1. Pharmacokinetics in the critically ill adult patient: A focus on vancomycin and aminoglycosides
Kurt A. Wargo, Pharm.D., BCPS (AQ-ID)
Associate Clinical Professor
Auburn University Harrison School of Pharmacy

2. Objectives Discuss the basic concepts of pharmacokinetics
Demonstrate the clinical utility of pharmacokinetic dosing and monitoring
Discuss vancomycin dosing guidelines and implications to clinical practice
Discuss aminoglycoside dosing options

3. Pharmacokinetics Absorption Distribution Metabolism Elimination
Therapeutic Drug Monitoring
Peaks and troughs

4. 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 ;37:840-51

5. 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

6. Changes to antibiotic half-life
t1/2 = (0.693 X Vd) / Cl
(t1/2 = / ke)
Both ↑ Vd and ↓ Cl can increase the half-lives of antibiotics
Management of hypotension increases Cl

7. Effects of critical illness on PK parameters
Sepsis
Leaky Capillaries
Increased Vd
Low Serum Concentrations
Increased CO
Increased Cl
Normal organ function
Unchanged Vd
Normal Serum Concentrations
Organ dysfunction
Decreased Cl
High Serum Concentrations
Roberts et al. Crit Care Med ;37:840-51

8. Pharmacodynamic (PD) Relationships
MIC Goal: %T > MIC = 50%
%T > MIC
AUC Goal: AUC/MIC > 125 for G (-),
and >35 for G(+)
Cmax
Goal: Cmax/MIC >10
Concentration
(mg/L)
Schematic of antimicrobial pharmacodynamics depicting possible dynamic relationships of showing the possible integration of concentration (Cmax), AUC and / or time of exposure with available MIC data.
Time (h)
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:

9. Pharmacodynamic Properties
Time-Dependent
Concentration-Dependent
Mixed
Antibiotics
β-lactams
Carbapenems
Erythromycin
Clarithromycin
Aminoglycosides
Metronidazole
Daptomycin
Vancomycin
Linezolid
Fluoroquinolones
Azithromycin
Tigecycline
Tetracyclines
PD Parameter
%T > MIC
Cmax / MIC
AUC24 / MIC

10. When to draw peaks and troughs
Steady State: 5 half-lives of the drug (steady state)

11. Vancomycin

12. 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

13. 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 mg/dL

14. 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 mg/L to attain AUC/MIC of 400 is desirable”
“Trough serum concentrations can be used as a surrogate marker of AUC/MIC”

15. 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

16. Vancomycin “traditional” dosing
t1/2 = / [( x CrCl) ]
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: (2.3 x inches > 60)
Ideal Weight Female: (2.3 x inches >60)
Adjusted Weight: 0.4(Actual – Ideal) + Ideal

17. 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 Nomogram
CrCl (mL/min)
AUC Dose (mg)*
> 125
1500 Q12h
1250 Q12h
70-99
1000 Q12h
50-69
1500 Q24h
30-49
1000 Q24h
*Assumes MIC = 1

18. Step-wise approach to traditional dosing of Vancomycin
Determine if loading dose is necessary
Calculate maintenance dose (either mg/kg or 19 mg/kg of actual body weight)
Calculate necessary weight for CrCl equation
Calculate CrCl
Calculate half-life
Calculate dosing interval
Determine when/if you want to check a trough

19. 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

20. 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 mg IV x 1, then 1500 mg IV q24hrs

21. Vancomycin Example 1 (AUC dosing)
CrCl = 58
Dose = 1500 mg IV Q24h, assuming MRSA has an MIC = 1 mg/L
CrCl (mL/min)
AUC Dose (mg)*
> 125
1500 Q12h
1250 Q12h
70-99
1000 Q12h
50-69
1500 Q24h
30-49
1000 Q24h

22. 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

23. 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

24. Vancomycin Example 2 (AUC dosing)
CrCl = 105 mL/min
Dose = 1250 mg IV Q12h
CrCl (mL/min)
AUC Dose (mg)*
> 125
1500 Q12h
1250 Q12h
70-99
1000 Q12h
50-69
1500 Q24h
30-49
1000 Q24h

25. 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

26. Aminoglycosides

27. 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

28. The Bad Reputation

29. 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

30. 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

31. 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

32. So what is their utility???
Any infection where Pseudomonas aeruginosa is suspected and you want to “double cover”
→ increasing FQ resistance

33. 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

34. 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

35. 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.

36. High-dose aminoglycoside nomogram (Tobra/Gent)

37. “Traditional” dosing Tobra/Gent
UTI: – 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: / [( x CrCl) ]
Check BOTH Peak and Trough around 5 half-lives 30 minutes before and after dose

38. Step-wise approach to dosing AGs
Determine if pt. is candidate for high-dose
Calculate CrCl
Calculate dose / determine appropriate wt.
If on high-dose, check 10-hr random level and plot on nomogram
If on traditional dose, check peak AND trough at 5 half-lives
Calculate t1/2 and interval

39. 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
What dose of tobramycin would you use?
What interval?
When would you check levels?

40. 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.

41. 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
What dose of gent do you recommend?
What interval?
When do you want to check levels?

42. Aminoglycoside Example 2
Is the patient a candidate for high-dose?
No—Cirrhosis/Ascites
CrCl:
50 mL/min
Dose:
mg/kg; what weight do you use?
75 kg (actual wt)
150 – 190 mg

43. Aminoglycoside Example 2
Interval:
t1/2: / [( x 50) ]
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

44. 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

45. 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

46. CE question 1
Which of the following are true regarding “concentration-dependent” antibiotics?
Rely upon the time above the minimum inhibitory concentration of the bacteria
Rely upon the peak concentration achieved in relation to the minimum inhibitory concentration of the bacteria
Rely upon the total area under the inhibitory curve in relation to the minimum inhibitory concentration of the bacteria
Both B and C

47. CE question 2
Which of the following is a true statement regarding half-lives of antibiotics in the critically ill?
The half-lives of hydrophilic antibiotics will be increased
The half-lives of hydrophilic antibiotics will be decreased
The half-lives of lipophilic antibiotics will be increased
The half-lives of lipophilic antibiotics will be decreased

48. CE question 3
The most appropriate way to dose Vancomycin, based upon the current evidence is:
Based upon a goal trough of 10 – 15 mg/dL
Based upon a goal peak of 30 – 40 mg/dL
Based upon a goal AUC/MIC > 400
Any of the above

49. CE question 4
The use of Aminoglycosides has fallen out of favor because of which of the following?
Ototoxicity
Nephrotoxicity
Neuromuscular blockade
All of the above

50. 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?
560 mg IV q24h, check random level in 12 hours
560 mg IV q24h, goal trough of 2 mg/dL
160 mg IV q12h, check random level in 12 hours
80 mg IV q8h, goal trough of 1mg/dL

51. Pharmacokinetics in the critically ill adult patient: A focus on vancomycin and aminoglycosides
Kurt A. Wargo, Pharm.D., BCPS (AQ-ID)
Associate Clinical Professor
Auburn University Harrison School of Pharmacy