Aminoglycoside Pharmacokinetic Information & Bayesian Dosing Calculators for Adults

Aminoglycoside Dosing Tools
Excel Aminoglycoside Bayesian Dosing Calculator, open compartment open model, for steady state or Non-Steady State dosing using the method of superposition. The tool creates a data file of data fittings that may be used to perform Medication Usage Evaluations and parameter optimization. The Solver Add-in must be available for the file to run. In Excel do the following: Click File, Click Options, Click Add-ins, Manage Excel Add-in Click Go, Check Solver Add-in, and select OK.
Excel Program Instructions
Aminoglycosides Once-daily Dosing: Pharmacy & Therapeutics Review
Amikacin Once-daily Dosing 15 mg/kg Graphic Tool
Gentamicin & Tobramycin Once-daily Dosing 3 mg/kg Graphic Tool
Gentamicin & Tobramycin Once-daily Dosing 5 mg/kg Graphic Tool
Gentamicin & Tobramycin Once-daily Dosing 7 mg/kg Graphic Tool
Aminoglycoside Once-daily Dosing Calculator and Data Fitting For Troughs, Web-Based
Aminoglycoside Traditional Dosing Calculator and Data Fitting for a Peak and Trough, Web-Based

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© 2020 Marshall Pierce

Aminoglycoside Pharmacokinetic Dosing Information
Spectrum of activity: Gram-negative bacteria display concentration-dependent killing with an optimal Peak/MIC ratio of ~10 or an AUC/MIC of 80-120 per day. Aminoglycosides are also used for synergistic effect with certain gram-positive bacteria
Bioavailability (F): Oral absorption is negligible, therefore these agents are given IV
Fraction IV: 1, IM: 1
Salt: 1
Vd: 0.25 L/kg Ideal Body Weight + (0.4 (Total Body Weight -Ideal body weight) if total body weight is greater than lean body weight. Critical care patients may have an expanded Vd.
Cl: 1.4 L/kg/hr, which is similar to creatinine clearance with a small amount of non-renal elimination
K: 0.0026*(Creatinine clearance based on IBW) + 0.014
T': 0.5-1 hour
Usual Interval: Traditional dosing: every 8,12, 16, 24, 36, 48 hours; Pulse dosing/extended interval dosing: every 24, 36, or 48 hours

Usual Dose:
Traditional Dosing:
Gentamicin/Tobramycin:
Load: 2 mg/kg, Maintenance:1-1.5 mg/kg
Amikacin:
Load: 7.5 mg/kg, Maintenance: 5 mg/kg
Pulse Dosing:
Large infrequent doses are thought to have equal efficacy and decrease toxicity.
Gentamicin/Tobramycin:
Maintenance: 5 mg/kg for pathogens with MIC <= 1-2 mcg/ml, 7 mg/kg for pathogens with MIC of up to 2 mcg/ml.
Amikacin:
Maintenance: 15 mg/kg
Hemodialysis Dosing:
Gentamicin/tobramycin: Loading dosing: 2 mg/kg, Maintenance Dose: 1-1.5 mg/kg post dialysis depending on the severity of infection. Mild UTI: Re-dose when the pre-hemodialysis trough is less than 1 mcg/ml, moderate to severe UTI re-dose when the trough < 1.5-2 mcg/ml, for systemic gram-negative infections, 1.5-2 mg/kg and re-dose when the pre-hemodialysis trough is less than 3-5 mcg/ml.
Amikacin: Loading dose 5-7.5 mg/kg, Maintenance Dose: 3-5 mg/kg depending on the severity of infection. Mild UTI: Re-dose when the pre-hemodialysis trough is less than 3 mcg/ml, moderate to severe UTI re-dose when the trough < 5 mcg/ml, for systemic gram-negative infections 5 mg/kg and re-dose when pre-hemodialysis trough is less than 10 mcg/ml re-dose.

Therapeutic Levels
Gentamicin/tobramycin:
Traditional dosing: systemic infection: peak 6-10 mcg/ml, Trough: < 1.5 mcg/ml; UTI peak 4-6 mcg/ml, trough less than 1 mcg/ml
Hemodialysis: Mild UTI: Re-dose when the pre-hemodialysis trough is less than 1 mcg/ml, moderate to severe UTI re-dose when trough < 1.5-2 mcg/ml, for systemic gram-negative infections, re-dose when the pre-hemodialysis trough is less than 3-5 mcg/ml.
Pulse dosing: peak ~ 20 mcg/ml, trough less than 0.5 mcg/ml
Amikacin:
Traditional dosing: systemic infection: peak 20-30 mcg/ml, Trough < 5 mcg/ml; UTI peak 15 mcg/ml; trough less than 5 mcg/ml
Pulse dosing: peak ~ 60 mcg/ml, trough less than 0.9 mcg/ml

Serum Sampling Times:
Dosage calculations and predictions are best when samples are drawn close to steady state, after 3-5 doses for traditional doses. In order to avoid the distribution phase when administering large doses such as pulse doses or once-daily doses in cystic fibrosis patients peaks should be drawn at least two hours from the start of the dose.
Traditional dosing:
Draw both levels after the same dose. Peak 0.5-1 hour post-dose, Trough before the next dose
Hemodialysis: Peak 0.5-1 hour post-dose, Trough 0.5 hours before the next dose. Both levels after the same dose. If post-dialysis levels are drawn wait at least 2 hours post-dialysis, as redistribution occurs after dialysis and levels will be falsely low if drawn too early.
Pulse Dosing: Draw level 10-14 hours post-dose to ensure the level is low enough to be within assay range and high enough to differentiate elimination rate curves. Do not draw true troughs as the levels will be very low as elimination lines for different renal function capacities will converge and it will be impossible to determine the correct dosing interval. If a peak level is drawn at least two hours post-infusion to avoid the distribution phase.

Pharmacokinetic Model: one-compartment open:
Aminoglycosides have been modeled with 1, 2, and 3-compartment models. If the peak is drawn 0.5-1 hour post-dose for traditional dosing and 2 hours post-dose for pulse dosing, a one-compartment model is adequate for pharmacokinetic calculations and dosing.

Pulse Dosing also known as Extended Interval Dosing or Once-daily Dosing Overview:
Aminoglycosides display concentration-dependent killing, time-dependent toxicity, and a prolonged post-antibiotic effect. Peaks of 8-10 times the MIC of the gram-negative pathogens are desired to optimize dose-dependent killing or concentration-dependent killing and to prevent the emergence of resistant pathogens. A dose of gentamicin/tobramycin 5 mg/kg is recommended, for pathogens with a MIC <=1 mcg/ml and will achieve a peak of 15-20 mcg/ml, and a dose of 7 mg/kg is recommended for pathogens with a MIC of approximately 2 mcg/ml and will achieve a peak of 25-30 mcg/ml. Gentamicin and tobramycin true troughs less than 0.5 mcg/ml for approximately 4-8 hours are desired to allow for redistribute from tissues and elimination. The initial dosing interval is based on creatinine clearance, then a single level post-dose level is plotted on the graphic (below) to determine if the dosing interval needs to be changed. True troughs should not be measured as the elimination rate curves converge, dosing interval determination can not be made, and the level may be below the assay range. Two authors, J Lee 2014 and AW Wallace 2012, reviewed the predicted performance of pulse dosing methods. Both authors found nomograms performed poorly and recommended serum level monitoring or individualizing dosing methods. Monitor serum levels by obtaining a peak 2 hours post-infusion to avoid the distribution phase and a 10-hour post-dose level to calculate kinetic parameters (elimination rate constant, volume of distribution) to individualize dosing using a one-compartment model equations. When a one-compartment model is used the calculated/extrapolated peak will be lower than the true peak immediately post-infusion, the Vd calculated will be higher, and the AUC calculated will also be lower than the true AUC when the medication follows a two-compartment model. When making dosing adjustments keep in mind that the true peak will be higher, dosage interval calculated will be longer than needed if the true peak is used rather than the extrapolated peak in the calculations. A peak level, immediately post-infusion, during the distribution phase, would be useful to see if the goal peak is being achieved. Any changes in dose will produce proportional changes in the post-infusion peak. Dosage interval adjustments may be based on K calculated and the extrapolated peak from the original dose.
Hartford Nomogram commentary: The nomogram was designed to cover pseudomonas aeruginosa (median gentamicin MIC 2 mcg/ml) which is not a common pathogen. The linear dosing nomogram was developed from a very small set of 20 patients' data. The mean volume of distribution was 0.39 l/kg which is large compared to approximately 0.25-0.27 l/kg in most references and other studies. This would cause an under-prediction of serum levels. Using a linear regression analysis of non-linear data is less than optimal and creates additional errors in the model allowing a shorter dosing interval to be selected than an exponential decay curve would suggest. Dosing patients with a creatinine clearance of less than 30 ml/min will most likely result in high trough levels.

Cystic Fibrosis(CF):
Patients with cystic fibrosis have higher clearance rates than patients of similar demographics without CF. Tobramycin is usually prescribed due to lower MICs for pseudomonas aeruginosa which is the usual pathogen. The most common dose for patients over 5-8 years of age is 10 mg/kg per day either as divided doses three times a day or once daily. Some studies have used 15 mg/kg/day as divided doses three times a day or once daily. The goal peak is 10 times the MIC of the pathogen or AUC/MIC of 70-100. Target levels for pulse dosing 20-30 mcg/ml and trough levels less than 1 mcg/ml. Target levels for three times a day dosing is 10-12 mcg/ml and trough less than 2 mcg/ml. The infusion period for pulse dosing is 60 minutes and 0.5 hours for three times a day dosing. Peaks 2 hours from the start of the dose are recommended to ensure the prolonged distribution phase is over and allow a once-compartment model to be used for dosing adjustments. Serum levels 2 hours and 10 hours from the start of infusion are used to calculate the elimination rate constant and volume of distribution using the method of Sawchuk and Zaske.
     K_(1/hours) = ln(Cmax_(mcg/ml)/Cmin_(mcg/ml)) / Time between levels in hours
     Vd_(L) = S*F*Dose(mg)(1-exp((-KT')*exp(-K*Time post-dose) / (Cmax*K*T'*(1-exp(-K*Tau)))

Dosage Calculations:

Lean Body Weight:
LBW_(kg) Adult Males (18 years and older) in kg: 50 kg + 2.3*(Height in inches-60)
LBW_(kg) Adult Female (18 years and older): 45.5 + 2.3*(Height in inches-60)

Dosing Weight_(kg) = LBW_kg+ (0.4 (Total Body Weight_kg - LBW_kg) if TBW > LBW)

Creatinine Clearance:
Adult Males: Creatinine Clearance _(mL/min)= (140-age_(years))*LBW /(serum creatinine_(mg/dl)*72)
Adult Females: Creatinine Clearance _(mL/min) = 0.85 *( (140-age_(years))*LBW /(serum creatinine_(mg/dl)*72))

K_(1/hours)=: 0.0026(Crcl)+0.014, Aminoglycoside Creatinine Clearance Versus Half-Life

Tau_(hours) = ((ln(Cmaxxss_(mcg/ml) desired)/Cminss_(mcg/ml) desired))/K) + T'

Vd_(L) = 0.25*Dosing weight_(kg)

Loading Dose_(mg) = Cp_(mg/L)desired *Vd*K*T'/(1-e^(-KT'))

Maintenance Dose_(mg) = Cpmaxss desired*(Vd*K*T'*(1-e^(-KTau))) / (S*F*(1-e^(-KT')))

Traditional Dosing Aminoglycosides

aminoglycoside dosing weight

Pulse Dosing (also known as larger dose extended interval)

Puse Dosing Gentamicin Tobramycin 5 mg per kg

Pulse Dosing Gentamicin Tobramycin 3 mg per kg

Pulse Dosing Gentamicin Tobramycin 7 mg per kg

Pulse Dosing Amikacin 15 mg per kg

Dialysis Dosing

Elimination occurs during and between dialysis. Bolus dosing equations may be applied because little drug elimination occurs during the medication infusion. Clearance in units of L/hr is recommended as clearance is not weight-related. Use L/hr and Vd in liters in the equations below to calculate K and individualize dosing. The graphics below, of post-dialysis dosing or doses at the end of dialysis, demonstrate that using a set dose in mg/kg achieves dissimilar levels and that the dose should be individually calculated using clearance and Vd. Larger patients need lower doses in mg/kg to obtain similar trough levels to smaller patients. Standard or fixed doses have similar pre-dialysis troughs but have varying peaks. Dosing before dialysis allows for high peaks and troughs that are lower.

Cpmaxss = S*F*D/(Vd*(1-e^{(-((Krenal*Tau)+(Kdialysis*Tdialysis))})), assuming dialysis every Tau
Cpminsspredialysis = Cpmaxss*e^{(-Krenal*(Tau-Tdialysis))} , assume trough drawn just before dialysis and dialysis is at end of dosage interval.

As dialysis is usually 3 days a week the method of superposition would give a more accurate representation of levels.
Cpmax after Dose1-3 = S*F*D/(Vd*(1-e^{(-((Krenal*7*24)+(Kdialysis*Tdialysis*3))})), each dose administered once weekly, with 3 dialysis sessions.

The highest level of the week is after the dose on the last dialysis day of M/W/F or T/Th/S series. The highest trough is before the third dialysis in the series. The lowest tough is before the first dialysis in the series.
Highest Peak in the series. Dose1 is Monday or Tuesday depending on series.
Cmax1 =D1/(Vd*(1-e^{(-((Krenal*7*24)+(Kdialysis*Tdialysis*3)))}))e^{(-(Krenal*24*4+Kdialysis*Tdialysis*2))}
Cmax2 =D2/(Vd*(1-e^{(-((Krenal*7*24)+(Kdialysis*Tdialysis*3)))}))e^{(-(Krenal*24*2+Kdialysis*Tdialysis*1))}
Cmax3 =D3/(Vd*(1-e^{(-((Krenal*7*24)+(Kdialysis*Tdialysis*3)))}))
Highest Cmaxss in series = Cmax1+Cmax2+Cmax3
Lowest Trough in series is just before first dialysis is the series = Highest Cmaxss in series*e^{(-(Krenal*(3*24)-Tdialysis))}

The lowest trough and peak are just before and after the dose in the first dialysis in M/W/F or T/Th/S series.
Lowest Peak in the series. Dose1 is Wednesday or Thursday in the series.
Cmax1 =D1/(Vd*(1-e^{(-((Krenal*7*24)+(Kdialysis*Tdialysis*3)))}))e^{(-(Krenal*24*5+Kdialysis*Tdialysis*2))}
Cmax2 =D2/(Vd*(1-e^{(-((Krenal*7*24)+(Kdialysis*Tdialysis*3)))}))e^{(-(Krenal*24*3+Kdialysis*Tdialysis*1))}
Cmax3 =D3/(Vd*(1-e^{(-((Krenal*7*24)+(Kdialysis*Tdialysis*3)))}))
Lowest Cmaxss in series = Cmax1+Cmax2+Cmax3

The highest trough is just before the third dialysis in M/W/F or T/Th/S series.
Highest trough in the series. Dose1 is Friday or Saturday in the series.
Cmax1 =D1/(Vd*(1-e^{(-((Krenal*7*24)+(Kdialysis*Tdialysis*3)))}))e^{(-(Krenal*24*5+Kdialysis*Tdialysis*2))}
Cmax2 =D2/(Vd*(1-e^{(-((Krenal*7*24)+(Kdialysis*Tdialysis*3)))}))e^{(-(Krenal*24*2+Kdialysis*Tdialysis*1))}
Cmax3 =D3/(Vd*(1-e^{(-((Krenal*7*24)+(Kdialysis*Tdialysis*3)))}))
Cmaxss after middle dose in series = Cmax1+Cmax2+Cmax3
Highest trough in series = Cmax after middle dose *e^{(-(Krenal*(2*24)-Tdialysis))}
Serum sampling for dialysis