Pharmacokinetics: Monitoring
Aminoglycoside and Vancomycin
Serum Levels
Betty Lee, Pharm.D.
Lucile Packard Children’s Hospital
July 3, 2012
Outline
• Vancomycin pharmacokinetics
• Aminoglycosides pharmacokinetics
• Guidelines for monitoring aminoglycoside
and vancomycin serum levels at LPCH
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) + 0.22 (TBW in kg) + 15
• Eliminated primarily by the renal route;
approximately 5% of the dose is metabolized
(Vancomycin Cl ~ Clcr)
Winter ME. Basic Clinical Pharmacokinetics. 5th ed. Philadelphia: Lippincott
Williams and Wilkins, 2010.
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
Lexicomp Online, June 2012
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%.
Winter ME. Basic Clinical Pharmacokinetics. 5th ed. Philadelphia: Lippincott
Williams and Wilkins, 2010.
Aminoglycosides
• Volume of distribution is ~0.25 L/kg
• 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)
5
• Obese patients:
V (obese pt) = (0.25 L/kg) (IBW) + 0.1 (TBW-IBW)
Winter ME. Basic Clinical Pharmacokinetics. 5th ed. Philadelphia: Lippincott
Williams and Wilkins, 2010.
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
Winter ME. Basic Clinical Pharmacokinetics. 5th ed. Philadelphia: Lippincott
Williams and Wilkins, 2010.
Lexicomp Online, June 2012
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 = 2.396 x e0.01863 (height in cm)
• Adjusted body weight = IBW + [0.4 x (TBW-IBW)]
Winter ME. Basic Clinical Pharmacokinetics. 5th ed. Philadelphia: Lippincott
Williams and Wilkins, 2010.
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. 2000
Jun;14(2):475-87.
Winter ME. Basic Clinical Pharmacokinetics. 5th ed. Philadelphia: Lippincott Williams and Wilkins, 2010.
Once-daily Aminoglycosides
• Less intensive monitoring of serum concentrations
• Nomogram developed by Nicolau D et al.
Antimicrob Agents Chemother 1995; 39:650-655.
• 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; 39:650-655.
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; 39:650-655.
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)
Guidelines for Monitoring Aminoglycoside and
Vancomycin Serum Levels
• Vancomycin:
• 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
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.
Guidelines for Monitoring Aminoglycoside
and Vancomycin Serum Levels
Aminoglycosides
Trough
Peak
Peak (synergy)
Peak (CF patients)
Once-daily Peak
Once-daily Random
(at 18-20 hours)
Vancomycin
Trough
Peak
Gentamicin/Tobramycin
< 2 mcg/ml
4-10 mcg/ml
3-5 mcg/ml
8-12 mcg/ml
15-25 mcg/ml
<1 mcg/ml
Amikacin
< 10 mcg/ml
20-30 mcg/ml
N/A
N/A
30-55 mcg/ml
<5 mcg/ml
*10-20 mcg/ml
25-40 mcg/ml
*For patients with meningitis or osteomyelitis, the goal trough levels should be 15-20 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 1991 27, Suppl. C,113-120.
Trujillo H, Robledo J et al. Single daily dose amikacin in paediatric patients with severe Gram-negative infections.
Journal of Antimicrobial Chemotherapy 1991 27, Suppl. C, 141-147.
Some Useful PK Formulas
• K = ln (C1 / C2 )
(t2 – t1)
• K = Cl
V
• t1/2 = 0.693 / 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.
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
Preterm infants up to 1 year
Full-term infants up to 1 year
1-12 years
13-21 years female
13-21 years male
Winter ME. Basic Clinical Pharmacokinetics. 5th ed. Philadelphia: Lippincott
Williams and Wilkins, 2010.
K
0.33
0.45
0.55
0.55
0.70
Some Useful PK Formulas
• BSA in m2 =
Patient’s weight in kg
70 kg
0.7
(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)
Winter ME. Basic Clinical Pharmacokinetics. 5th ed. Philadelphia: Lippincott
Williams and Wilkins, 2010.
Clinical Calculators
• Clinical calculator available at LPCH Intranet:
Lane Library  Specialty Portals  Pharmacy-Calculators
 Drug Levels-Vancomycin & Aminoglycoside
Pharmacokinetics
• http://medcalc.com.laneproxy.stanford.edu/pk/
• Other calculators available at Pharmacy Network:
Pharmacy Network  Pharmacokinetic Monitoring
•
•
CF Kinetics - by Dr. Carlos Milla
NICU Drug Kinetics - by Dr. William Benitz
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
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):95-108.
CF Kinetics - by
Dr. Carlos Milla
NICU - Drug Kinetics
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
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; 39:650-655.
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):95108.