# Aminoglycoside Initial Dosing – Traditional Method

# Dose Adjustment – Traditional Method

# Initial Dose – Extended Interval

# Dose Adjustment – Nomograms

**Description of Aminoglycoside Calculators**

**Initial dosing – Traditional method**- Ideal body weight (IBW):
- IBW for men = 50 kg + 2.3(height – 60 inches)
- IBW for women = 45.5 kg + 2.3(height – 60 inches)

- Volume of distribution (V):
- 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.
- IBW is used to calculate V for non-obese patients.
- When patients weigh >120% of their IBW, adjusted BW
is used._{0.4}- Adjusted BW
_{0.4 }= IBW + 0.4(actual BW – IBW)

- Adjusted BW
- If underweight, actual BW is used to calculate V.

- 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.

- 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.
- Elimination rate constant (K) is estimated as follows:
- K = 0.0024(CrCl) + 0.01
- CrCl is calculated using the Cockcroft-Gault equation
- CrCl = [(140 – age) IBW] / (72 x SCr) *0.85 if female
- When patients weigh >130% of their IBW, adjusted BW
is used in the CG equation instead of IBW._{0.2}- Adjusted BW
_{0.2 }= IBW + 0.2(actual BW – IBW)

- Adjusted BW
- If underweight, actual BW is used instead of IBW.

- When patients weigh >130% of their IBW, adjusted BW
- CrCl is capped at 120 mL/min.

- CrCl = [(140 – age) IBW] / (72 x SCr) *0.85 if female

- Half-life: T
_{1/2}= 0.693/ K - Dosing interval (T): T = [Ln (Peak/ Trough)/ K] + 0.5
- Dose = 0.5*V*K*Peak*(1 – e
^{–K*T})/(1 – e^{-K*0.5}) - Distribution
- Aminoglycosides distribute well into synovial, peritoneal, ascitic, and pleural fluids, but poorly into CNS and the vitreous humor of the eye.

- Goal serum concentrations:
- Gentamicin for gram positive synergy, such as for endocarditis
- Peak: 3- 4 mcg/mL
- Trough: 0.5- <1 mcg/mL

- Gentamicin/Tobramycin
- Peak
- 5-7 mcg/mL for infection sites with more susceptible bacteria such as intra-abdominal infections
- 8-10 mcg/mL for infection sites that are difficult to penetrate and with bacteria that have higher MIC values such as pseudomonal pneumonia

- Trough: 0.5- <2 mcg/mL

- Peak
- Amikacin
- Peak: 15- 35 mcg/mL (usual range is 20- 30 mcg/mL)
- Trough: 1- 8 mcg/mL

- Gentamicin for gram positive synergy, such as for endocarditis
- Calculated peak from the estimated dose
- Peak = Dose (1 – e
^{–K*ti}) / [ti*K*V*(1 – e^{-K*T})]

- Peak = Dose (1 – e
- Calculated trough from the estimated dose
- Trough = Peak*e
^{-K (T – ti)}

- Trough = Peak*e
- Loading dose = V*Peak
_{SS}- This equation is based upon administration of the loading dose as the first dose on the maintenance dosing schedule.

- Inappropriate populations
- 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.

- Ideal body weight (IBW):
**Dose adjustments – Traditional method**- K = Ln(Peak/Trough)/(HoursToTrough – HoursToPeak)
- V = Dose* (1 – e
^{(-K*ti)})/ (K*ti* (Cmax – (Cmin * e^{(-K*ti)}))) - Cmax = MeasuredPeak/(e
^{-K*HoursPeakDrawnLate})- 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.

- Cmin = Cmax*e
^{-K*(T-1)} - New dose, dosing interval, and estimated peak and trough are calculated based on the same equations as the initial dosing calculator.

**Extended interval dosing method**- Extended interval dosing may NOT be appropriate for the following patient populations or those who require a higher degree of clinical judgment:
- Ascites
- Anasarca
- Burns (>20% total body surface area)
- Children (<18 years old)
- CNS infections (such as meningitis)
- Cystic fibrosis
- Elderly (>80 years old)
- Gram positive synergy (such as endocarditis)
- Neutropenia
- Obesity (BMI >35- 40 kg/m
^{2}) - Pregnancy
- Severe renal impairment (CrCl < 30 ml/min)
- Severe sepsis

- Rationale for using extended interval dosing
- Aminoglycosides have concentration dependent bactericidal activity. They require a high peak/MIC ratio for bacterial killing.
- Aminoglycosides have a post-antibiotic effect. They inhibit bacterial growth even after drug concentrations decrease to undetectable levels.
- Extended interval dosing results in equal or less nephrotoxicity and/or ototoxicity when compared to traditional dosing.

- Nomograms
- Hartford Nomogram
- One of the first published extended interval nomograms (1995).
- 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.

- Urban-Craig Nomogram
- Published two years later (1997), it uses the maximal daily dose of gentamicin/tobramycin approved by the FDA (5 mg/kg).
- Designed to have drug concentrations <1 mg/mL for at least 4 hours, with a maximal post-antibiotic effect of 16 hours.
- Includes a 12-hour dosing interval for patients with very fast clearance.
- Designed for use with amikacin (15 mg/kg per dose) by multiplying the vertical drug level scale by 3.

- Dosage calculations
- The same method is used for calculating dosing weight for the Hartford and Urban-Craig nomograms:
- IBW is used to calculate doses for non-obese patients.
- When patients weigh >120% of their IBW, adjusted BW
_{4}is used.- Adjusted BW
_{4 }= IBW + 0.4(actual BW – IBW)

- Adjusted BW
- If underweight, actual BW is used.

- The same method is used for calculating dosing weight for the Hartford and Urban-Craig nomograms:
- Determining the dosing interval
- Check a random level 6- 14 hours after the
**first dose**, and plot the result on the nomogram to determine the dosing interval. - If the result is on the line, the longer interval is chosen to avoid drug accumulation and provide a sufficient drug-free period.
- 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.

- Check a random level 6- 14 hours after the

- Hartford Nomogram

- Extended interval dosing may NOT be appropriate for the following patient populations or those who require a higher degree of clinical judgment:

**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:**

- Matthews SJ. Aminoglycosides. In: Schumacher GE, ed. Therapeutic Drug Monitoring. Norwalk, CT: Appleton & Lange; 1995:237-294.
- Sarubbi FA, Hull JH. Amikacin serum concentrations: Prediction of levels and dosage guidelines.
*Ann Intern Med.*1978;89(pt 1):612-618. - 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. - Bauer LA. The Aminoglycoside Antibiotics. In: Applied Clinical Pharmacokinetics, 3rd Ed. New York: McGraw Hill, 2014:89-104.
- 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. - Urban AW, Craig WA. Daily dosage of aminoglycosides.
*Curr Clin Top Infect Dis.*1997;17:236-55.

**Downloads:**

Aminoglycoside-Monitoring-Form.doc

Aminoglycoside-Monitoring-Form.pdf

**IDMS:** The Cockcroft-Gault equation has not been updated for use with the serum creatinine methods traceable to IDMS. Use with IDMS-traceable serum creatinine methods may overestimate renal function; use with caution.

**Disclaimer:** The author and contributors make no claims of the accuracy of the information contained herein; these suggested doses are not a substitute for clinical judgment. The persons involved in the preparation of this program shall not be liable for the use of or reliance upon this material.