Clinical Pharmacokinetics of

VANCOMYCIN
WELLA AFRIANI
1111012041
VancomycinA glycopeptide











http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=1399

INTRODUCTION
Inhibits bacterial cell wall synthesis
Time-dependent effect
Gram positive bacteria
Indications :
Documented infections:
Methicillin/Cephalosporin-Resistant Staphycoccal infection.
Penicillin/Cephalosporin-Resistant Streptococcal infection.
Staphy./Strep. infection in patient allergic to penicillin.
Staphy. infection in patient with renal disease undergoing
hemodialysis.
Penicillin-Resistant Diphtheroid infection.
Severe antibiotic-associated enterocolitis.
Indications (cont) :
Empiric Therapy:
Suspected MRSA nosocomial infection.
Meningitis in patient who had neurosurgery.
Neutropenic febrile patient not responding or allergic to
penicillin.
Suspected Staphy. infection in patient with renal disease
undergoing hemodialysis.
Prophylaxis:
Endocarditis in patient allergic to penicillin.
Prosthetic valve placement in patient allergic to
penicillin.
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 ~ Cl
cr
)
Winter ME. Basic Clinical Pharmacokinetics. 5th ed. Philadelphia: Lippincott
Williams and Wilkins, 2010.
Vancomycin
t
1/2
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
ADVERSE DRUG REACTION
Ototoxicity (tinnitus, fullness in the ear)
Nephrotoxicity
An increase in SrCr of 0.5mg/dL or greater, or as 50% increase
from baseline.
Occurs at a rate of 5% with Vancomycin alone and increase to
22% with addition of Aminoglycosides.
Red-Man Syndrome (hypotension, upper body
maculopapular rash)
Cutaneous reaction (urticaria, angioedema,
erythema)
Neutropenia (within 15 30 days of drug initiation)
Fever
PHARMACOKINETIC CHARACTERISTICS
Two- or three-compartment model.
Bioavailability
Per oral < 5%
Intravenous 100%
Protein binding 30 55%
Excretion
Renal: >90% unchanged in urine
KEY PARAMETERS
C
target
Conventionally P = 40 50 mg/L
T = 10 15 mg/L
Continuous inf usion C
ave
ss
= 12 18 mg/L
F <0.05 PO
V
d
0.7 (0.5 1.0) (L/kg)
CL
Vanco
0.65CL
Cr
x 0.06 (L/H)
t 7 (H)
K
e
0.00083(CL
Cr
) + 0.0044 (H
-1
)

*CL
Cr
in ml/min
Some Useful PK Formulas
K = ln (C
1
/ C
2
)
(t
2
t
1
)

K = Cl
V
t
1/2
= 0.693 / K

For steady state, bolus model :
Dose

= (Css
1
) (V) (1- e
-K
)
(e
-Kt
1

)


Winter ME. Basic Clinical Pharmacokinetics. 5th ed. Philadelphia: Lippincott
Williams and Wilkins, 2010.
Some Useful PK Formulas
CL
cr
for Children = (K) (Height in cm) (BSA)
(ml/min) SCr
ss
(1.73m
2
)

where the K value is based on the infant/childs age:
Age K
Preterm infants up to 1 year 0.33
Full-term infants up to 1 year 0.45
1-12 years 0.55
13-21 years female 0.55
13-21 years male 0.70
Winter ME. Basic Clinical Pharmacokinetics. 5th ed. Philadelphia: Lippincott
Williams and Wilkins, 2010.
Some Useful PK Formulas
BSA in m
2
= Patients weight in kg (1.73 m
2
)


CL
cr
for males = (140 - Age) (Weight)
(ml/min) (72) (SCr
ss
)


CL
cr
for females = (0.85) (140 - Age) (Weight)
(ml/min) (72) (SCr
ss
)


Winter ME. Basic Clinical Pharmacokinetics. 5th ed. Philadelphia: Lippincott
Williams and Wilkins, 2010.
70 kg
0.7
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)= C
0
= initial concentration (mg/L)
k elimination rate constant (hr
-1
)
Gentamicin and Tobramycin:
AUC
24
= 70 100 mg.hr/L
Cystic fibrosis patients: tobramycin AUC
24
~ 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.
Guidelines for Monitoring Aminoglycoside
and Vancomycin Serum Levels

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 N/A
Once-daily Peak 15-25 mcg/ml 30-55 mcg/ml
Once-daily Random
(at 18-20 hours)
<1 mcg/ml <5 mcg/ml
Trough *10-20 mcg/ml
Peak 25-40 mcg/ml
Aminoglycosides
Vancomycin
*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.

INITIATING VANCOMYCIN
Cultures
Appropriate C&S obtain within 48hrs before
starting therapy.
Antibiotic therapy modified (if necessary) within
24hrs of the C&S results.
Renal Function
Estimated CL
Cr
within 24hrs of initiating therapy.
Monitoring CL
Cr
every 3 5 days during therapy.
INITIATING VANCOMYCIN (CONT)
Dosage Regimen & Monitoring Needs
Conventional dosing
Peak & Trough concentration method
Continuous infusion
Trough concentration method

INITIATING VANCOMYCIN (CONT)
Conventional Dosage Regimen
Initial per dose is between 10 15 mg/kg body wt
Dosage interval based on estimated CL
Cr
.
Rate of infusion not more than 20 mg/min.
Adjustment based on measured levels.
Serum Drug Concentration
Levels taken at steady-state.
If stable renal function, repeat trough levels once a
week.
Trough levels obtained if with other nephrotoxic drugs.
Trough and peak levels obtained if:
Not responding to therapy.
Altered physiologic parameters
INITIATING VANCOMYCIN (CONT)
Continuous Infusion Regimen
Infusion rate is based on estimated CL
Cr
and
targeted C
ave
ss
(15 mg/L).
Rate of infusion, R
o
(mg/H)
R
o
= CL
vanco
C
ave
ss

= V
d
K
e
C
ave
ss

Adjustment based on measured C
ave
ss

INITIATING VANCOMYCIN (CONT)
Lakes Method
Target serum levels:
T = 5 10 mg/L (30 min before the next infusion)
P = 20 30 mg/L (15 min after the end of infusion)
Maintenance dose (per dose) = 8 mg/kg (LBW)
To be give at Q H interval:
CL
Cr
(ml/min) (H)
>90 6
70 89 8
46 69 12
30 45 18
15 29 24
Rodvolds Method
Target serum levels:
T = 5 10 mg/L (30 min before the next infusion)
P = 30 40 mg/L (15 min after the end of infusion)
Daily maintenance dose
Dose (mg/kg TBW per 24H) = (0.227(CL
Cr
) + 5.67
Interval:
CL
Cr
(ml/min) (H)
>65 8
46 65 12
20 39 24
10 19 48
INITIATING VANCOMYCIN (CONT)
ADJUSTING THE DOSAGE REGIMEN
ln C
p

t
i


t
C
min

C
max

C*
predose

C*
C
postdos
e

C
t,max

Sawchuck-Zaske Method
(Conventional/Multiple short infusion)
Determine the t
K
e
= ln (C
peak
/C
trough
) / (t
trough
t
peak
)
t = 0.693 / K
e

Determine the V
d

V
d
= R
o
x 1 e
-K
e
t
i

.
K
e
(C
max
(C
min
e
-K
e
t
i
)
*R
o
= mg/H infusion
Determine the
new


new
= ln (C
max

desired
/ C
min

desired
) + t
i
K
e


ADJUSTING THE DOSAGE REGIMEN (CONT)
Sawchuck-Zaske Method (cont)
Determine the R
o
new
()
R
o
new
= K
e
V
d
C
max desired
x 1 e
-K
e

1 e
-K
e
t
i

Predict C
t,max
at t after the end of infusion and C
min

C
t,max
= R
o
x 1 e
-K
e
t
i

x e
-K
e
t
K
e
(C
max
(C
min
e
-K
e

)
C
min
= C
t,max
e
-K
e
( - (t
i
t)
ADJUSTING THE DOSAGE REGIMEN (CONT)
Continuous Infusion Method
Determine the CL
vanco
CL
vanco
*
= R
o
/ achieved C
ave
ss
Determine the new R
o
(mg/H)
R
o
= CL
vanco
*
x

targeted C
ave
ss

ADJUSTING THE DOSAGE REGIMEN (CONT)
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