TDM of Aminoglycoside Antibiotics

Transcription

1 TDM Lecture 3 5 th 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 1

2 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. 2

3 9 - Calculate maintenance dose (D in case of IV bolus or K0 in case of IV infusion) 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 / mg/dl women / mg/dl b - Normal creatinine clearance levels: men / ml/min women / ml/min 3

4 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 = Kg for each inch over 5 feet Ideal body weight for women = Kg for each inch over 5 feet Foot = 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) = = 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: [ (140 - age) * BW] 72 * SCr [ ( years) * 70 kg] 72 * 0.9 mg/dl 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 = (CrCl) Ke = (97 ml/min) = h 1 4

5 b - From elimination rate constant (Ke), the half-life (t1/2) is estimated: t1/2 = /Ke = / 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. 5

6 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) / 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 * h 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 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 97 ml/min (more than 60 ml/min) - The loading dose should not be given to the patient. 6

7 LD=k 0 / (1-e -ke. τ ) LD= 170 mg / (1-e hr-1 * 8 hr ) LD= 170 mg / 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 1 - Find out patient conditions: - The patient weight still normal (70 kg), but serum creatinine level indicating renal impairment. 2 - Estimate creatinine clearance (CrCl est ): - By using Cockcroft-Gault equation: [ (140 - age) * BW] 72 * SCr [ ( years) * 70 kg] 72 * 3.5 mg/dl 25 ml/min 3 - Estimate elimination rate constant (Ke) and half-life (t1/2): a - From creatinine clearance (CrCl), the elimination rate constant (Ke) is estimated: Ke = (CrCl) Ke = (25 ml/min) = h 1 b - From elimination rate constant (Ke), the half-life (t1/2) is estimated: t1/2 = / Ke = / h 1 = 8 h 7

8 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): - 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. 8 - Calculate dosage interval (τ) tau : By using the following equation: τ = [ lncmax,ss lncmin,ss / Ke ] τ = [ ln 9 μg/ml ln 1 μg/ml / h 1 ] τ = 25 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 8

9 rounded to 24 hours. τ = 24 h 9 - Calculate maintenance dose (D): By using the following equation: (Note: μg/ml = mg/l) D = Cmax,ss V (1 e Keτ ) D = 9 mg/l * 18.2 L (1 e (0.087 hr 1) (24h) ) D = 143 mg - This maintenance dose should be rounded to the nearest (5-10 mg) and becomes 145 mg. The prescribed maintenance dose would be 145 mg every 24 hours Calculate loading dose (LD) if needed: Loading doses should be considered for patients with creatinine clearance values below 60 ml/min. Note: In this example 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. 9

10 Answer 1 - Find out patient conditions: - The patient weight still normal (70 kg), but serum creatinine level indicating renal impairment. 2 - Estimate creatinine clearance (CrCl est ): - By using Cockcroft-Gault equation: [ (140 - age) * BW] 72 * SCr [ ( years) * 70 kg] 72 * 3.5 mg/dl 25 ml/min 3 - Estimate elimination rate constant (K e ) and half-life (t 1/2 ): a - From creatinine clearance (CrCl), the elimination rate constant (Ke) is estimated: Ke = (CrCl) Ke = (25 ml/min) = h 1 b - From elimination rate constant (Ke), the half-life (t1/2) is estimated: t1/2 = / Ke = / h 1 = 8 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 or more than 20 μg/ml; steady-state trough concentrations (Cmin,ss) should be less than 1 μg/ml to avoid toxicity. 10

11 Therefore, we will select the following values: Cssmax = 20 μg/ml Cssmin = 0.5 μg/ml 6 - Select equations (either IV bolus equations or IV infusion equations): - We will choose IV bolus equations because it is more simple and creatinine clearance is 25 ml/min (less than 30 ml/min) 7 - Select dosing (conventional or extended): As requested in the example, we will select extended interval dosing. 8 - Calculate dosage interval (τ) tau : By using the following equation: τ = [ lncmax,ss lncmin,ss) / Ke ] τ = [ ln 20 μg/ml ln 0.5 μg/ml) / h 1 ] τ = 42 h - Note: Dosage intervals should be rounded to clinically acceptable intervals of 8, 12, 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): By using the following equation: (Note: μg/ml = mg/l) D = Cmax,ss V (1 e Keτ ) D = 20 mg/l * 18.2 L (1 e (0.087 hr 1) (48h) ) D = 358 mg - This maintenance dose should be rounded to the nearest (5-10 mg) and becomes 360 mg. The prescribed maintenance dose would be 360 mg every 48 hours. 11

12 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 - Find out patient conditions: The patient is obese (her weight is 150 kg) Ideal body weight for this patient = (2.3 * 5) = = 57 kg - Her serum creatinine is 1.1 mg/dl (within normal range). 2 - Estimate creatinine clearance (CrCl est ): Since this patient is obese, the Salazar and Corcoran equation can be used to estimate creatinine Cl: ( age ) [ ( * BW ) + ( 9.74 * Ht2 ) ] 60 * SCr ( y ) [ (0.287 * 150 kg) + (9.74 * {1.65m} 2 ) ] 60 * 1.1 mg/dl 117 ml/min 3 - Estimate elimination rate constant (Ke) and half-life (t1/2): a - From creatinine clearance (CrCl), the elimination rate constant (Ke) is estimated: Ke = (CrCl) Ke = (117 ml/min) = h 1 b - From elimination rate constant (Ke), the half-life (t1/2) is estimated: t1/2 = / Ke = / h 1 = 1.9 h 4 - Estimate volume of distribution (V): Since this patient is obese, this equation can be used to estimate V: IBD: Ideal body weight TBW: Total body weight 12

13 V = 0.26 L/Kg * { IBD (TBW - IBD) } V = 0.26 L/Kg * { 57 kg (150 kg-57 kg) } V = 24.5 L 5 - Select steady-state concentrations: 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 6 - Select equations (either IV bolus equations or IV infusion equations): 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). 7 - Select dosing (conventional or extended): As requested in the example, we will select conventional dosing. 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 6 μg/ml ln 0.5 μg/ml) / h 1 ] + 1 h 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 = 6 mg/l * h 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. 13

14 10 - Calculate loading dose (LD) if needed: Loading doses should be considered for patients with creatinine clearance values below 60 ml/min. Note: In this example 117 ml/min - The loading dose should not be given to the patient. LD= K 0 / (1-e -Ke. τ ) LD=165 mg/ (1-e 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. 14

15 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 Amikacin Kanamycin mg/kg 4-10 μg/ml mg/kg 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. 15

16 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 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. Answer 1 - Estimate creatinine clearance: This patient has a stable serum creatinine and is not obese. The Cockcroft-Gault equation can be used to estimate creatinine clearance: [ (140 - age) * BW] 72 * SCr [ ( years) * 70 kg] 72 * 0.9 mg/dl 97 ml/min 2 - Choose desired steady-state serum concentrations: Gram-negative pneumonia patients treated with aminoglycoside antibiotics require steady-state peak concentrations (Cssmax) equal to 8 10 μg/ml. 16

17 Usual Loading Dose mg/kg Expected Peak Serum Concentrations μg/ml 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. 17

18 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: [ (140 - age) * BW] 72 * SCr [ ( years) * 70 kg] 72 * 3.5 mg/dl 25 ml/min 2 - Choose desired steady-state serum concentrations: Gram-negative pneumonia patients treated with aminoglycoside antibiotics require steady-state peak concentrations (Cssmax) equal to 8 10 μg/ml. 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 9.9 hours, the maintenance dose (MD) is 57% of the loading dose and the dosage interval is 12 hours. MD = 0.57 * LD MD = 0.57 * 140 mg = 79.8 mg - Doses should be rounded to the nearest 5 10 mg. The prescribed maintenance dose would be 80 mg every 12 hours. 18

19 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 = (2.3 * 5) = = 57 kg Since this patient is obese, the Salazar and Corcoran equation can be used to estimate creatinine Clearance: ( age ) [ ( * BW ) + ( 9.74 * Ht 2 ) ] 60 * SCr ( y ) [ (0.287 * 150 kg) + (9.74 * {1.65m} 2 ) ] 60 * 1.1 mg/dl 117 ml/min 2 - Choose desired steady-state serum concentrations: Intra-abdominal infections patients treated with aminoglycoside antibiotics require steady-state peak concentrations (Cssmax) equal to 5 7 μg/ml. 19

20 3 - Select loading dose: - 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 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 * 160 mg = 144 mg - Doses should be rounded to the nearest 5 10 mg. The prescribed maintenance dose would be 145 mg every 8 hours. 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 20

21 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 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 extended interval dosing. Answer: 1 - Estimate creatinine clearance: This patient has a stable serum creatinine and is not obese. The Cockcroft-Gault equation can be used to estimate creatinine clearance: [ (140 - age) * BW] 72 * SCr [ ( years) * 70 kg] 72 * 0.9 mg/dl 97 ml/min 21

22 2 - Choose desired steady-state serum concentrations: 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. 22