Vancomycin : 2
❶ Clinical uses
is a glycopeptide antibiotic used to treat severe gram-positive infections due to
organisms that are resistant to other antibiotics such as methicillin-resistant
staphylococci and ampicillin-resistant enterococci.
Vancomycin is bactericidal and exhibits:
❶ Time-dependent killing or concentration independent i.e kill bacteria most
effectively if serum conc. 3-5 > MIC of bacteria.
❷ Mechanism of action
inhibition of cell wall synthesis.
❸ Method of administration
By intermittent IV infusion during 1hr (at least) to reduce incidence of adverse
effects like anaphylactic like reaction, ototoxicity, nephrotoxicity.
Vancomycin : 3
❹ Summary of kinetic parameters
Bioavailability (F) IV = 100%, orally <5% but used to treat P.M.C
0.7L/Kg
Volume of Distribution (Vd) - Penetrate only into inflamed meninges
- Penetrate poorly into lung (serum : lung conc.)=(6:1)
Fraction unbound (Fu) ≈45% (Bind to albumin )
Elimination Renally by GFR as unchanged
Clearance (Cl) 0.695*CrCl+0.05
Elimination half life (t0.5) 4- 6 hrs at normal renal function
L.D = 25-30 mg/kg (based on ABW) given at rate 1g/hr 2 or 4
Dosing (iv only)
dose/day
Compartmental model Two compartmental model with distribution phase
Vancomycin : 4
❺ When to sample
1 hr after the end of infusion to get Cmax
0.5 hr before next infusion to get Cmin
1hr after infusion end is required to allow the distribution phase to complete
Plasma conc. At the end of
100
infusion
Plasma conc. During
infusion Plasma conc. 1hr after end of infusion
(end of distribution phase)
Conc. (mg/liter)
Plasma conc. During
10 elimination phase
1
5 10 15 20 25
Time (hrs)
Vancomycin : 5
❻ Infusion rate related adverse effects
Urticarial or erythematous reactions,
intense flushing (known as the “red-man” or “red-neck” syndrome),
tachycardia, and hypotension
All can be reduced by slowing the rate of infusion
❼ Concentration related adverse effects
① Nephrotoxicity
↑ if Trough cpss > 15 μg/mL
is reversible if antibiotic is drawn or dose adjusted if renal function was declined
① Ototoxicity
↑ if serum conc. Is high like 80 mg/liter
Vancomycin : 6
❽ Conditions alter its pharmacokinetics parameters
Vancomycin : 7
❽ Conditions alter its pharmacokinetics parameters
Vancomycin : 8
❽ Other Conditions alter its pharmacokinetics parameters
① Age
Volume of distribution not significantly changed,
Clearance is changed with age according to creatinine clearance and maturation of
kidneys
Age Creatinine clearance Half life
Premature infant 15ml/min 10hr
Full term baby 30ml/min 7hr
3months 50ml/min 4hr
4-8years 130-150ml/min 2-3hr
12>=years 130-150ml/min 2-3hr
Vancomycin : 9
❽ Other Conditions alter its pharmacokinetics parameters
① Age
for new babies the dose is depended on neonatal age & body weight
Magnitude of single dose per Kg is not changed but the frequency is changed
Frequency
Weight dose
Age <7days Age > 7days
<1.2kg 15mg/kg Every 24hrs Every 24hrs
1.2 -2kg 10 -15mg/kg 12-18hr 8-12hr
>2kg 10 -15mg/kg 8-12hr 6-8hr
Vancomycin : 10
❽ Other Conditions alter its pharmacokinetics parameters
① Age
for Children, Magnitude of single dose per Kg is changed & the frequency is changed
Changes depends majorly on severity of infection
Infection type dose Frequency
Meningitis 60mg/kg Every 6hrs
Sever Systemic infection 40 -60mg/kg Every 6 hours
Other infections 40mg/kg Every 6-8hours
Changes depends majorly on severity of infection
Vancomycin : 11
❽ Other Conditions alter its pharmacokinetics parameters
② Hemodialysis
for low flux dialysis, (<10%) of the total vancomycin body stores is removed during a 3- to
4-hour dialysis period
high-flux” filter, serum concentrations decrease by 1/3 during the dialysis period
then slowly increase or “rebound” for the next 10–12 hours reaching nearly 90% of pre-
dialysis values. So it need to measure plasma conc. after high flux dialysis
③ Peritoneal dialysis
removes only a negligible amount of vancomycin
Patient that has peritonitis during peritoneal dialysis:
90% of vancomycin is removed from peritoneal dialysate containing vancomycin
during 6 hr
50% of vancomycin is removed from peritoneal dialysate containing vancomycin
during 6 hr if patient has renal failure
Vancomycin : 12
❽ Other Conditions alter its pharmacokinetics parameters
④ HemoFilteration
will remove Vancomycin from the body
The hemofiltration sieving coefficient for vancomycin is 0.80
Recommended initial doses for critically ill patients with acute renal failure undergoing
continuous venous hemofiltration (CVVH) are :
loading dose of 15–20 mg/kg followed by 250–500 mg every 12 hours
continuous ateriovenous hemofiltration (CAVH) are:
Initial dose is 500 mg every 24–48 hours
Because of pharmacokinetic variability, vancomycin concentrations should be measured
in hemofiltration patients
Vancomycin : 13
❾ Drug interactions
① With aminoglycosides
will increase incidence of nephrotoxicity
② With warfarin
45% increase in prothrombin time over baseline values
Vancomycin : 14
❿ Initial dose determination methods
① Pharmacokinetic dosing method
Example 1 JM is a 50-year-old, 70-kg (5 ft 10 in) male with a methicillin-resistant S. aureus
(MRSA) wound infection. His current serum creatinine is 0.9 mg/dL, and it has been
stable over the last 5 days since admission. Compute a vancomycin dose for this patient.
Answer 1 Generally vancomycin is given as loading dose initially or given as intermittent
infusion with determined frequency.
If we need to calculate loading dose the equation will be
= ∗
.
LD= 980 mg ≈ 1000mg
20 mg/liter 0.7Liter * 70kg =49 liters
Vancomycin : 15
❿ Initial dose determination methods
① Pharmacokinetic dosing method
If we need to calculate daily dose the equation will be
= ∗
.(1- e k T )
τ= (ln Cssmax − ln Cssmin)/ke
20 mg/liter K=CL/vd
0.7L/kg *70 kg= 49 Liters Cmin= 7mg/L according to infection
Cl= 0.695CrCl +0.05
So it is better to solve it step by step
Vancomycin : 16
❿ Initial dose determination methods
① Pharmacokinetic dosing method
Estimate creatinine clearance
Patient is not obese and serum creatinine is stable. The Cockcroft-Gault equ. Is used
= 97
CrCl= [( ml/min
− ) ]/( ⋅ )
50 years 70kg 0.9mg/ dl
Estimate Vancomycin clearance
Cl= 71.05
= . ml/min
∗ = 4.263
+ L/hr
.
97 ml/min
Vancomycin : 17
❿ Initial dose determination methods
① Pharmacokinetic dosing method
Estimate Vd
Vd = . / ∗ =
Estimate Ke & T0.5
Ke=
Ke= Cl /vd
0.087/hr Vd = 49L
Cl= 4.263 l/hr
T0.5= 0.693 /Ke
T0.5 = 8 hr Ke= 0.087/hr
Select Cmin & Cmax
Cmax usually 20 mg/L while Cmin For Staph . aureus Infection is 7mg/L
Vancomycin : 18
❿ Initial dose determination methods
① Pharmacokinetic dosing method
Estimate T (taw)
T=Cssmax
τ= (ln 12.1hr − ln Cssmin)/k
Cmax =20mg/L Cmin= 7mg/L K=0.087/hr
Dosage intervals should be rounded to clinically acceptable intervals of 12 hours,18 hours,
24 hours, 36 hours, 48 hours, 72 hours, and multiples of 24 hours
Estimate daily dose
−k τ) T= 12.1hr
Dose=
D =Css635mg
max V(1− e K=0.087/hr
Cmax =20mg/L Vd=49L T= 12.1hr
Vancomycin doses should be rounded to the nearest 100–250 mg. This dose would
berounded to 750 mg.
For Obese patient use Salazar and Corcoran. Equ to estimate creatinine clearance
Vancomycin : 19
❿ Initial dose determination methods
Estimation of creatinine clearance methods
For obese patient . use Salazar and Corcoran
to estimate creatinine clearance for children and young adults
age 0–1 year, CrCl (in mL/min / 1.73 m2) = (0.45 ⋅ Ht (in meter))/SCr
age 0–20 year, CrCl (in mL/min / 1.73 m2) = (0.55 ⋅ Ht (in meter))/SCr
Vancomycin : 20
❿ Initial dose determination methods
② Moellering Nomogram Method
The stated goal of the nomogram is to provide average steady-state vancomycin
concentrations equal to 15 μg/mL (or 15 mg/L).
the patient’s creatinine clearance is computed and divided by their body weight so that
the units for creatinine clearance are mL/min/kg.
A modification of the vancomycin clearance/creatinine clearance equation can be made
that provides a direct calculation of the vancomycin maintenance dose.
M = ∗
Cl (in mL/min/kg) = 0.695(CrCl in mL/min/kg) + 0.05
D (in mg/h/kg) = [(15 mg/L ⋅ 60 min/h) /1000 mL/L][0.695(CrCl in mL/min/kg) + 0.05]
D (in mg/h/kg) = 0.626(CrCl in mL/min/kg) + 0.05
Vancomycin : 21
❿ Initial dose determination methods
② Moellering Nomogram Method
Example 1 JM is a 50-year-old, 70-kg (5 ft 10 in) male with a methicillin-resistant S. aureus
(MRSA) wound infection. His current serum creatinine is 0.9 mg/dL, and it has been
stable over the last 5 days since admission. Compute a vancomycin dose for this patient.
Answer Estimate Creatinine clearance
= 97
CrCl= [( ml/min
− ) ]/( ⋅ )
50 years 70kg 0.9mg/ dl
Determine dosage interval and maintenance dose.
D (in mg/h/kg) = 0.626(CrCl in mL/min/kg) + 0.05
0.918mg/kg/hr 97ml/min/70kg=1.386
0.918mg/kg/hr .70kg = 64.2Dose
mg/hr = X 12hrby=770mg/12
is suggested hr ===750mg/12hr
the Moellering nomogram
Loading dose =15mg/kg * 70kg =1050 mg ===1000mg
Vancomycin : 22
❿ Initial dose determination methods
② Moellering Nomogram Method
Vancomycin : 23
❿ Initial dose determination methods
③ Matzke nomogram method
This method has been shown to provide precise and unbiased dosage recommendations,
Vancomycin : 24
❿ Initial dose determination methods
③ Matzke nomogram method
Example 1 JM is a 50-year-old, 70-kg (5 ft 10 in) male with a methicillin-resistant S. aureus
(MRSA) wound infection. His current serum creatinine is 0.9 mg/dL, and it has been
stable over the last 5 days since admission. Compute a vancomycin dose for this patient.
Answer Estimate Creatinine clearance
= 97
CrCl= [( ml/min
− ) ]/( ⋅ )
50 years 70kg 0.9mg/ dl
Determine dosage interval and maintenance dose.
Dose= 19mg/kg * 70kg =1330 mg
The dose rounded to nearest 250 or 100mg so 1250 mg is suggested
The dose is given every 0.6 day according to nomogram or 12 hr
Dose is suggested by the matzke nomogram
Loading dose =25mg/kg * 70kg =1750 mg
Vancomycin : 25
❿ Initial dose determination methods
④ Iiterature based method
Due to variability in vancomycin pharmacokinetics; clinicians preferred to use standard
vancomycin doses for pediatric patients is warranted.
Example 1 MM is a 3-day-old, 1015-g male with suspected methicillin-resistant S. aureus
(MRSA) sepsis. His serum creatinine has not been measured, but it is assumed
that it is typical for his age and weight. Compute an initial vancomycin dose for this patient.
a patient in this age and weight category should receive vancomycin 15 mg/kg every 24
hours. (see slide 9)
Dose= 15mg/kg * 1.015kg =15 mg given every 24 hr
Vancomycin : 26
⓫ Use vancomycin conc to alter the Dose
① Linear Pharmacokinetics Method
use Dnew/Css,new = Dold/Css,old or Dnew = (Css,new/Css,old)Dold
Example 1 JM is a 50-year-old, 70-kg (5 ft 10 in) male with a methicillin-resistant S. aureus
(MRSA) pneumonia. His current serum creatinine is 0.9 mg/dL, and it has been stable
over the last 5 days since admission. A vancomycin dose of 1000 mg every 12 hours was
prescribed and expected to achieve steady-state peak and trough concentrations equal
to 35 μg/mL and 15 μg/mL, respectively. After the 3rd dose, steady-state peak and trough
concentrations were measured and equaled 22 μg/mL and 10 μg/mL, respectively.
Calculate a new vancomycin dose that would provide a steady-state trough of 15 μg/mL.
Dose new = (15 / 10)*1000 =1500mg every 12hr
Check the new dose by using cmax css new = (1500 / 1000)*22 =33mg /L
Vancomycin : 27
⓫ Use vancomycin conc to alter the Dose
② Trough only Method
use τnew = (Css,old/Css,new)τold
Example 1 UI is a 55-year-old, 78-kg (height = 6 ft 1 in) male with a methicillin-resistant S.
aureus (MRSA) pneumonia. His current serum creatinine is 1.5 mg/dL, and ithas been
stable over the last 3 days since admission. A vancomycin dose of 1000 mgevery 24 hours
was prescribed and expected to achieve a steady-state trough concentra-tion equal to 15
μg/mL. After the second dose, the steady-state trough concentration equaled 7 μg/mL.
Calculate a new vancomycin dose that would provide a steady-state trough of 15 μg/mL.
τnew = (Css,old/Css,new)τold = (7 μg/mL / 15 μg/mL) 24 h = 11 h, round to 12 h
The dose will be 1000mg every 12 hrs
Vancomycin : 28
⓫ Use vancomycin conc to alter the Dose
③ Pharmacokinetic Concepts Method
By estimating actual pharmacokinetic parameters or surrogates for pharmacokinetic
parameters
The only requirement is a steady-state peak and trough vancomycin serum concentration
pair obtained before and after a dose
Example 1 JM is a 50-year-old, 70-kg (height = 5 ft 10 in) male with a methicillin-resistant
S. aureus (MRSA) wound infection. His current serum creatinine is 3.5 mg/dL, and it has
been stable over the last 5 days since admission. A vancomycin dose of 800 mg every 24
hours was prescribed and expected to achieve steady-state peak and trough conc. equal
to 20 μg/mL and 5 μg/mL, respectively. After the fourth dose, steady-state peak and
trough concentrations were measured and equaled 25 μg/mL and 12 μg/mL, respectively.
Calculate a new vancomycin dose that would provide a steady-state peak of 20 μg/mL
and a trough of 5 μg/mL.
use graph method to estimate no of half life present with dosing interval then find out
half life by dividing Taw on number of half life
Then estimate new dose by using Dnew = (ΔCnew/ΔCold)Dold
Then estimate Taw by estimate no of T0.5 required to change from Cmax to Cmin
Vancomycin : 29
⓫ Use vancomycin conc to alter the Dose
③ Pharmacokinetic Concepts Method
Same thing if we draw new cMax plot line to Cmin and find out no of half lives
100 Cmax=25mg /L Extrapolated Cmin=12 mg/L
Cmin=12 mg/L
LOG Conc. (mg/liter)
∆C=13mg/L
10
∆T=22.5hr
1
5 10 15 20 25
1.5 24
Time (hrs)
Vancomycin : 30
⓫ Use vancomycin conc to alter the Dose
③ Pharmacokinetic Concepts Method
Then 12/25 ≈ ½ ie Cmax change to cmin required 1half life
Since change from Cmax to next Cmin required 22.5 hr
So Half life will be 22.5 hr
Estimate the new dose
Dnew = (ΔCnew/ΔCold)Dold
Dose New =[(20 -5)/(25-12)]*800= 923 mg ≈ 1000mg
Estimate the new Taw
Then 5/20= 1/4 if we use (1/2)n ie n=2 half lives required to change from new Cmax to
new Cmin
Since founded t0.5 was 22.5 so the new taw will be 2*22.5 =45 hr ≈48hr
So the new estimated dose will be 1000mg given every 48 hrs
Vancomycin : 31
⓫ Use vancomycin conc to alter the Dose
③ Pharmacokinetic Concepts Method
Same thing if we draw new cMax plot line to Cmin and find out no of half lives
100
New Cmax After 1 half life = 10mg/L
20mg/L
=20mg/L
After 2 T0.5 =5mg/L
LOG Conc. (mg/liter)
10
1
10 20 30 40 50
Time (hrs)
Vancomycin : 32
⓫ Use vancomycin conc to alter the Dose
④ Standard one compartment model parameters method
It does not require steady-state concentrations. Just trough & max Concentration peri
infusion process
and 1–2 additional post dose serum vancomycin concentrations are obtained ideally with
one half life apart
The postdose serum concentrations are used to calculate the vancomycin elimination
rate constant and half-life The
STEADY-STATE ONE-COMPARTMENT MODEL PARAMETER METHOD
If Cssmax and Css Min are known then use same method above to find K eleimination,
Half life
ke = (ln Cssmax − ln Cssmin)/ (τ− t′ ); where (τ− t′ )= Taw – infusion time
Vd =Dose/ (CssMax-Cssmin)
In this method the patient’s real pharmacokinetic parameters are used in
the equations instead of population pharmacokinetic estimates.
Vancomycin : 33
⓫ Use vancomycin conc to alter the Dose
④ Standard one compartment model parameters method
Example 1 JM is a 50-year-old, 70-kg (height = 5 ft 10 in) male with a methicillin-resistant
S. aureus (MRSA) wound infection. His current serum creatinine is 3.5 mg/dL, and it has
been stable over the last 5 days since admission. A vancomycin dose of 800 mg every 24
hours was prescribed and expected to achieve steady-state peak and trough conc. equal
to 20 μg/mL and 5 μg/mL, respectively. After the fourth dose, steady-state peak and
trough concentrations were measured and equaled 25 μg/mL and 12 μg/mL, respectively.
Calculate a new vancomycin dose that would provide a steady-state peak of 20 μg/mL
and a trough of 5 μg/mL.
ke = (ln Cssmax − ln Cssmin)/ (τ− t′ ); where (τ− t′ )= Taw – infusion time
=(ln25-ln12)/(24-1.5) == ke =0.0326/hr
Vd =Dose/ (CssMax-Cssmin)
Vd =800mg /(25-12) =61.5 L
Determine Taw =τ= (ln Cssmax − ln Cssmin)/ke = (ln 20 μg/mL − ln 5 μg/mL)/0.0326 h−1
new Taw =τ= 42 hr rounded to 48 hr
D =Cssmax V(1 − e−keτ) = 20 mg/L ⋅ 61.5 L [1 − e−(0.0326 h−1)(48 h)]= 974 mg, rounded to
1000 mg
THANKS
