TDM of Aminoglycoside Antibioticsihuc.edu.iq/uploadiraq/029ed29f850397TDM 5th Stage Lec 3.pdf · 6 - Select equations (either IV bolus equations or IV infusion equations): How you

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TDM

Lecture 3

5th Stage

TDM of Aminoglycoside Antibiotics

The aminoglycoside antibiotics are widely used for the treatment of gram-negative

infections, often in combination with a β-lactam antibiotic such as penicillins.

Aminoglycosides include gentamicin, tobramycin, netilmicin, kanamycin, and

amikacin. Aminoglycosides are excreted mainly through the kidneys; therefore,

their elimination is greatly affected by renal impairment.

Conventional dosing vs extended-interval dosing

The conventional method of dosing aminoglycoside antibiotics is to administer

multiple daily doses (usually three times, every 8 hours). In order to take advantage

of concentration-dependent bacterial killing and the post-antibiotic effects,

extended-interval (once per day) aminoglycoside administration is a simple and

effective dosing option today. Studies have shown comparable microbiologic and

clinical cure rates for many infections and about the same rate of nephrotoxicity as

with conventional dosing.

Because of these two different methods of dosage administration, it is important to

identify which is being used when discussing therapeutic drug monitoring and

pharmacokinetics calculations.

Therapeutic drug monitoring (TDM) of aminoglycosides includes:

1 - Initial dosage determination of aminoglycosides.

2 - Use of aminoglycosides serum concentrations to alter dosage

Initial dosage determination methods

1 - Pharmacokinetic Dosing Method

2 - Hull and Sarubbi Nomogram Method

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3- Hartford nomogram method

4- Literature based recommended dosing.

1 - Pharmacokinetic Dosing Method

It is the classic and most commonly used method for initial dosage determination of

aminoglycosides.

- What are the strength points of this method?

1 - It is the most flexible method.

2 - It is the most individualized method.

3 - It is the most customized method for each specific disease conditions (obesity,

renal impairment, etc.).

4 - Can be used for both type of dosing (conventional and extended-interval).

- What are the weak points of this method?

It is mathematically complicated as compared to other methods (its calculations are

usually long).

Steps of Solution

1 - Find out patient conditions (if the patient is obese or not, have renal impairment or not).

2 - Estimate creatinine clearance (CrClest).

3 - Estimate elimination rate constant (Ke) and half-life (t1/2).

4 - Estimate volume of distribution (V).

5 - Select steady-state concentrations.

6 - Select equations (either IV bolus equations or IV infusion equations).

7 - Select dosing (conventional or extended).

8 - Calculate dosage interval (τ) “tau”.

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9 - Calculate maintenance dose (D in case of IV bolus or K0 in case of IV infusion).

10 - Calculate loading dose (LD) if needed.

Examples

Example1

JM is a 50 years old, 70-kg (5 ft 10 in) male with gram-negative pneumonia. His

current serum creatinine is 0.9 mg/dL, and it has been stable over the last 5 days

since admission. Compute a gentamicin dose for this patient using conventional

dosing?

Before answer, we should consider the following notes:

Note1

a - Normal serum creatinine levels:

men / 0.5-1.5 mg/dL

women / 0.6-1.2 mg/dL

b - Normal creatinine clearance levels:

men / 97-137 mL/min

women / 88-128 mL/min

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Note2

We consider the patients as obese if they have a 30% increase in body weight more

than their ideal body weight.

Ideal body weight for men = 50 + 2.3 Kg for each inch over 5 feet

Ideal body weight for women = 45.5 + 2.3 Kg for each inch over 5 feet

Foot = 30.48 cm

Inch = 2.54 cm

1 foot = 12 inch

Answer:

1 - Find out patient conditions:

He is normal (why?) no obesity - (his weight is 70 Kg) and no renal impairment – (his

serum Creatinine is 0.9 mg/dL)

Ideal body weight for this patient = 50 + (2.3 * 10) = 50 + 23 = 73 kg

2 - Estimate creatinine clearance (CrClest):

When the patient has a stable serum creatinine and is not obese, Cockcroft-Gault

equation can be used to estimate creatinine clearance:

CrClest = [ (140 - age) * BW]

72 * SCr

CrClest = [ (140 - 50 years) * 70 kg]

72 * 0.9 mg/dL CrClest = 97 mL/min

Note that you should multiply the results by 0.85 for females.

3 - Estimate elimination rate constant (Ke) and half-life (t1/2):

a - From creatinine clearance (CrCl), the elimination rate constant (Ke) is estimated:

Ke = 0.00293 (CrCl) + 0.014

Ke = 0.00293 (97 mL/min) + 0.014 = 0.298 h−1

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b - From elimination rate constant (Ke), the half-life (t1/2) is estimated:

t1/2 = 0.693 /Ke = 0.693 / 0.298 h−1 = 2.3 h

4 - Estimate volume of distribution (V):

The patient is normal (not obese), so we use the following equation:

V = 0.26 L/Kg * (body weight)

V = 0.26 L/Kg * (70 Kg)

V = 18.2 L

5 - Select steady-state concentrations:

Gram-negative pneumonia patients treated with aminoglycoside antibiotics require

steady-state peak concentrations (Cmax,ss) equal to 8–10 μg/mL; steady-state

trough concentrations (Cmin,ss) should be less than 2 μg/mL to avoid toxicity.

Therefore, we will select the following values:

Cssmax = 9 μg/mL Cssmin = 1 μg/mL

6 - Select equations (either IV bolus equations or IV infusion equations):

How you choose equations in step 8 and step 9 of solution?

a - IV bolus equations:

Strength points: More simple and save time.

Weak point: Used if CrCl is equal or less than 30 mL/min and if CrCl is more than 30

mL/min you should use IV infusion equations only.

b - IV infusion equations:

Strength point: Used in all conditions whatever CrCl value is (less than or more than

30 mL/min).

Weak point: More complicated and consume time.

In this example, we should use IV infusion method, why?

Because CrCl is 97 mL/min (more than 30 mL/min).

7 - Select dosing (conventional or extended):

As requested in the example, we will select conventional dosing.

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Note: The pharmacokinetic method can be used for both conventional & extended

dosing methods.

8 - Calculate dosage interval (τ) “tau”:

By using the following equation:

(Note: t΄ is the Infusion time)

τ = [ (lnCmax,ss − lnCmin,ss) / Ke ] + t΄

τ = [ (ln 9 μg/mL− ln 1 μg/mL) / 0.298 h−1 ] + 1 h

τ = 8.4 h

- Note: Dosage intervals should be rounded to clinically acceptable intervals of 8, 12,

24, 36, 48, and 72 hrs whenever possible. In this case, the dosage interval would be

rounded to 8 hours (τ = 8 h)

9 - Calculate maintenance dose (K0):

By using the following equation: (Note: μg/mL = mg/L)

K0 = Cmax,ss ∗ Ke ∗ V [ ( 1−e−Keτ) / ( 1−e−Ket΄) ]

K0 = 9 mg/L * 0.298 h−1 ∗ 18.2 L [ (1 − e−(0.298 hr−1) (8h) ) / (1−e−(0.298 hr−1) (1h) ) ]

K0 = 172 mg

- This maintenance dose should be rounded to the nearest (5-10 mg) and becomes

170 mg.

- The prescribed maintenance dose would be 170 mg every 8 hours.

10 - Calculate loading dose (LD) if needed:

Loading doses should be considered for patients with creatinine clearance values

below 60 mL/min. The administration of a loading dose in these patients will allow

achievement of therapeutic peak concentrations quicker than if maintenance doses

alone are given.

Note: In this example CrClest = 97 mL/min (more than 60 mL/min)

- The loading dose should not be given to the patient.

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LD=k0 / (1-e-ke. τ)

LD= 170 mg / (1-e-0.298 hr-1 * 8 hr)

LD= 170 mg / 0.907

LD= 187 mg (very close to maintenance dose that’s why it should not be

calculated).

Example2

The same patient in example 1, but with serum Creatinine 3.5 mg/dL

Answer


- The patient weight still normal (70 kg), but serum creatinine level indicating renal

impairment.


- By using Cockcroft-Gault equation:


72 * SCr

CrClest = [ (140 - 50 years) * 70 kg]




Ke = 0.00293 (CrCl) + 0.014

Ke = 0.00293 (25 mL/min) + 0.014 = 0.087 h−1


t1/2 = 0.693 / Ke = 0.693 / 0.087 h−1 = 8 h

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V = 0.26 L/Kg * (70 Kg)

V = 18.2 L



steady-state peak concentrations (Cmax,ss) equal to 8–10 μg/mL; steady-state

trough concentrations (Cmin,ss) should be less than 2 μg/mL to avoid toxicity.


Cssmax = 9 μg/mL

Cssmin = 1 μg/mL


- We will choose IV bolus equations in step 8 and step 9 because it is more simple

and creatinine clearance is 25 mL/min (less than 30 mL/min)

7 - Select dosing (convential or extended):

As requested in the example, we will select convential dosing.



τ = [ lnCmax,ss − lnCmin,ss / Ke ]

τ = [ ln 9 μg/mL− ln 1 μg/mL / 0.087 h−1]

τ = 25 h


24, 36, 48, and 72 hrs whenever possible. In this case, the dosage interval would be

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rounded to 24 hours.

τ = 24 h

9 - Calculate maintenance dose (D):


D = Cmax,ss ∗ V (1−e−Keτ)

D = 9 mg/L * 18.2 L (1 − e−(0.087 hr−1) (24h) )

D = 143 mg


145 mg. The prescribed maintenance dose would be 145 mg every 24 hours.



below 60 mL/min. Note: In this example CrClest = 25 mL/min

LD = Cmax,ss ∗ V

LD = 9 mg/L * 18.2 L

LD = 164 mg

- This loading dose is rounded to 165 mg.

- We will give this patient a loading dose of 165 mg followed by a maintenance dose

of 145 mg every 24 hours.

Example3

The same patient in example 2, but use extended interval dosing instead of

conventional dosing.

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Answer


- The patient weight still normal (70 kg), but serum creatinine level indicating renal

impairment.


- By using Cockcroft-Gault equation:


72 * SCr

CrClest = [ (140 - 50 years) * 70 kg]




Ke = 0.00293 (CrCl) + 0.014

Ke = 0.00293 (25 mL/min) + 0.014 = 0.087 h−1


t1/2 = 0.693 / Ke = 0.693 / 0.087 h−1 = 8 h




V = 0.26 L/Kg * (70 Kg)

V = 18.2 L



steady-state peak concentrations (Cmax,ss) equal to or more than 20 μg/mL;

steady-state trough concentrations (Cmin,ss) should be less than 1 μg/mL to avoid

toxicity.

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Cssmax = 20 μg/mL

Cssmin = 0.5 μg/mL


- We will choose IV bolus equations because it is more simple and creatinine

clearance is 25 mL/min (less than 30 mL/min)


As requested in the example, we will select extended interval dosing.



τ = [ lnCmax,ss − lnCmin,ss) / Ke ]

τ = [ ln 20 μg/mL− ln 0.5 μg/mL) / 0.087 h−1]

τ = 42 h


24, 48, and 72 hrs whenever possible. In this case, the dosage interval would be

rounded to 48 hours.

τ = 48 h

9 - Calculate maintenance dose (D):


D = Cmax,ss ∗ V (1−e−Keτ)

D = 20 mg/L * 18.2 L (1 − e−(0.087 hr−1) (48h) ) D = 358 mg


360 mg. The prescribed maintenance dose would be 360 mg every 48 hours.

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Example4

ZW is a 35 years old, 150-kg (5 ft 5 in) female with an intra-abdominal infection. Her

current serum creatinine is 1.1 mg/dL, and is stable. Compute a tobramycin dose for

this patient using conventional dosing?

Answer


The patient is obese (her weight is 150 kg)

Ideal body weight for this patient = 45.5 + (2.3 * 5) = 45.5 + 11.5 = 57 kg

- Her serum creatinine is 1.1 mg/dL (within normal range).


Since this patient is obese, the Salazar and Corcoran equation can be used to

estimate creatinine Cl:

CrClest = ( 146 - age ) [ ( 0.287 * BW ) + ( 9.74 * Ht2 ) ]

60 * SCr

CrClest = ( 146 - 35 y ) [ (0.287 * 150 kg) + (9.74 * {1.65m}2) ]




Ke = 0.00293 (CrCl) + 0.014

Ke = 0.00293 (117 mL/min) + 0.014 = 0.357 h−1


t1/2 = 0.693 / Ke = 0.693 / 0.357 h−1 = 1.9 h


Since this patient is obese, this equation can be used to estimate V:

IBD: Ideal body weight TBW: Total body weight

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V = 0.26 L/Kg * { IBD + 0.4 (TBW - IBD) }

V = 0.26 L/Kg * { 57 kg + 0.4 (150 kg-57 kg) } V = 24.5 L


Intra-abdominal infection patients treated with aminoglycoside antibiotics require

steady-state peak concentrations (Css max) equal to 5–7 μg/mL; steady-state trough

(Cssmin) concentrations should be less than 2 μg/mL to avoid toxicity.

Therefore, we will select the following values: Cssmax = 6 μg/mL

Cssmin = 0.5 μg/mL


In this example, we will use IV infusion equations in step 8 and step 9

Because CrCl is 117 mL/min (more than 30 mL/min).


As requested in the example, we will select conventional dosing.


By using the following equation: (Note: t΄ is the Infusion time)

τ = [ lnCmax,ss − lnCmin,ss) / Ke ] + t΄

τ = [ ln 6 μg/mL− ln 0.5 μg/mL) / 0.357 h−1] + 1 h τ = 8 h

9 - Calculate maintenance dose (K0):


K0 = Cmax,ss ∗ Ke ∗ V [(1−e−Keτ) / (1−e−Ket΄) ]

K0 = 6 mg/L * 0.357 h−1 ∗ 24.5 L [ (1 − e−(0.357 hr−1) (8h) ) / (1−e−(0.357 hr−1) (1h) ) ]

K0 = 165 mg

- The prescribed maintenance dose would be 165 mg every 8 hours.

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below 60 mL/min.

Note: In this example CrClest = 117 mL/min

- The loading dose should not be given to the patient.

LD= K0/ (1-e-Ke. τ)

LD=165 mg/ (1-e-0.357 h-1*8)

LD=175 mg very close to maintenance dose.

2 - Hull and Sarubbi Nomogram Method

- For patients who do not have conditions that alter volume of distribution (V), i.e.

the only two patient-specific factors that change when using the pharmacokinetic

dosing method is patient weight and creatinine clearance.

Because of this, it is possible to make a simple nomogram to handle uncomplicated

patients with a standard volume of distribution.

The Hull and Sarubbi aminoglycoside dosing nomogram is a quick and efficient way

without using complicated pharmacokinetic equations. With a simple modification,

it can also be used for obese patients.

What are the strength points of this method?

Simple, efficient, and not complicated.

What are the weak points of this method?

- Cannot be used in all diseases and conditions.

- Cannot be used for extended interval dosing (only for conventional dosing).

Steps of solution

1 - Estimate creatinine clearance (CrCl) using Cockcroft-Gault method. Note that

you should multiply the results by 0.85 for females. Use the Salazar and Corcoran

method if weight more than 30% above IBW.

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2 - Choose desired steady-state serum concentrations.

3 - Select loading dose in mg/kg to provide peak serum concentrations in range

listed in following table for the desired aminoglycoside antibiotic:

Aminoglycoside Usual Loading Dose Expected Peak Serum Concentrations

Tobramycin

Gentamicin

Netilmicin

1.5-2 mg/kg 4-10 μg/mL

Amikacin

Kanamycin

5-7.5 mg/kg 15-30 μg/mL

Note: Use patient weight if within 30% of IBW, otherwise use adjusted body weight

(ABW) equation:

ABW = IBW + [0.40 (TBW − IBW)]

4 - Select maintenance dose (as a percentage of loading dose) to continue peak

serum concentrations indicated in the previous table according to desired dosage

interval and the patient creatinine clearance.

Note: To maintain usual peak/trough ratio, use dosage intervals in clear areas.

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Summary of steps of solution:

1 - Estimate creatinine clearance (CrCl)

2 - Choose desired steady-state serum concentrations

3 - Select loading dose

4 - Select maintenance dose (as a percentage of loading dose)

Examples

Example1

JM is a 50-year-old, 70-kg (5 ft 10 in) male with gram-negative pneumonia. His


since admission. Compute a gentamicin dose for this patient using conventional

dosing.

Answer

1 - Estimate creatinine clearance:

This patient has a stable serum creatinine and is not obese. The Cockcroft-Gault



72 * SCr

CrClest = [ (140 - 50 years) * 70 kg]

72 * 0.9 mg/dL

CrClest = 97 mL/min

2 - Choose desired steady-state serum concentrations:


steady-state peak concentrations (Cssmax) equal to 8–10 μg/mL.

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Usual Loading Dose

mg/Kg

Expected Peak Serum

Concentrations μg/mL

1.5 4

1.6 5

1.7 6

1.8 7

1.9 8

2 9

2 10

3 - Select loading dose:

A loading dose (LD) of 2 mg/kg will provide a peak concentration of 8–10 μg/mL.

LD = 2 mg/kg * Body weight

LD = 2 mg/kg * 70 kg

LD = 140 mg

4 - Select maintenance dose (as a percentage of loading dose):

From the nomogram, the estimated half-life is 2–3 hours, the maintenance dose

(MD) is 90% of the loading dose and the dosage interval is 8 hours.

MD = 0.90 * LD

MD = 0.90 * 140 mg = 126 mg

- Doses should be rounded to the nearest 5–10 mg. The prescribed maintenance

dose would be 125 mg every 8 hours.

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Example 2

The same patient in example 1, but with serum Creatinine 3.5 mg/dL

Answer

1 - Estimate creatinine clearance (CrCl):

This patient is not obese. The Cockcroft-Gault equation is used to estimate CrCl:


72 * SCr

CrClest = [ (140 - 50 years) * 70 kg]






A loading dose (LD) of 2 mg/kg will provide a peak concentration of 8–10 μg/mL.

LD = 2 mg/kg * Body weight

LD = 2 mg/kg * 70 kg

LD = 140 mg


From the nomogram, the estimated half-life is 9.9 hours, the maintenance dose


MD = 0.57 * LD

MD = 0.57 * 140 mg = 79.8 mg



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Example3

The same patient in example 2, but use extended interval dosing instead of

conventional dosing.

Answer

Hull and Sarubbi nomogram method cannot be used for extended interval dosing

(only for conventional dosing).

Example4

ZW is a 35 years old, 150-kg (5 ft 5 in) female with an intra-abdominal infection. Her

current serum creatinine is 1.1 mg/dL, and is stable. Compute a tobramycin dose for

this patient using conventional dosing?

Answer

1 - Estimate creatinine clearance (CrCl):

The patient is obese (her weight is 150 kg)

Ideal body weight for this patient = 45.5 + (2.3 * 5) = 45.5 + 11.5 = 57 kg

Since this patient is obese, the Salazar and Corcoran equation can be used to

estimate creatinine Clearance:

CrClest = ( 146 - age ) [ ( 0.287 * BW ) + ( 9.74 * Ht2 ) ]

60 * SCr

CrClest = ( 146 - 35 y ) [ (0.287 * 150 kg) + (9.74 * {1.65m}2) ]

60 * 1.1 mg/dL

CrClest = 117 mL/min


Intra-abdominal infections patients treated with aminoglycoside antibiotics require


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- A loading dose of 1.7 mg/kg will provide a peak concentration of 5–7 μg/mL.

- Because the patient is obese, we will use adjusted weight (ABW) equation:

ABW = IBW + [ 0.40 ( TBW − IBW ) ]

ABW = 57 Kg + [ 0.40 ( 150 Kg − 57 Kg ) ] = 94 Kg

LD = 1.7 mg/Kg * ABW

LD = 1.7 mg/Kg * 94 Kg = 160 mg


From the nomogram, the estimated half-life is 2–3 hours, the maintenance dose


MD = 0.90 * LD

MD = 0.90 * 160 mg = 144 mg



Comparison of results

Method Example 1

Dosage

Example 2

Dosage

Example 4

Dosage

Pharmacokinetics Dosing

Method

170 mg every

8 hours

145 mg every

24 hours

165 mg every

8 hours

Hull and Sarubbi

Nomogram Method

125 mg every

8 hours

80 mg every

12 hours

145 mg every

8 hours

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3- Hartford nomogram method:

This method is used mainly for extended interval dosing of aminoglycoside

antibiotics.

Estimated creatinine clearance can be used to determine dosage interval as seen in

the following table:

Example:

JM is a 50-year-old, 70-kg (5 ft 10 in) male with gram-negative pneumonia. His


since admission. Compute a gentamicin dose for this patient using extended interval

dosing.

Answer:

1 - Estimate creatinine clearance:

This patient has a stable serum creatinine and is not obese. The Cockcroft-Gault



72 * SCr

CrClest = [ (140 - 50 years) * 70 kg]

72 * 0.9 mg/dL

CrClest = 97 mL/min

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A dose of 7 mg/kg gentamicin will provide a peak concentration >20 μg/mL.

3- Calculate initial dose (D):

D= 7 mg/Kg*70 Kg

D= 490 mg rounded into 500 mg.

4- Determine dosage interval using Hartford nomogram:

Since creatinine clearance is greater than 60 ml/min then a dose of 500 mg should

be given every 24 hour.

5- Literature based recommended dosing:

This method is mainly used for calculating aminoglycoside antibiotics in neonate

patients.

Homework:

PQ is a 75-year-old, 62-kg (5 ft 9 in) male with gram negative sepsis. His current

serum creatinine is 1.3 mg/dL, (stable since admission). Compute a gentamicin

dose for this patient to provide a steady-state peak concentration of 8 μg/mL and

a steady-state trough concentration of 1.5 μg/mL using conventional dosing.

Documents

TDM of Aminoglycoside Antibioticsihuc.edu.iq/uploadiraq/029ed29f850397TDM 5th Stage Lec 3.pdf · 6 - Select equations (either IV bolus equations or IV infusion equations): How you