1. Lucile Packard Children’s Hospital
Pharmacokinetics: Monitoring Aminoglycoside and Vancomycin Serum Levels
Betty Lee, Pharm.D.
Lucile Packard Children’s Hospital
July 3, 2012

2. Outline Vancomycin pharmacokinetics Aminoglycosides pharmacokinetics
Guidelines for monitoring aminoglycoside and vancomycin serum levels at LPCH

3. Vancomycin Volume of distribution: An average value of 0.7 L/kg or
For patient older than 18 years:
V (L) = 0.17 (age in yr) (TBW in kg) + 15
Eliminated primarily by the renal route; approximately 5% of the dose is metabolized (Vancomycin Cl ~ Clcr)
Volume of distribution ranges between 0.5 and 1 L/kg
TBW = total body weight including any excess adipose and/or third space fluid weight
Poorly adsorbed orally (F oral <5%)
Winter ME. Basic Clinical Pharmacokinetics. 5th ed. Philadelphia: Lippincott Williams and Wilkins, 2010.

4. Vancomycin t1/2 elimination Newborns: 6-10 hours
Infants & Children 3 months to 4 years: 4 hours
Children > 3 years: 2.2 – 3 hours
Adults: 5 – 11 hours; significantly prolonged with renal impairment
Half-life elimination: Biphasic: Terminal:
End-stage renal disease: hours
Lexicomp Online, June 2012

5. Vancomycin
Bactericidal for most gram-positive organisms, except against enterococci
Vancomycin-induced ototoxicity has been primarily reported in patients with vancomycin concentrations > 80 mg/L.
As a single agent, vancomycin is associated with a low incidence of nephrotoxicity; however, when it is combined with aminoglycoside, the incidence may be as high as 30%.
Vancomycin exhibits concentration-independent killing
Pediatric patients—high clearances and short half-lives
Winter ME. Basic Clinical Pharmacokinetics. 5th ed. Philadelphia: Lippincott Williams and Wilkins, 2010.

6. Aminoglycosides Volume of distribution is ~0.25 L/kg Obese patients:
Pediatric patients younger than 5 years tend to have a larger volume of distribution, declining from an initial value of 0.5 L/kg to adult value of 0.25 L/kg
V(children 1-5 yrs) = [(0.5 L/kg) - (age in years x 0.25)] (wt in kg)
Obese patients:
V (obese pt) = (0.25 L/kg) (IBW) (TBW-IBW) 5
Correct time to sample collection is important because aminoglycosides have a relative short half-life and a small but significant distribution phase.
Volume of distribution wide range of 0.1 to 0.5 L/lg
Distribute pooly into adipose tissue, use lean body weight.
Winter ME. Basic Clinical Pharmacokinetics. 5th ed. Philadelphia: Lippincott Williams and Wilkins, 2010.

7. Aminoglycosides
Aminoglycosides are eliminated almost entirely by the renal route (Cl = Clcr)
t1/2 elimination (Gentamicin)
Infants < 1 week: 3 – 11.5 hours
Infants 1 week to 6 months: 3 – 3.5 hours
Adults: 1.5 – 3 hours
End-stage renal disease: 36 – 70 hours
Correct time to sample collection is important because aminoglycosides have a relative short half-life and a small but significant distribution phase.
T1/ hr for normal renal function adult pt; hr for anephric adult pt
Elimination half-life is a function of the volume of distribution and clearance. Since renal function varies considerably among individuals, the half-life is also variable.
Cl hemodialysis = 1.8 L/hr
Winter ME. Basic Clinical Pharmacokinetics. 5th ed. Philadelphia: Lippincott Williams and Wilkins, 2010.
Lexicomp Online, June 2012

8. Aminoglycosides Dose based on lean weight
If total body weight (TBW) >20% ideal body weight (IBW), use adjusted body weight
Children (1-18 years) IBW calculation (IBW in kg, height in cm):
IBW = (height2 x 1.65)/1000
IBW = x e (height in cm)
Adjusted body weight = IBW + [0.4 x (TBW-IBW)]
Adjusted body weight = Non-obese weight
Winter ME. Basic Clinical Pharmacokinetics. 5th ed. Philadelphia: Lippincott Williams and Wilkins, 2010.

9. Aminoglycosides Bactericidal activity is concentration-dependent
Postantibiotic effect that results in depressed bacterial growth after plasma concentrations have fallen below the MIC
Decreased risk of adaptive resistance
Saturable uptake mechanisms within the renal cortex and inner ear indicate that extended interval dosing may also minimize the likelihood of developing nephrotoxicity and ototoxicity.
Fisman DN, Kaye KM. Once-daily dosing of aminoglycoside antibiotics. Infect Dis Clin North Am Jun;14(2):
Winter ME. Basic Clinical Pharmacokinetics. 5th ed. Philadelphia: Lippincott Williams and Wilkins, 2010.

10. Once-daily Aminoglycosides
Less intensive monitoring of serum concentrations
Nomogram developed by Nicolau D et al. Antimicrob Agents Chemother 1995; 39:
Recommends a single level be drawn 6 to 14 hours after the dose
With extended interval dosing there should be no significant accumulation with multiple dosing, therefore, measurements can be obtained after any dose.
Nicolau D et al. Experience with a once-daily aminoglycoside program administered to 2,184 adult patients. Antimicrob Agents Chemother 1995; 39:

11. Nicolau D et al. Antimicrob Agents Chemother 1995; 39:650-655
Nicolau D et al. Experience with a once-daily aminoglycoside program administered to 2,184 adult patients. Antimicrob Agents Chemother 1995; 39:

12. Guidelines for Monitoring Aminoglycoside and Vancomycin Serum Levels at LPCH
Order serum levels two times a week for aminoglycoside and at least once a week for vancomycin
Order serum creatinine once or twice per week
For patients undergoing intermittent hemodialysis, vancomycin random levels every three to four days are indicated to ensure serum levels are greater than 10 mcg/mL (or 3 to 4 times above the MIC of the infecting organisms)

13. Guidelines for Monitoring Aminoglycoside and Vancomycin Serum Levels
Order a single trough level before the 4th dose of vancomycin
Trough is drawn within 30 minutes before the next dose
Routine peak levels are not necessary for most patients
Consider ordering peak level after the 3rd dose in patients with selected circumstances, such as bacterial meningitis
Peak level is drawn 60 minutes after the end of a 60-min infusion

14. Guidelines for Monitoring Aminoglycoside and Vancomycin Serum Levels
Aminoglycosides:
Order peak after the 3rd dose of aminoglycosides and trough before the 4th dose
Peak is drawn 30 minutes after end of a 30-min infusion
Trough is drawn within 30 minutes before the next dose
If once-daily dosing, order a peak level 60 minutes after end of a 60-min infusion and order a random level at hour 20.

15. Guidelines for Monitoring Aminoglycoside and Vancomycin Serum Levels
Aminoglycosides
Gentamicin/Tobramycin
Amikacin
Trough
< 2 mcg/ml
< 10 mcg/ml
Peak
4-10 mcg/ml
20-30 mcg/ml
Peak (synergy)
3-5 mcg/ml
N/A
Peak (CF patients)
8-12 mcg/ml
Once-daily Peak
15-25 mcg/ml
30-55 mcg/ml
Once-daily Random
(at hours)
<1 mcg/ml
<5 mcg/ml
Extended-Interval Once-daily Dosing of Aminioglycosides in Adult and Pediatric Patients with Cystic Fibrosis. Pharmacotherapy 2010;30(1):95-108
CF Gent/tobra naïve patient dose 10 mg/kg once daily
Cmax mg/L
Cmin < 1 mg/L
AUC ~100 mg.hr/L ( mg.hr/L)
CF Amikacin dose mg/kg once daily
Cmax mg/L
Cmin mg/L
AUC mg.hr/kg
Vancomycin
Trough
*10-20 mcg/ml
Peak
25-40 mcg/ml
*For patients with meningitis or osteomyelitis, the goal trough levels should be mcg/ml.
Viscoli C, Dudley, M et al. Serum Concentrations and safety of single daily dosing of amikacin in children undergoing bone marrow transplantation. Journal of Antimicrobial Chemotherapy , Suppl. C,
Trujillo H, Robledo J et al. Single daily dose amikacin in paediatric patients with severe Gram-negative infections. Journal of Antimicrobial Chemotherapy , Suppl. C,

16. Some Useful PK Formulas
K = ln (C1 / C2 )
(t2 – t1)
K = Cl V
t1/2 = / K
For steady state, bolus model :
Dose = (Css1 ) (V) (1- e-Kτ )
(e-Kt1 )
Winter ME. Basic Clinical Pharmacokinetics. 5th ed. Philadelphia: Lippincott Williams and Wilkins, 2010.

17. Some Useful PK Formulas
CLcr for Children = (K) (Height in cm) (BSA)
(ml/min) SCrss (1.73m2)
where the K value is based on the infant/child’s age:
Age K
Preterm infants up to 1 year 0.33
Full-term infants up to 1 year 0.45
1-12 years
13-21 years female
13-21 years male
Winter ME. Basic Clinical Pharmacokinetics. 5th ed. Philadelphia: Lippincott Williams and Wilkins, 2010.

18. Some Useful PK Formulas
0.7
BSA in m2 = Patient’s weight in kg (1.73 m2)
CLcr for males = (140 - Age) (Weight)
(ml/min) (72) (SCrss)
CLcr for females = (0.85) (140 - Age) (Weight)
(ml/min) (72) (SCrss)
70 kg
BSA = square root of (wt in kg x ht in cm/3600)
Winter ME. Basic Clinical Pharmacokinetics. 5th ed. Philadelphia: Lippincott Williams and Wilkins, 2010.

19. Clinical Calculators Clinical calculator available at LPCH Intranet:
Lane Library  Specialty Portals  Pharmacy-Calculators  Drug Levels-Vancomycin & Aminoglycoside Pharmacokinetics
Other calculators available at Pharmacy Network: Pharmacy Network  Pharmacokinetic Monitoring
CF Kinetics - by Dr. Carlos Milla
NICU Drug Kinetics - by Dr. William Benitz

20. Additional Information
Area Under the Curve (AUC) = area under the plasma drug concentration vs. time curve
AUC = dose administered/drug clearance
AUC (mg.hr/L)= C0 = initial concentration (mg/L) k elimination rate constant (hr-1)
Gentamicin and Tobramycin:
AUC24 = 70 – 100 mg.hr/L
Cystic fibrosis patients: tobramycin AUC24 ~ 100 to 125
Cystic fibrosis patients—aiming Tobramycin AUC24 = 100 to 125
Amikacin AUC24 approximately threefold higher than gent and tobra
Prescott WA Jr, Nagel JL. Extended-interval once-daily dosing of aminoglycosides in
adult and pediatric patients with cystic fibrosis. Pharmacotherapy 2010 Jan;30(1):

21. CF Kinetics - by Dr. Carlos Milla
Cystic fibrosis patients—aiming Tobramycin AUC24 = 100 to 125
t1 and t2 is the time from the START of the infusion.
Goal AUC is typically 100 – 125 for CF patients
CF team typically checks the level after the FIRST dose. Since trough is usually undetectable, accumulation of the drug over time is not significant. After reaching goal AUC, team will usually check a trough level to make sure the level is < 1.
You can always manually calculate AUC using the following equations, which will give a similar result as the program

22. NICU - Drug Kinetics

23. Additional Information
Vancomycin—some oncology or ICU patients may need up to q 6 hour dosing
Never give aminoglycoside more frequent than q 8 hour
Aminoglycoside—if long term therapy, need hearing test

24. References
Michael E. Winter. Basic Clinical Pharmacokinetics. 5th edition. Lippincott Williams & Wilkins, 2010.
Nicolau D et al. Experience with a once-daily aminoglycoside program administered to 2,184 adult patients. Antimicrob Agents Chemother 1995; 39:

25. References
Rybak M, Lomaestro B, Rotschafer JC et al. Therapeutic monitoring of Vancomycin in adult patients: A consensus review of the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, and the Society of Infectious Diseases Pharmacists. Am J Health-Syst Pharm 2009;66:82-98.
Prescott WA Jr, Nagel JL. Extended-interval once-daily dosing of aminoglycosides in adult and pediatric patients with cystic fibrosis. Pharmacotherapy 2010 Jan;30(1):