Aminoglycoside Calculator

Description of Aminoglycoside Calculators

1. Initial dosing – Traditional method
   1. Ideal body weight (IBW):
      1. IBW for men = 50 kg + 2.3(height – 60 inches)
      2. IBW for women = 45.5 kg + 2.3(height – 60 inches)
   2. Volume of distribution (V):
      1. For non-obese adults the average volume of distribution is 0.26 L/kg (range 0.2-0.3 L/kg). For patients with cystic fibrosis the average V is 0.35 L/kg.
         1. IBW is used to calculate V for non-obese patients.
         2. When patients weigh >120% of their IBW, adjusted BW_0.4 is used.
            1. Adjusted BW_0.4 = IBW + 0.4(actual BW – IBW)
         3. If underweight, actual BW is used to calculate V.
      2. When patients are overhydrated the extra weight can be added to the estimated V. Since 1 L of water weighs 1 kg, if a 70 kg patient was 4 kg over his/her dry weight (weight in normal fluid balance), then 4 L could be added to the estimated V: 0.26 L/kg (70 kg) = 18.2, + 4 L = 22.2 L.
   3. Elimination rate constant (K) is estimated as follows:
      1. K = 0.0024(CrCl) + 0.01
      2. CrCl is calculated using the Cockcroft-Gault equation
         1. CrCl = [(140 – age) IBW] / (72 x SCr) *0.85 if female
            1. When patients weigh >130% of their IBW, adjusted BW_0.2 is used in the CG equation instead of IBW.
               1. Adjusted BW_0.2 = IBW + 0.2(actual BW – IBW)
            2. If underweight, actual BW is used instead of IBW.
         2. CrCl is capped at 120 mL/min.
   4. Half-life: T_1/2 = 0.693/ K
   5. Dosing interval (T): T = [Ln (Peak/ Trough)/ K] + 0.5
   6. Dose = 0.5*V*K*Peak*(1 – e ^–K*T)/(1 – e^-K*0.5)
   7. Distribution
      1. Aminoglycosides distribute well into synovial, peritoneal, ascitic, and pleural fluids, but poorly into CNS and the vitreous humor of the eye.
   8. Goal serum concentrations:
      1. Gentamicin for gram positive synergy, such as for endocarditis
         1. Peak: 3- 4 mcg/mL
         2. Trough: 0.5- <1 mcg/mL
      2.  Gentamicin/Tobramycin
         1. Peak
            1. 5-7 mcg/mL for infection sites with more susceptible bacteria such as intra-abdominal infections
            2. 8-10 mcg/mL for infection sites that are difficult to penetrate and with bacteria that have higher MIC values such as pseudomonal pneumonia
         2. Trough: 0.5- <2 mcg/mL
      3.  Amikacin
         1. Peak: 15- 35 mcg/mL (usual range is 20- 30 mcg/mL)
         2. Trough: <8 mcg/mL (ideal target 1- 4 mcg/mL)
   9. Calculated peak from the estimated dose
      1. Peak = Dose (1 – e ^–K*ti) / [ti*K*V*(1 – e^-K*T)]
   10. Calculated trough from the estimated dose
       1. Trough = Peak*e^{-K (T – ti)}
   11. Loading dose = V*Peak_SS
       1. This equation is based upon administration of the loading dose as the first dose on the maintenance dosing schedule.
   12. Inappropriate populations
       1. This calculator is NOT appropriate for the following patient populations or those who require a higher degree of clinical judgment: < 18 years old, unstable renal function, or hemodialysis.
2. Dose adjustments – Traditional method
   1. K = Ln(Peak/Trough)/(HoursToTrough – HoursToPeak)
   2. V = Dose* (1 – e^(-K*ti))/ (K*ti* (Cmax – (Cmin * e^(-K*ti))))
   3. Cmax = MeasuredPeak/(e^{-K*HoursPeakDrawnLate})
      1. Cmax occurs 1 hour after the start of infusion. If a 1-hour infusion is used, Cmax occurs when the infusion is completed. If a ½-hour infusion is used, a ½-hour waiting period is allowed for distribution to finish before peak concentrations are measured.
   4. Cmin = Cmax*e^-K*(T-1)
   5. New dose, dosing interval, and estimated peak and trough are calculated based on the same equations as the initial dosing calculator.
3. Extended interval dosing method
   1. Extended interval dosing may NOT be appropriate for the following patient populations or those who require a higher degree of clinical judgment:
      1. Ascites
      2. Anasarca
      3. Burns (>20% total body surface area)
      4. Children (<18 years old)
      5. CNS infections (such as meningitis)
      6. Cystic fibrosis
      7. Elderly (>80 years old)
      8. Gram positive synergy (such as endocarditis)
      9. Neutropenia
      10. Obesity (BMI >35- 40 kg/m²)
      11. Pregnancy
      12. Severe renal impairment (CrCl < 30 ml/min)
      13. Severe sepsis
   2. Rationale for using extended interval dosing
      1. Aminoglycosides have concentration dependent bactericidal activity. They require a high peak/MIC ratio for bacterial killing.
      2. Aminoglycosides have a post-antibiotic effect. They inhibit bacterial growth even after drug concentrations decrease to undetectable levels.
      3. Extended interval dosing results in equal or less nephrotoxicity and/or ototoxicity when compared to traditional dosing.
   3. Nomograms
      1. Hartford Nomogram
         1. One of the first published extended interval nomograms (1995).
         2. It uses the highest dose of gentamicin and tobramycin (7 mg/kg). This results in higher peak levels which may be beneficial for hospitals with higher average MICs to gentamicin or tobramycin.
      2. Urban-Craig Nomogram
         1. Published two years later (1997), it uses the maximal daily dose of gentamicin/tobramycin approved by the FDA (5 mg/kg).
         2. Designed to have drug concentrations <1 mg/mL for at least 4 hours, with a maximal post-antibiotic effect of 16 hours.
         3. Includes a 12-hour dosing interval for patients with very fast clearance.
         4. Designed for use with amikacin (15 mg/kg per dose) by multiplying the vertical drug level scale by 3.
      3. Dosage calculations
         1. The same method is used for calculating dosing weight for the Hartford and Urban-Craig nomograms:
            1. IBW is used to calculate doses for non-obese patients.
            2. When patients weigh >120% of their IBW, adjusted BW₄ is used.
               1. Adjusted BW₄ = IBW + 0.4(actual BW – IBW)
            3. If underweight, actual BW is used.
      4. Determining the dosing interval
         1. Check a random level 6- 14 hours after the first dose, and plot the result on the nomogram to determine the dosing interval.
         2. If the result is on the line, the longer interval is chosen to avoid drug accumulation and provide a sufficient drug-free period.
         3. Consider re-checking a random level after the second dose to confirm the dosing interval, and then re-check a random level and SCr about every 2- 3 days.

Symbol Key:

• Cmax = max serum concentration. Occurs 60 minutes after the start of infusion.
• Cmin = min serum concentration. Occurs just prior the next dose.
• CrCl = Creatinine clearance
• IBW = Ideal body weight
• K = Elimination rate constant
• T_1/2 = half-life
• ti = infusion time (hrs)
• T = dosing interval (hrs)
• V = Volume of distribution

References:

1. Matthews SJ. Aminoglycosides. In: Schumacher GE, ed. Therapeutic Drug Monitoring. Norwalk, CT: Appleton & Lange; 1995:237-294.
2. Sarubbi FA, Hull JH. Amikacin serum concentrations: Prediction of levels and dosage guidelines. Ann Intern Med. 1978;89(pt 1):612-618.
3. Baddour LM, Wilson WR, Bayer AS, et al. Infective Endocarditis in Adults: Diagnosis, Antimicrobial Therapy, and Management of Complications: A Scientific Statement for Healthcare Professionals From the American Heart Association. Circulation. 2015; 132:1435.
4. Bauer LA. The Aminoglycoside Antibiotics. In: Applied Clinical Pharmacokinetics, 3rd Ed. New York: McGraw Hill, 2014:89-104.
5. Nicolau DP, Freeman CD, Belliveau PP, et al. Experience with a once-daily aminoglycoside program administered to 2,184 adult patients. Antimicrob Agents Chemother. 1995;39(3):650-5.
6. Urban AW, Craig WA. Daily dosage of aminoglycosides. Curr Clin Top Infect Dis. 1997;17:236-55.