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

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Challenges in Therapeutic Drug Monitoring:

Focus on Vancomycin Pharmacodynamics and Pharmacokinetics

Katherine Gallaga, PharmD PGY1 Pharmacy Practice Resident CHRISTUS Spohn Health System

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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

6/1/18 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 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

6/1/18 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 ¤ 30-60 minutes ¤ β-elimination phase ¤ 6-12 hours

Matzke, G.R., Zhanel, G.G. & Guay, D.R.P. Clin-Pharmacokinet (1986) 11: 257.

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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

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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

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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

• bserved 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.

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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

• bserved 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.

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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

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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

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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 4th 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

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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 Nephrotoxicity Vancomycin exposures between monitoring strategies

Finch NA, et al. Antimicrob. Agents Chemother.AAC.01293-17

Clinical AUC Outcomes

AUC- guided dosing results

Lower nephrotoxicity Lower total daily vancomycin doses Lower AUC values Lower trough concentrations

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

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AUC/MIC Formulas

Estimating AUC-24 using Dose and Clearance

• AUC24 = D/{[(CrClest • 0.79) + 15.4] • 0.06}

Computing AUC-24 using Steady State Concentrations

• AUCinf = [(Cssmin + Cssmax)/2]}Δtinf
• AUCelim = {(Cssmax − Cssmin)/[ln (Cssmax/Cssmin)]}Δtelim
• 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

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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. 2011 Jun; 55(6): 2704–2709.

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Rocío Álvarez et al. Antimicrob. Agents Chemother. 2016;60:2601-2609

Vancomycin Concentration and Renal Impairment

Gray Black Intermittent Infusion Continuous Infusion

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: 743–748 2. Rocío Álvarez et al. Antimicrob. Agents Chemother. 2016;60:2601-2609 Rocío Álvarez et al. Antimicrob. Agents Chemother. 2016;60:2601-2609

Mortality and Nephrotoxicity

Gray Black Continuous Infusion Intermittent Infusion

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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;60:2601-2609

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. 2015 Aug;49(8):861-8

Divided-Load Dosing Protocol

IBW Percentage IBW CrCl (mL/min) Initial Dosing Strategy

≤ 83 ≥ 137 > 60 1 gm q6h. Not to exceed 20 mg/kg IBW for each dose, check level before the 3rd and 5th doses. Change to dosing frequency dictated by function once level moves into target range ≤ 83 ≥ 137 21-60 1 gm q6h. Not to exceed 17 mg/kg IBW for each dose, check level before the 3rd and 5th doses. Change to dosing frequency dictated by function once level moves into target range

Denetclaw TH. et al Ann Pharmacother. 2015 Aug;49(8):861-8

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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. 2015 Aug;49(8):861-8

Divided-Load Vancomycin

¤ Results

• 48 (89%) study patients exhibited trough concentrations of 10-

20 mcg/mL averaging 14.5 mcg/mL

• 51 (94%) study patients exhibited trough concentrations > 10

mcg/mL

12 hours after dosing initiation

• 31 study patients second trough concentration

average was 15.0 mcg/mL 24 hours after dosing initiation

• 24 study patients had a total of 32 trough

concentrations drawn during maintenance dosing, averaging 15.1 mcg/mL

Throughout maintenance dosing

Denetclaw TH. et al Ann Pharmacother. 2015 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. 2015 Aug;49(8):861-8

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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. 2015 Aug;49(8):861-8

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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