Challenges in Therapeutic Drug Monitoring:

Transcription

1 Challenges in Therapeutic Drug Monitoring: Focus on Vancomycin Pharmacodynamics and Pharmacokinetics Katherine Gallaga, PharmD PGY1 Pharmacy Practice Resident CHRISTUS Spohn Health System 1

2 Pharmacist Objectives 1) Describe the pharmacokinetic and pharmacodynamic properties of vancomycin 2) Identify the challenges with achieving therapeutic concentrations 3) Apply pharmacokinetic and pharmacodynamic principles to therapeutic drug monitoring of vancomycin using AUC parameters 4) Review novel concepts in vancomycin administration and dosing Technician Objectives 1. Describe the history of vancomycin 2. Recognize side effects of vancomycin 3. Explain red man s syndrome 2

3 Background History Lesson Discovered in 1952 from a sample of dirt in Borneo Streptomyces orientalis was isolated from that sample producing the substance compound In vitro experiments demonstrated preserved susceptibility to staphylococci compared to penicillin Levine DP. Clinical Infectious Diseases 2006; 42:S5 12 Mississippi mud Levine DP. Clinical Infectious Diseases 2006; 42:S5 12 3

4 Pharmacokinetics and Pharmacodynamics Pharmacokinetics and Pharmacodynamics Glycopeptide with molecular weight of ~ 1450 Da Not appreciably absorbed or metabolism Distribution ~50% protein bound Penetration into most body tissues Excretion Half-life: 6-8 hours >80% excreted unchanged in the urine Rybak, MJ. Clinical Infectious Diseases 2006; 42:S35 9 PK/PD Model 1-,2-, and 3-compartment model α-distribution phase minutes β-elimination phase 6-12 hours Matzke, G.R., Zhanel, G.G. & Guay, D.R.P. Clin-Pharmacokinet (1986) 11:

5 PK/PD Parameters Time-dependent killing AUC/MIC Peak/MIC Time above MIC AUC and MIC Defined Area Under the Curve Total exposure to the drug The bioavailability for a drug can be calculated by taking the ratio of AUCs for each route of administration Minimum Inhibitory Concentration The lowest antimicrobial concentration that prevents visible growth of an organism after approximately 24 hours of incubation in a specified growth medium Rybak MJ, Laboratory Tests to Direct Antimicrobial Pharmacotherapy. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. eds. Pharmacotherapy: A Pathophysiologic Approach, 10e New York, NY: McGraw-Hill Rybak MJ, Laboratory Tests to Direct Antimicrobial Pharmacotherapy. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. eds. Pharmacotherapy: A Pathophysiologic Approach, 10e New York, NY: McGraw-Hill 5

6 Relationship between Pharmacokinetic Parameters and MIC Dudley MN, et al. Am J Med Dec 30;91(6A):45S-50S Relationship between PK/PD parameters for vancomycin Ebert S. Program and abstracts of the 27th Interscience Conference on Antimicrobial Agents and Chemotherapy (New York). Washington, DC: American Society for Microbiology, 1987:173 PK/PD Parameters AUC/MIC Best predicting clinical efficacy of vancomycin May be the simplest means of expressing the reality of individual patient differences in pharmacokinetics and individual organism differences in susceptibility Vandecasteele SJ, et al. J Antimicrob Chemother 2013; 68: Moise-Broder PA, et al. Clin Pharmacokinet 2004; 43 (13):

7 Challenges with Achieving Therapeutic Concentrations S. aureus MIC Breakpoints Susceptible Intermediate Resistant MIC 2 mg/l 4 8 mg/l 16 mg/l Performance Standards for Antimicrobial Susceptibility Testing; Twenty-Second Informational Supplement. CLSI Document M100-S26. Wayne, PA: Clinical and Laboratory Standards Institute; Significance of MIC Creep Wang et al. investigated vancomycin MICs for S. aureus between at a single institution Results: significant shift in MICs from 0.5 to 1.0 mg/l was observed when 2004 was compared with 2000 (70.4 vs 19.9%, respectively; p < 0.01) This phenomenon seems not to be generalized; as a result each institution should systematically monitor MRSA vancomycin MIC over time. Silvestre J, et al. BMC Res Notes. 2013; 6: 65. 7

8 Dose-response relationship Vandecasteele SJ, et al. J Antimicrob Chemother 2013; 68: Red Man s Syndrome Associated with a rapid infusion of the first dose over < 60 min Symptoms: 4 10 min after an infusion started or soon after its completion red rash on the face, neck, and torso, diffuse burning and itching, dizziness, agitation, headache, chills, fever Sivagnanam S, Deleu D. Red man syndrome. Critical Care. 2003;7(2): doi: /cc1871. Nephrotoxicity Higher troughs ( 15 mg/liter) were associated with increased odds of nephrotoxicity (odds ratio [OR], 2.67) An incremental increase in nephrotoxicity was also observed with longer durations Short-term dialysis required only in 3% of nephrotoxic episodes AKI is more likely to occur with the concurrent use of nephrotoxic agents, and in critically ill patients who are susceptible to poor renal perfusion 1. van Hal, SJ. Antimicrob. Agents Chemother.February 2013 vol. 57 no Bamgbola, O. Ther Adv Endocrinol Metab Jun; 7(3):

9 Ototoxicity Retrospective analysis of patients whom audiograms were performed after an average of 27 days of vancomycin therapy showed a 12% rate of highfrequency hearing loss A significant rate of high-frequency hearing loss in patients older than 53 years (p = 0.008) Forouzesh, A. Antimicrob Agents Chemother Feb;53(2): Difficult Populations Elderly patients Debate still exists over how to calculate CrCL Lower empiric maintenance dosing with earlier concentration monitoring is advised Obese patients Increased volume of distribution, increased circulating proteins, increased blood flow Burn patients Higher total body clearance Cystic Fibrosis patients Higher volumes of distribution and total body clearance 1. Barber KE, et al. Drugs Aging. 2016; 33(12): Grace E, et al. J Antimicrob Chemother 2012; 67: Rocio A, et al. Antimicrob. Agents Chemother. May 2016 vol. 60 no Vancomycin Dosing Strategies Nomograms and Therapeutic Drug Monitoring 9

10 Nomograms Most of the available nomograms have determined the doses according to body weight and renal function Initial nomograms were not designed to achieve troughs greater than 15 mcg/ml Initial predicting success rate % for non-critically ill patients % for critically ill patients 54% for one nomogram specifically designed for hemodialysis 71% for one nomogram developed for neonates Elias, S. Eur J Clin Pharmacol (2016) 72: Nomogram Pro Based on validation studies, in most of cases, using a vancomycin dosing nomogram significantly improved and accelerated achievement of target trough concentration Elias, S. Eur J Clin Pharmacol (2016) 72: Nomogram Cons Most nomograms were developed for non-critically ill patients Limited data about clinical and microbiological outcomes The percentage of target level achievement has been between 40 and 70% in most of cases, which is not ideal, and thus it seems necessary to continue development of more accurate nomograms for vancomycin dosing Elias, S. Eur J Clin Pharmacol (2016) 72:

11 Guideline Recommendations Dose Loading dose of mg/kg in severe infections Maintenance dose of mg/kg every 8-12 hours Monitoring AUC-24/MIC> 400 is the preferred parameter Trough concentrations are recommended as AUC surrogate due to ease and accuracy Drawn before 4 th dose Rybak M, et al. Am J Health-Syst Pharm. 2009; 66:82-98 Are Troughs Adequate Enough? AUC values can vary as much as 30-fold between patients On average, traditional trough-only therapeutic drug monitoring will underestimate the true AUC by about 25% 50-60% of adults who have an AUC of 400 mg h/liter are not expected to have a trough concentration of >15 mg/liter Neely, MN. Et al. Antimicrob Agents Chemother Jan; 58(1): Out with the Troughs, In with the AUC M.P. Pai et al. / Advanced Drug Delivery Reviews 77 (2014)

12 Clinical AUC Outcomes The Impact of Vancomycin Area Under the Concentration- Time Curve-Guided Dosing on Vancomycin-Associated Nephrotoxicity: a Quasi-Experiment Single center, retrospective quasi-experiment including 1,280 patients Primary Outcomes Incidence of Nephrotoxicity Secondary Outcomes Vancomycin exposures between monitoring strategies Finch NA, et al. Antimicrob. Agents Chemother.AAC Clinical AUC Outcomes Lower total daily vancomycin doses Lower AUC values Lower nephrotoxicity AUCguided dosing results Lower trough concentrations Finch NA, et al. Antimicrob. Agents Chemother.AAC AUC/MIC Monitoring Strategies 1. Estimate the AUC24, using the patient s dose and an estimate of vancomycin clearance using CrCl 2. Compute the AUC24, using a measured steady-state peak and trough pair of vancomycin concentrations 3. Compute the AUC24, using a Bayesian pharmacokinetic computer program with one or more vancomycin concentrations Vancomycin. In: Bauer LA. eds. Applied Clinical Pharmacokinetics, 3e New York, NY: McGraw-Hill 12

13 AUC/MIC Formulas Estimating AUC-24 using Dose and Clearance AUC24 = D/{[(CrCl est 0.79) ] 0.06} Computing AUC-24 using Steady State Concentrations AUC inf = [(Css min + Css max )/2]}Δt inf AUC elim = {(Css max Css min )/[ln (Css max /Css min )]}Δt elim Vancomycin. In: Bauer LA. eds. Applied Clinical Pharmacokinetics, 3e New York, NY: McGraw-Hill Vancomycin. In: Bauer LA. eds. Applied Clinical Pharmacokinetics, 3e New York, NY: McGraw-Hill Computing AUC using Bayesian Pharmacokinetic Computer Programs Patient s drug dosage schedule and serum concentration are input into the computer Using population estimates based on demographic information for the patient supplied by the user, the computer program then computes estimated serum concentrations at each time there are actual serum concentrations Bayesian Programs DrugCalc Kinetidex ADAPT BestDose ID-ODS Many more! Vancomycin. In: Bauer LA. eds. Applied Clinical Pharmacokinetics, 3e New York, NY: McGraw-Hill 13

14 Challenges to Implication 1. Drawing two levels High peak levels Obtained after distribution phase 2. Training for healthcare involved Pharmacists Nursing Physicians/prescribers Novel administration and dosing strategies Continuous-infusion and divided-load vancomycin Continuous-Infusion Vancomycin Loading dose of 35 mg/kg (TBW) is necessary to achieve steady state concentrations of 20 mg/l or greater Followed by a daily dose adjusted to CrCl A daily dose of at least 35 mg/kg would be necessary to maintain steady-state The suggested steady-state concentrations to be reached in vancomycin continuous infusion should be between 20 and 30 mg/liter to avoid nephrotoxicity Roberts JA, et al. Antimicrob Agents Chemother Jun; 55(6):

15 Vancomycin Concentration and Renal Impairment Gray Intermittent Infusion Black Continuous Infusion Rocío Álvarez et al. Antimicrob. Agents Chemother. 2016;60: Continuous-Infusion Vancomycin Advantages: Faster achievement of the target steady-state Lower inconsistency in drug exposure Simpler therapeutic drug monitoring Ease of administration Lower rates of nephrotoxicity, costs, and mortality Disadvantages: Compatibility issues 1. Vandecasteele SJ, et al. J Antimicrob Chemother 2013; 68: Rocío Álvarez et al. Antimicrob. Agents Chemother. 2016;60: Mortality and Nephrotoxicity Gray Continuous Infusion Black Intermittent Infusion Rocío Álvarez et al. Antimicrob. Agents Chemother. 2016;60:

16 Continuous-Infusion Vancomycin Patient population that may benefit from continuous infusion High risk of nephrotoxicity Requiring high vancomycin doses Burn patients Patients under continuous renal replacement therapy Rocío Álvarez et al. Antimicrob. Agents Chemother. 2016;60: Divided-Load Vancomycin Performance of a Divided-Load Intravenous Vancomycin Dosing Strategy for Obese Patients Objective: Assessed the performance of a novel, obese-specific, divided-load vancomycin protocol for attaining target trough concentrations within 12 to 24 hours of dosing initiation, and during maintenance dosing, in obese patients Study Design: Prospective medical record review in 54 consecutive obese patients Denetclaw TH. et al Ann Pharmacother Aug;49(8):861-8 Divided-Load Dosing Protocol IBW Percentage IBW CrCl (ml/min) Initial Dosing Strategy > 60 1 gm q6h. Not to exceed 20 mg/kg IBW for each dose, check level before the 3 rd and 5 th doses. Change to dosing frequency dictated by function once level moves into target range gm q6h. Not to exceed 17 mg/kg IBW for each dose, check level before the 3 rd and 5 th doses. Change to dosing frequency dictated by function once level moves into target range Denetclaw TH. et al Ann Pharmacother Aug;49(8):

17 Divided-Load Vancomycin Methods: 2-phase dosing protocol was developed Compared to historical patients who received a protocol by Reynolds et al. 10 mg/kg IV q12 h or 15 mg/kg q24 h Denetclaw TH. et al Ann Pharmacother Aug;49(8):861-8 Divided-Load Vancomycin Results 12 hours after dosing initiation 24 hours after dosing initiation Throughout maintenance dosing 48 (89%) study patients exhibited trough concentrations of mcg/ml averaging 14.5 mcg/ml 51 (94%) study patients exhibited trough concentrations > 10 mcg/ml 31 study patients second trough concentration average was 15.0 mcg/ml 24 study patients had a total of 32 trough concentrations drawn during maintenance dosing, averaging 15.1 mcg/ml Denetclaw TH. et al Ann Pharmacother Aug;49(8):861-8 Divided-Load Vancomycin Conclusion Obese-specific, divided-load dosing achieved trough concentrations of 10 to 20 µg/ml for 89% of obese patients within 12 hours of initial dosing and 97% of obese patients within 24 hours of initial dosing while preventing doses given during supratherapeutic trough levels; 97% of troughs measured during steady state were within target range Denetclaw TH. et al Ann Pharmacother Aug;49(8):

18 Divided-Load Vancomycin Limitations Small, single center design No clinical outcomes or patient oriented outcomes Maintenance data are less generalizable Historical comparison is not based on guideline recommendations Denetclaw TH. et al Ann Pharmacother Aug;49(8):

19 Conclusion The best pharmacokinetic and pharmacodynamics parameter for vancomycin is AUC/MIC Challenges such as MIC creep, vancomycin narrow therapeutic index, and patient specific parameters have made achieving therapeutic concentrations difficult AUC can be estimated using the patient s dose and an estimate of vancomycin clearance, using a measured steady-state peak and trough pair of vancomycin concentrations, or using a Bayesian pharmacokinetic computer program Divided load and continuous infusion vancomycin may be implemented in a specific patient population Challenges in Therapeutic Drug Monitoring: Focus on Vancomycin Pharmacodynamics and Pharmacokinetics Katherine Gallaga, PharmD PGY1 Pharmacy Practice Resident CHRISTUS Spohn Health System 19