Kurt A. Wargo, Pharm.D., BCPS (AQ-ID)

Associate Clinical Professor

Auburn University Harrison School of Pharmacy

Pharmacokinetics in the critically ill adult patient:

A focus on vancomycin and aminoglycosides

Objectives

1. Discuss the basic concepts of pharmacokinetics

2. Demonstrate the clinical utility of pharmacokinetic dosing and monitoring

3. Discuss vancomycin dosing guidelines and implications to clinical practice

4. Discuss aminoglycoside dosing options

Pharmacokinetics• Absorption

• Distribution

• Metabolism

• Elimination

• Therapeutic Drug Monitoring

• Peaks and troughs

Pharmacokinetics in the critically ill

Hydrophilic ABX Lipophilic ABX

Examples •β-lactams•Aminoglycosides•Vancomycin•Linezolid

•Fluoroquinolones•Macrolides•Clindamycin•Tigecycline/Tetracyclines

General PK •Low Vd

•Primary renal clearance•Low intracellular concentrations

•High Vd

•Primary hepatic clearance

•Good intracellular concentrations

Critically Ill PK

• Increased Vd

•Cl ↑ or ↓ based on renal fx

•Vd unchanged•Cl ↑ or ↓ based on hepatic function

Roberts et al. Crit Care Med. 2009;37:840-51

Vd changes in the critically ill

• Increased Vd of hydrophilic drugs• Hypoalbuminemia and capillary leak (fluid

shifts to interstitial spaces) • Decreases serum concentrations

• Other factors:• Ventilation• Post-surgical drains• Cardiopulmonary bypass circuits• Burns

• No change in Vd of lipophilic drugs

Changes to antibiotic half-life

• t1/2 = (0.693 X Vd) / Cl

• (t1/2 = 0.693 / ke)

• Both ↑ Vd and ↓ Cl can increase the half-lives of antibiotics

• Management of hypotension increases Cl

Effects of critical illness on PK parameters

Roberts et al. Crit Care Med. 2009;37:840-51

T=time; Cmax=maximum concentration; AUC=area under the curve;

MIC=minimum inhibitory concentration.

Moore RD et al. J Infect Dis. 1987;155:93-99;

Gilbert DN. Antimicrob Agents Chemother. 1991;35:399-405.

Concentration (mg/L)

MIC90 Goal: %T > MIC = 50%%T > MIC

AUC Goal: AUC/MIC > 125 for G (-), and >35 for G(+)

Cmax

Time (h)

Pharmacodynamic (PD) Relationships

Goal: Cmax/MIC >10

Pharmacodynamic Properties

Time-DependentTime-Dependent Concentration-Concentration-DependentDependent

MixedMixed

Antibiotics β-lactamsCarbapenemsErythromycinClarithromycin

AminoglycosidesMetronidazoleDaptomycin

VancomycinLinezolid

FluoroquinolonesAzithromycinTigecycline

TetracyclinesPD Parameter %T > MIC Cmax / MIC AUC24 / MIC

When to draw peaks and troughs

• Steady State: 5 half-lives of the drug (steady state)

Vancomycin

Vancomycin Exhibits both concentration- and time-

dependent characteristics Optimally needs to spend 100% of time above

MIC AUC/MIC > 400

Absorption: IV only (PO no systemic absorption) Distribution: Widely in tissues and fluids (poor

lung and CSF penetration); avg: 0.7 L/kg (relatively hydrophilic)

Metabolism: Negligible Elimination: Kidneys

Vancomycin Therapeutic Drug Monitoring

Ototoxicity with high peaks (>80 mg/dL) Nephrotoxicity with high troughs (>25

mg/dL) and in combination with other nephrotoxic drugs

Red Man’s Syndrome with fast infusion (infuse no faster than 1 g/hr)

Ideal Levels▪ Trough of 15-20 mg/dL

Vancomycin dosing guidelines conundrum• Am J Health-Syst Pharm. 2009; 66:82-98

• “AUC/MIC is most useful PD parameter to predict effectiveness”

• “Increasing trough concentrations to 15-20 mg/L to attain AUC/MIC of 400 is desirable”

• “Trough serum concentrations can be used as a surrogate marker of AUC/MIC”

Vancomycin “traditional” dosing• Cellulitis/Endocarditis

• Dose: 10 – 15 mg/kg of actual body weight

• Interval: Every 1.5 half lives

• Pneumonia/Meningitis/Abscess—Matzke Nomogram

• Loading Dose: 25 mg/kg of actual body weight

• Maintenance Dose: 19 mg/kg of actual body weight

• Interval: Every 2 half lives

• DO NOT EXCEED 4 grams daily

Vancomycin “traditional” dosing t1/2

= 0.693 / [(0.00083 x CrCl) + 0.0044]

CrCl = [(140 – age) x Weight] / (72 x Cr) [x 0.85 if female]

Weight is lower of actual or ideal, or an adjusted weight if patient is obese Ideal Weight Male: 50 + (2.3 x inches > 60) Ideal Weight Female: 45.5 + (2.3 x inches

>60) Adjusted Weight: 0.4(Actual – Ideal) + Ideal

Vancomycin “AUC/MIC” dosing• Goal AUC/MIC = 400

• AUC/MIC = Dose24 / [((CrCl x 0.79) +15.4) x 0.06]

• Dose24 = 400 x [((CrCl x 0.79) +15.4) x 0.06]

• Wargo NomogramCrCl CrCl (mL/min)(mL/min)

AUC Dose AUC Dose (mg)*(mg)*

> 125 1500 Q12h

100-124 1250 Q12h

70-99 1000 Q12h

50-69 1500 Q24h

30-49 1000 Q24h*Assumes MIC = 1

Step-wise approach to traditional dosing of Vancomycin

1. Determine if loading dose is necessary

2. Calculate maintenance dose (either 10-15 mg/kg or 19 mg/kg of actual body weight)

3. Calculate necessary weight for CrCl equation

4. Calculate CrCl

5. Calculate half-life

6. Calculate dosing interval

7. Determine when/if you want to check a trough

Vancomycin Example 1• HB is a 71 year old male admitted for MRSA

pneumonia. • Height: 6’0”• Weight: 185#• Cr: 1.3 mg/dL

• Ideal weight:

78 kg• Actual weight:

84kg• CrCl:

58 mL/min

• t1/2:

13 hrs

Vancomycin Example 1

Loading dose: 25 mg/kg x 1 = 2000 mg

Maintenance dose: 19mg/kg = 1500 mg

Interval: Every 2 half lives = 24 hrs

Goal trough: 15 – 20 mg/dL

Order: Vancomycin 2000 mg IV x 1, then 1500 mg IV q24hrs

Vancomycin Example 1 (AUC dosing)• CrCl = 58

• Dose = 1500 mg IV Q24h, assuming MRSA has an MIC = 1 mg/L

CrCl CrCl (mL/min)(mL/min)

AUC Dose AUC Dose (mg)*(mg)*

> 125 1500 Q12h

100-124 1250 Q12h

70-99 1000 Q12h

50-69 1500 Q24h

30-49 1000 Q24h

Vancomycin Example 2• AJ 51 year old female with MRSA cellulitis

• Wt: 285 #

• Ht: 5’4”

• Cr: 1 mg/dL

• Ideal Wt:

• 55 kg

• Actual Wt:

• 130 kg

• CrCl:

• 105 mL/min (Adjusted wt of 85 kg)

• t1/2:

• 8 hrs

Vancomycin Example 2• Dose:

• 10-15 mg/kg = 1300 – 2000 mg

• Interval:

• 1.5 x t1/2 = 12 hrs

• What you order:

• Vancomycin 2000 mg IV q12hrs

• When do you check a trough?

• In 40 hrs or before the 3rd or 4th dose

Vancomycin Example 2 (AUC dosing)• CrCl = 105 mL/min

• Dose = 1250 mg IV Q12h

CrCl CrCl (mL/min)(mL/min)

AUC Dose AUC Dose (mg)*(mg)*

> 125 1500 Q12h

100-124 1250 Q12h

70-99 1000 Q12h

50-69 1500 Q24h

30-49 1000 Q24h

Vancomycin “what-if’s”

• What if the trough comes back high (>20 mg/dL)?• Option 1: Hold a dose, then increase interval

• Option 2: Increase your interval without holding dose (20-25 mg/dL range)

• Option 3: Do nothing—ASSESS Patient

• What if the trough comes back too low?• Option 1: Decrease the interval (RARE to go to q8h dosing)

• Option 2: Increase the dose

• Option 3: Change therapy

• Option 4: Do nothing—ASSESS Patient

• What if the creatinine increases on therapy?• Check the volume status of the patient

• Consider changing therapy

Aminoglycosides

Aminoglycosides• Tobramycin, Gentamicin, Amikacin

• Concentration-dependent

• Peak level should be 10x the MIC for optimal bactericidal activity

• Absorption: IV/IM, Not PO

• Distribution: Hydrophilic (Vd ≈ 0.24 L/kg)

• Metabolism: Negligible

• Excretion: Urine

The Bad Reputation

Ototoxicity• Associated with high peaks, extremes in

age, >14 days of therapy, concurrent meds (loops and vanco)

• Alters Na-K pump, changing electrical potential and osmotic pressure in the endolymph, leading to cochlear then vestibular dysfunction. If recognized early (fullness and tinnitus), it is reversible.

• Vestibular damage is permanent: vertigo, nausea, dizziness, nystagmus

Nephrotoxicity• Associated with high troughs, extremes in

age, volume contraction, >14 days therapy, meds (vanco, ampho B)

• Excreted via proximal tubule, but when [ ] is high, it is absorbed via pinocytosis in the brush border cells. Vacuole ruptures and AG interferes with phosphorylation and ATP synthesis—cell death

• Early sign: casts in urine

• Generally reversible upon discontinuation

Neuromuscular blockade• RARE, but fatal

• Greatest risk in patients with Myasthenia Gravis or on NMBAs

• Hypocalcemia, hypomagnesemia, and calcium-channel blocker use may all contribute

• AG interferes with presynaptic uptake of Ca2+ causing immediate release of acetylcholine and postsynaptic nerve binding

• Reverse with Ca-gluconate or Neostigmine

• Manifestations: dilated pupils, weak respiration, flaccid paralysis

Any infection where Pseudomonas aeruginosa is suspected and you

want to “double cover”

→ increasing FQ resistance

So what is their utility???

Aminoglycoside dosing• Tobramycin/Gentamicin: Traditional vs. High-

dose

• Traditional: Peaks range from 4 mg/dL for UTIs to 10 mg/dL for pneumonia; Troughs < 2 mg/dL

• High-dose: Attempting to get a peak of at least 20 mg/dL; Troughs: undetectable

• Amikacin: Reserved for multi-drug resistant organisms

High-dose aminoglycosides• Advantages:

• Easier

• Optimizes pharmacodynamics

• Can decrease incidence of adverse reactions by only using for ≤ 5 days

• Disadvantages:

• Not for use in patients with a large Vd or rapid elimination

• Burns, dialysis/renal failure, pregnancy, peds, ascites

Aminoglycoside dosing• High-Dose Tobra/Gent

• Dose: 5-7 mg/kg (actual or adjusted, if obese)

• Do not exceed 600 mg

• Interval: dependent on 6 – 14 hour random level

• Goal trough: Undetectable, in order to allow kidneys time to recover from high dose, a drug-free period of ≈ 6 hours is necessary.

High-dose aminoglycoside nomogram (Tobra/Gent)

“Traditional” dosing Tobra/Gent• UTI: 1.25 – 1.5 mg/kg every 2 t1/2

• Pneumonia/Sepsis: 2 – 2.5 mg/kg every 3 t1/2

• Endocarditis: 1 mg/kg every 2 t1/2

• t1/2: 0.693 / [(0.00285 x CrCl) + 0.015]

• Check BOTH Peak and Trough around 5 half-lives 30 minutes before and after dose

Step-wise approach to dosing AGs1. Determine if pt. is candidate for high-dose

2. Calculate CrCl

3. Calculate dose / determine appropriate wt.

a. If on high-dose, check 10-hr random level and plot on nomogram

b. If on traditional dose, check peak AND trough at 5 half-lives

a. Calculate t1/2 and interval

Aminoglycoside Example 1• GM is a 77 year old male who develops

VAP, as one of your 3 drug regimen, you select tobramycin.

• Ht: 5’8”

• Wt: 78 kg

• Cr: 1 mg/dL

1.What dose of tobramycin would you use?

2.What interval?

3.When would you check levels?

Aminoglycoside Example 1• Dose:

• 5-7 mg/kg ; what weight do you use?

• Actual: 78

• 390 – 546 mg

• Interval/when to check levels:

• Start with q24h, but after 1st dose check a 10-hr level to determine if q24h will work

• What you order:

• Tobramycin 520 mg IV Q24, check random level 10 hrs after first dose.

Aminoglycoside Example 2• FJ is a 47 year old cirrhotic female with

pneumonia. It is decided to start her on gentamicin therapy.

• Ht: 5’8”

• Wt: 75 kg

• Cr: 0.8 mg/dL

1.What dose of gent do you recommend?

2.What interval?

3.When do you want to check levels?

Aminoglycoside Example 2

• Is the patient a candidate for high-dose?

• No—Cirrhosis/Ascites

• CrCl:

• 50 mL/min

• Dose:

• 2 - 2.5 mg/kg; what weight do you use?

• 75 kg (actual wt)

• 150 – 190 mg

Aminoglycoside Example 2• Interval:

• t1/2: 0.693/ [(0.00285 x 50) + 0.015]

• t1/2 = 4.4 hrs

• Interval = (3 x 4.4) = 13hr

• When do you check levels?• 5 x 4.4 = 18 hrs

• What you order: • Gentamicin 160 mg IV q12h, check

peak/trough around 3rd dose

Aminoglycoside “what-if’s”• What if the peak comes back too low?

• Increase the dose, or decrease the interval

• What if the peak comes back too high (>20 mg/dl)?• Decrease the dose, or increase the interval

• What if the trough is too high (>2 mg/dL)?• Increase the interval

• What if the creatinine increases on therapy?• Assess volume status

• Obtain U/A—casts

• Consider changing therapy

Summary• Critical illness alters PK of drugs

• Vanco and AGs are hydrophilic, so Vd can be increased

• Vancomycin dosing has become controversial

• AUC/MIC has the most evidence

• Aminoglycoside dosing should employ “high-dose” in order to maximize PD

CE question 1• Which of the following are true regarding

“concentration-dependent” antibiotics?

a) Rely upon the time above the minimum inhibitory concentration of the bacteria

b) Rely upon the peak concentration achieved in relation to the minimum inhibitory concentration of the bacteria

c) Rely upon the total area under the inhibitory curve in relation to the minimum inhibitory concentration of the bacteria

d) Both B and C

CE question 2• Which of the following is a true statement

regarding half-lives of antibiotics in the critically ill?

a) The half-lives of hydrophilic antibiotics will be increased

b) The half-lives of hydrophilic antibiotics will be decreased

c) The half-lives of lipophilic antibiotics will be increased

d) The half-lives of lipophilic antibiotics will be decreased

CE question 3• The most appropriate way to dose

Vancomycin, based upon the current evidence is:

a) Based upon a goal trough of 10 – 15 mg/dL

b) Based upon a goal peak of 30 – 40 mg/dL

c) Based upon a goal AUC/MIC > 400

d) Any of the above

CE question 4• The use of Aminoglycosides has fallen out

of favor because of which of the following?

a) Ototoxicity

b) Nephrotoxicity

c) Neuromuscular blockade

d) All of the above

CE question 5• A patient presents to your outpatient clinic with

shortness of breath and coughing up yellow sputum. Upon questioning you find out that he has COPD and has had 6 exacerbations in the past year. The physician would like to admit the patient to the hospital and start Tobramycin for suspected pseudomonas pneumonia. The patient weighs 80 kg and has normal kidney function. Which of the following would be the most appropriate dosing schemes?

a) 560 mg IV q24h, check random level in 12 hours

b) 560 mg IV q24h, goal trough of 2 mg/dL

c) 160 mg IV q12h, check random level in 12 hours

d) 80 mg IV q8h, goal trough of 1mg/dL

Kurt A. Wargo, Pharm.D., BCPS (AQ-ID)

Associate Clinical Professor

Auburn University Harrison School of Pharmacy

Pharmacokinetics in the critically ill adult patient:

A focus on vancomycin and aminoglycosides