Pharmacokinetics in the critically ill adult patient: Associate Clinical Professor

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 School of Pharmacy
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
• Vd unchanged
• Cl ↑ or ↓ based on renal fx • 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
Sepsis
Leaky
Capillaries
Increased CO
Normal organ
function
Organ
dysfunction
Increased Vd
Increased Cl
Unchanged Vd
Decreased Cl
Normal Serum
Concentrations
High Serum
Concentrations
Low Serum
Concentrations
Roberts et al. Crit Care Med. 2009;37:840-51
Pharmacodynamic (PD) Relationships
CmaxGoal: Cmax/MIC >10
AUC
Concentration
(mg/L)
Goal: AUC/MIC > 125 for G (-),
and >35 for G(+)
%T>MIC
MIC Goal: %T>MIC = 50%
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;35:399-405.
Pharmacodynamic Properties
Antibiotics
PD Parameter
Time-Dependent
ConcentrationDependent
Mixed
β-lactams
Carbapenems
Erythromycin
Clarithromycin
Aminoglycosides
Metronidazole
Daptomycin
Vancomycin
Linezolid
Fluoroquinolones
Azithromycin
Tigecycline
Tetracyclines
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 Nomogram
CrCl (mL/min) AUC Dose (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
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
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 Ca 2+ causing
immediate release of acetylcholine and postsynaptic
nerve binding
• Reverse with Ca-gluconate or Neostigmine
• Manifestations: dilated pupils, weak respiration, flaccid
paralysis
So what is their utility???
Any infection where Pseudomonas
aeruginosa is suspected and you want
to “double cover”
→ increasing FQ resistance
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 (actualor adjusted if obese)
• Do not exceed 600 mg
• Interval: dependent on 10-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 t 1/2
• Pneumonia/Sepsis: 2 – 2.5 mg/kg every 3 t 1/2
• Endocarditis: 1 mg/kg every 2 t 1/2
• 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 AGs
1. 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 1 st 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