Challenges in Therapeutic Drug Monitoring: Focus on Vancomycin - PDF document

6/1/18 Challenges in Therapeutic Drug Monitoring: Focus on Vancomycin Pharmacodynamics and Pharmacokinetics Katherine Gallaga, PharmD PGY1 Pharmacy Practice Resident CHRISTUS Spohn Health System 1

6/1/18 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

6/1/18 Background History Lesson • Discovered in 1952 from a sample of dirt in Borneo • Streptomyces orientalis was isolated from that sample producing the substance “compound 05865” • 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

6/1/18 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 ¤ 30-60 minutes ¤ β -elimination phase ¤ 6-12 hours Matzke, G.R., Zhanel, G.G. & Guay, D.R.P. Clin-Pharmacokinet (1986) 11: 257. 4

6/1/18 PK/PD Parameters ¤ Time-dependent killing ¤ AUC/MIC ¤ Peak/MIC ¤ Time above MIC AUC and MIC Defined Minimum Inhibitory Area Under the Curve Concentration Total exposure to the drug The lowest antimicrobial • • concentration that • The bioavailability for a prevents visible growth of drug can be calculated by an organism after taking the ratio of AUCs for approximately 24 hours of each route of incubation in a specified administration 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

6/1/18 Relationship between Pharmacokinetic Parameters and MIC Dudley MN, et al. Am J Med. 1991 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: 743–748 Moise-Broder PA, et al. Clin Pharmacokinet 2004; 43 (13): 925-942 6

6/1/18 Challenges with Achieving Therapeutic Concentrations S. aureus MIC Breakpoints MIC Susceptible ≤ 2 mg/L Intermediate 4–8 mg/L Resistant ≥ 16 mg/L Performance Standards for Antimicrobial Susceptibility Testing; Twenty-Second Informational Supplement. CLSI Document M100-S26. Wayne, PA: Clinical and Laboratory Standards Institute; 2016. Significance of ‘MIC Creep’ ¤ Wang et al. investigated vancomycin MICs for S. aureus between 2000-2004 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

6/1/18 Dose-response relationship Vandecasteele SJ, et al. J Antimicrob Chemother 2013; 68: 743–748 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):119-120. doi:10.1186/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. 2734-744 2. Bamgbola, O. Ther Adv Endocrinol Metab. 2016 Jun; 7(3): 136–147. 8

6/1/18 Ototoxicity ¤ Retrospective analysis of patients whom audiograms were performed after an average of 27 days of vancomycin therapy showed a 12% rate of high- frequency hearing loss ¤ A significant rate of high-frequency hearing loss in patients older than 53 years (p = 0.008) Forouzesh, A. Antimicrob Agents Chemother. 2009 Feb;53(2):483-6. 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): 845–854. 2. Grace E, et al. J Antimicrob Chemother 2012; 67: 1305 –1310 3. Rocio A, et al. Antimicrob. Agents Chemother. May 2016 vol. 60 no. 5 2601-2609 Vancomycin Dosing Strategies Nomograms and Therapeutic Drug Monitoring 9

6/1/18 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 ¤ 44–76 % for non-critically ill patients ¤ 42–84 % 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) 72:777–788 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) 72:777–788 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) 72:777–788 10

6/1/18 Guideline Recommendations ¤ Dose ¤ Loading dose of 25-30 mg/kg in severe infections ¤ Maintenance dose of 15-20 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. 2014 Jan; 58(1): 309–316. Out with the Troughs, In with the AUC M.P. Pai et al. / Advanced Drug Delivery Reviews 77 (2014) 50–57 11

6/1/18 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 Secondary Outcomes Incidence of Vancomycin exposures Nephrotoxicity between monitoring strategies Finch NA, et al. Antimicrob. Agents Chemother.AAC.01293-17 Clinical AUC Outcomes Lower total Lower AUC daily vancomycin values doses Lower Lower trough AUC- nephrotoxicity concentrations guided dosing results Finch NA, et al. Antimicrob. Agents Chemother.AAC.01293-17 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