s with goal of discovering antibiotics against penicillin- resistant staphylococcus b. Compound i. Discovered in dirt sample sent from Borneo in 1952 ii. Produced by Streptomyces orientalis iii. Dubbed Mississippi mud due to characteristic brown color and required significant purification prior to use in clinical trials iv. Resulting drug was named vancomycin from the word vanquish c. Approved by the Food and Drug Administration (FDA) in 1958 II. Delayed use 1 a. Methicillin was preferred over vancomycin due to safety and efficacy concerns i. Initial use reserved for resistance or severe beta lactam allergy b. Dramatic increase in vancomycin was seen in the 1980s with its role in pseudomembranous enterocolitis and the emergence of methicillin- resistant Staphylococcus aureus (MRSA) c. Now one of the most widely used antibiotics for the treatment of serious gram- positive infections III. Rate of MRSA at University Hospital 2 Vancomycin overview % Methicillin Resistant Year Figure 1. MRSA Rates at University Hospital I. Class and chemical structure 3 a. Large, tricyclic glycopeptide (molecular weight Da) II. Mechanism of action (MOA) 3-5 a. Bacterial cell wall synthesis inhibitor i. Forms complexes with two peptidoglycan precursors (D- alanyl- D- alanine) via 5 hydrogen bonds ii. Blocks incorporation (transpeptidation) of these subunits into peptidoglycan Figure 2. Chemical structure of vancomycin 3 Figure 3. MOA of vancomycin 5 Badwal 3

4 III. Spectrum of activity 3 a. Gram positive organisms Staphylococcus Enterococcus Streptococcus Bacillus Corynebacterium Clostridium Pepto- streptococcus Actinomyces Propioni- bacterium Nocardia b. Gram negative organisms: nongonococcal Neisseria spp., Chryseobacterium meningosepticum c. Intrinsically resistant organisms: Leuconostoc spp., Pediococcus spp., Erysipelothrix rhusiopathiae, Lactobacillus spp. IV. Mechanism of resistance (MOR) 3,5-7 a. Alteration of target i. D- alanyl- D- alanine à - D- lactate or - D- serine ii. Results in loss of H- bond and decreased vancomycin binding affinity iii. Examples: vancomycin- resistant enterococcus (VRE) and S. aureus (VRSA) b. Increased thickness of cell wall i. Excessive production of D- alanyl- D- alanine ii. Vancomycin trapped by excess and cannot reach target site (division septum) iii. Example: vancomycin- intermediate S. aureus (VISA) c. Concern of increased incidence of resistance due to extensive use V. Adverse effects 4 Figure 4. MORs of vancomycin 5,7 Red man syndrome Nephrotoxicity Ototoxicity Local phlebitis Hypersensitivity Thrombocytopenia VI. Vancomycin induced nephrotoxicity 8-11 a. Generally mild- moderate and reversible b. Controversy whether cause or effect of impaired renal function c. Infectious Diseases Society of America (IDSA): 2 consecutive documented increases in serum creatinine (of 0.5 mg/dl or 50% from baseline) after several days of vancomycin therapy d. Zasowski EJ, et al. (2017) i. Nephrotoxicity was significantly higher in patients with greater area under the curve (AUC) and trough values 1. AUC mg h/l, AUC mg h/l, and trough mg/l Badwal 4

5 ii. Daily AUC values between mg h/l during the first 48 hours were associated with a 3-4 x increased risk of nephrotoxicity VII. Common clinical uses 3 Skin and soft tissue Endocarditis Meningitis Pseudomembranous colitis Bacteremia Pneumonia Ventriculitis Osteomyelitis Vancomycin pharmacokinetics I. Pharmacokinetics (PK) 4,9,12 a. Absorption i. Poor systemic absorption with oral administration ii. Time to peak: immediate after intravenous infusion b. Distribution i. Volume of distribution (Vd): L/kg ii. Cerebrospinal fluid (CSF) concentrations increase with inflammation iii. Distribution phase: 30 minutes 1 hour iv. Protein binding: ~50-55% c. Metabolism: potential increased half- life and decreased clearance in impaired liver function d. Half- life elimination i. Adults: 6-12 hours (prolonged with renal impairment) ii. End- stage renal disease (ESRD): 7.5 days e. Excretion: glomerular filtration (75% as unchanged drug) Vancomycin pharmacodynamics I. General pharmacodynamic (PD) properties 13,14 a. Area under the curve (AUC) vs trough i. AUC: cumulative exposure of agent over a defined time period AUC = F x D / Cl F = bioavailability, D = Dose, Cl =clearance ii. Trough: single point exposure measurement at the end of the dosing interval b. MIC: lowest concentration of antimicrobial that will visually inhibit growth after hours of incubation i. Breakpoint is determined by the Clinical and Laboratory Standards Institute (CLSI) Susceptible Isolates inhibited by usually achievable concentrations Likely clinical efficacy Intermediate Isolates with MICs that approach attainable blood and tissue levels Response rates may be lower Clinical efficacy varies depending on site and dose Resistant Isolates not inhibited by usually achievable concentrations MICs or diameters in range where resistance mechanisms are likely Clinical efficacy not likely c. Concentration vs time dependent killing i. Three major measures of efficacy 1. T>MIC: time above MIC 2. AUC/MIC: area under the curve over MIC 3. Cmax/MIC: maximum concentration over MIC Badwal 5

6 II. Vancomycin specific pharmacodynamics a. Method of action à slowly bactericidal 9,10 i. Dependent on site of infection, bacterial inoculum size, MIC, and organism b. Optimal parameter 8-10 i. AUC/MIC shown to be best predictor of clinical outcomes ii. In- vitro studies showed that increasing 24- hour AUC/MIC values had the highest correlation with decreasing bacterial counts c. MIC breakpoints 6,14-16 i. Lowering of S. aureus susceptibility breakpoints in 2006 due to: 1. Association between higher vancomycin MICs with treatment failure 2. Increased incidence of heteroresistant strains ii. Heterogenous vancomycin- intermediate S. aureus (hvisa) 1. MIC is within susceptibility range but some of the cells present are in the intermediate range iii. MIC creep 1. Increasing vancomycin MICs over time however exact mechanism is unknown 2. Associated with poor outcomes, even with susceptible MICs iv. MIC > 1 of S. aureus has been reported as independent predictor of treatment failure, however this is controversial Table CLSI MIC breakpoints for vancomycin 14 Susceptible (S) Intermediate (I) Resistant (R) S. aureus 2 µg/ml 4-8 µg/ml 16 µg/ml Coagulase negative Staphylococcus 4 µg/ml 8-16 µg/ml 32 µg/ml Enterococcus spp. 4 µg/ml 8-16 µg/ml 32 µg/ml d. Controversy in susceptibility testing 17 i. Significant concern with ability to differentiate MIC 1 vs 2 ii. Standard used by CLSI is the broth microdilution (BMD) reference method iii. Comparison vs BMD testing 1. Etest and Microscan systems are more likely to overcall MICs 2. BD Phoenix and Vitek 2 systems are more likely to under- call MICs Table 2. MIC testing comparison 17 Etest MicroScan Vitek 2 Phoenix Absolute agreement 36.7% 61.8% 54.3% 66.2% Current guideline recommendations Figure 5. Vancomycin bacteriologic efficacy against MSSA 8 I. Background 8 a. First and only guideline on vancomycin therapeutic dose monitoring (TDM) published in 2009 b. Supported by American Society of Health System Pharmacists (ASHP), Infectious Diseases Society of America (IDSA), and Society of Infectious Disease Pharmacists (SIDP) c. Guideline is currently in the process of being updated Badwal 6

7 II. Dosing and monitoring recommendations 8 TDM parameters Optimal PD parameter is AUC/MIC, however lack of consensus on ideal calculation Troughsrecommended as "surrogate" markers for AUC Trough monitoring Obtained at steady state (prior to 4th dose) Monitoring recommended for patients with high risk of nephrotoxicity, unstable renal function, or receiving prolonged courses of therapy ( > 3-5 days) Once- weekly monitoring recommended in stable patients with long- term treatment Optimal trough concentration Troughs should always be > 10 mg/l to avoid development of resistance If MIC = 1 mg/l, minimum trough concentration should be at least 15 mg/l to achieve target AUC/MIC Trough concetrations of mg/l are recommended in complicated infections Adult dosing regimen Loading dose (LD) = mg/kg x 1; Maintenace dosing (MD) = mg/kg every 8-12 hours All dosing based on actual body weight (ABW) Evidence basis for dosing and monitoring recommendations I. Clinical effectiveness of AUC/MIC 400 target Table 3. Literature review of outcomes associated with AUC/MIC target Study Design Results Retrospective review n = 108 patients S. aureus respiratory tract infection eradication (p = ) vs % time/mic Moise- Broder PA, et al. (2004) 18 Holmes NE, et al. (2013) 19 Prybylski JP, et al. (2015) 20 Observational study n = 182 patients S. aureus bacteremia Meta- analysis 14 cohort studies n = 1677 patients S. aureus bacteremia Men P, et al. Meta- analysis 9 cohort studies (2016) 21 S. aureus infections High ( 400) vs low (<400) AUC/MIC AUC/MIC 400 associated with superior clinical and bacteriological response (p = ), and more rapid bacterial AUC/MIC > 373 (not 400) using BMD was associated with reduced mortality (P = 0.043) Higher AUC/MIC associated with reduced treatment failure (OR 0.41, CI ), persistent bacteremia (OR 0.53, CI ), and mortality (OR 0.47, CI ) Troughs 15 mg/l were not associated with the above Regression analysis mean AUC/MIC = 418 Lower mortality [RR = 0.47 (95% CI ), p < 0.001] and treatment failure [RR = 0.39( ), p = 0.001] with high AUC/MIC II. Troughs as surrogate markers a. Many studies have shown that lower troughs (< 15 mg/l) are able to achieve goal AUC/MIC 400 mg h/l b. Targeting AUC/MIC 400 mg h/l may reduce unnecessary vancomycin exposure and lower nephrotoxicity risk Badwal 7

8 Table 4. Literature review of trough and AUC/MIC correlation Study Design Results Patel N, et al. (2011) 22 Monte Carlo simulation Probability of target attainment (PTA) of AUC/MIC 400 With troughs 15-20, all regimens produced PTA of 100% at MIC 1 With trough 10-15, all three regimens of 1g, 1.5g, and 2g every 12 hrs produced PTA > 70% when MIC 1 Neely MN, et al. (2014) 23 Bel Kamel A, et al. (2017) 24 Pharmacokinetic data analysis from 3 studies n = 47 patients Retrospective analysis n = 88 elderly patients Assumed MIC = 1 Trough- only and peak- trough data sets underestimated true AUCs vs full data set: 23% (11-33%; P = ) and 14% (7-19%; p < ) Normal renal function, therapeutic AUC of 400, and MIC = 1 o ~ 60% were expected to have a trough < 15 vs ~ 32% a trough < 10 AUC 24 and C min correlation (R 2 = 0.51) AUC 24 was 400 in 95% (53/88) of cases when Cmin 15, 37% (35/88) when Cmin < 15, and 76% (81/88) when Cmin 10 Logistic regression: Cmin of 10.8 mg/l optimal predictor of AUC 24 > 400 III. Support for suggested targets a. Troughs < 10 mg/l are associated with increased resistance development Table 5. Literature review of trough levels associated with resistance Study Design Results Retrospective review n = 25 reduced vancomycin susceptibility S. aureus (SA- RVS) Howden BP, et al. (2004) 25 Charles PG, et al. (2006) 26 Retrospective review MRSA (n = 53) vs hvisa (n = 5) bacteremia Vancomycin failure: 16 patients (76%) 80% patients with recorded vancomycin levels had a low trough (<10 mg/l) during the first week of therapy hvisa group was more likely to have: High bacterial load infections (p = 0.001), vancomycin treatment failure (p <0.001), initial trough levels <10 µg/ml (p = 0.006) b. Very limited clinical data to support the goal range of mg/l à goal is to have a higher likelihood of achieving target AUC/MIC Table 6. Literature review of trough goal mg/l Study Design Results0 Kullar R, et al. (2011) 15 Retrospective review Single- center n = 320 with MRSA bacteremia Vancomycin failure = 52.5% Troughs associated with lower failure rates (39.5% vs 57.8%) CART analysis: higher failure with AUC 24 < 421 (61.2% vs 48.6%, p = 0.038) Independent predictors of failure: endocarditis, initial trough < 15, and MIC > 1 by E test Zelenitsky S, et al. (2013) 27 Retrospective review Multicenter n = 35 with MRSA septic shock Survival rate was 2.5x higher with initial troughs 15 [70.6% (12/17) vs. 27.8% (5/18); p = 0.001] CART analysis: greater survival seen with AUC 24 /MIC 451 (p = 0.006) and 578 (p = 0.012) c. Even when targeting troughs of mg/l, PK data has shown that AUC/MIC > 400 mg h/l is not likely to be achieved if MIC 2 mg/l for S. aureus 22 Figure 6. PTA of AUC/MIC > 400 with target troughs in S. aureus infections 22 Badwal 8

9 Calculation methodologies for AUC/MIC I. Equation- based approach 28 a. Methods i. Based on first- order pharmacokinetic equations to estimate the AUC value ii. Requires collection of two timed steady- state vancomycin concentrations iii. No consensus recommendation on single, validated method iv. Trapezoidal equations are one of the most commonly used methods (Appendix B) b. Availability à Free online calculators (Appendix C) Table 7. Application of equation- based approach II. Bayesian approach 23,28,29 a. Methods i. Software based program using population modeling to optimize vancomycin dosing ii. iii. Pros Manually and/or electronically calculated Can be programed into Microsoft Excel or EMR Allows prediction of next dose Only one vancomycin concentration required (not at steady state) Based on Bayes theorem 1. Patient s PK parameter values (volume or clearance) prior to administering the drug based on how drug has behaved in prior patients ( Bayesian prior ) 2. Measured drug concentrations collected from patient after administration of drug regimen 3. Revised probability distribution of patient s PK based on their dosing and drug concentration data ( Bayesian conditional posterior ) a. Allows estimation of vancomycin AUC value with low bias and computes further AUC- optimized dosing recommendations b. Availability i. BestDose program from University of Southern California ii. Free online download for Windows only (Appendix D) iii. In process of updating to new web- based program Table 8. Application of Bayesian approach Pros Free, available software Only one level required (no steady state requirement) Adaptive to physiologic changes Quick prediction of next dose and level III. Correlation between methods a. Neely MN, et al. (2014) 23 i. Pharmacokinetic data analysis from combination of three studies (total n = 47 adults) ii. Bayesian vs trapezoidal 1. Use of trough- only data to calculate AUC with Bayesian program allowed for 97% (95% CI %, p = 0.23) accurate estimation Cons Complex formulas Population- based assumptions Time and workflow commitment Non- adaptive to physiologic changes Requires 2 levels at steady state Cons Electronic calculation only Training, time, and workflow commitment Patient data security Unknown cost/extent of next update Badwal 9

10 b. Kishk OA, et al. (2017) 29 i. Study comparing three different AUC calculation methods (Trapezoidal, Chang, and Le) in pediatric patient population 1. Likelihood of achieving AUC/MIC > 400 varied from 16.4% to 90.9% 2. Trapezoidal method: r 2 = 0.59, median AUC/MIC (IQR ) 3. Chang method: median AUC/MIC (IQR ) 4. Le method: median AUC/MIC (IQR ) Clinical Question Should AUC/MIC be the preferred method for vancomycin therapeutic drug monitoring? I. Hale CM, et al. (2017) 30 Are vancomycin trough concentrations of mg/l associated with increased attainment of an AUC/MIC 400 in patients with presumed MRSA infection? Objective To determine whether there is an association between different target ranges of vancomycin trough concentrations and attainment of a calculated AUC/MIC 400 Methods Design Retrospective chart analysis 472- bed, tertiary care academic medical center (November 2013 January 2015) Patient population 100 patients Stratified by their initial troughs (<10, , 15-20, and >20 mg/l) Inclusion criteria Exclusion criteria Positive MRSA culture Steady state vancomycin concentration Inappropriately timed troughs Unstable renal function or HD Vancomycin doses based on each level Outcomes Primary Secondary Association between goal trough and reaching calculated AUC/MIC 400 Corrected average trough associated with development of acute kidney injury Calculations and definitions Statistics Baseline characteristics AUC = TDD vanc /Cl vanc Estimated Cl vanc = (CrCl x ) x 0.06 CrCl = creatinine clearance (ml/min) o Cockcroft- Gault equation on date of admit (capped at 120 ml/min) AUC/MIC = calculated AUC divided by MIC of isolated MRSA (by VITEK 2) Acute kidney injury (AKI) = increase in SCr by 0.5 mg/dl or a 50% increase from pretreatment levels Average vancomycin trough = ([trough 1 x number of days] + [trough 2 x number of days] + [trough n x number of days]) / (total number of days on vancomycin) Categorical variables à Chi- square test or Fisher exact test Continuous variables à Student t test or Mann- Whitney U test All tests were two- tailed and p < 0.05 was considered significant Results Characteristic Value Characteristic Value Mean age, years (SD) 59.2 (17.1) MIC = 1, n(%) 94 (94) Non- ICU, n(%) 86 (86) MIC = 2, n(%) 1 (1) Badwal 10

11 Primary outcome Secondary outcomes Author s conclusions Strengths Limitations Overall conclusion Median SCr, (IQR) 0.7 ( ) Median AUC/MIC (IQR) 378 ( ) Median CrCl, (IQR) Mean weight- based dose, 102 ( ) mg/kg/day (SD) 26.3 (9.4) Mean 24- hour dose, Mean weight- based dose, (820.3) mg/day (SD) mg/kg (SD) 15.3 (3.1) Culture source Value Culture source Value Wound, n(%) 32 (32) Biopsy/tissue, n(%) 18 (18) Sputum, n(%) 23 (23) Blood, n(%) 13 (13) Patients that met goal AUC/MIC (%) = 42 (42%) Troughs < 10 mg/l had 73% decreased likelihood of attaining goal vs troughs 10 mg/l (OR 0.27, 95% CI: , P = 0.018) Statistically significant difference between trough < 10 mg/l and 10 mg/l groups for median AUC/MIC (367 [IQR ] vs [IQR ]; P = 0.041) No difference in target attainment between troughs mg/l and mg/l Trough >20 mg/l group had significantly lower mean age, higher mean weights, and higher median CrCl Only 97/100 patients had assessable renal function AKI analysis: 9/97 (9.3%) developed AKI within first 10 days of treatment o Corrected average vancomycin trough was significantly higher in patients who developed AKI (19.5 +/- 3.6 vs /- 4.2 mg/l, P < 0.001) Limited association between higher serum vancomycin trough concentrations and attaining goal AUC/MIC 400 when troughs are above 10 mg/l Findings consistent with current recommendations of maintaining troughs above 10 mg/l to achieve target Significantly higher correct average vancomycin troughs were associated with development of AKI, however other causes of nephrotoxicity were not assessed Reviewer s critique Outcome comparison between different trough ranges All levels at steady state Variety of infection sites Retrospective study Limited patient population Trough timing and dosing deviations Exclusion of patients with AKI/renal dysfunction Non- standardized AUC/MIC calculation Majority skin and soft tissue infections Majority non- critically ill patients No analysis of concomitant nephrotoxins No analysis of clinical outcomes Overall higher likelihood of achieving goal AUC/MIC with troughs > 10 mg/l, but troughs in mg/l range were not associated with increased target attainment as suggested by guidelines No direct comparison of dosing methodologies on clinical outcomes à unable to recommend AUC/MIC based dosing over trough based, however general trough goal > 10 mg/l may be appropriate Abbreviations: MRSA = methicillin resistant Staphylococcus aureus, SCr = serum creatinine, AUC = area under the curve, MIC = minimum inhibitory concentration; TDD vanc = total daily dose of vancomycin, Cl vanc = estimated vancomycin clearance, CrCl = creatinine clearance (ml/min), AKI = acute kidney injury, HD = Hemodialysis, SD = standard deviation, IQR = interquartile range, CI = confidence interval Badwal 11

12 II. Neely MN, et al. (2017) 31 A prospective trial on the use of trough concentration versus area under the curve (AUC) to determine therapeutic vancomycin dosing Objective To test hypothesis that dosing vancomycin to target troughs > 15 mg/l leads to more overdosing in adult patients compared to AUC- guided dosing Methods Design 3 year, prospective, serial cohort study Los Angeles County University of Southern California Medical Center Patient 252 adult patients (n) à Year 1 (n = 75); Year 2 (n = 88); Year 3 (n = 89) population Inclusion criteria Exclusion criteria 18 years old IV vancomycin with 1 concentration Therapy 48 hours Any form of renal replacement Expected survival of < 72 hours Intervention Controls = Year 1 = dosing on targeted troughs of mg/l Cohort = dosing based on target AUC/MIC 400 to max 800 o Year 2 = use of BestDose Bayesian software (MM BestDose) o Year 3 = use of BestDose Bayesian software (MMopt BestDose) Additional functionality to calculate most optimal date/time for next level Calculations Site- specific validated non- parametric population model BestDose Bayesian software à trapezoidal approximation to calculate AUC Outcomes Primary Secondary Statistics Baseline characteristics Primary outcome Proportion of all available troughs that were therapeutic vs proportion of all corresponding AUCs Vancomycin TDM Treatment outcomes Nephrotoxicity Alpha = 5% and power = 80% à required sample size of 90 patients in each group Univariate analysis à Mann- Whitney test and Student s t- test Multivariate analysis à Kruskal- Wallis test and linear regression Categorical data à Fisher s exact or chi- square tests All tests were two- tailed and p < 0.05 was considered significant Results No significant differences in age, weight, serum creatinine, or CrCl Most common infection = SSTIs (46%) Year 3 had more pneumonia (6% vs 10% vs 27%, p = ) and bacteremia (5% vs 8% vs 19%, p = 0.006) Most common isolated organism = S. aureus (n = 54) MRSA isolates à 88% had MIC 1 mg/l 19% of troughs vs 70% of associated AUCs were therapeutic (P < 0.001) 40/128 (31%) AUCs 400 mg h/l were associated with trough concentration < 10 mg/l, and 87/128 (68%) were associated with troughs <15 mg/l o Close to simulation in previous study 28 Year 1 (n = 233) Year 2 (n = 189) Year 3 (n = 201) p- value Appropriate trough 84 (36%) 87 (46%) 43 (21%) 0.02 # per conc range (mg/l) < < >20 40 (47%) 14 (17%) 22 (26%) 8 (10%) 61 (70%) 19 (22%) 5 (6%) 2 (2%) 17 (40%) 20 (46%) 4 (9%) 2 (5%) < Badwal 12

13 target Secondary outcomes Author s conclusions Strengths Limitations Overall conclusion % within target trough Overall Target 10- <15 Target % within AUC/MIC Overall 400 and < and <800 28% 13% 15% 75% 68% 7% 13% 11% 2% 63% 56% 7% 15% 9% 6% 73% 70% 3% Vancomycin therapy: mean (min max) or median (IQR = 25 th, 75 th percentile) Year 1 (n = 75) Year 2 (n = 88) Year 3 (n = 89) p- value Avg daily dose (mg) 1818 ( ) 1750 ( ) 1577 ( ) 0.46 Year 1 (n = 44) Year 2 (n = 51) Year 3 (n = 56) p- value Days of vancomycin 7.8 (4.1, 14.3) 5.4 (4, 8.6) 4.7 (3.2, 8.7) 0.05 # samples/patient 3.6 (1-15) 2.1 (1-8) 2.4 (1-12) Trough conc (mg/l) 14.4 ( ) 9.7 ( ) 10.9 ( ) Daily AUC (mg h/l) 510 ( ) 459 ( ) 459 ( ) 0.29 Treatment outcomes Resolved: 59 (71%) vs 60 (67%) vs 66 (74%) Relapsed: 1 (1%) vs 0 vs 0 Toxicity: 2 (2%) vs 0 vs 0 Failure or Death: 0 vs 0 vs 0 Nephrotoxicity Mean SCr in each arm was 0.76, 1.05, and 1.2 (p < ) Vancomycin- associated nephrotoxicity: 6 (8%) vs 0 vs 2 (2%) (p = 0.01) o Median concentration was 15.7 mg/l in nephrotoxicity group vs 8.7 mg/l o Median length of stay was higher in nephrotoxicity group (20 vs 6 days, p = 0.002) More patients achieved therapeutic success when AUC/MIC was targeted Trough targeting was associated with a higher risk of nephrotoxicity No difference in clinical treatment outcomes between any of the groups Trough- guided dosing should be replaced by Bayesian AUC- guided dosing Reviewer s critique Direct comparison between trough vs AUC targeted dosing Similar results with trough and AUC association as seen in prior study Single- center Unclear trough- based dosing Did not meet sample size requirement Creators of Bayesian dosing program Multiple MIC methodologies No comparison of baseline severity of illness or concomitant nephrotoxins Less than half of patients had documented positive cultures Conclusions not supported by outcomes There was no difference in target AUC obtainment nor treatment outcomes between all three groups In most cases goal AUC can be achieved with troughs < 15 mg/l Nephrotoxicity conclusions based on limited occurrence and no in depth of analysis of any concomitant causes Bayesian methodology was associated with lower average duration and decreased number of blood samples however not clinically significant Final conclusion was not supported by any primary or secondary endpoints Abbreviations: conc = concentrations, TDM = therapeutic drug monitoring, h = hours, SCr = serum creatinine, CrCl = creatinine clearance, VAN = vancomycin, d/c = discharge, # = number, SSTI = skin and soft tissue infections, IQR = interquartile range Badwal 13

14 III. Finch NA, et al. (2017) 32 A quasi- experiment to study the impact of vancomycin area under the concentration- time curve- guided dosing on vancomycin- associated nephrotoxicity Objective To assess the impact of switching from trough to AUC- guided dosing Methods Design Single- center, retrospective quasi- experiment Detroit Medical Center (DMC) à January 2014 December 2015 Recent switch to target AUC 24 of mg h/l Patient 1280 patients population 546 patients in trough group vs 734 patients in AUC group Inclusion criteria Exclusion criteria Documented or suspected infection Treatment of meningitis, SSTIs without IV vancomycin for 72 hours and concomitant bacteremia, UTIs, or level drawn 96 hours of therapy surgical prophylaxis Trough group: 1 near steady state Concomitant piperacillin- tazobactam AUC group: 2 concentrations (pip- tazo) Calculations Trapezoidal Rule AUC Calculations o AUC inf = [(C max+ C min )/2] x time of infusion; AUC elim = (C max + C min)/k e o AUC dose = AUC inf + AUC elim ; AUC 24 = AUC dose x Number of daily doses Outcomes Primary Secondary Incidence of nephrotoxicity (3 different definitions) Impact on vancomycin exposures (dose, AUC, and troughs) Statistics Chi- square/fisher exact test or the Student t test/mann- Whitney U test Multivariable logistic and Cox proportional hazards regression Model fit was assessed with the Hosmer- Lemeshow goodness- of- fit test All tests were two- tailed and p 0.05 associated with significance Results Baseline No difference in age, SCr, or CrCl characteristics Variable Trough (n = 546) AUC (n = 734) p- value Median (IQR) APACHE II score 12 (7 17) 14 (9-22) <0.001 Nephrotoxins, n (%) 324 (59.4) 476 (64.9) IV contrast 46 (8.4) 93 (12.7) Furosemide 187 (34.4) 309 (42.1) Indication, n (%) Pneumonia 198 (36.3) 369 (50.3) <0.001 Bacteremia 77 (14.1) 88 (12) Sepsis of unknown source 70 (12.8) 107 (14.6) Bone/joint 68 (12.5) 83 (11.3) Other 86 (15.8) 50 (6.8) <0.001 Outcomes Trough (n = 546) AUC (n = 734) p- value Vancomycin exposure (median (IQR)) Median (IQR) cumulative vancomycin dose (mg) 0 24 h 0 48 h 0 72 h 3250 ( ) 5250 ( ) 7500 ( ) 3000 ( ) 5000 ( ) 7000 ( ) <0.001 <0.001 <0.001 Median (IQR) days of VAN 5.6 ( ) 5.3 ( ) Median (IQR) trough conc (mg/l) 15.0 ( ) 12.0 ( ) Median (IQR) AUC 24 (mg h/l) Not calculated ( ) Badwal 14

15 Nephrotoxicity, n(%) 2009 guideline definition 54 (9.9) 54 (5.4) or worse 106 (19.4) 132 (18) Akin Stage 2 or worse 3 64 (11.7) 17 (3.1) 65 (8.9) 22 (3) Rifle category Risk or worse Injury or worse Failure Time to nephrotoxicity by Cox proportional hazards regression 99 (18.1) 38 (7) 17 (3.1) 139 (18.9) 43 (5.9) 22 (3) Multivariable logistic regression Adjustments for severity of illness, comorbidity, duration of therapy, concomitant receipt of nephrotoxins on guideline- defined nephrotoxicity After correction, AUC- guided dosing was associated with less frequent nephrotoxicity (adjusted OR 0.514; 95% CI , [p = ]) Author s conclusions Strengths Limitations Overall conclusion Bayesian estimated vancomycin exposure profile (subgroup analysis) Trough (n = 150) AUC (n = 150) Variable p- value (median, IQR) (median, IQR) AUC 0-24 (mg h/l) 705 ( ) 474 ( ) <0.001 AUC (mg h/l) 663 ( ) 532 ( ) <0.001 AUC- guided dosing was associated with significantly reduced nephrotoxicity after controlling for clinical differences AUC- guided dosing was associated with lower total daily vancomycin doses, AUC values, and trough concentrations This approach shows promise in reducing vancomycin- associated nephrotoxicity, however additional studies are required to examine impact on clinical efficacy against invasive S. aureus infections Reviewer s critique Well defined nephrotoxicity outcomes and comparisons of different definitions Analysis of concomitant nephrotoxins Assessment and correction of differences in baseline characteristics Greater sample size than previous studies Single- center No assessment of clinical outcomes Limited external validity - - exclusion of Baseline MICs not reported pip/tazo and SSTIs Non- standardized AUC calculation Supports idea that current trough- based goals increase vancomycin exposure and further increase risk of nephrotoxicity à troughs >15 mg/l not required to reach goal AUC/MIC AUC/MIC targeted dosing was associated with less nephrotoxicity after adjusting for baseline characteristics Agree with final conclusion that additional studies are required to compare clinical success as primary outcome Abbreviations: inf = infusion, elim = elimination, conc = concentration, SCr = serum creatinine (mg/dl), CrCl = creatinine clearance (ml/min), VAN = vancomycin, pip/tazo = piperacillin/tazobactam, SSTI = skin and soft tissue infections, IQR = interquartile range, CI = confidence interval Badwal 15

16 Summary Design Population Baseline Hale 2017 Neely 2017 Finch 2017 Retrospective Prospective, Serial cohort Retrospective, Quasi Single- center Single- center Single- center n = 252 patients n = 1280 patients n = 100 patients Years 1 (n=75), 2 (n=88), Trough (n=546) vs Stratified based on trough level 3 (n= 89) AUC (n=734) 86% non- ICU 94% MIC = 1 50% SSTI, 13% bacteremia Correlation AUC/MIC 400: Troughs = 51.6% Troughs = 45.7% No significant difference Nephrotoxicity Higher troughs associated with increased AKI risk Clinical - - Efficacy 88% MIC 1 46% SSTI Outcomes AUC/MIC 400: Troughs < 15 = 68% No significant difference Trough > AUC/MIC No difference in resolution, relapse, failure, or death Higher APACHE II score, furosemide use, and pneumonia in AUC group Median trough of 12 associated with median AUC mg h/l Trough > AUC - - Conclusions I. Correlation a. Troughs are not more likely to achieve goal AUC/MIC than troughs b. Limited evidence behind maintaining higher trough concentration for extended duration even in the most invasive infections II. Importance of reaching target AUC/MIC a. Mortality benefit only assessed with MRSA bacteremia and pneumonia b. Unclear applicability to other organisms and sites of infection III. Practicality a. New online programs add simplicity to AUC/MIC calculations b. Significant variation in calculation methodologies still exist c. Switch to AUC/MIC- targeted dosing would require significant workflow changes and education IV. Safety a. Trough- targeted dosing associated with higher risk of nephrotoxicity vs AUC/MIC b. Vancomycin- induced nephrotoxicity is controversial, yet can be managed with simple dose adjustments c. Dependent on concomitant nephrotoxins and duration of therapy, which majority of studies did not assess V. Efficacy a. Only one study attempted assessing treatment success as a secondary endpoint and found no significant differences between different targets b. Future studies need to be designed to evaluate this as a primary outcome Badwal 16

17 Final recommendations I. AUC/MIC- targeted dosing should not yet replace all trough- based guideline recommendations a. No validated calculation method b. Unclear recommendations for non- studied indications and non- MRSA organisms c. Difference in clinical outcomes not supported by current studies II. Future studies are still needed before current vancomycin dosing protocols are changed III. Recommended trough goal adjustment a. General trough target of mg/l is appropriate for most patients regardless of indication b. If patient is not clinically improving on vancomycin, then trough target should be reassessed or alternative therapies should be evaluated Badwal 17

18 Appendices Appendix A. Abbreviations AUC area under the curve mg milligrams AUC inf area under the curve for infusion MIC minimum inhibitory concentration AUC elim area under the curve for elimination MOA mechanism of action avg average MOR mechanism of resistance BMD broth microdilution MRSA methicillin resistance S. aureus CART classification and regression tree analysis MSSA methicillin susceptible S. aureus Cmax maximum concentration PD pharmacodynamics Cmin minimum concentration PK pharmacokinetics Conc concentration PTA probability of target attainment CrCl creatinine clearance (ml/min) S. aureus Staphylococcus aureus CSF cerebrospinal fluid SCr serum creatinine d/c discharge SSTI skin and soft tissue infection ESRD end stage renal disease T time h or hrs hours TDM therapeutic drug monitoring HD hemodialysis UTI urinary tract infection hvisa heterogeneous vancomycin- intermediate VAN vancomycin S. aureus g grams Vd volume of distribution kg kilograms VISA VAN- intermediate S. aureus L liters VRE VAN- resistant enterococcus LD loading dose VRSA VAN- resistant S. aureus MD maintenance dosing # number Appendix B. Trapezoidal AUC calculation formulas Calculation of elimination rate constant (Ke) o C1 = peak, C2 = trough o t = difference in time between C1 and C2 2. Back- extrapolation and forward- extrapolation to compute theoretical concentrations Z o Ceoi = concentration at end of infusion = Cmax o Csoi = concentration at start of infusion o Ct = trough concentration = Cmin o t = infusion time, t1 = time of end of infusion, t2 = time of end of dosing interval 3. AUC calculation o Scenario 1: estimating Ceoi and assuming Csoi = Ct, or samples can be collected prior to dose (trough) and after dose (peak) Under- predicts true AUC at end of infusion and ignores alpha- phase o Scenario 2: back- extrapolate the concentration to Csoi Slightly over- predicts true AUC at start of infusion o Final AUC calculation: Ln Ke ¼ C1 C2 t C p = C 0 x e (- kt) - k (T t) Ct = Ceoi x e AUC t0 t2 ¼ t0 Ceoi 0 þ Ct þ Ceoi 0 Ct : 2 Ke Z ¼ t0 Z AUC t0 t2 ¼ Csoi 0 Ct Ke AUC 24 = AUC t0- t2 x (# doses/day) Badwal 18

19 Appendix C. Vancomycin AUC/MIC online calculators 1. calculator.com/ aucmic- estimator/ Appendix D. Bayesian AUC/MIC online program 1. Appendix E. Nephrotoxicity outcome definitions 32 Outcome Definition 2009 vancomycin consensus guideline SCr increase of 0.5 mg/dl and 50% the baseline SCr for 2 consecutive measurements Akin stage 1 SCr increase of 0.3 mg/dl or 1.5 times baseline SCr 2 SCr increase of 0.5 mg/dl or 2 times baseline SCr 3 SCr increase of 3 times baseline SCr or acute increase of 0.5 mg/dl if SCr is 4 mg/dl Rifle category Risk Injury Failure SCr increase of 1.5 times baseline SCr or CL CR decrease of 25% SCr increase of 2 times baseline SCr or CL CR decrease of 50% SCr increase of 3 times baseline SCr or CL CR decrease of 75% a The baseline SCr was defined as the SCr value immediately preceding the first dose of vancomycin, if available. In cases in which SCr was determined after the first Badwal 19

20 References 1. Levine DP. Vancomycin: a history. Clin Infect Dis. 2006;42 Suppl 1:S University Health System. Inpatient antibiogram. Rates of MRSA ( ). Accessed February 5, Murray BE, Arias CA, Nannini EC. Glycopeptides (vancomycin and teicoplanin), streptogramins (quinupristin- dalfopristin), lipopeptides (daptomycin), and lipoglycopeptides (telavancin). In: Mandell GL, Bennett JC, Dolin R, editors. Principles and practice of infectious diseases. 8th ed. Philadelphia, PA: Elsevier/Saunders; ClinicalKey website. Available at: clinicalkey- com.proxy.lib.wayne.edu/#!/content/book/3- s2.0- B ?scrollTo=%23hl Accessed January 7, Vancomycin. Lexi- Drugs Online. Lexi- Comp Online. Wolters Kluwer Health, Inc. Riverwoods, IL. Available at: Accessed January 7, Lowy FD. Antimicrobial resistance: the example of Staphylococcus aureus. J Clin Invest. 2003;111(9): Howden BP, Davies JK, Johnson PD, et al. Reduced vancomycin susceptibility in Staphylococcus aureus, including vancomycin- intermediate and heterogeneous vancomycin- intermediate strains: resistance mechanisms, laboratory detection, and clinical implications. Clin Microbiol Rev. 2010;23(1): Mirza HC. Glycopeptide Resistance in S. aureus. In: Enany S, eds. Immunology and Microbiology The rise of virulence and antibiotic resistance in staphylococcal aureus. INTECH; Available at rise- of- virulence- and- antibiotic- resistance- in- staphylococcus- aureus/glycopeptide- resistance- in- s- aureus. Accessed March 1, Rybak M, Lomaestro B, Rotschafer JC, et al. Therapeutic monitoring of vancomycin in adult patients: a consensus review of the American Society of Health- System Pharmacists, the Infectious Diseases Society of America, and the Society of Infectious Diseases Pharmacists. Am J Health Syst Pharm. 2009;66(1): Rybak MJ. The pharmacokinetic and pharmacodynamic properties of vancomycin. Clin Infect Dis. 2006;42 Suppl 1:S Álvarez R, López cortés LE, Molina J, et al. Optimizing the clinical use of vancomycin. Antimicrob Agents Chemother. 2016;60(5): Zasowski EJ, Murray KP, Trinh TD, et al. Identification of vancomycin exposure- toxicity thresholds in hospitalized patients receiving intravenous vancomycin. Antimicrob Agents Chemother. 2018;62(1). 12. Brown N, Ho DH, Fong KL, et al. Effects of hepatic function on vancomycin clinical pharmacology. Antimicrob Agents Chemother. 1983;23(4): Levison ME, Levison JH. Pharmacokinetics and pharmacodynamics of antibacterial agents. Infect Dis Clin North Am. 2009;23(4): CLSI. Performance standards for antimicrobial susceptibility testing. Clinical and Laboratory Standards Institute. 2016; Kullar R, Davis SL, Levine DP, et al. Impact of vancomycin exposure on outcomes in patients with methicillin- resistant Staphylococcus aureus bacteremia: support for consensus guidelines suggested targets. Clin Infect Dis. 2011;52(8): Van hal SJ, Lodise TP, Paterson DL. The clinical significance of vancomycin minimum inhibitory concentration in Staphylococcus aureus infections: a systematic review and meta- analysis. Clin Infect Dis. 2012;54(6): Rybak MJ, Vidaillac C, Sader HS, et al. Evaluation of vancomycin susceptibility testing for methicillin- resistant Staphylococcus aureus: comparison of Etest and three automated testing methods. J Clin Microbiol. 2013;51(7): Moise- broder PA, Forrest A, Birmingham MC, et al. Pharmacodynamics of vancomycin and other antimicrobials in patients with Staphylococcus aureus lower respiratory tract infections. Clin Pharmacokinet. 2004;43(13): Holmes NE, Turnidge JD, Munckhof WJ, et al. Vancomycin AUC/MIC ratio and 30- day mortality in patients with Staphylococcus aureus bacteremia. Antimicrob Agents Chemother. 2013;57(4): Prybylski JP. Vancomycin trough concentration as a predictor of clinical outcomes in patients with Staphylococcus aureus bacteremia: a meta- analysis of observational studies. Pharmacotherapy. 2015;35(10): Men P, Li HB, Zhai SD, et al. Association between the AUC0-24/MIC ratio of vancomycin and its clinical effectiveness: a systematic review and meta- analysis. PLoS ONE. 2016;11(1):e Patel N, Pai MP, Rodvold KA, et al. Vancomycin: we can't get there from here. Clin Infect Dis. 2011;52(8): Neely MN, Youn G, Jones B, et al. Are vancomycin trough concentrations adequate for optimal dosing? Antimicrob Agents Chemother. 2014;58(1): Bel Kamel A, Bourguignon L, Marcos M, et al. Is Trough Concentration of Vancomycin Predictive of the Area Under the Curve? A Clinical Study in Elderly Patients. Ther Drug Monit. 2017;39(1): Howden BP, Ward PB, Charles PG, et al. Treatment outcomes for serious infections caused by methicillin- resistant Staphylococcus aureus with reduced vancomycin susceptibility. Clin Infect Dis. 2004; 38: Charles PG, Ward PB, Johnson PD, Howden BP, Grayson ML. Clinical features associated with bacteremia due to heterogeneous vancomycin- intermediate Staphylococcus aureus. Clin Infect Dis. 2004;38(3): Zelenitsky S, Rubinstein E, Ariano R, et al. Vancomycin pharmacodynamics and survival in patients with methicillin- resistant Staphylococcus aureus- associated septic shock. Int J Antimicrob Agents. 2013;41(3): Pai MP, Neely M, Rodvold KA, Lodise TP. Innovative approaches to optimizing the delivery of vancomycin in individual patients. Adv Drug Deliv Rev. 2014;77: Kishk OA, Lardieri AB, Heil EL, et al. Vancomycin AUC/MIC and corresponding troughs in a pediatric population. J Pediatr Pharmacol Ther. 2017;22(1): Hale CM, Seabury RW, Steele JM, et al. Are vancomycin trough concentrations of 15 to 20 mg/l associated with increased attainment of an AUC/MIC 400 in patients with presumed MRSA infection? J Pharm Pract. 2017;30(3): Neely MN, Kato L, Youn G, et al. Prospective trial on the use of trough concentration versus area under the curve to determine therapeutic vancomycin dosing. Antimicrob Agents Chemother. 2018;62(2). 32. Finch NA, Zasowski EJ, Murray KP, et al. The impact of vancomycin area under the concentration- time curve- guided dosing on vancomycin- associated nephrotoxicity: a quasi- experiment. Antimicrob Agents Chemother. 2017;61(12). Badwal 20